Dermatol Clin 20 (2002) xi

Preface

Virology

Stephen K. Tyring, MD, PhD Guest Editor

Many viral infections have cutaneous manifestations: some are specific, but many are non-specific. Although many cutaneous manifestations of viral infections are a direct result of viral replication in the skin, others are related indirectly to the infections. In patients with HIV infection, most cutaneous manifestations result from opportunistic infections, neoplasia or inflammatory conditions. Other cutaneous manifestations result from drugs used to treat these conditions. This issue of the Dermatologic Clinics covers not only HIV, but also cutaneous manifestations of measles, enteroviruses, rubella, hepatitis viruses, parvoviruses, poxviruses, human papillomaviruses (HPV), herpes simplex viruses (HSV) 1 and 2, varicella zoster virus, Epstein Barr virus, cytomegalovirus, and human herpesviruses 6, 7 and 8. Several other viruses, not commonly seen in North America or Europe, can cause cutaneous manifestations such as Dengue virus, yellow fever virus and numerous hemorrhagic fever viruses. These latter viruses are not covered in this issue. Approximately 40 antiviral drugs now are available, almost all of which have become available in the last two decades. Currently, there are 16 Food and Drug Administration-approved agents for the therapy of HIV infections and 13 for the herpesvirus family. Two antiviral drugs are approved for anogenital HPV infections, and four agents are available for therapy of hepatitis B and C infections. Further-

more, four drugs are approved for treatment of influenza virus infections, and one drug is available for therapy of respiratory syncytial virus infection. These latter five agents, however, are not covered in this issue, because the corresponding viruses rarely have cutaneous manifestations. Much more effective and cost-effective than the antiviral drugs, however, are the antiviral vaccines. Although several such vaccines are available, only six of the viruses discussed in this issue have specific vaccines: measles, poliovirus, rubella, hepatitis B, smallpox, and varicella zoster virus. Although public health measures are important for control of other viral diseases, these interventions continue to play an important role in the management of viral diseases for which vaccines do exist. It is anticipated that although new antiviral drugs will become available in the near future, the greatest hope for control of epidemics caused by infection with HIV, HSV, HPV and hepatitis C (in addition to public health measures) will be the development of specific vaccines. Stephen K. Tyring, MD, PhD Guest Editor Center for Clinical Studies University of Texas Medical Branch 2060 Space Park Drive, Suite 200 Houston, TX 77058, USA E-mail address: styring@utmb.edu (S.K. Tyring).

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The cutaneous manifestations of HIV infection

Mary E. Garman, MDa, Stephen K. Tyring, MD, PhDb,*
b a Department of Dermatology, Baylor College of Medicine, Houston, TX, USA Department of Dermatology, University of Texas Medical Branch, Route 1070, Galveston, TX 77555, USA

Over 40 million men, women, and children around the world were estimated to be living with human immunodeficiency virus (HIV) infection at the end of the year 2001, though the disease was first described only 20 years ago [1]. The RNA retrovirus infects CD4+ cells, most notably T helper cells, and leads to a profound alteration of immune system function that predisposes patients to numerous opportunistic infections, malignancies, and neurologic disease. Patients progress to acquired immunodeficiency syndrome (AIDS) when CD4+ cell counts fall below 200/mm3 or certain clinical diseases manifest. Despite the dramatic impact of highly active antiretroviral therapy (HAART) on the morbidity and mortality associated with HIV infection, patients continue to ultimately have a dismal prognosis. Cutaneous findings in HIV disease are frequent and include viral, bacterial, fungal, and noninfectious etiologies. Dermatologic pathology common to the general population, such as seborrheic dermatitis, often has an increased prevalence or severity in these individuals. Susceptibility to otherwise rare infections, which are manifested in part or in whole as dermatologic findings, is significantly enhanced with HIV disease. Several skin diseases are nearly exclusive to HIV-infected individuals such as oral hairy leukoplakia, bacillary angiomatosis, and Kaposis sarcoma. Cutaneous findings more than double as CD4+ levels reach 100/mm3 or less [2], and certain skin conditions are associated with a more advanced HIV disease. Some dermatologic diseases exhibit atypical presentations that are sometimes misleading.

Standard therapy for HIV-associated skin disease often results in relapse or is otherwise not effective. Treatment regimens for common opportunistic infections and HIV disease itself often have cutaneous reactions. The spectrum of skin disease in individuals continues to change with the advent of HAART. While the severity and incidence of some HIVassociated skin diseases have fallen, others remain unaffected by combination antiviral therapy [3]. Recognizing HIV-associated skin disease may lead to early HIV diagnosis and appropriate management, thereby reducing the morbidity, mortality, and transmission of the disease. The epidemiology, pathogenesis, clinical findings, diagnosis, and treatment of selected skin findings that often present with HIV disease are discussed.

Infectious etiologies Viral disease HIV itself produces cutaneous findings shortly after exposure. In addition, gradual deterioration of the immune system renders HIV-infected patients susceptible to numerous cutaneous viral diseases including herpesviruses, human papillomavirus, and molluscum contagiosum. Primary HIV infection Approximately 2 6 weeks following HIV exposure, patients may present with a transient illness related to HIV replication and host response. More than 50% of patients report symptoms of acute HIV infection [4 6]. However, the syndrome is often recognized in retrospect, as the symptoms are vari-

* Corresponding author. E-mail addresses: styring@utmb.edu (S.K. Tyring); mg692342@bcm.tmc.edu (M.E. Garman).

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able and nonspecific. Potential benefits of recognizing HIV infection include decreased transmission with alteration of patient behavior and early antiretroviral therapy. Clinical findings of acute HIV infection include fever, fatigue, headache, lymphadenopathy, pharyngitis, myalgia or arthralgia, weight loss, nausea or vomiting, and diarrhea. A macular or morbilliform rash usually involving the trunk is present in 40% 80% of patients with acute HIV infection. The rash may resemble a drug hypersensitivity reaction or other viral exanthem such as measles or rubella. Mucocutaneous ulcerations involving the mouth and anogenital region have also been reported [5,7]. Primary HIV infection cannot be diagnosed by signs or symptoms alone. Screening questions to identify high-risk individuals are crucial in determining whether serologic testing is indicated. Because the standard enzyme immunoassay and Western blot are often negative with acute infection, additional tests may be needed when there is a high index of suspicion. While plasma viral load assay has a higher sensitivity, the p24 antigen assay has fewer false positives and may be a more cost effective way to diagnose primary HIV infection [7]. Viral RNA and CD4+ levels are highly variable with acute HIV infection. While both are often highest in the month following seroconversion, viral RNA levels steadily increase after reaching an inflection point as CD4+ levels decline [8]. HIV has not been isolated from the skin findings of primary infection. While primary HIV infection is typically selflimited and requires only supportive care, initiating antiretroviral therapy should be considered. The limited studies to date generally advocate starting HAART at this time. Early therapy rationale includes decreasing the severity of the acute syndrome, suppressing the initial burst of viral replication, altering the initial set-point that may affect disease progression, and limiting viral mutation. However, patients may experience significant side effects and lifestyle constraints, as well as possibly limit future treatment options due to development of drug resistance [9]. Herpesviruses Herpesvirus infections are one of the most important causes of opportunistic infections in patients with HIV and frequently have cutaneous manifestations. The double-stranded DNA herpesviruses include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV),

and human herpesvirus type 8 (HHV-8). While in the healthy host they are often self-limited, herpesvirus infections cause significant morbidity in the immunocompromised. Viral AIDS defining opportunistic infections of the skin include localized or disseminated HSV and VZV. Herpes simplex virus HSV-1 and HSV-2 are typically associated with herpes labialis and anogenital disease, respectively. However, there is increasing crossover infection, possibly due to orogenital sexual exposure [10]. Transmission occurs via mucosal membrane contact. HSV infection is particularly important to recognize and treat for several reasons. HSV-2 has been well documented to facilitate the transmission HIV [11 14]. In addition, HSV infection has been shown to activate HIV and promote replication [15 18]. Lesions present as grouped vesicles on an erythematous base and resolve within 2 weeks without treatment in the immunocompetent host. However, as immune function declines, lesions may become chronic and progress to painful ulceration with possible epidermal necrosis. Lesions frequently affect the mouth, esophagus, external genitalia, perianal region, and distal finger (herpetic whitlow). Histologic examination reveals intraepidermal, acantholytic, and vesicular dermatitis with characteristic changes of epithelial cells. Large pink to purple intranuclear inclusions (Cowdry A bodies) cause margination of chromatin. Diagnosis is confirmed by Tzanck smear, viral culture, or antigen detection. Treatment with oral acyclovir, famciclovir, or valacyclovir for 1 week is usually effective. Intravenous acyclovir may be required for severe mucocutaneous HSV infection. Immunocompromised patients exhibit a higher prevalence of acyclovirresistant HSV [19,20], most commonly due to a mutation in the viral thymidine kinase. Prior exposure to acyclovir is not related to resistance [19,20], and acyclovir may even improve survival of patients [21]. Intravenous foscarnet is an FDA-approved treatment for acyclovir-resistant HSV, though its use is limited by side effects including substantial renal toxicity. Varicella zoster virus Approximately 25% of patients experience herpes zoster, which has been described as an indicator of HIV infection in patients at risk [22,23]. VZV transmission occurs via aerosol droplets or direct contact. Following the widespread eruption of chickenpox (varicella) with primary infection, VZV remains latent in dorsal root ganglion. With reactivation the

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patient develops shingles (herpes zoster). Herpes zoster may paradoxically develop within several months of initiating HAART [24 26]. With primary infection, successive crops of vesicular lesions with surrounding erythema resemble dewdrops on a rose petal. The pruritic eruption starts on the face and scalp and spreads caudally. Adults experience a more severe disease, often with prodromal symptoms. While usually selflimited, chickenpox may be severe and prolonged in HIV-infected individuals. Dermatomal VZV reactivation is characterized by stabbing pains and paresthesias with subsequent formation of grouped vesicles on an erythematous base. Herpes zoster may be complicated by repeated bouts, involvement of multiple dermatomes, chronic verrucous zoster, or postherpetic neuralgia in HIV-seropositive patients. Rarely, herpes zoster may disseminate [2,27,28]. Like HSV, Tzanck preparation of vesicle base scraping reveals giant and multinucleated epidermal cells. However, viral culture is much more difficult. Antigen detection and seroconversion can also be used to evaluate for VZV infection. For immunocompromised patients with VZV infections, acyclovir, famciclovir, or valacyclovir must be given. Pain management includes nonsteroidal antiinflammatory agents or appropriate narcotics. HIVinfected individuals that are VZV-seronegative and have significant exposure to chickenpox or shingles should be given VZV immunoglobulin as prophylaxis. The VZV vaccine should be reserved for relatively immunocompetent patients. Cytomegalovirus CMV infection is associated with CD4+ cell counts of less than 100 cells/mm3 and has a spectrum of presentations including pulmonary, ocular, gastrointestinal, and neurologic involvement. Perianal ulceration with biopsy analysis suggestive of CMV has also been reported in patients [29 31]. Diagnosis can be achieved by visualization of cytoplasmic inclusion bodies and immunohistochemistry of a biopsy specimen. Treatment includes ganciclovir or foscarnet in addition to topical anesthetics for painful perianal lesions. Oral hairy leukoplakia (Epstein-Barr virus) While a majority of adults harbor EBV in latent phase, oral hairy leukoplakia is a rare disorder found almost exclusively in HIV-infected individuals. The condition is a result of EBV infection of epithelial cells that leads to hyperkeratotic thickening. Approximately 25% of HIV-infected individuals may be affected [32].

White, verrucous, confluent plaques that are most commonly located on the lateral aspects of the tongue characterize oral hairy leukoplakia. Unlike pseudomembranous candidiasis, the lesions do not scrape off with a tongue depressor. The lesions are typically asymptomatic but may cause dysphagia with advanced disease. Microscopically, there is epithelial hyperplasia with little associated inflammation. The presence of vacuolated cells, or koilocytes, implies viral infection. Oral hairy leukoplakia does not require treatment. Lesions usually respond to topical therapy with podophyllin or systemic antivirals, though recurrence is common. Recent studies have demonstrated a decreased prevalence of oral hairy leukoplakia with HAART [33]. Kaposis sarcoma (human herpesvirus type 8) Kaposis sarcoma is the most common AIDSassociated cancer in the United States. AIDS-associated Kaposis sarcoma is unique to other described clinical variants including classic, endemic, and immunosuppression-associated Kaposis sarcoma [34]. Kaposis sarcoma is more common in homosexual or bisexual men with HIV infection than in patients with other risk factors, suggesting a sexually transmitted agent [35]. While its role in pathogenesis is unclear, over 95% of all Kaposis sarcoma lesions have been associated with HHV-8, also known as Kaposis sarcoma-associated herpesvirus [34]. Proliferation of primitive mesenchymal cells is driven by cytokines and growth factors from both HIV-infected T-cells and the tumor cells. Present even with multicentric Kaposis sarcoma, the monoclonal origin of the lesions suggests that they are indeed neoplastic [36]. Formation of vascular channels leads to the clinical findings of Kaposis sarcoma, which may be an early or late manifestation of HIV disease. Compared to classic Kaposis sarcoma, the lesions are often widespread and more aggressive in HIVinfected individuals. The skin is most commonly affected, but mucous membranes, gastrointestinal tract, lymph nodes, and lungs may all be involved. Skin lesions of Kaposis sarcoma typically present with multifocal asymptomatic reddish-purple patches that sometimes progress to raised plaques or nodules. Lesions may be millimeters to centimeters in diameter and may be isolated or number in the hundreds. The face, trunk, and arms are often affected, though the anatomic distribution of Kaposis sarcoma is highly variable. One third of patients experience oral cavity lesions characterized by red-to-purple plaques or nodules of the hard and soft palate, gums, tongue, and oropharynx. Periorbital, genital, and lower extremity

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lesions sometimes become edematous. Kaposis sarcoma may also be complicated by ulceration, bleeding, and pain [37]. Microscopic examination of a biopsied lesion reveals proliferation of atypical spindle cells and hemosiderin laden macrophages. Depending on symptomatology, other diagnostic procedures such as chest radiograph or stool occult blood test may be needed to assess for associated internal lesions. HAART is associated with inhibited progression and even regression of Kaposis sarcoma. Because of unpredictable response, other therapies are often instituted as well. Radiation, systemic cytotoxic agents, and interferon alpha have all been reported as effective. Additional treatments, such as angiogenesis inhibitors, and the effectiveness of prophylactic therapy are also being studied [34]. Human papillomavirus Human papillomavirus, a double-stranded circular DNA virus, is a common pathogen of immunocompetent individuals. Transmission occurs via skin-to-skin contact and is facilitated by breaks in stratum corneum. HIV is associated with a higher prevalence of HPV infection [38] resulting in both nongenital and genital warts. Extensive disease often presents with CD4+ counts lower than 500 cells/mm3. Over 80 types have been identified based on differences in nucleotide sequences. Perhaps the most important clinical use of HPV typing is identification of high-risk oncogenic types. It is well established that types 16, 18, 31, and 33 are associated with cervical and anal carcinomas [39]. More recently, HPV infection has also been shown to facilitate HIV gene expression [40]. The white or tan firm round papules of verruca vulgaris (common warts) can reside on any skin surface. Verruca plana (flat warts) are well-circumscribed flat-topped papules 1 2 mm in height that are most commonly found on the face and dorsal hand, but may also affect the vulva and penis. Verruca plantaris (plantar warts) have an early papule that progresses to a hyperkeratotic plaque with characteristic black dots from capillary thrombosis. Condyloma acuminatum (venereal warts), the most common sexually transmitted disease in developed countries, represent mucosal HPV infection. They are characterized by flesh-colored, soft, cauliflowerlike papules or nodules of the anogenital region. Cervical HPV infection is typically asymptomatic. A non-resolving erythematous plaque on the penile shaft typifies Bowenoid papulosis. HPV infection in HIV disease may become extensive and resistant to treatment.

Clinical, colposcopic, and microscopic evaluations are all used to diagnose HPV. While nonspecific, the acetowhite test involves application of 3% 5% acetic acid and results in whitening of subclinical mucosal lesions due to swelling and maceration of the virally induced hyperplasia. A biopsy should be performed on suspicious lesions to rule out malignancy. Microscopic examination reveals epidermal hyperplasia with koilocytosis. Bowenoid papulosis additionally shows atypical keratinocytic changes and features of squamous cell carcinoma in situ. While insensitive and subject to sampling error, the Papanicolaou smear is an important means of diagnosing asymptomatic cervical HPV infection and identifying HPV induced malignant changes. Finally, in situ hybridization can be used to identify type specific HPV DNA. There is no indication for treatment of subclinical HPV infection or uncomplicated nongenital lesions. Patients wanting treatment of nongenital lesions should be warned that it is often painful and scarring. Nongenital lesions may be treated with salicylic acid, cryotherapy, or electrodesiccation. Carbon dioxide laser ablation may be a suitable alternative for unresponsive and extensive warts, though care must be taken to avoid transmission of the HPV in the laser plume [41,42]. Genital lesions may benefit from these same treatment options in addition to podofilox, imiquimod, or trichloroacetic acid. Unfortunately, no treatment has been shown to fully eradicate HPV. Immune system reconstitution with HAART sometimes improves lesions. Molluscum contagiosum Molluscum contagiosum, caused by a DNA poxvirus especially adapted to epidermal cells, generally presents as CD4+ fall below 100 cells/mm3 [43]. Molluscum contagiosum is spread by direct contact. Typical lesions of molluscum contagiosum include pearly flesh-colored papules that are 2 5 mm in diameter and sometimes with central umbilication. The face and anogenital region are often affected. While they spontaneously resolve in the immunocompetent host, the lesions are often extensive and progressive with HIV coinfection. HIV-infected individuals are subject to so-called giant molluscum contagiosum with lesions ranging from 1 6 cm in diameter [43 46]. Molluscum contagiosum is usually a clinical diagnosis. Curd-like material expressed from lesions contains pathognomonic ellipsoid cytoplasmic inclusions, or molluscum bodies, that are visible under light microscopy with Giemsa stain.

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The goal of treatment with molluscum contagiosum is to decrease disfiguring lesions rather than eradicate the virus. Curettage, topical retinoids, cryotherapy, imiquimod, or electrodesiccation may be effective. Dark skinned individuals should be warned of possible hypopigmentation following treatment. Resolution of refractory molluscum contagiosum after initiating combination antiviral therapy has been reported [46 49].

Methicillin resistant organisms require vancomycin. Patients with recurrent furunculosis may benefit from eradication of the organism by intranasal application of mupirocin for 1 2 weeks. Because nasal carriage is a risk factor for S. aureus infection in HIV-infected patients, studies are needed to determine if prophylactic eradication of the organism in selected patients is indicated [54]. Bacillary angiomatosis

Bacterial disease A number of host defense defects may predispose HIV-infected patients to bacterial infections including diminished antibody response, diminished B-cell mitogenic response, immunoglobulin G subclass deficiencies, and neutrophil and macrophage abnormalities. Long-term urinary or intravenous catheterization, encephalopathy, and malnutrition may also contribute to this susceptibility [50]. Staphylococcal infection and folliculitis Staphylococcus aureus is the most common cutaneous bacterial pathogen in HIV-seropositive patients. S. aureus colonization is significantly increased in HIV-infected patients [51,52]. In one series, 54% of patients with AIDS experienced clinical symptoms of S. aureus infection during the course of their illness [53]. HIV-infected patients are also prone to streptococcal impetigo or axillary lymphadenitis and Pseudomonas folliculitis. Staphylococcal infection may result in furuncles, carbuncles, or abscesses characterized by erythematous, tender, and indurated lesions. Impetigo may exhibit honey-colored crusts or bullous lesions. Staphylococcus may result in a superimposed infection of eczema, scabies, herpetic ulcer, Kaposis sarcoma, or at the sites of lines or chest tubes. HIVinfected patients are susceptible to staphylococcal cellulitis, which often has an identifiable portal of entry. Local staphylococcal infection may be complicated by bacteremia or sepsis [54,55]. Grams stain of pus reveals Gram-positive cocci in clusters or chains with staphylococcal or streptococcal infection. The culture of a biopsy specimen in cellulitis is positive in only one quarter of patients. A blood culture is indicated if the patient has fever or other symptoms suggestive of sepsis. Furuncles, carbuncles, and abscesses improve following incision and drainage in addition to systemic antibiotics. As with cellulitis, a penicillinase-resistant penicillin or cephalosporin should be employed.

The Gram-negative bacilli of the Bartonella genus include B. henselae, the cause of cat scratch disease in immunocompromised patients, and B. Quintana, the cause of trench fever during World War I. These organisms are also the etiology of bacillary angiomatosis, a disease that occurs primarily in patients with advanced HIV disease with CD4+ counts of less than 100 cells/mm3. Transmission occurs via traumatic inoculation of the skin, such as with a cat scratch or bite. Vascular proliferations of the skin are the most common manifestation, though virtually any tissue including bone, liver, and spleen may be involved. The nodules, up to several centimeters in diameter, are firm, red or violaceous, nonblanching, and frequently resemble pyogenic granulomata or Kaposis sarcoma. Bacillary angiomatosis lesions are more associated with pain compared to Kaposis sarcoma. Patients may also have palpable subcutaneous nodules. Widespread disease may be associated with systemic symptoms of fever, chills, night sweats, and weight loss. Intralesional microorganisms were first detected in 1983 using the Warthin-Starry stain [56]. This method remains the most reliable way to identify the bacilli, and can be used to distinguish bacillary angiomatosis from Kaposis sarcoma. In 1990, bacillary angiomatosis was found to be related to the Bartonella genus (formerly Rochalimaea) using polymerase chain reaction to identify a unique gene fragment [57]. Serology may also be useful, including fluorescent antibody staining or enzyme immunoassay to detect anti-Bartonella antibodies. Treatment includes erythromycin or doxycycline, with lesions typically resolving over 1 2 weeks. Relapse indicates the need for prophylaxis. Mycobacterial infection HIV-infected patients are susceptible to mycobacterial infections that can sometimes produce an array of skin manifestations. The incidence of cutaneous tuberculosis has been increasing and is sometimes

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associated with AIDS. Cutaneous inoculation can result in a tuberculous chancre in the nonimmune host or tuberculosis verrucosa cutis in the immune host. Disseminated Mycobacterium tuberculosis may also involve the skin. All patients with tuberculosis should be offered HIV testing because of the high incidence of coinfection and benefits of early HIV diagnosis [58]. Other species such as Mycobacterium haemophilum and Mycobacterium avium-intracellulare complex can sometimes produce cutaneous findings. Interestingly, the development of mycobacterial infections following initiation of HAART is occasionally reported [59 61]. The tuberculous chancre is a painless ulceration at the exposure site with undermined margins and associated lymphadenopathy. Tuberculosis verrucosa cutis is characterized by a hyperkeratotic plaque and the absence of lymphadenopathy. Skin findings of disseminated tuberculous infection include lupus vulgaris, scrofuloderma, and metastatic tuberculous abscess. Cutaneous miliary tuberculosis exhibits a diffuse maculopapular skin eruption often with multi-organ disseminated disease [62 64]. Tuberculous lymphadenitis has been associated with HIV-infected intravenous drug users [65]. Nontuberculous disseminated mycobacterial infections may produce an acute pustular eruption [66]. M. haemophilum has also been reported in association with soft tissue swelling, skin nodules, and ulcerating skin lesions [67,68]. HIV-infected individuals with induration of 5 mm or greater following a tuberculin skin test are considered positive, though patients with advanced disease may be anergic. Acid fast staining, mycobacterial cultures, and drug-susceptibility testing are all recommended. Unlike in the healthy host, the histology of mycobacterial skin lesions patients with AIDS reveals absent or ill-formed granuloma, extensive necrosis, and numerous acid fast bacilli [63,66]. Tuberculous lesions limited to the skin may not require systemic therapy. However, pulmonary or extrapulmonary disseminated mycobacterium tuberculosis with HIV disease requires multi-drug therapy including a combination of isoniazid, rifampin, pyrazinamide, ethambutol, or streptomycin. Multidrug resistance, more common in HIV-infected individuals, is associated with a high mortality and is an indication for directly observed therapy. Treatment regimens should be considered carefully with patients receiving HAART due to drug interactions [69]. Treatment of nontuberculous mycobacterial infection with skin involvement is not well defined. Surgical debridement may be appropriate in some cases.

Syphilis The spirochete Treponema pallidum causes syphilis, a sexually transmitted disease characterized by sequential stages. While most patients with syphilis and HIV coinfection experience the usual natural history of syphilis, some may have an accelerated course with progression to neurosyphilis. Some authors have observed that approximately 25% of cases of syphilis develop in HIV-infected hosts [70]. Syphilis is often the presenting infection of HIV disease [71]. A nontender solitary genital ulceration (chancre), which may increase the transmission of HIV, usually develops 3 weeks after spirochete exposure. In one quarter of patients, primary syphilis is followed by secondary syphilis with a rash, generalized lymphadenopathy, and condyloma latum. The polymorphic, symmetric, and nonpruritic rash often includes the palms and soles. Secondary syphilis assumes a variety of manifestations in HIV-infected patients including oral erosions, nodules, papules, vesicles, hyperkeratotic plaques, and papulosquamous or maculopapular eruptions [72]. A small percentage of patients develop tertiary syphilis, with cardiovascular, neurologic, or cutaneous findings. While this phase typically manifests decades after primary infection, HIV-infected patients may develop neurosyphilis within months or despite adequate therapy [73]. Gummatous tertiary syphilis is characterized by destructive granulomatous lesions that affect virtually any organ system. The often painless and slowly progressive skin lesions appear in asymmetric groups on the face, trunk, and extremities. Serologic tests for syphilis include nontreponemal (VDRL and RPR) and treponemal (MHA-TP and FTA-ABS) tests. While HIV-infected patients may have a higher RPR, some patients fail to produce an antibody response and serology is not useful. Therefore, specific treponemal tests are required to absolutely rule out the diagnosis of syphilis in the setting of HIV disease. When patients have clinical findings consistent with syphilis but negative or confusing serology, dark-field examination or direct fluorescent antibody staining of a lesion specimen may confirm the diagnosis. T. pallidum has never been successfully cultured and does not take up the Grams stain. Penicillin is the treatment of choice for all stages of syphilis infection. Higher doses and longer treatment course are often necessary, as relapse has been reported [71]. Unlike many of the other diseases discussed, there has been no reported decrease in incidence of syphilis with the introduction of HAART.

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Fungal disease Patients with HIV are subject to opportunistic infection with many fungal pathogens that produce mucocutaneous findings. While infection is often asymptomatic or self-limited in the immunocompetent host, HIV-infected individuals suffer significant morbidity and mortality due to mycotic infection. Disease may be localized to a single tissue, such as with dermatophytes and Candida. These highly prevalent superficial infections are fortunately usually benign and sometimes simple to treat. In contrast, cryptococcosis, histoplasmosis, and coccidioidomycosis frequently result in a multi-system disseminated disease with advanced HIV infection. Following aerosol inoculation and primary pulmonary infection, the organism may invade and disseminate hematogenously. The treatment of cutaneous fungal complications due to these pathogens is not well defined. It is clear, however, that some type of maintenance therapy in addition to amphotericin B may be required to prevent relapse. While many other rare species are sporadically reported, the most common fungal pathogens affecting HIV-seropositive patients are presented. Dermatophyte infection Common dermatophyte pathogens include species of the Epidermophyton, Microsporum, and Trichophyton genera. The organisms are transmitted via fomites, animals, or soil and have specific tropisms for the epidermis, hair, or nails. While dermatophytes are common in the general population, disease is often extensive and refractory to treatment with HIV disease. In one series of HIV-infected patients, over 50% of the patients experienced tinea or onychomycosis [74]. Fortunately, however, dermatophytic infections have a low morbidity and no associated mortality. Trichophyton rubrum, the most common dermatophyte in HIV-infected individuals, commonly infects the web spaces of the feet. Atopic patients may develop moccasin type tinea pedis with erythema, scaling, and hyperkeratosis of the entire plantar surface of the foot. Unlike healthy hosts, HIVinfected patients with tinea unguium exhibit a proximal chalky-white nail discoloration. Rather than having both feet and the dominant hand affected, HIV-infected patients often have involvement of all extremities. The well-demarcated erythematous and scaling plaques of tinea corporis and tinea cruris may be more extensive and resistant to treatment. Trichomycotic infections include dermatophytic folliculitis, tinea capitus, and tinea barbae. Dermatophyte infec-

tions in HIV disease may be complicated by abscess or Majoccis granuloma formation [75]. Potassium hydroxide preparation of the affected tissue reveals hyphae or mycelia. Periodic acid-Schiff staining of nail clippings or lesion biopsy may be required to confirm the diagnosis. While uncommon in HIV disease, Microsporum species fluoresce with Woods lamp examination. Fungal cultures are less helpful [75]. Onychomycosis responds to long-term oral treatment with terbinafine, itraconazole, or fluconazole. Tinea corporis, cruris, and pedis may require systemic therapy if topical antifungal agents are not effective. When HAART is initiated early in HIV disease, there is no increased incidence of dermatophyte infection in HIV-seropositive compared to HIV-seronegative individuals. In addition, HAART may improve dermatophyte infections in patients with advanced HIV disease [75]. Candidial infection Candida, a ubiquitous yeast, is a normal inhabitant of the human oropharynx and gastrointestinal tract that has a variety of manifestations in the HIVinfected host at all stages of disease. Oral thrush secondary to Candida is the most common fungal disease of HIV-seropositive patients, and develops in approximately 30% 50% of patients according to one review [76]. Patients may also exhibit chronic and refractory vaginal candidiasis, paronychia and onychodystrophy, and cutaneous infection. Candida albicans is the most common human pathogen of the species, though others may also cause infection. Candidal superficial infection of the oral mucosa and skin are common. Several types of oral candidiasis exist: pseudomembranous (thrush), erythematous (atrophic), hyperplastic, and angular chelitis. With pseudomembranous candidiasis, removal of the characteristic white plaques of the tongue or buccal mucosa leaves an erythematous, friable surface. Erythematous candidiasis may be a precursor to thrush and shows red macular patches on the buccal mucosa and loss of filiform papillae on the dorsum of the tongue. Chronic white, nonremovable lesions that may be associated with smoking define hyperplastic candidiasis. While usually of fungal origin in HIV-infected patients, angular chelitis has a variety other causes including bacterial infection, anemia, vitamin B12 deficiency, and poorly fitting dentures [77]. Oropharyngeal candidiasis may coexist with Candida esophageal disease, which is the most common cause of odynophaygia and dysphagia in HIV-infected patients [78]. Vaginal candidia-

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sis presents with vaginal pruritis, discharge, and soreness. Candida onychomycosis resembles dermatophyte infection. Cutaneous candidiasis evolves to erythematous patches with satellite pustulosis of the axilla, glans penis, groin, or inframammary area. Candida infrequently invades to cause fungemia, though patients are at an increased risk with prolonged neutropenia. While generally a clinical diagnosis, culture or microscopic visualization of hyphae, pseudohyphae, and yeast forms can be used to confirm the diagnosis of mucocutaneous candidiasis. Blood cultures should be drawn if there is any suspicion of disseminated disease. Oropharyngeal candidiasis often responds to local application of nystatin or clotrimazole. However, patients who have progressed to AIDS may require oral fluconazole, itraconazole, or even amphotericin B suspension. Oral itraconazole is most appropriate for Candida onychomycosis. Candida infection of the skin can be treated with topical azoles or polyenes. Management of vaginal candidiasis includes a topical azole, oral itraconazole, or oral fluconazole. Candidemia treatment involves removal of central venous catheters and administration of either fluconazole or the more toxic amphotericin B. Because some non-albicans species are resistant to fluconazole, speciation and susceptibility testing may be indicated. HAART is instrumental in preventing and controlling candidal infections [79]. Cryptococcosis Cryptococcus neoformans is an encapsulated yeast that is spread via inhalation of contaminated soil or bird droppings. Central nervous system or pulmonary cryptococcal infection is sometimes the initial manifestation of AIDS [80]. The organism causes dermatologic manifestations in only 10% 20% of HIV-infected patients according to one review [81]. The clinical manifestations of disseminated cryptococcal infection are varied. Erythematous papules, nodules, and pustules, as well as ulceration of the palate and tongue have been reported [81,82]. Biopsy and culture of affected skin aid in the diagnosis of Cryptococcus. Mucicarmine or India ink stains elucidate the wide polysaccharide capsule not found in other fungal pathogens. Serum cryptococcal antigen is also a reliable alternative, as skin findings result from disseminated infection. All HIV-infected patients with cryptococcal disease require therapy. Nonmeningeal disease can be managed with a combination of fluconazole and

flucytosine, but amphotericin B should be added with central nervous system involvement. Lifelong fluconazole maintenance therapy prevents relapse [83]. Histoplasmosis Histoplasma capsulatum, a dimorphic saprophyte endemic to the Mississippi and Ohio River valleys, rarely causes symptomatic illness in the immunocompetent host. Transmission occurs via inhalation of spores that reside in soil, where fungal growth is promoted by bird or bat excrement. Disseminated infection most commonly presents with fever and weight loss, but may lead to multisystem organ failure. Mucocutaneous lesions have been reported in 10% 20% of HIV-infected patients with disseminated infection [67,84]. Mucocutaneous ulceration, maculopapular rashes, nodules, pustules, and psoriasiform lesions have all been described [85 88]. The face, trunk, and extremities are most commonly involved, though the lesions may be diffuse [84]. Diagnosis is achieved by culture or biopsy, where Wright-Giemsa or methenamine-silver stains improve visualization of the budding yeast with its unique fruiting body. Amphotericin B, itraconazole, and fluconazole have all been effective treatment for disseminated histoplasmosis in a majority of reported cases involving patients with AIDS. However, lifelong maintenance therapy with one of these agents is required to prevent relapse [89]. Coccidioidomycosis The soil-dwelling Coccidioides immitis is endemic to the southwestern United States. Reactivation of a pulmonary focus can result in granulomatous infections of the skin, lung, bone, or meninges. Immunocompromise is a strong risk factor for dissemination. Patients may experience erythema nodosum or erythema multiforme. Other lesion types are varied and include papules, pustules, nodules, and plaques. C. immitis is also a dimorphic species and the characteristic tissue spherule enclosing numerous endospores is visible by light microscopy. Diagnosis is confirmed by skin test, serology, or culture. Treatment of extrapulmonary nonmeningeal coccidioidomycosis includes oral azoles and surgical debridement as necessary. Amphotericin B is typically used in patients with coccidioidomycosis respiratory failure or rapidly progressive disease. Chronic suppressive therapy with an oral azole is indicated in the immunocompromised host [90].

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Infestations Scabies The Sarcoptes scabiei mite results in the most common ectoparasitic infestation of HIV-infected individuals. Scabies is highly contagious in HIVinfected patients via direct contact. In one reported case, 72 health care workers and patients became infested following admission of an HIV-infected patient with undiagnosed crusted scabies [91]. Some authors suggest that an extremely high mite burden and atypical presentations, such as papular and crusted scabies, occur in HIV-infected patients as a result of decreased functional Langerhans cells and cell-mediated immunity [92]. Scabies may present as in the immunocompetent host. The female mite burrows under the stratum corneum and causes a superficial dermatitis characterized by extremely pruritic papules and linear burrows of the axilla, groin, and digital webs. Papular scabies, also called atypical or exaggerated scabies, involves generalized papules with associated burrows and severe pruritis. Crusted scabies, also called Norwegian or hyperkeratotic scabies, is remarkable for thick, scaling, white-gray plaques with minimal pruritis that are often localized to the scalp, face, back, buttocks, nails, and feet. Potassium hydroxide or mineral oil mounts of lesion scrapings often reveal mites, eggs, or feces with low-power light microscopy. While rarely performed, biopsy of a suspected scabies lesion may be indicated and reveals mite particles in the corneum. The Centers for Disease Control and Prevention recommend treatment of the affected individual and close contacts with 5% permethrin cream applied from the neck down and washed off after 8 14 hours, in addition to appropriate decontamination of bedding and clothing [93]. Retreatment after one week is appropriate if patients remain symptomatic. Oral ivermectin is reported as a safe and efficacious alternative treatment for scabies including the crusted variety [94,95]. While topical lindane is another alternative, epidermal fissures, particularly with crusted scabies, may facilitate systemic absorption and lead to neurotoxicity [96]. Demodicidosis Demodicidosis involves the proliferation of Demodex mites within the pilosebaceous unit and is sporadically reported in association with HIV infection. Clinically, infestation results in a mildly pruritic erythematous papular dermatitis with perifollicular

scaling that is localized to areas rich in sebaceous glands. The presentation must be distinguished from rosacea, acne, and folliculitis. Abundant Demodex mites reside within the follicular infundibula. Associated eosinophils and neutrophils within and around the follicle may also be visible by light microscopy. Permethrin cream is the treatment of choice. Permethrin cream used with topical gamma benzene hexachloride [97] or oral ivermectin [98] has also been reported to be effective. While not known to be a mitocidal drug, complete resolution of lesions has also been achieved with oral and topical metronidazole [99].

Noninfectious etiologies Noninfectious cutaneous disorders are common in HIV infection and can occur at all stages of disease. An explosive episode of psoriasis or severe seborrheic dermatitis can be the first indicator of HIV disease. Some findings, such as dry skin and seborrheic dermatitis, frequently occur in the general population but may be more prevalent or severe with HIV disease. Cutaneous drug reactions are common and may be life threatening. While not directly associated with an infectious agent, the pathogenesis of these findings is often related to immune alterations. Xerosis and eczema As many as 30% of HIV-infected individuals experience xerosis or acquired ichthyosis [100]. While the exact reasoning is unclear, the pathogenesis may be related to poor nutritional status, immunocompromise, or chronic illness. Eczema is an inflammatory skin condition more common in children that may be exacerbated by dry skin. While both conditions are common in the general population, HIV-infected individuals often exhibit severe or unremitting disease. Fine white scales and cracking skin without erythema typify xerosis, which may be diffuse or preferentially affect the anterior tibia, dorsal hand, and forearm. Ichthyosis is a more severe disorder involving skin thickening and fish-like scales. Atopic dermatitis is characterized by erythematous scaling plaques with associated papules or vesicles. Patients may demonstrate the triad of allergic rhinitis, asthma, and eczema. HIV-infected individuals often suffer severe disease that may progress to erythroderma. Both conditions are associated with pruritis that can lead to secondary skin changes such as lichenification and excoriations with superimposed bacterial infection.

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Whereas xerosis reveals minimal inflammation microscopically, eczema is superficial perivascular infiltrate of lymphocytes and eosinophils with epidermal hyperplasia and foci of spongiosis. While nonspecific, elevated IgE and eosinophilia is associated with eczema. Both xerosis and eczema benefit from emollients, topical steroids, avoidance of irritants, and antihistamines to relieve pruritis. Acquired ichthyosis may also respond to topical keratolytic agents. Seborrheic dermatitis Seborrheic dermatitis is a common disease affecting 2% 4% of the general population that involves epidermal hyperplasia, increased epidermal turnover, and scaling. Up to 85% of HIV-infected individuals experience seborrheic dermatitis at some point during their illness [101]. It may occur at any level of disease, but persistent and refractory manifestations correlate to declining CD4+ levels. Some authors provide evidence that seborrheic dermatitis is associated with Pityrosporum infection [102 104]. However, the role of this organism in seborrheic dermatitis remains unclear. Involved skin exhibits erythematous macules with white or yellow scaling that may appear greasy. Affected skin is concentrated to locations of increased sebaceous glands, such as the scalp and face. Less common areas such as the chest, back, axilla, and groin are often involved in HIV-seropositive patients. Extensive disease may lead to erythroderma. Seborrheic dermatitis is typically a clinical diagnosis. Biopsy reveals characteristic neutrophils at the dilated hair follicle ostia. Treatment modalities for seborrheic dermatitis include ketoconazole shampoo or cream, topical corticosteroids, coal tar, sulfur, and salicylic acid shampoos. Multi-drug antiviral therapy reduces the frequency of refractory cases. Psoriasis and Reiters syndrome Like seborrheic dermatitis, psoriasis is common in the general population and characterized by epidermal hyperplasia, increased epidermal turnover, and scaling. While the incidence of psoriasis in HIV disease is similar to the general population, it is often more severe, refractory to treatment, and has a higher prevalence of psoriatic arthritis [105]. Unlike the presence of psoriasis alone, psoriasis with rheumatic symptoms may signal a poor prognosis [106]. Psoriasis may also be seen within a spectrum leading to Reiters syndrome in HIV-infected individuals. The

interaction of the increased CD8+ cells found in HIV disease with human leukocyte antigen (HLA) class I molecules, which have been associated with psoriasis, may account for the acute onset and greater severity [107]. Increased susceptibility to streptococcal infections, which are known to cause psoriatic flares, may also contribute to the clinical picture of psoriasis with HIV disease. Some patients may present with the typical reddish annular plaques with silvery-white scales. Nail pitting, onycholysis, and subungal hyperkeratosis are also common. However, an explosive and severe episode of psoriasis is sometimes associated with initial HIV infection, whether or not the patient experienced psoriasis previously. Multiple subtypes of psoriasis, including guttate, pustular, or erythrodermic disease, may appear in the same patient. Severe onychodystrophy is common in HIV-infected individuals. Skin lesions may progress to disabling and disfiguring disease. Psoriasis is typically a clinical diagnosis. Reiters syndrome, characterized by arthritis, urethritis, and conjunctivitis, may be associated with plaque-type psoriasis and keratoderma blennorrhagica in HIV-infected individuals. Keratoderma blennorrhagica is characterized by papules or macules that evolve to pustular or hyperkeratotic lesions of the palms and soles. While the HLA-B27 antigen is found in only 5% of the general population, it is present in 80% 90% of patients with Reiters syndrome [108]. Zidovudine often effectively treats psoriasis in HIV-infected patients [105,109,110]. Some authors advocate avoiding phototherapy, methotrexate, and other standard psoriasis treatment modalities that may be immunosuppressive [105]. A regimen with minimal complications such as topical therapy, minimal ultraviolet phototherapy, and etretinate may be most appropriate for severely affected patients [110]. Eosinophilic folliculitis Eosinophilic folliculitis is a rare idiopathic eruption that typically occurs with advanced HIV disease. The papular pruritic eruption of AIDS usually refers to an analogous entity with a similar presentation and treatment where the diagnostic criteria for eosinophilic folliculitis or other pruritic cutaneous disorders cannot be met [111]. A shift toward Th2 cells and their related cytokines in the course of HIV infection induces IgE production and eosinophilia, thereby leading to an allergic response that may at least in part explain the pathogenesis of eosinophilic folliculitis [112].

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Eosinophilic folliculitis is characterized by perifollicular papules and pustules of the trunk and may also involve the head, neck, and proximal extremities. The associated intense pruritis may interfere with normal activity and lead to skin changes due to scratching such as excoriations, secondary infections, lichenification, and prurigo nodularis. Lesion biopsy reveals intrafollicular infiltration of eosinophils. Eosinophilic folliculitis is sometimes associated with peripheral eosinophilia and elevated IgE. The treatment for eosinophilic folliculitis is notoriously difficult and not well defined. Topical therapy with steroids or permethrin cream and systemic therapy with prednisone, isotretinoin, or itraconazole have all been reported as effective. Antihistamines, topical steroids, or ultraviolet B phototherapy may pacify the intense pruritis of eosinophilic folliculitis [105]. HAART may improve eosinophilic folliculitis or make other treatment modalities more effective [3]. Adverse cutaneous drug reactions HIV-infected individuals are prone to side effects associated with antimicrobial and antiviral medications. Cutaneous drug reactions represent the most common drug hypersensitivity manifestation and are especially common in HIV-infected individuals. Trimethoprim-sulfamethoxazole is the treatment of choice for Pneumocystis carinii infection. However, 1 2 weeks after initiating therapy, up to 50% 60% of HIV-infected patients may develop a morbilliform rash [113]. Rarely, patients can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. Foscarnet is clearly indicated for acyclovir-resistant mucocutaneous HSV infections, but the many side effects limit its role as a primary antiviral agent in other environments. Dermatologic side effects include the development of genital ulceration in 5% 30% of patients, most commonly located on the periurethral glans penis [114]. This contact dermatitis, thought to be secondary to urine concentration of the drug, may be avoided with adequate hydration and proper hygiene [10]. The nucleoside reverse transcriptase inhibitors zidovudine and abacavir have significant cutaneous side effects. Zidovudine has been associated with nail dyschromia characterized by blue or brown longitudinal bands that spread from the proximal to distal nail plate 4-8 weeks after initiating therapy [115,116]. Other cutaneous side effects of zidovudine include skin pigmentation, pruritis, urticaria, and a nonspe-

cific maculopapular rash [117]. Abacavir has been associated with a hypersensitivity reaction approximately 10 days after initiating treatment in 5% of patients. The syndrome is characterized by an evolving maculopapular rash, fever, and malaise. Remission occurs with cessation of the abacavir treatment, though rechallenge may produce a more severe and possibly fatal reaction [117]. The nonnucleoside reverse transcriptase inhibitors nevirapine and delavirdine sometimes result in a cutaneous eruption. Approximately 50% of patients taking nevirapine transiently experience a pruritic maculopapular rash [118 120]. Starting with a low dose and titrating to desired levels sometimes avoid this side effect. Patients having a severe rash or any rash with constitutional symptoms such as fever should permanently discontinue the medication [118,121]. Rarely, patients may develop StevensJohnson syndrome [122]. Finally, protease inhibitors have also been associated with cutaneous reactions. Both indinavir and amprenavir may produce a rash. Nearly one third of patients taking amprenavir experience a maculopapular rash. Stevens-Johnson syndrome occurs in 1% of these patients [117]. Photosensitivity disorders HIV-infected individuals have an increased incidence of photosensitivity reactions in which lesions are limited to sun-exposed areas. Chronic actinic dermatitis, a rare photosensitivity reaction of unknown etiology, is sometimes the presenting manifestaion of HIV seropositivity [123]. Findings include an eczematous eruption with lichenified, scaly, pruritic, and hyperpigmented plaques. Episodes may be precipitated by an allergic reaction to certain drugs or other substances, which should be avoided once identified [124]. Management also involves topical steroids, emollients, avoidance of sunlight, and sunscreens [123]. Porphyria cutanea tarda is reported more frequently in HIV-infected individuals compared to the general population. Patients may be predisposed to this condition as a result of abnormal porphyrin metabolism related to anemia or hepatitis, which are both commonly associated with HIV disease. Patients exhibit blistering, crusting, and scarring and may also have dark urine [125,126]. Distinctive epidermal aggregations of necrotic keratinocytes, or caterpillar bodies, may be visualized microscopically [127]. Diagnosis is confirmed by demonstration of elevated urinary uroporphyrins and coproporphyrins. Management may include phlebotomy, antimalarial medica-

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M.E. Garman, S.K. Tyring / Dermatol Clin 20 (2002) 193208 [9] Centers for Disease Control and Prevention. Report to the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Acute HIV infection. Morb Mortal Wkly Rep 1998;47(no. RR-5):56 8. [10] Brown TJ, Vander Straten M, Tyring SK. Antiviral agents. Dermatol Clin 2001;19(1):23 34. [11] Boulos R, Ruff AJ, Nahmias A, et al. Herpes simplex virus type 2 infection, syphilis, and hepatitis B virus infection in Haitian women with human immunodeficiency virus type 1 and human T lymphotropic virus type I infections. J Infect Dis 1992;166(2):418 20. [12] Holmberg SD, Stewart JA, Gerber AR, et al. Prior herpes simplex virus type 2 infection as a risk factor for HIV infection. JAMA 1988;259(7):1048 50. [13] Hook EW, Cannon RO, Nahmias AJ, et al. Herpes simplex virus infection as a risk factor for human immunodeficiency virus infection in heterosexuals. J Infect Dis 1992;165(2):251 5. [14] Stamm WE, Handsfield HH, Rompalo AM, et al. The association between genital ulcer disease and acquisition of HIV infection in homosexual men. JAMA 1988;260(1):1429 33. [15] Golden MP, Kim S, Hammer SM, et al. Activation of human immunodeficiency virus by herpes simplex virus. J Infect Dis 1992;166(3):494 9. [16] Heng MC, Heng SY, Allen SG:Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex virus-1. Lancet 1994;343(8892):255 8. [17] Mole L, Ripich S, Margolis D, et al. The impact of active herpes simplex virus infection on human immunodeficiency virus load. J Infect Dis 1997;176(3): 766 70. [18] Mosca JD, Bednarik DP, Raj NB, et al. Herpes simplex virus type-1 can reactivate transcription of latent human immunodeficiency virus. Nature 1987; 325(6099):67 70. [19] Christophers J, Clayton J, Craske J, et al. Survey of resistance of herpes simplex virus to acyclovir in northwest England. Antimicrob Agents Chemother 1998;42(4):868 72. [20] Fife KH, Crumpacker CS, Mertz GJ, et al. Recurrence and resistance patterns of herpes simplex virus following cessation of > 6 years of chronic suppression with acyclovir. J Infect Dis 1994;169(6):1338 41. [21] Ioannidis JP, Collier AC, Cooper DA, et al. Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: A meta-analysis of randomized individual patient data. J Infect Dis 1998;178(2):349 59. [22] Melbye M, Grossman RJ, Goedert JJ, et al. Risk of AIDS after herpes zoster. Lancet 1987;1(8535): 728 31. [23] Naburi AE, Leppard B. Herpes zoster and HIV infection in Tanzania. Int J STD AIDS 2000;11(4): 254 6. [24] Aldeen T, Hay P, Davidson F, et al. Herpes zoster infection in HIV-seropositive patients associated with

tions, and avoidance of sunlight, hepatotoxic medications, and alcohol [128].

Summary Dermatologic disease is extremely common and varied in HIV-infected patients. While some cutaneous findings are nearly exclusive to HIV-seropositive individuals, many are found in the general population. However, HIV-infected individuals often have an increased prevalence or severity, atypical presentations, or difficulty with treatment of the disease. Immune reconstitution with HAART significantly reduces the prevalence of many dermatologic diseases, but also has associated cutaneous side effects. Correct and early diagnosis of skin disease in HIV-infected individuals allows for early management and improved quality of life. Because dermatologic manifestations may be the first clue of HIV infection, offering HIV testing to affected individuals can lead to early diagnosis and treatment of HIV infection and, ideally, a decrease in disease progression and transmission.

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Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. N Engl J Med 1987;316(25):1569 72. Uthayakumar S, Nandwani R, Drinkwater T, et al. The prevalence of skin disease in HIV infection and its relationship to the degree of immunosuppression. Br J Dermatol 1997;137(4):595 8. Johnson RA:Dermatophyte infections in human immune deficiency virus (HIV) disease. J Am Acad Dermatol 2000;43(5 Suppl):S135 S42. Samaranayake LP. Oral mycoses in HIV infection. Oral Surg Oral Med Oral Pathol 1992;73(2):171 80. Schiodt M, Greenspan D, Greenspan JS. HIV-related oral lesions: Fungal infections. J Respir Dis 1996; 17(5):385 8. Laine L. Bonacini M. Esophageal disease in human immunodeficiency virus infection. Arch Intern Med 1994;154(14):1577 82. Rex JH, Walsh TJ, Sobel JD, et al. Practice guidelines for the streatment of candidiasis. Clin Infect Dis 2000;30(4):662 78. Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med 1989;321(12):794 9. Dimino-Emme L, Gurevitch AW. Cutaneous manifestations of disseminated cryptococcosis. J Am Acad Dermatol 1995;32(5 Pt 2):844 50. Lynch DP, Naftolin LZ. Oral Cryptococcus neoformans infection in AIDS. Oral Surg Oral Med Oral Pathol 1987;64(4):449 53. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000;30(4):710 8. Cohen PR, Grossman ME, Silvers DN. Disseminated histoplasmosis and human immunodeficiency virus infection. Int J Dermatol 1991;30(9):614 22. Chaker MB, Cockerell CJ. Concomitant psoriasis, seborrheic dermatitis, and disseminated cutaneous histoplasmosis in a patient infected with human immunodeficiency virus. J Am Acad Dermatol 1993; 29(2 Pt 2):311 13. Hazelhurst JA, Vismer HF. Histoplasmosis presenting with unusual skin lesions in acquired immunodeficiency syndrome (AIDS). Br J Dermatol 1985; 113(3):345 8. Kalter DC, Tschen JA, Klima M. Maculopapular rash in a patient with acquired immunodeficiency syndrome. Disseminated histoplasmosis in acquired immunodeficiency syndrome (AIDS). Arch Dermatol 1985;121(11):1455 9. Lindgren AM, Fallon JD, Horan RF. Psoriasiform papules in the acquired immunodeficiency syndrome. Disseminated histoplasmosis and AIDS. Arch Dermatol 1991;127(5):722 6.

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A review of measles virus

Jennifer R. Stalkup, MD *
Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Fondren Brown 840, Houston, TX 77030, USA

Measles virus is an epidemic disease with a worldwide distribution. Since the development of the live attenuated vaccine, the incidence of reported measles cases has declined by greater than 99% in the United States. Measles causes a systemic illness manifested by a characteristic prodrome and pathognomonic rash. Although usually a self-limited disease, measles can cause severe complications, especially in adults and the immunocompromised. A two-dose vaccination schedule is advocated by the ACIP and AAP for all preschool and school-aged children. Recent research has demonstrated clinical benefit in patients with severe measles virus infections treated with ribavirin and vitamin A supplementation. Measles virus is a large ssRNA virus that belongs to the family Paramyxoviridae and genus Morbillivirus. Although three distinct viruses constitute the Morbillivirus genus, measles is the only one that generates disease in humans. Measles consists of an outer lipoprotein envelope and internal helical nucleocapsid (N) that contains several proteins important in its pathogenesis [1]. The nucleocapsid is a coiled helix of viral RNA which has been completely mapped [2]. Three proteins are of particular importance in measles pathogenesis. A major immunogen, hemagglutinin (HA) is an outer membrane surface projection that aids in viral attachment to target cell membranes. Fusion protein (F) is a dumbbell-shaped glycoprotein on the outer membrane that permits viral fusion to cell surfaces and cell-to-cell transmission [1]. On the inner surface of the viral envelope, M proteins are responsible for the production of intact viral particles via a budding process [3].

Pathogenesis Measles virus is transmitted via respiratory secretions, predominantly aerosols but also by direct contact of larger droplets. Only a small amount of droplets is needed to infect the host [4]. Virus can survive for at least 2 hours in fine droplets, thus permitting sustained airborne spread in settings where droplets are numerous, such as in medical facilities or daycare centers [5]. No long-term infectious carrier states or animal reservoirs have been found to exist [6]. Measles virus invades the nasopharynx and replicates in the respiratory epithelium and local lymphoid tissues, resulting in a primary viremia with subsequent spread via the bloodstream to the reticuloendothelial system. A second viremia erupts 5 to 7 days later and establishes infection in multiple tissues such as the skin, respiratory tract, kidney, and liver [3, 6 8]. A pathologic hallmark of cells infected by the measles virus is their ability to fuse and form multinucleated giant cells called Warkthin-Finkeldey cells [9]. Laboratory abnormalities can include monocytosis, leukopenia, and thrombocytopenia [1,7]. Virus is usually shed in the nasopharynx from prodrome onset until 3 to 4 days after the beginning of the rash [3]. Both the humoral and cell-mediated immune responses are important in fighting measles virus infection. Measles antibody is first detectable with rash onset and is primarily IgM followed by measlesspecific IgG [9]. The humoral response is thought to be critical in controlling viral replication and conferring protection. The cell-mediated immune response is necessary in overcoming acute measles infection by eliminating infected cells. The long-term immunity against measles virus is not well understood. It has been postulated that the replication of measles virus in lymphoid tissue is so extensive that the antigenpresenting cell/viral antigen interaction is maximized,

* Address for correspondence: 7675 Phoenix, Apt. 615, Houston, TX 77030, USA. E-mail address: js041307@bcm.tmc.edu (J.R. Stalkup).

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 0 2 - X

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resulting in viral antigen retention in lymphoid tissue and subsequent long-term maintenance of circulating measles-specific IgG [7]. Paradoxically, a transient immunosuppression accompanies measles virus infection. As the normal immune response tries to eliminate virus, abnormalities can develop such as depressed delayed-type hypersensitivity (DTH), increased susceptibility to bacterial infections, and depressed T-cell counts despite a normal ratio of CD4+ and CD8+ cells [3,7]. The observed decrease in immune function despite substantial immune activation is not well understood. Griffin et al. reported that natural measles virus infection preferentially induces a TH-2 cellmediated response, resulting in substantial antibody production. The authors proposed that a weak TH-1 response to measles virus causes the depressed DTH and T-cell number and accounts for the transient immunosuppression and dysregulation [7]. Further research is needed to elucidate the exact etiology of this phenomenon.

Clinical manifestations In uncomplicated measles cases, the mean incubation period ranges from 10 12 days. Patients usually have a 2 to 4 day history of a respiratory prodome, consisting of cough, coryza, conjunctivitis, nasal discharge, malaise, and fever as high as 104 105F. Infectivity peaks during this phase. The prodrome period of measles is often mistaken for influenza virus infection [6]. Patients develop the pathognomonic enanthem of measles called Koplik spots which are 1 2 mm blue-white macules that appear on the bright red background of the buccal mucosa alongside the second molars, beginning 2 days before and lasting up to 2 days after rash onset. The characteristic measles rash appears 2 to 4 days after the prodrome period. It begins as an erythematous, nonpruritic, maculopapular rash of the face that subsequently spreads to the trunk and extremities. The rash eventually becomes confluent, especially on the face. Rash biopsy usually reveals infected capillary endothelial cells with a mononuclear cell infiltrate [7]. Fever as well as rash start to resolve on the fourth day after exanthem appearance. The rash fades in the order of its appearance. The entire illness may last up to 10 days [1,5,6]. Patients may also experience diarrhea, vomiting, lymphadenopathy, abdominal pain, pharyngitis, splenomegaly, leukopenia, and thrombocytopenia in a typical measles infection [1]. Modified measles occurs in individuals with preexisting partial immunity induced by passive measles

antibody. Such occurrences include individuals who have received exogenous immunoglobulin and infants less than 1 year of age who acquired the placental transfer of maternal immunoglobulin. In this clinical syndrome, the symptoms of measles tend to be less intense with a prolonged incubation period of 14 to 20 days [1,9]. Atypical measles is a phenomenon which is rarely seen since the introduction of live attenuated vaccine. This syndrome occurred in individuals who received formalin-inactivated measles vaccine during 1963 1967 and who were subsequently exposed to wildtype measles virus [10]. Formalin inactivation apparently destroys the antigenicity of F protein which is necessary in halting the cell-to-cell transmission of virus [11]. Although the incubation period is the same as typical measles, the symptom severity is worse in atypical measles. Instead of starting at the head and spreading down the body, the rash of atypical measles spreads centipetally and not only can be maculopapular, but also hemorrhagic, vesicular, or urticarial. Coryza, conjunctivitis, and Koplik spots usually dont occur in atypical measles. However, interstitial pneumonia is a prominent feature of atypical measles as well as pleural effusions, extremity edema, hepatitis, and hyperesthesias [12]. Atypical measles is often confused with Rocky Mountain spotted fever [8]. The infection typically resolves without any longterm complications. Measles has an increased risk of causing more severe disease in immunocompromised individuals, such as organ transplant, cancer, and HIV patients [13 16]. Measles can present in the immunocompromised person without the typical rash and is commonly associated with severe pneumonitis or encephalitis [15]. Viral shedding also tends to persist longer in an immunocompromised host [14]. Measles virus has a significant morbidity and mortality among these patients. Kaplan et al reviewed 117 published cases of measles in immunocompromised patients from 1963 1991 and reported severe complications in 80%, absence of rash in 30%, and disease fatality in 55% of patients [13]. In patients with HIV, measles virus infection may worsen the level of immunosuppression, thus accelerating the progression to AIDS [17].

Complications Although measles is typically a self-limited disease, complications can occur [13]. Pneumonia (6%), diarrhea (7%), and otitis media (8%) are the most commonly reported complications of measles. Other

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complications include hepatitis, thrombocytopenia, and encephalitis [18]. Age-specific rates of complications are highest among children less than 5 years of age and adults greater than 20 years. Measlesrelated complications are lowest for children 5 19 years old [6]. Death occurs in 0.1% of cases, usually the result of pneumonitis or encephalitis [19]. Pneumonia is the most common cause of death in children with measles [20]. It is also the most common complication of measles in adults, either caused by the virus itself or by a secondary bacterial infection [6]. Patients present with tachypnea and a bark-like cough. Chest radiographs often reveal a fine reticular infiltrate with a lower lobe predominance [21]. Measles pneumonia is often worse in the immunocompromised and severely malnourished and can result in an entity called Hechts giant cell pneumonia. It is characterized by an interstitial infiltrate on chest x-ray with mononuclear and multinucleated giant cells on histopathology [12]. There are three different neurological complications of measles virus infection in the brain. Acute post-infectious measles encephalitis (APME) occurs once in every 1000 reported cases [3]. It presents with fever, headache, seizures, and altered mental status [22]. It is a complication of supposedly healthy patients that begins 2 weeks after rash onset. The etiology of APME is thought to be an autoimmune process, resulting from immune dysregulation and an increase in antibodies against myelin basic protein. After further evaluation, it has been found that patients who develop APME actually have slight immunologic abnormalities, such as having an increased production of IgE antibody or less soluble IL-2 receptors [23]. Periventricular demyelination is observed; however, brain biopsy demonstrates an absence of viral particles and inclusion bodies [24]. Mortality occurs in 10% 20% of all cases [3]. Measles inclusion body encephalitis (MIBE), also known as subacute measles encephalitis (SME), is a complication that occurs in immunocompromised patients 1 6 months after primary measles infection [3]. It is characterized by seizures and altered mental status in the absence of fever [22]. The etiology of SME is due to nonrestricted viral replication in neurons in immunocompromised patients. Viral particles and inclusion bodies are isolated in glial cells and neurons on brain biopsy. Minimal inflammation and demyelination is observed [24]. Subacute sclerosing panencephalitis (SSPE) is another neurologic measles complication that occurs in 1/1,000,000 measles cases in the United States [25]. It affects immunologically intact adolescent and young adults who had a previous measles infection

and recovered without problems [3]. SSPE is a fatal inflammatory CNS disease with an incubation period of 7 to 10 years that results in progressive deterioration of mental and motor function. It is also associated with prominent myoclonus [22,26]. Brain biopsy reveals inclusion bodies, diffuse inflammation, and minimal viral particles. Laboratory analysis demonstrates high levels of measles antibodies in the blood and cerebrospinal fluid [3]. The patient will progress to seizures, coma, and death within 1 2 years [22].

Diagnosis and laboratory findings Although early diagnosis of measles virus infection is desirable, it may be delayed due to the nonspecific symptoms of the prodrome period. Clinical diagnosis is most likely to occur at the time of rash onset [6]. Measles can be cultured in respiratory secretions, urine, and tears; however, culturing the virus has proven to be a difficult as well as an insensitive test [27]. Other methods used to detect measles virus include assays for complement fixation (CF), hemagglutinin inhibition (HAI), direct immunofluorescence (DIF), and indirect enzyme-linked immunoassay (ELISA). ELISA has largely replaced other assay testing due to its higher sensitivity and ease to perform. Measles serology detects infection by documenting an increase in serum IgM or IgG antibody titers. IgG antibodies usually appear 2 weeks after rash onset and peak 4 to 6 weeks later while IgM antibodies appear immediately after rash onset, peaking 1 to 2 weeks later, and then declining to undetectable levels by one month [6,27]. Polymerase chain reaction (PCR) is a relatively recent technique that detects measles virus RNA. A highly specific and sensitive test, PCR has recently been used to successfully detect measles virus in brain tissue of patients with measles encephalitis [22].

Epidemiology Measles is an epidemic disease with a worldwide distribution. Prior to the development of the measles vaccine, an estimated 4 5 million cases occurred in the United States annually [4,5,28]. Nearly 99% of adults had serologic evidence of previous infection with close to 95% of all persons having had measles by age 15 [29]. In the prevaccination era, measles was a cyclical disease resulting in epidemics every 2 5 years with the peak of cases in winter and spring [1]. However, with the successful development of the

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live attenuated vaccine by Enders in 1963, the incidence of reported measles cases in the United States has fallen by over 99% [8]. The number of cases reported to the Centers for Disease Control and Prevention (CDC) reached a nadir of 1497 in 1983 [6]. A mean of 3700 cases was reported yearly from 1984 through 1988 [4]. With the use of the measles vaccine over the past 30 years, global measles morbidity and mortality has fallen by 74% and 85%, respectively [14]. The measles-associated mortality rate in the United States is 0.3% [3]. However, in some developing countries, the mortality rate of measles is as high as 10% [30]. In the prevaccination era, the highest incidence rates of measles virus were in children ages 5 9 years old [1]. The introduction of the measles vaccine reduced the number of reported cases in all age groups. From 1980 through 1989, the incidence of measles in 5 to 9 year olds was lower than any other age group, with the exception of adults greater than 20 years old. This trend was most likely the result of stricter enforcement of immunization laws that advocated having had first-dose measles vaccination prior to grade school entry [4]. In the 1980s, children less than 5 years old and school-aged children (ages 10 to 19) had the highest incidence rates of measles infection [6,8]. Two reasons have been postulated for measles outbreaks in this particular bimodal age distribution. First, children less than 5 years old who developed measles were more likely to be unvaccinated, resulting from a failure to implement a national measles elimination strategy to vaccinate infants by 15 months with a single dose. Second, infection in persons between ages 10 19 years of age was most likely the result of vaccination failure, i.e. failure to mount an adequate immune response after first vaccination (primary vaccine failure). The development of a two-dose vaccination schedule was advocated to eliminate outbreaks in this latter population [5]. Between 1989 and 1991, a measles resurgence occurred, resulting in an increased incidence of measles among all age groups. An upsurge of greater than 27,000 cases was reported in 1990 with more than 55,622 cases reported overall [4]. The epidemiology of measles also changed in 1989 to 1991. During this time period, the proportion of patients less than 5 years of age almost doubled, while the proportion of measles cases in school-aged children (5 19 years old) decreased from a median of 57% of reported cases during 1980 1988 to 29% in 1990. The largest outbreaks primarily involved unvaccinated black and Hispanic preschoolers less than 5 years old in cities with large, poor urban areas such

as Los Angeles, Dallas, Houston, Chicago, Philadelphia, New York, and Milwaukee. These outbreaks differed from those in 1985 1989 which predominantly involved previously vaccinated school-aged children who suffered primary vaccine failure [6]. The measles resurgence in 1989 to 1991 was thought to be due to the failure to achieve adequate vaccine coverage for inner-city areas as well as lack of public awareness, immunization barriers for the poor, and missed vaccination opportunities [1,8]. There has been a rapid decline in measles cases since 1991. In 1993, a low of 312 cases was reported in the United States with incidence decreasing even further in 1995 [4,31]. Since 1991, measles has been confined predominantly to the age groups described before its resurgence in 1989 through 1991. Although it is not entirely understood why reported measles cases rapidly declined after 1991, increased vaccination coverage of preschool and school-aged children as well as the implementation of a two-dose vaccination schedule most likely contributed significantly to this observed decrease. Currently, the epidemiology of measles is driven solely by importations [14,32]. Since 1991, the Pan American Health Organization (PAHO) measles elimination initiative has reduced the risk of importations from the Americas, although measles remains common on all other continents. The initiative consisted of a one time catch-up vaccination campaign that targeted all children between ages 9 months to 14 years of age, regardless of previous measles vaccination status. As a result of this initiative, the average annual number of imported cases detected in the United States decreased from 145 in the 1986 1991 period to 61 in the 1992 1994 period and has continued to be on the decline [32 34]. During 1999 and again in 2000, fewer than 100 measles cases were reported annually in the United States.

Prevention, vaccination, and postexposure prophylaxis The prevention of measles virus depends largely on vaccination coverage and enforcement. With the advent of the two-dose vaccination schedule and increased targeting of all children to immunize, infection with measles virus in the United States has dropped significantly. In his article Epidemiology and the Prevention of Measles, Atkinson suggests the following useful strategies to help eliminate measles in the medical setting: (1) triage of suspect measles-infected individuals to separate waiting

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rooms, (2) institution of appropriate isolation precautions once a diagnosis of measles has been made, (3) availability of prompt measles virus vaccination and prophylaxis for all susceptible patients, and (4) requirement of measles immunity in health care workers [40] Live attenuated measles vaccine was developed by Enders and collegues in 1963, with the Moraten strain being the only available measles vaccine as of 1968 in the United States. The vaccine is usually administered as part of the trivalent measles-mumpsrubella (MMR) vaccine but can be given by itself [35]. Seroconversion is induced in greater than 95% of individuals and confers life-long protection against measles virus. Measles vaccination produces subclinical symptoms of fever and transient rash in about 10% of cases which promptly resolve [8,19]. Due to the failure of some individuals to mount an adequate immune response after one-dose vaccination (primary vaccine failure), a two-dose vaccination schedule was established in 1989 for all persons receiving measles vaccinations. The two-dose schedule was further aimed to eliminate outbreaks in school-age children due to waning vaccine-induced immunity (secondary vaccine failure) [5]. The Advisory Committee on Immunologic Practices (ACIP) recommended in 1994 that the first dose be given by at least 12 months of age, because most infants have lost then their maternal passive immunity to measles. The ACIP advocates that the second dose be given by 4 to 6 years of age [5]. The American Academy of Pediatrics (AAP) also supports a two-dose vaccination schedule but recommends that the second dose be given by at least 12 years of age [36]. Both dose schedules are currently acceptable in the United States. All children greater than 1 year of age, as well as all susceptible individuals should be vaccinated against measles. Persons who are not susceptible to measles virus include those who have been previously infected with the virus, have documented proof of adequate immunization, or were born prior to 1957. Individuals born before 1957 are at lower risk than the general population of becoming infected with measles virus since they are more likely to have been exposed to wild-type measles virus and already have long-term immunity [35]. All exposed and susceptible persons to measles virus should receive measles prophylaxis within 6 days of exposure. If given within 72 hours of exposure, the virus can be completely prevented from infecting the individual. Children less than one, pregnant women, the unimmunized, and immunocompromised who are exposed to measles virus are

especially urged to obtain prophylaxis. Intramuscular (IM) administration of standard immunoglobulin comprises measles postexposure prophylaxis at a dose of 0.25 mL/kg for healthy individuals or 0.5 mL/kg for the immunocompromised for a maximum dose of 15 mL in both [37]. Exposed patients should also be given the live attenuated vaccine five months later since passive measles antibody is already waning by this time. Rivera et al. illustrated the importance of measles postexposure prophylaxis. Their study compared the attack rates of patients who were exposed to measles and received measles prophylaxis to those who did not and found a 7.5% attack rate in those not treated. The patients who received measles prophylaxis did not become infected [38]. Common adverse reactions to measles vaccination include fever (5% 10%) and rash (5%). Transient neurologic reactions were reported to occur in 1 in one million cases [19,35]. The measles virus vaccination has been implicated in the development of inflammatory bowel disease (IBD) in children. However, Afzal et al. reviewed this hypothetical link and found no serological evidence of association [2]. Transient thrombocytopenia has been documented as a vaccination side effect [6]. Extreme precaution should be taken in vaccinating persons with a history of anaphylaxis to eggs or neomycin. Mild illness with fever, history of seizures, and low-dose steroid or antibiotic administration are not contraindicated in measles vaccination [19]. However, vaccination is contraindicated in instances of moderate to severe illness as to not complicate primary disease management. All asymptomatic HIV children should receive the measles vaccination. In symptomatic HIV children, the vaccine should be considered and given with greater precaution because of the risk of severe measles sequlae in immunocompromised patients. However, there has been no report of increased incidence of adverse reactions in HIV patients to measles vaccine since 1992 [1]. Measles vaccination is absolutely contraindicated in pregnant women and individuals with impaired immune systems, resulting from immunosuppressive therapy, non-HIV immune deficiency disease, and cancer. Vaccination can be given to patients who have been off chemotherapy or immunosuppressive agents for at least three months [6]. The development of DNA-based measles vaccination is a subject of current research. Plasmids containing H, F, and N protein cDNAs that are expressed from a cytomegalovirus promotor have been studied in murine models with encouraging humoral and cell-mediated responses. Future work

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is also being conducted in the induction of the TH-1 cell-mediated immune response in humans. So far, IM inoculation of man-made measles DNA has produced the desired TH-1 response; however, very large amounts of DNA were needed to elicit the reaction [39].

Treatment Treatment for measles virus infections is largely supportive and symptom-based. Appropriate antibiotics may be necessary in patients with courses complicated by secondary bacterial infections such as pneumonia or otitis media. Patients who develop APME mainly receive supportive care and are monitored for any increases in intracranial pressure. Ribavirin has shown to inhibit measles virus in tissue culture and may be considered as a treatment in measles complications. Although clinical experience has varied, ribavirin has been shown to reduce the severity and duration of measles [40]. The drug is currently licensed in aerosol form for the treatment of RSV and in the oral form for the therapy of hepatitis C. Forni et al. examined the ribavirin treatment of 6 adults who were hospitalized with measles pneumonitis. All patients were hypoxic on room air with oxygen saturations between 40 to 61 mmHg with 4 patients on mechanical ventilation. IV ribavirin was administered to all patients with dosages ranging from 20 to 35 mg/kg/day for one week. All patients improved with IV ribavirin and tolerated it well except for one patient who had HIV [20]. Mustafa et al. reported the use of ribavirin in 2 young, immunocompromised patients with SME. Ribavirin was given to both patients, resulting in complete recovery in one after a 15 week course of the drug. The other patient died early in treatment secondary to seizures [22]. Trials, however, in patients with SSPE treated with ribavirin have shown no benefit in outcome [25]. Vitamin A deficiency disrupts epithelial integrity as well as depresses cell-mediated immunity and can increase the severity and incidence of childhood infections [41]. Infection with measles virus decreases serum levels of vitamin A, which has been associated with an increased mortality from disease [42]. Recent trials of treatment with vitamin A have suggested a clinical benefit in patients with severe measles. Hussey et al. concluded that treatment of measles with vitamin A substantially reduces the morbidity and mortality associated with measles [43]. The study examined 189 children who were hospitalized secondary to measles complications at a

regional medical center in South Africa. Beginning within five days of rash onset, patients received either 400,000 units of vitamin A or a placebo pill. The results of the study showed that children treated with vitamin A recovered more quickly than the ones given placebo. Approximately 84% of deaths from measles complications occurred in the control group. The study recommended that all children with severe measles be given vitamin A supplements [44]. Fawzi et al. pooled results of community-based trials of vitamin A supplementation of children with and without measles infections and found a 39% reduction in measles-related mortality as well as an overall decrease in mortality in general [44].

Conclusion Since the development of the live attenuated vaccine in 1963, the number of reported measles cases has declined by greater than 99% in the United States. However, physicians need to be familiar with the characteristic prodrome and pathognomic features of measles virus in order to accurately diagnose the cases that do occur. The two-dose vaccination schedule outlined by the ACIP and AAP should be strictly enforced for all children. Further research in new measles vaccine developments as well as treatment with ribavirin and vitamin A continues to be pursued.

References
[1] Adcock LM, Bissey JD, Feigen RD. A new look at measles. Infect Dis Clin North Am 1992;6(1):133 48. [2] Afzal MA, Minor PD, Schild GC. Clinical safety issues of measles, mumps and rubella vaccines. Bull World Health Organ 2000;78(2):199 204. [3] Resnick SD. New aspects of exanthematous diseases of childhood. Dermatol Clin 1997;15(2):257 66. [4] Banks G, Fernandez H. Clinical use of ribavirin in measles: a summarized review. In: Smith RA, Knight V, Smith JAD, editors. Clinical complications of ribavirin. Orlando, FL: Academic Press; 1984. p. 203 9. [5] Atkinson WL. Epidemiology and prevention of measles. Dermatol Clin 1995;13(3):553 9. [6] Villamor E, Fawzi WW. Vitamin A supplementation: implications for morbidity and mortality in children. J Infect Dis 2000;182(Suppl 1):S122 33. [7] Griffin DE, Ward BJ, Esolen LM. Pathogenesis of measles virus infection: an hypothesis for altered immune responses. J Infect Dis 1994;170(Suppl 1): S24 31. [8] Lutwick LI. Postexposure prophylaxis. Infect Dis Clin North Am 1996;10(4):899 915.

J.R. Stalkup / Dermatol Clin 20 (2002) 209215 [9] Gershon A. Measles. In: Fauci AS, Braunwald E, Isselbacher KJ, et al., editors. Harrisons principles of internal medicine. New York: McGraw-Hill; 1998. p. 1123 5. [10] Norrby E, Kristensson K. Measles virus in the brain. Brain Res Bull 1997;3:213 20. [11] Mustafa MM, Weitman SD, Winick NJ, et al. Subacute measles encephalitis in the young immunocompromised host: report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature. Clin Infect Dis 1993;16:654 60. [12] Cutts FT, Henao-Restrepo AM, Olive JM. Measles elimination: progress and challenges. Vaccine 1999; 17:S47 52. [13] Centers for Disease Control. Measles-United States. MMWR 1996;45:305. [14] De Serres G, Gay NJ, Farrington CP. Epidemiology of transmissible diseases after elimination. Am J Epidemiol 2000;151(11):1039 48. [15] Hinman AR, Orenstein WA, Bloch AB, et al. Impact of measles in the United States. Rev Infect Dis 1983; 5(3):439 44. [16] Yang E, Rubin BK. Childhood viruses as a cause of pneumonia in adults. Semin Respir Infect 1995;10(4): 232 43. [17] Hussey GD, Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 1990;323:160 4. [18] Moss WJ, Cutts F, Griffin DE. Implications of the human immunodeficiency virus epidemic for control and eradication of measles. Clin Infect Dis 1999;29: 106 12. [19] Centers for Disease Control. Measles prevention: recommendations of the immunization practices advisory committee (ACIP). MMWR 1989;38:1 18. [20] Markowitz LE, Preblud SR, Orenstein WA, et al. Patterns of transmission in measles outbreaks in the United States, 1985 1986. N Engl J Med 1989;320: 75 81. [21] Wood DL, Brunell PA. Measles control in the United States: Problems of the past and challenges for the future. Clin Microbiol Rev 1995;8(2):260 7. [22] Atkinson WL, Orenstein WA. The resurgence of measles in the United States, 1989 1990. Annu Rev Med 1992;43:451 63. [23] Gavish D, Kleinman Y, Morag A et al. Hepatitis and jaundice associated with measles in young adults: an analysis of 65 cases. Arch Intern Med 1983;143: 674 7. [24] Rivera ME, Mason WH, Ross LA, et al. Nosocomial measles infection in a pediatric hospital during a community-wide epidemic. J Pediatr 1991;199:183. [25] Gremillion DH, Crawford GE. Measles pneumonia in young adults. Am J Med 1981;71:539 42. [26] American Academy of Pediatrics. Measles: reassessment of the current immunization policy. Pediatr 1989;84(6):1110 3.

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[27] PeBenito R, Naqvi SH, Arca MM, et al: Fulminating subacute sclerosing panencephalitis: case report and literature review. Clin Pediatr 1997;36(3):149 54. [28] Wild TF. Measles vaccines, new developments and immunization strategies. Vaccine 1999;17(13 14): 1726 9. [29] Kaplan LJ, Daum RS, Smaron M, et al. Severe measles in immunocompromised patients. JAMA 1992;267(9): 1237 41. [30] De Quadros CA, Olive JM, Hersh BS, et al. Measles elimination in the Americas: evolving strategies. JAMA 1996;275(3):224 29. [31] Forni AL, Schluger NW, Roberts RB. Severe measles pneumonitis in adults: evaluation of clinical characteristics and therapy with intravenous ribavirin. Clin Infect Dis 1994;19:454 62. [32] Hutchins S, Markowitz L, Atkinson W, et al. Measles outbreaks in the United States, 1987 through 1990. Pediatr Infect Dis J 1996;15(1):31 8. [33] Keller MA, Stiehm ER. Passive immunity in prevention and treatment of infectious diseases. Clin Microbiol Rev 2000;(4):602 14. [34] Martin DB, Weiner LB, Neiburg PI, et al. Atypical measles in adolescents and young adults. Ann Intern Med 1979;90:877. [35] Krasinski K, Borkowsky W. Measles and measles immunity in children infected with human immunodeficiency virus. JAMA 1989;261(17):2512 6. [36] Boyd AS. Laboratory testing in patients with morbilliform viral eruptions. Dermatol Clin 1994;12(1): 69 82. [37] Sable CA, Hayden FG. Orthomyxoviral and paramyxoviral infections in transplant patients. Infect Dis Clin North Am 1995;9(4):987 1003. [38] Fawzi WW, Chalmers TC, Herrera MG, et al. Vitamin A supplementation and child mortality: a meta-analysis. JAMA 1993;269(7):898 903. [39] Liebert UG. Measles virus infections of the central nervous system. Intervirology 1997;40:176 84. [40] Vitek CR, Redd SC, Redd SB, et al. Trends in importation of measles to the United States, 1986 1994. JAMA 1997;277(24):1952 6. [41] Olive JM, Aylward RB, Melgaard B. Disease eradication as a public health strategy: is measles next? Wld Hlth Statist Quart 1997;50:185 7. [42] Singer C, Lang AE, Suchowersky O. Adult-onset subacute sclerosing panencephalitis: case reports and review of the literature. Mov Disord 1997;12(3): 342 53. [43] Markowitz LE, Nzilambi N, Driskell WJ, et al. Vitamin A levels and mortality among hospitalized measles patients, Kinshasa, Zaire. J Trop Pediatr 1989;35: 109 12. [44] Ehrnst A. Separate pathways of C activation by measles virus cytotoxic antibodies: subclass analysis and capacity of F(ab) molecules to activate C via the alternative pathway. J Immunol 1978;121:1206 12.

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Enterovirus infections: A review of clinical presentation, diagnosis, and treatment

Jennifer R. Stalkup, MD*, Suneel Chilukuri, MD
Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Fondren Brown 840, Houston, TX 77030, USA

The enteroviruses are small (30 nm), nonenveloped, single-stranded RNA viruses that belong to the family Picornaviridae and cause a variety of diseases [1]. Composed of more than 70 serotypes, the enteroviruses are morphologically indistinguishable, ubiquitous pathogens with a worldwide distribution [2]. Although most of the enterovirus infections commonly seen are relatively mild and result in complete recovery of the patient, these viruses can also cause severe and sometimes fatal illnesses such as meningitis, encephalitis, myocarditis, neonatal sepsis, and polio [3 7]. With control of poliovirus infections in much of the world through the efforts of the World Health Organization, attention has turned to the nonpolio enterovirus infections, particularly their clinical manifestations, complications, diagnosis, and treatment. Enteroviruses can often be misdiagnosed as bacterial or other viral infections and lead to unnecessary treatment, procedures, and diagnostic tests [5]. Although the exact identification of a serotype may not be necessary to the clinician, the exclusion of bacterial infection is important. With the advances of polymerase chain reaction technology in accurately identifying enteroviruses in patient fluids as well as the recent development of new antiviral therapies, severe enterovirus infections are being diagnosed and treated earlier with better prognostic outcomes.

Pathogenesis and epidemiology Human enteroviruses consist of more than 70 different serotypes and include the following: echovirus (31 serotypes), coxsackievirus A (23), coxsackievirus B (6), enterovirus 68 71 (4), and poliovirus (3) [6]. Enteroviruses cause more than 15 to 20 million infections in the United States annually [6,8 10]. Only a few serotypes cause disease each year within a community, with certain serotypes producing illness more often than others. Although some enteroviruses infect certain tissues preferentially, these tissue tropisms are neither unique nor specific [9]. Enterovirus epidemics occur predominately in the summer and fall with a few sporadic cases occurring year-round [1]. Although all age groups are affected, young children are the most likely to be infected. The most commonly reported age group is one to four years old [1]. The increased reporting of enterovirus disease as well as lack of cross-reacting immunity in young children have been proposed to account for this tendency [6,11]. In addition to young age, low socioeconomic status and crowding also are risk factors for developing enterovirus infections [1]. Transmission is mainly via fecal-oral contact and less commonly by respiratory droplets [12]. There are no known non-human reservoirs, but water-borne, foodborne, and blood-borne transmissions have been reported [13,14]. Once the virus enters through oral or respiratory mucosa, it replicates in lymphoid tissues (mainly of the lower gastrointestinal tract) before spreading via blood to cause a minor viremia [15]. During this stage, enterovirus may seed the central nervous system, heart, liver, and lungs. Fur-

* Corresponding author. 7675 Phoenix, Apt. 615, Houston, TX 77030, USA. E-mail addresses: js041307@bcm.tmc.edu (J.R. Stalkup), suneelchilukuri@yahoo.com (S. Chilukuri).

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 0 9 - 2

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ther replication at these sites may lead to major viremia with clinical symptoms [12]. Through the efforts of the World Health Organization (WHO) and other organizations, polio has been eliminated in most of the world. In the prevaccine era, large epidemics of polio spread across the United States and Europe, resulting in a case fatality rate as high as 10% [4]. With the creation of the formalininactivated vaccine (IPV) by Jonas Salk in the 1950s and live attenuated vaccine (OPV) by Albert Sabin in the 1960s, there has been a 90% reduction in poliovirus incidence globally [16,17]. Prior to vaccine development, over 21,000 cases of paralytic polio were reported each year in the United States; now there are less than ten cases occurring annually with each case being vaccine-associated [4]. In 1995, OPV prevented at least 400,000 cases of paralytic polio worldwide [4]. The incidence of paralytic polio secondary to OPV is one in 530,000 first-time vaccinees [17]. There is no epidemiologic evidence that the live attenuated polio vaccine will revert to wild-type virus and cause epidemic disease [16]. In 1988, the World Health Assembly called on WHO to carry out the goal of global polio eradication by the year 2000. This world initiative was structured around the following: National Immunization Days (NIDS) during which two doses of supplemental OPV were administered to all young children regardless of their previous immunization status, routine immunization for all children, specific targeting of high-risk areas, and disease surveillance [16,18]. Through the efforts of WHO, all of the Americas as well as China and the Western Pacific are free of disease, with the last reported case of wild-type polio in 1992 and 1997, respectively [16,17]. During the time period of 1988 to 1995, a decrease in reported polio cases of over 80% occurred [18]. The number of polio-infected continents has decreased from five to two, and the number of polio-infected countries has declined from 100 to 53 [17]. In some developing countries in Africa, the Middle East, and the Eastern Mediterranean, poliovirus eradication is not complete. WHO has encountered problems in these countries such as inadequate funding, poor health infrastructure, and civil discord, all of which make a national polio vaccination initiative difficult to implement [17]. These countries will continue to be a target for polio eradication in the future [16,19]. Since polio has been mostly eliminated from the world, the nonpolio enteroviruses (NPEV) have become the focus of increased attention. Although they affect all ages, NPEV infection is most common in children [11,20]. NPEV incidence and severity appear to be inversely proportional to patient age

[21]. NPEV infections account for greater than 30% of reported viral illness [7]. Most infections are benign in a nonepidemic setting; however, they are capable of causing catastrophic infections in the early newborn period and in very young children during epidemics [3]. During 1970 1983, 23,309 cases of NPEV infections were reported to the Centers for Disease Control and Prevention (CDC) [9]. Actual cases of NPEV infections are many times greater than the number of reported cases since most NPEV illness is mild and not commonly reported. Reports to the CDC include primarily more severe illness with 35% NPEV meningitis, 21% respiratory infection, 11% encephalitis, 6% febrile illness, 4% rash, and 1% paralytic disease [9,22]. NPEV infections are the leading cause of viral meningitis, accounting for 80% 92% of all identifiable cases of aseptic meningitis [5]. Due to the rapid identification of NPEV infection via polymerase chain reaction (PCR), at least 75,000 cases of NPEV meningitis are known to occur annually; however, an estimated 600,000 cases are not reported to the CDC [5,23]. The incidence of NPEV encephalitis reported to the CDC is approximately several thousand cases per year and is the second most common cause of viral encephalitis in the United States along with arboviruses [23]. Herpes simplex virus (HSV) is the most common etiology of viral encephalitis in the United States. The true incidence of NPEV encephalitis is underreported because of diagnostic difficulties, such as the reluctance to perform brain biopsy [5]. The absolute incidence of NPEV myocarditis is largely unknown since most cases of NPEV cardiac disease are subclinical. However, an estimated 67% of reported viral cases with cardiovascular symptoms are thought to be due to NPEV [7]. Some specific epidemiologic parameters have been defined about NPEV infection. When a specific enterovirus circulates, frequently young infants are more susceptible to disease. Lake et al. reviewed 27 infected neonates to determine specific epidemiologic factors of NPEV [3]. The study found that greater than 80% of infected infants were healthy newborns, 59% had mothers with recent viral illness, and 72% were males [3]. Strikas et al. also found that the more severe infections of NPEV meningitis and neonatal sepsis more commonly occur in male infants [22].

Clinical presentation and prognosis Clinical presentation of enterovirus infection ranges from minor respiratory illnesses to aseptic

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meningitis, encephalitis, acute hemorrhagic conjunctivitis, myocarditis, paralysis, and multiorgan failure [24]. While several different serotypes may cause the aforementioned illnesses, certain enteroviruses cause specific clinical manifestations [25]. The most studied enterovirus is the poliovirus. While 90% of poliovirus infections are subclinical, paralytic poliomyelitis can occur both sporadically and in large epidemics [4]. With minor illness, known as abortive poliomyelitis, the patient may complain of fever, sore throat, malaise, drowsiness, headache, nausea, and vomiting. In nonparalytic and paralyitic illness there is nuchal rigidity and back pain in addition to minor illness symptoms. Paralytic disease usually stems from lower motor neuron damage leading to temporary or permanent flaccid paralysis [4]. Nonpolio enterovirus infections are common, the majority being minor, nonspecific febrile illnesses. Symptoms include fever, general malaise, anorexia, vomiting, diarrhea, respiratory symptoms, and viral exanthem [2]. The skin manifestations vary markedly but are frequently generalized, nonpruritic, erythematous macules and papules in a morbilliform pattern [26]. However, lesions have also been described as urticarial, scarlatiniform, vesicular, zosteriform, petechial, or purpuric [26,27]. The rash typically occurs during the febrile period. In addition to nonspecific findings, enterovirus infection also causes distinct syndromes such as hand-foot-mouth (HFM) syndrome, herpangina, and hemorrhagic conjunctivitis. The appropriately named HFM syndrome was first described in the 1950s and may occur as isolated cases or in epidemic form (both horizontal and vertical spread) [26]. While coxsackievirus A16 is typically implicated in HFM disease, coxsackieviruses A5, A9, A10, A16, B1, and B3 have occasionally been identified as etiologic agents [15]. After a one to two day mild prodrome of low-grade fever, sore throat, and malaise, small red macules present on the oral mucosa typically among children younger than four years of age. These progress to one to three millimeter vesicles that then ulcerate. The tongue is involved in 44% of cases with lesions suggestive of aphthous stomatitis [28]. Thirty-three percent of patients will have involvement of the palate, uvula, and anterior tonsillar pillars [26,28]. Between 25% and 65% of patients may also have the classic vesicular lesions on the hands and feet [28]. Three to five millimeter grayish vesicles surrounded by a red areola typically involve the lateral borders of the feet, dorsal aspect of fingers and toes, acral surfaces and buttocks. Occasionally the arms, legs, and face are involved. Lesions typically resolve in

seven days [26]. While prognosis is usually excellent, acute flaccid paralysis similar to that caused by poliovirus was reported 320 cases in a recent 90,000 case outbreak in Taiwan. Fifty-five of these children died, usually within the first day of hospitalization [29]. Rare cases of myocarditis, pneumonia, and meningitis have also been reported [30,31]. Herpangina usually presents with onset of fever, sore throat, and malaise in children one to seven years old. Twenty-five percent of patients will also develop abdominal pain, nausea, and vomiting [32]. Cutaneous lesions occur as sparse one to four millimeter grayish white vesicles over the posterior palate, uvula, and tonsillar pillars. Usually fewer than twenty vesicles are noted and are surround by erythema. Symptoms improve in five days and complete recovery is within one week of onset [32]. Hemorrhagic conjunctivitis may be seen sporadically or in large outbreaks. This disorder usually presents after a 24 hour incubation period. Patients report rapid onset of eyelid edema with lacrimation, congestion, and pain. Epithelial keratitis and subconjunctival hemorrhages are common. Although most infections resolve without permanent sequelae, neurologic complications, including paralysis, have been reported [33]. While the majority of enterovirus infections are mild, these viruses sometimes cause severe, lifethreatening disease. As mentioned previously, enteroviruses are the most common cause of aseptic meningitis in children in the United States, with an estimated 75,000 cases per year [34]. Clinical presentation varies with the age of the afflicted patient. Neonates usually have nonspecific findings with fever and no nuchal rigidity [35]. Young children with CNS infection typically present with fever and irritability, while older children complain of fever and headache [11]. Nuchal rigidity, photophobia, nausea, and vomiting are common [36]. Coxsackievirus A9 is commonly implicated in aseptic meningitis and may often cause an exanthem. During the febrile period, erythematous macules and papules erupt on the face and neck and then spread to the extremities [26]. Lesions are usually discrete, but urticarial and petechial lesions mimicking meningiococcemia have been reported [34]. The rash typically lasts from one to seven days. The course of the illness is usually benign and prognosis is excellent [37]. However, progression to encephalitis with permanent neurological deficits including seizures and coma occurs in a small percentage of patients [38]. Enteroviruses may also lead to myocarditis with permanent sequelae and/or death. Adults between twenty and forty years of age are typically afflicted.

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Symptoms reflect the extent of cardiac involvment varying from mild palpitations and chest pain to fatal arrhythmias and congestive heart failure [39]. Patients may report recent respiratory illness, fever, and strenuous exercise preceding chest pain. While most patients recover completely, some develop chronic myocarditis, dilated cardiomyopathy, and congestive heart failure [40 42].

Diagnosis Confirmation of enterovirus infection by specific diagnosis is important since virus detection can affect patient management, such as antibiotic administration or hospital longevity. Until recently, viral culture (VC) has been the gold standard for diagnosis of enterovirus infection [9]. Enterovirus can be cultured from the blood, cerebrospinal fluid, urine, and most tissues [6]. The advantage of VC is that the test can differentiate between specific serotypes of enterovirus [5]. The results of VC for enterovirus infections must be interpreted cautiously since virus is shed from the oropharynx and stool for a long time after infection has resolved [6]. However, there are significant limitations to VC. Although enteroviruses grow more rapidly than most viruses, they may take up to eight days to grow in culture. Some serotypes of enteroviruses are difficult to grow at all. By the time the virus has started to grow, the patients symptoms may have already resolved. Another disadvantage of VC is its low sensitivity. For example, the sensitivity of VC for enteroviral meningitis is less than 75% and for general infection is as low as 65% [43]. Furthermore, 25% 35% of enterovirus specimens can have falsely negative cell cultures [2]. Although serology can detect an antibody response to enterovirus infection, it usually plays no role in routine diagnosis. Serology is a slow diagnostic test and of limited clinical value since it does not differentiate among enterovirus serotypes [6]. Polymerase chain reaction (PCR) has become the new, cutting-edge, diagnostic test that rapidly and accurately detects enterovirus infection. Since all enteroviruses share common genomic sequences, PCR can detect almost all serotypes via three wellcharacterized sets of PCR primers derived from the 50 nontranslated region of enterovirus RNA [5,15,44]. PCR is an ideal technique for virus detection since it requires small clinical samples and is both sensitive and specific. Results are back in 5 24 hours, which is fast enough to affect patient management and reduce cost [45]. Rotbart et al. found that

hospitalization for enteroviral meningitis in children can cost up to US $18,000 per child [46]. Enterovirus infection is a significant economic strain on physician practices as well [9]. Therefore, it is necessary to have a diagnostic test that detects infection rapidly and accurately. Two recent prospective studies found that PCR detection of enterovirus infection reduced patient hospitalization by at least one day, decreased antibiotic use, and cut overall patient management costs [47,48]. Recent studies have conclusively shown that PCR is superior to VC, with a sensitivity almost double that of VC [5]. Sawyer et al. showed that PCR of cerebrospinal fluid is significantly better than VC in diagnosing enteroviral meningitis and demonstrated that PCR can detect cases that were undetectable by VC [49]. Furthermore, the study found that PCR can detect even defective viral particles that are incapable of infecting cells since these particles contain nucleic acid [49]. PCR currently shows a sensitivity of 100% and specificity of 97% for enteroviral meningitis [46]. Enterovirus PCR can also diagnose disease in urine, serum, and throat swabs [6]. Pichichero et al. demonstrated that PCR of throat specimens was the most sensitive diagnostic test of enterovirus infection in their patients [9]. Another study by Johnston et al. showed that PCR achieved at least three times the detection rate of enterovirus in respiratory illness compared to that of VC [50]. Enterovirus PCR is available for physician use and is presently being used more frequently in clinical practice to detect enterovirus infection.

Vaccination and treatment Since poliovirus has been eradicated from most of the world via the introduction of the polio vaccines and efforts of a global vaccination initiative, treatment of enterovirus infection presently focuses more on the nonpolio serotypes. With the development of a more rapid diagnostic technique and new potential antiviral therapies, patient management of enteroviruses has vastly improved. Antibody plays an important role in enterovirus pathogenesis and viral neutralization. Therefore, immunoglobulin has been used prophylactically and therapeutically in individuals with serious enterovirus infections [51]. Immunoglobulin has demonstrated limited success in patients with agammaglobulenemia and chronic enterovirus disease. One randomized, blinded study showed a reduction in viral titer of neonates receiving immunoglobulin

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preparations [21]. However, this study had too small a patient sample to conclusively demostrate a clinical benefit [21]. Other studies have shown disease stabilization involving treatment with immunoglobulin of agammaglobulenemic patients with severe enterovirus infections such as chronic meningitis or meningoencephalitis [52]. Antiviral drugs which inhibit enterovirus replication have been part of continuing research to find a potential therapy for enterovirus infection. Pleconaril has been the first of such drugs studied in clinical trials. Pleconaril has a broad antiviral spectrum and acts by preventing viral uncoating and attachment to host cell receptors [6]. Several features of the drug are that it approaches 70% bioavailability, has a long halflife, and is well absorbed from the gastrointestinal tract [23]. Pleconaril has demonstrated an antiviral activity of greater than 90% in common enterovirus infections at concentrations less than 0.1 mg/ml. In the serum and cerebrospinal fluid, pleconaril can achieve drug levels of more than 0.1 mg/ml [6]. Several studies have demonstrated pleconarils efficacy in treating benign enterovirus infections as well as serious disease such as meningitis. Sawyer et al. studied pleconarils effects in patients suffering from enterovirus meningitis [53]. In this study, 221 patients, ages four through fourteen with clinical manifestations of viral meningitis received either 2.5 mg/kg pleconaril, 5.0 mg/kg pleconaril, or placebo three times daily for a seven day period. Enteroviral meningitis was confirmed by PCR of the cerebrospinal fluid in 82% of patients. Pleconaril showed a 38% 50% improvement in the group of patients treated with the drug versus those who received placebo with responses occurring as early as 24 hours after pleconaril administration. No adverse side effects were reported [53]. Pleconaril has also shown promising results in immunocompromised patients with severe enterovirus infections. A study of sixteen agammaglobulinemic patients with chronic enteroviral meningoencephalitis showed a significant clinical benefit when treated with pleconaril [51]. Approximately 75% of the patients had symptomatic improvement with pleconaril therapy while symptoms of the remaining patients stabilized on the medication [51]. Furthermore, pleconaril has been shown to reduce viral titers by greater than 99% in patients with mild coxsackievirus A21 respiratory infection [54]. Because of its few side effects, good bioavailability, and broad antiviral effects, pleconaril is an attractive therapy for enterovirus infection. Further research is being conducted to determine the exact role of pleconaril in halting enterovirus pathogenesis.

Summary The enteroviruses, RNA viruses of the Picornaviridae family, are ubiquitous pathogens which include more than 70 different serotypes that infect people of all ages and tend to occur seasonally in the summer and fall. Clinical manifestations may vary diversely with one serotype, while multiple serotypes can present with identical symptoms and may mimic bacterial infections. Most enterovirus infections cause benign, self-limiting disease; however, they can also produce severe and sometimes fatal illnesses such as meningitis, encephalitis, myocarditis, neonatal sepsis, and polio. Severe enterovirus infections are being diagnosed and treated earlier with better prognostic outcomes due to the advances of polymerase chain reaction technology in accurately detecting virus in patient fluids as well as the recent development of new antiviral therapies.

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J.R. Stalkup, S. Chilukuri / Dermatol Clin 20 (2002) 217223 infection in an infant associated with coxsackievirus group A, type 16. N Engl J Med 1963;268:1041 4. Parrott RH, Ross S, Burke FG, et al. Herpangina: clinical studies of a specific infectious disease. N Engl J Med 1951;245:275 80. Wadia NH, Wadia PN, Katrak SM, et al. A study of the neurological disorder associated with acute hemorrhagic conjunctivitis due to entervirus 70. J Neurol Neurosurg Psychiatry 1983;46:599 610. Rotbart HA. Meningitis and encephalitis. In: HA Rotbart, editor. Human enterovirus infections. Washington, DC: ASM Press; 1995. p. 271 89. Schlesinger Y, Sawyer MH, Storch GA. Enteroviral meningitis in infancy: potential role for polymerase chain reaction in patient management. Pediatrics 1994; 94:157 62. Rorabaugh ML, Berlin LE, Heldrich E, et al. Aseptic meningitis among infants less than two years of age: acute illness and neurologic complications. Pediatrics 1993;92:206 11. Bergman I, Painter MJ, Wald ER. Outcome in children with enteroviral meningitis during the first year of life. J Pediatr 1987;110:705 9. Whitley RJ, Cobbs CG, Alford CA, et al. Diseases that mimic herpes simplex encephalitis: diagnosis, presentation, and outcome. JAMA 1989;262:234 9. Fujiola S, Koide H, Kitaura Y, et al. Molecular detection and differentiation of enteroviruses in endomyocaridal biopsies and pericardial effusions from dilated cardiomyopathy and myocarditis. Am Heart J 1996; 131:760 5. Andreoletti L, Wattre P, Decoene C, et al. Detection of enterovirus-specific RNA sequences in explanted myocardium biopsy specimens from patients with dilated ischemic cardiomyopathy. Clin Infect Dis 1995;21: 1315 7. Arola A, Kallajoki M, Ruuskanen O, et al. Detection of enteroviral RNA in endstage dilated cardiomyopathy in children and adolescents. J Med Virol 1998;56: 364 71. Kandolf R, Sauter M, Aepinus C, et al. Mechanisms and consequences of enterovirus persistence in cardiac myocytes and cells of the immune system. Virus Res 1999;62:149 58. Rotbart HA, Ahmed A, Hickey S, et al. Diagnosis of enterovirus infection by polymerase chain reaction of multiple specimen types. Pediatr Infect Dis J 1997; 16(4):409 11. Graves PM, Norris JM, Pallansch MA, et al. The role of enteroviral infections in the development of IDDM: limitations of current approaches. Diabetes 1997;46: 161 8. Hamilton MS, Jackson MA, Abel D. Clinical utility of polymerase chain reaction testing for enteroviral meningitis. Pediatr Infect Dis J 1999;18:533 7. Marshall GS, Hauck MA, Buck G, et al. Potential cost savings through rapid diagnosis of enteroviral meningitis. Pediatr Infect Dis J 1997;16(11):1086 7. Parasuraman TV, Deverka PA, Toscani MR, et al. Esti-

[13] Dahlquist CG, Ivarsson S, Lindberg B, et al. Maternal enteroviral infection during pregnancy as a risk factor for childhood IDDM: a population based case-control study. Diabetes 1995;44:408 13. [14] Keswick BH, Gerba CP, Goyal SM. Occurrence of enteroviruses in community swimming pools. Am J Public Health 1981;71:1026 30. [15] Santti J, Vainionpaa R, Hyypia T. Molecular detection and typing of human picornaviruses. Virus Res 1999; 62:177 83. [16] Dowdle WR, Featherstone DA, Birmingham ME, et al. Poliomyelitis eradication. Virus Res 1999;62:185 92. [17] Minor PD. Minireview: eradication of polio by vaccination. Virology 2000;268:231 2. [18] Cochi SL, Hull HF, Sutter RW, et al. Commentary: the unfolding story of global poliomyelitis eradication. J Infect Dis 1997;175(Suppl 1):S1 3. [19] Kaplan MH, Klein SW, McPhee J, et al. Group B coxsackievirus infections in infants younger than three months of age: a serious childhood illness. Rev Infect Dis 1983;5(6):1019 32. [20] Dagan R, Jenista JA, Menegus MA. Association of clinical presentation, laboratory findings, and virus serotypes with the presence of meningitis in hospitalized infants with enterovirus infection. J Pediatr 1988;113 (6):975 8. [21] Abzug MJ, Keyserling HL, Lee ML, et al. Neonatal enterovirus infection: virology, serology, and effects of intravenous immune globulin. Clin Infect Dis 1995; 20:1201 6. [22] Strikas RA, Anderson LJ, Parker RA. Temporal and geographic patterns of isolates of nonpolio enterovirus in the United States, 1970 1983. J Infect Dis 1986; 153:346 51. [23] Pevear DC, Tull TM, Seipel ME, et al. Activity of pleconaril against enterovirses. Antimicrob Agents Chemother 1999;43(9):2109 15. [24] Grist NR, Bell EJ, Assaad F. Enteroviruses in human disease. Prog Med Virol 1978;114 57. [25] Singer JI, Maur PR, Riley JP, et al. Management of central nervous system infections during an epidemic of enteroviral aseptic meningitis. J Pediatr 1980;96 (3):559 63. [26] Cherry JD. Enteroviruses: poliovirus (poliomyelitis), coxsackieviruses, echoviruses, and enteroviruses. In: Feigin RD, Cherry JD, editors. Textbook of pediatric infectious diseases. Philadelphia: WB Saunders; 1987. p. 1729 90. [27] Meade RH, Chang T. Zoster-like eruption due to echovirus 6. Am J Dis Child 1979;133:283 4. [28] Tindall JP, Miller GD. Hand, foot, and mouth disease. Cutis 1972;9:457 63. [29] Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. N Engl J Med 1999;341: 929 35. [30] Goldberg MF, McAdams AJ. Myocarditis possibly due to coxsackie group A, type 16, virus. J Pediatr 1963; 62:762 5. [31] Wright HT, Landing BH, Lennette EH, et al. Fatal

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[51] Rotbart HA. Antiviral therapy for enteroviral infections. Pedi Infect Dis J 1999;18(7):632 3. [52] McKinney Jr. RE, Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 1987;9:334 56. [53] Sawyer MH, Saez-Llorenz X, Aviles CL, et al. Oral pleconaril reduces the duration and severity of enteroviral meningitis in children. Presented at the Pediatric Academic Societies Annual Meeting, San Francisco, 1999. [54] Schiff GM, McKinlay MA, Sherwood JR. Oral efficacy of VP 63843 in coxsackievirus A21 infected volunteers. Proceedings of the 36th Interscience Conference on Antimicrobial agents and Chemotherapy, New Orleans, LA, 1996.

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Rubella
Melody R. Vander Straten, MD1, Stephen K. Tyring, MD, PhD*
Departments of Dermatology and Microbiology/Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA

Rubella, also known as German measles, is a viral exanthem of childhood that is generally subclinical and inconsequential. Devastating teratogenic effects (also known as congenital rubella syndrome [CRS]), however, make rubella a virus of major public health importance. Although immunization, when achieved in high numbers and in the necessary age groups, can nearly eradicate the infection, many countries lack the resources to implement proper vaccination programs. Outbreaks still occur in the United States; many of them are initiated when an immigrant unknowingly imports the infection from a country that has a newly implemented vaccination policy (or none at all). Recognizing and accurately diagnosing the acute illness, as well as maintaining high standards for vaccination and continuing education for health care providers, are necessary to prevent further epidemics and resulting CRS. Structure Rubella is an enveloped, single-stranded RNA virus in the rubivirus genus of the family Togaviridae. It is spherical and 50 to 60 nm in diameter. Its surface is studded with five to six projections that function as hemagglutinins. Incidence Rubella occurs worldwide; human beings are the only known host [1]. The infection occurs most

commonly during winter and spring. Transmission, by way of respiratory droplets, occurs either directly or by contact with surfaces contaminated by infected secretions; close contact is required. Infected persons shed large amounts of the virus in nasal and throat secretions and from other areas, and they may do so for 5 to 7 days before and 2 weeks after the onset of disease. Congenitally infected infants shed the virus for varying lengths of time, sometimes for up to months after birth [1,2]. Since the introduction of rubella vaccination in 1969, the incidence of rubella and congenital rubella syndrome has decreased by 99% [3,4]. Early vaccination efforts focused on infants approximately 1 year old and on school-aged children. Despite these efforts, 5% to 25% of women of childbearing age lack antibodies and are therefore susceptible to primary infection. Recent efforts have focused on immunization of women of childbearing age and testing for susceptibility [1,2].

Epidemiology Before the licensing and use of vaccine in 1969, major rubella epidemics occurred every 6 to 9 years, the last of which was in 1964. Pandemics occurred every 10 to 20 years [1]. No widespread epidemics have occurred in the United States since then, although localized ones have surfaced in various parts of the country. Many of these outbreaks involved close living or working environments, such as in the military, or ones with employees from countries that have suboptimal or nonexistent immunization programs [4 10]. The peak age of incidence before vaccination was 5 to 14 years; it has shifted to involve 15- to 19-year-olds more

* Corresponding author. E-mail address: styring@utmb.edu (S.K. Tyring). 1 Also corresponding author.

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 0 5 - 5

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frequently. The attack rate in susceptible populations with prolonged, intimate exposure is 95% to 100%; the frequency of transmission after brief exposures is low [1].

Clinical manifestations Primary rubella infection is usually a mild, subclinical process involving children and young adults. In fact, it is more likely to be subclinical in adults, whereas only 25% to 50% of exposed, susceptible children present with no signs or solely lymphadenopathy without the characteristic exanthem. The incubation period is 14 to 21 days (mean, 18 days). Rash is usually the presenting sign in children, whereas adolescents and adults often experience prodromal symptoms 1 to 5 days before rash onset. Symptoms and signs include eye pain or conjunctivitis, sore throat, headache, lymphadenopathy (frequently involving the posterior auricular, suboccipital, and posterior cervical chains), lowgrade fever, body aches, cough, chills, anorexia, nausea, and malaise. Viremia occurs approximately 1 week before the rash; the rash is seen when circulating antibodies appear. The face is usually the first area of involvement, then there is centrifugal spread to the extremities. The entire body may be involved within a day. The second day, there is clearing of the face, and the rash commonly clears by the third. The rash is maculopapular, erythematous, discrete, and pruritic. It can take on a more macular form, giving it a scarlatiniform appearance, or it may become confluent with a morbilliform character [1,11]. The exanthem may mimic those of numerous other common infections, such as erythema infectiosum (parvovirus B19, or fifth disease) [12 14], roseola, and exanthem subitum (human herpesvirus 6 infection) [15]. Lymphadenopathy lasts 5 to 8 days. Fever and pharyngitis are usually mild. Petechial lesions occasionally involve the soft palate and uvula. Arthralgias or arthritis lasting weeks to months also may occur, more commonly in adult women. Large and small joints are involved, with or without swelling. It has been hypothesized that joint involvement is secondary to deposition of rubella-specific immune complexes [1,2,11]. Other rare complications of rubella infection include encephalitis, progressive panencephalitis, myelitis, optic neuritis, peripheral neuritis, myocarditis, pericarditis, and hepatitis [1]. A few cases of hemolytic anemia, including two cases of hemolyticuremic syndrome, have been reported. Interstitial pneumonia has occurred in congenitally or perina-

tally infected infants, apparently by way of hematogenous spread [1]. Transient thrombocytopenic purpura occurs in 1 in 3000 children, more often in girls. It usually appears 4 days to 2 weeks after rash onset and lasts days to months. Most cases are self-limited, but some deaths have occurred [1,16]. syndrome has been seen in assoGuillain-Barre ciation with rubella infection, but many cases also involve concurrent or recent upper respiratory or gastrointestinal infections as well, causing some to question the association [2]. A few cases of Stills disease have been associated with rubella infection [17]. One case of virus-associated hemophagocytic syndrome caused by rubella in an adult has been reported [18]. One case of erythema multiforme exudativum with arthritis has been linked to rubella infection [1].

Pathology The virus has been cultured from skin (with and without rash) in both congenital and postnatal rubella cases. Cutaneous findings are believed to be secondary to inflammatory response to viral infection or to antigen-antibody response. Occasionally, a mild, perivascular lymphocytic infiltrate can be seen [2].

Laboratory findings Nonspecific laboratory tests are generally not helpful; a leukopenia with relative neutropenia may be seen on complete blood count. Viral culture, although specific, can be time consuming or challenging because the virus is somewhat unstable. Rubella virus, however, can be cultured from numerous sources, such as nose, throat, urine, stool, blood, cerebrospinal fluid, conjunctiva, feces, bone marrow, breast milk, and synovial fluid. Diagnosis more often is made through serology, by (1) detecting rubellaspecific IgM (for up to 8 weeks after infection) or (2) documenting a fourfold rise in antibody titer in paired sera. Techniques used to detect antibodies include hemagglutination-inhibition, complement fixation, neutralization, radioimmunodiffusion, ELISA, single radial hemolysis, or immunofluorescence. Neutralization identifies antibodies that inhibit specific biologic functions of the virus, whereas the other methods detect the formation of antigen-antibody complexes. Antibodies detectable by hemagglutination-inhibition are present 2 to 3 days after rash onset and peak at 3 to 4 weeks. Complement fixation antibodies peak at 4 to 6 weeks [1].

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Differential diagnosis Numerous exanthematous illnesses should be considered in the differential diagnosis for rubella. Although many of these illnesses have characteristics that can distinguish them from rubella, they also can appear quite similar, making diagnosis on a clinical basis more difficult and emphasizing the need for specific viral testing. Enteroviruses and adenoviruses can produce a similar rash [1]. Measles (roseola) can be similar clinically, although the exanthem tends to be a darker, coppery color, and the patient usually experiences more prominent respiratory symptoms. Another distinguishing sign of roseola is the presence of Kopliks spots. High fever precedes the rash in roseola, and the rash has a different pattern of appearance (trunk first, then face and extremities). Cutaneous findings in fifth disease (erythema infectiosum) tend to be more protracted and can worsen with sun exposure or increased activity. Infectious mononucleosis (Epstein-Barr virus) can be distinguished by heterophil agglutination testing [1,2].

Treatment Most uncomplicated cases of rubella (in persons who are not pregnant) resolve without sequelae. Treatment of primary rubella is largely supportive. Patients with arthritic symptoms generally respond well to nonsteroidal anti-inflammatory medications. If a pregnant, susceptible woman is treated within 72 hours of exposure, immune globulin (20 mL intramuscularly) can prevent infection. More than 72 hours after exposure, immune globulin can be used if the patient is not likely to terminate the pregnancy. Gamma globulin is not used because it can suppress disease symptoms and may not prevent infection or viremia [2]. Vaccination (RA 27/3, live, attenuated rubella vaccine) is contraindicated during pregnancy because of the theoretical risk of live virus to the fetus, although no evidence for vaccine-related teratogenicity exists. Vaccine is obviously better used as a prophylactic measure, not only for prevention of a mild illness with rare (but important) complications but also for potential elimination of a devastating (and ideally, totally preventable) syndrome [1,2].

Congenital rubella syndrome Neonates can contract rubella infection postnatally. Two thirds of these infections are asymptomatic; most pose little or no threat to the infant and

resolve without sequelae. In cases involving maternal infection during pregnancy, although the signs and symptoms experienced by the mother may be minor, silent, or unrecognized, the effects on the fetus can be profound. Most cases of CRS are caused by primary infection, although a few cases secondary to maternal reinfection (usually after a subclinical case) have been reported [2,19]. It also has been shown, however, that if no specific IgM is detected in subclinical reinfection during pregnancy, then the fetus is unlikely to be at risk. The risk of fetal infection with maternal infection occurring during the first trimester is greater than 80%; the risk decreases to 50% during 12 to 16 weeks, and it is essentially zero after 16 weeks [1,2]. The rate of congenital defects resulting from fetal infection during the first trimester approaches 100% and declines to 30% during the second trimester, with virtually no risk after that time [1]. After maternal viremia occurs in primary infection, rubella virus causes necrosis of the placental vascular endothelium, which subsequently embolizes, infecting the fetus through transplacental passage. The infection in an infant with CRS can persist for months to years. The infant may excrete large amounts of virus through urine, blood, nasal or throat secretions, and cerebrospinal fluid and therefore may transmit the virus to other susceptible hosts [1]. Mechanisms of teratogenesis include (1) direct cellular destruction, causing altered formation or function of developing tissues; (2) blood vessel obliteration with resultant hypoxic damage; (3) chromosomal injury; (4) ongoing cellular destruction or immunopathologic damage to tissues; and (5) formation of circulating antigen-antibody complexes, with deposition into certain tissues [1]. The sequelae can include fetal death (spontaneous abortion or stillbirth), intrauterine growth retardation, ocular abnormalities (such as cataracts, glaucoma, and retinopathy), sensorineural hearing loss, cardiovascular abnormalities (patent ductus arteriosus, pulmonary stenosis, supravalvular stenosis, valvular stenosis, renal artery stenosis, ventricular septal defect, tetralogy of Fallot, neonatal myocarditis, and possibly, cerebrovascular stenosis), hepatomegaly, hepatitis, jaundice, purpura, meningoencephalitis, thrombocytopenia, and mental or psychomotor retardation [1,2]. The features in CRS can be grouped into three broad categories: transient (those that clear after a few months), such as thrombocytopenic purpura or hepatitis; permanent (i.e., persistent or worsening), such as congenital heart defects, cataracts, or hearing loss; and developmental (which do not emerge until later in childhood or young adulthood), such as behavioral

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disorders or endocrine dysfunctions [1]. Deafness is the most common finding, present in up to 67% of cases of CRS [3]; however, it may not develop until months to years after birth, probably because of the persistence of viral replication causing continued neural damage. Hearing loss and neurologic deficits may appear long after birth in children previously thought to be well [1]. There are numerous cutaneous findings in CRS as well. Blueberry muffin spots (purple to dark-blue macules, papules, or nodules representing extramedullary hematopoiesis) and thrombocytopenic purpura are considered poor prognostic signs. Other skin findings include morbilliform rash, similar to that of postnatal rubella; reticulated erythema of face and acral areas; facial seborrhea; hyperpigmentation of face, umbilicus, and areas of skin trauma; vasomotor instability, with mottling, cyanosis of extremities with dependency and temperature-dependent flushing; dermatoglyphic changes; increased whorls on fingerprints in patients not treated with gamma-globulin; and increased ulnar loops on fingerprints in patients treated with gammaglobulin. One case of acute leukocytoclastic vasculitis also has been reported [2]. A case of circumscribed scleroderma has been described in a patient with CRS and hypogammaglobulinemia [20]. Longterm sequelae include not only deafness, cardiac defects, mental retardation, and ocular abnormalities but also other conditions that may not surface until late childhood or early adulthood. These late manifestations include reactive behavior disorder, behavior disorder with neurologic damage, chronic lymphocytic thyroiditis, thymic hypoplasia, abnormal dermoglyphics, chromosomal abnormalities, pancreatic insufficiency, and progressive panencephalitis. There are no known measures to prevent these lateonset conditions [11]. Differential diagnosis of the many features and sequelae of CRS is extensive. In general, it is important to consider other viral and bacterial infections in neonates with signs of acute infection. One also must consider other causes when evaluating many of the other manifestations as well, including disorders associated with prematurity, metabolic disorders, other congenital malformations, chromosomal abnormalities, hematologic disorders, perinatal anoxia, and many more. In any case of suspected perinatal infection, it is wise to obtain the proper cultures and treat with antibiotics until a bacterial infection is ruled out. Diagnosis of CRS can be achieved in several ways. Again, nonspecific laboratory tests (complete blood cell count, chemistries, urinalysis) are not helpful. The most direct method is to isolate rubella

virus in the neonate from the appropriate site at birth, such as the throat, in the urine, and in cerebrospinal fluid, especially in cases in which there is suspicion or confirmation of maternal infection during pregnancy. Serologic testing is not as sensitive, immediate, or direct, but it is the most readily available means for confirmation. TORCH is a rapid means to screen for many common or important infections of the neonate. Infections detected by the test include the following: toxoplasmosis; other (syphilis, tuberculosis, listeriosis, leptospirosis, hepatitis, enterovirus, adenovirus, varicella-zoster virus, Epstein-Barr virus, HIV, and parvovirus B19); rubella; cytomegalovirus; and herpes simplex virus. This test is only a screen, however, and confirmation of rubella infection must be achieved through proper timing of appropriate serologic tests [1,2]. There are three approaches to serologic diagnosis: (1) obtain maternal and infant serum at birth and 5 to 6 months after for antiviral antibody (IgG), (2) obtain neonatal serum for specific IgM, or (3) obtain neonatal serum for quantitative (nonspecific) total IgM. Cord blood obtained for quantitative IgM can be contaminated by maternal blood in half to two thirds of specimens. In addition, normal levels of quantitative IgM can be found in up to half of infants with proven congenital infection, especially if asymptomatic; however, elevated levels can prompt the investigator to look further for congenital infections. Maternal IgG (mothers antibody to rubella virus produced after exposure while pregnant) passes transplacentally starting at midgestation and peaks at birth. Fetal immunoglobulins remain low because of the protected environment (amniotic sac) and low antigenic challenge. The fetus can mount a humoral immune response if exposed to antigens while in utero; elevated levels of fetal IgM (specific or total) can be detected at birth in cord blood. After birth, levels of transplacentally passed maternal IgG in the neonate decline by 5 to 6 months until they are undetectable. Only after antigenic challenge (after birth) do fetal/neonatal immunoglobulins start to rise. Thus, testing neonatal serum at birth and at 6 months of age for IgG and at birth for specific IgM can determine whether infection likely occurred while in utero or after birth. Testing maternal serum (for specific IgM) at exposure can determine if she was rubella-susceptible or immune, and then testing for IgG at birth and 6 months after can demonstrate whether or not acute maternal infection occurred during pregnancy. False-positive and falsenegative results can occur with serologic testing; cross-reaction with other viruses, such as herpes simplex virus or presence of rheumatoid factor, can yield a false-positive result, whereas a poor or

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delayed neonatal humoral immune response can produce a falsely negative result [1]. Congenital rubella syndrome produces some characteristic pathologic findings in some tissues. Bone marrow can be hyperplastic or normal, and there can be a reduction in megakaryocytes. The metaphyses of the distal femur and proximal tibia may show an altered trabecular pattern. Dental enamel may be hypoplastic. Major arteries may demonstrate intimal hyperplasia, sometimes severe enough to be occlusive, whereas other vessels can be hypoplastic or calcified. Most of these findings are nonspecific and are not pathognomonic for CRS [2]. No specific treatment exists for rubella infection during pregnancy, except as previously discussed. Likewise, there is no specific treatment for CRS, except to address specific sequelae, such as early surgery for cataracts to save visual acuity and prevent learning disability. Neonates with CRS are contagious, so proper isolation techniques are necessary for several months to prevent transmission to susceptible persons [2]. Vaccination is the best way to prevent the disastrous effects of CRS. Current efforts focus on vaccination of children at 12 to 15 months and 4 to 6 years of age. More recently, immunization has focused on testing women of childbearing age for immunity and vaccinating those who are not immune [21]. Concerns about vaccination programs continue, such as the effects of reinfection with wild-type virus in the vaccine-immune, side effects of the vaccine, risks to the fetus when vaccinating someone unknown to be pregnant, waning immunity, failure of herd immunity during times of epidemic, and outbreaks of rubella among unvaccinated pregnant women or workers in custodial institutions or selected communities (including immigrants from countries with suboptimal or no immunization programs [2]). Adverse reactions include rash, lymphadenopathy (sometimes marked), mild fever, upper respiratory tract infection symptoms, arthralgias or arthritis (in up to 25% of postpubertal women; it can be infrequently chronic or recurrent), polyneuropathies, vasculitis, and myositis. Several less common conditions have been associated with the use of the measles, mumps, and rubella (MMR) vaccine. These conditions include thrombocytopenic purpura [16,22 24], hemophagocytic syndrome (one case report) [18], Gianotti-Crosti syndrome [4,26]. syndrome [25], and Guillain-Barre In most of these cases, the implicating agent of the vaccine is unknown. MMR is only one of several vaccines reported in cases of Stevens-Johnson and toxic epidermal necrolysis that have occurred after

vaccination. In none of the cases, however, was MMR the sole vaccine given [27]. Vaccination is contraindicated in women who are pregnant or planning to become pregnant within the next 3 months. The maximal theoretical risk to the fetus whose mother is immunized during pregnancy is estimated at 1.6%. Other conditions in which vaccination is contraindicated are immunodeficiency states; leukemia; lymphoma; other generalized malignancies; treatments with chronic steroids, chemotherapeutic agents, or radiation; and acute febrile illnesses. Vaccine should not be given within 3 months after receiving blood products or immunoglobulin [1]. Several small outbreaks of rubella have surfaced in the United States in the past 10 years, many having arisen in workplaces that employ a high number of workers from countries that do not have or only recently have begun vaccination efforts [4 10,12 14,21]. Most of these workers are of Hispanic origin. Because of good reporting, surveillance, and organized vaccination and community education efforts, these epidemics have been contained to a relatively small number of cases. Such an outbreak occurred among meatpacking plant workers and their household contacts in Nebraska between March and August of 1999. Crowded working environments among adults born in Latin American countries where vaccination had begun only recently contributed to the onset of the outbreak, and spread was facilitated by high population density. Pregnant women visiting prenatal clinics in the area were infected in high numbers, despite a pre-outbreak level of immunity of 87%, which normally is believed to be high enough to protect against community-based transmission. The disease finally spread to day-care centers distant from the outbreak, infecting mostly children younger than the minimum age of vaccination. Vaccination levels in the rest of the county were high enough to limit further spread. Only one infant was born with CRS as a result of the outbreak. Neither vaccine failure nor failure to implement required child vaccination programs caused the outbreak. Instead, the need to implement strategies to achieve high vaccination levels among non US-born adults working and living in crowded conditions (where rubella transmission is facilitated) was emphasized, as was the need for routine rubella vaccination of all susceptible women of childbearing age [5]. A similar outbreak occurred in Kansas between April and July of 1998 among employees at meatpacking plants, many of whom were born in Latin American countries as well. No cases of CRS ensued. Yet another outbreak occurred in Westchester County, New York,

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between December 1997 and May 1998, starting among non US-born workers of Hispanic descent. Of five pregnant women, three were infected during the first trimester, and all three elected to terminate the pregnancy. The other two delivered infants without CRS [7,9]. Epidemics continue to occur in countries in which immunization practices, for numerous reasons, remain substandard. Greece implemented a policy in 1975 to vaccinate all children at 1 year of age, with no policy to ensure high coverage or to protect adolescents or young adults. In 1993, an epidemic that was larger than any previous epidemics occurred in young adults, which in turn resulted in 25 confirmed cases of CRS, as opposed to only sporadic cases of 1 to 5 per year in selected years between 1950 and 1992. Theories exist, backed by computer modeling, that vaccinating young children only once for rubella interrupts the transmission of the virus and increases the age at which susceptible people are infected, which in turn can increase the age of incidence and lead to an increase in CRS. The 1993 epidemic in Greece provided the first evidence supporting these theories [4,8]. A study in Kumasi, Ghana, using prospective surveillance and retrospective review of hospital records, not only identified 18 confirmed or probable CRS cases but also provided evidence of a previously undocumented rubella epidemic in early 1995. The reported rate of 0.8 CRS cases per 1000 live births in this study probably was underestimated because of the low awareness of CRS and the likelihood that many cases remained undiagnosed or unreported [6].

and its potentially devastating effects, and continued surveillance for and reporting of cases in high-risk areas may be of benefit.

References
[1] Demis DJ, editor. Clinical dermatology. 25th revision. Philadelphia: Lippincott-Raven; 1998. p. 262, 474, 772, 856 73, 1652, 1922 41, 2749 50. [2] Feigin RD, Cherry JD, editors. Textbook of pediatric infectious diseases. 4th edition. Philadelphia: W.B. Saunders Company; 1998. Section 14 17: p. 1 5; section 31-1: p. 6 8; section 32-1: p. 8 10, 41 2. [3] Control of infectious diseases,1900 1999 (from the Centers for Disease Control and Prevention: Morbidity and Mortality Weekly Report). JAMA 1999;282: 1029 32. [4] Panagiotopoulos T, Antoniadou I, Valassi-Adam E. Increase in congenital rubella occurrence after immunization in Greece: retrospective survey and systematic review. BMJ 1999;319:1462 7. [5] Danovero-Holliday MC, LeBaron CW, Allensworth C, Raymond R, Borden TG, Murray AB, et al. A large rubella outbreak with spread from the workplace to the community. JAMA 2000;284:2733 9. [6] Lawn JE, Reef S, Baffoe-Bonnie B, Adadevoh S, Caul EO, Griffin GE. Unseen blindness, unheard deafness, and unrecorded death and disability: congenital rubella in Kumasi, Ghana. Am J Public Health 2000;90: 1555 61. [7] Martin RM, Huang AJ, Adel HN, Larsen CM, Daleo CE, Landrigan MM, et al. Rubella outbreakWestchester County, New York, 1997 1998 (from the Centers for Disease Control and Prevention: Morbidity and Mortality Weekly Report). Arch Dermatol 1999;135: 1284 5. [8] Panagiotopoulos T, Antoniadou I, Valassi-Adam E. Incidence of congenital rubella in Greece [letters]. BMJ 2000;321:1287. [9] Rubella among Hispanic adultsKansas, 1998, and Nebraska, 1999 (from the Centers for Disease Control and Prevention: Morbidity and Mortality Weekly Report). JAMA 2000;283:1819 20. [10] Zimmerman L, Reef S. Incidence of congenital rubella syndrome at a hospital serving a predominantly Hispanic population, El Paso, Texas [Pediatrics electronic pages]. Pediatrics 2001;107:e40. [11] Mancuso P. Dermatologic manifestations of infectious diseases in pregnancy. J Perinat Neonat Nurs 2000;14: 17 38. [12] Tookey PA, Peckham CS. Surveillance of congenital rubella in Great Britain, 1971 1996. BMJ 1999;318: 769 77. [13] Tookey PA, Peckham CS. Surveillance of congenital rubella in Great Britain: rubella can be mistaken for parvovirus B19 infection authors reply [letters]. BMJ 1999;319:58.

Summary Rubella is still a public health concern in this country. With the great numbers of immigrants welcomed in the United States also comes the risk of diseases that are little known or thought to be of little concern. Obviously, there is a need for continued vaccination of citizens, not only at approximately 1 year of age and school age but also in terms of continued screening for and immunization of susceptible women of childbearing age. Policies need to be developed to address the issue of rubella infection and susceptibility in areas where there is a high population density of people from countries that may not have such strict immunization practices. Vaccination at workplaces that employ high numbers of foreign-born workers or that involve a close working environment, education of workers and health care professionals in the recognition of rubella

M.R. Vander Straten, S.K. Tyring / Dermatol Clin 20 (2002) 225231 [14] Turner AJL. Surveillance of congenital rubella in Great Britain: rubella can be mistaken for parvovirus B19 infection [letters] BMJ 1999;319:57 8. [15] Tait DR, Ward KN, Brown DWG, Miller E. Exanthem subitum (roseola infantum) misdiagnosed as measles or rubella. BMJ 13 1996;312:101 2. [16] Pool V, Chen R, Rhodes P. Indications for measlesmumps-rubella vaccination in a child with prior thrombocytopenia purpura. Pediatr Infect Dis J 1997;16: 423 4. [17] Escuerdo FJ, Len O, Falco V, De Sevilla TF, Sellas A. Rubella infection in adult onset Stills disease. Ann Rheum Dis 2000;59:493. [18] Takenaka H, Kishimoto S, Ichikawa R, Shibagaki R, Kubota Y, Yamagata N, et al. Virus-associated haemophagocytic syndrome caused by rubella in an adult. Br J Dermatol 1998;139:877 80. [19] Bullens D, Smets K, Vanhaesebrouck P. Congenital rubella syndrome after maternal reinfection. Clin Pediatr 2000;39:113 6. [20] Espanol T, Pascual C, Huguet P, Caragol I, Hernandez M, Bertran JM. Circumscribed scleroderma in congenital rubella syndrome with hypogammaglobulinemia. Allergy 1998;53:1005 6.

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[21] Plotkin SA. Where rubella is still a problem. Pediatr Infect Dis J 1999;18:575 80. [22] Chang SKY, Farrell DL, Dougan K, Kobayashi B. Acute idiopathic thrombocytopenic purpura following combined vaccination against measles, mumps, and rubella. J Am Board Fam Pract 1996;9:53 5. [23] Miller E, Waight P, Farrington CP, Andrews N, Stowe J, Taylor B. Idiopathic thrombocytopenic purpura and MMR vaccine. Arch Dis Child 2001;84:227 9. [24] Vlacha V, Forman E, Miron D, Peter G. Recurrent thrombocytopenic purpura after repeated measlesmumps-rubella vaccination. Pediatrics 1996;97:738 9. [25] Velangi SS, Tidman MJ. Gianotti-Crosti syndrome after measles-mumps and rubella vaccination. Br J Dermatol 1998;139:1122 3. [26] Patja A, Paunio M, Kinnunen E, Junttila O, Hovi T, Peltola H. Risk of Guillain-Barre syndrome after measles-mumps-rubella vaccination. J Pediatr 2001; 138:250 4. [27] Ball R, Ball LK, Wise RP, Braun MM, Beeler JA, Salive ME. Stevens-Johnson syndrome and toxic epidermal necrolysis after vaccination: reports to the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J 2001;20:219 23.

Dermatol Clin 20 (2002) 233 247

The cutaneous manifestations of viral hepatitis

Allyson M. Jones, MDa,b, Kristyn Warken, MSc,*, Stephen K. Tyring, MD, PhDd
a Department of Internal Medicine, St. Josephs Hospital, Houston, TX, USA Department of Dermatology, Louisiana State University, New Orleans, LA, USA c University of Texas at Houston Medical School, Houston, TX, USA d Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX, USA b

Viral hepatitis is known as a worldwide cause of chronic liver problems, yet extrahepatitic manifestations are also a significant part of the disease. The three most common hepatitis viruses are hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Cutaneous manifestations are commonly seen in HBV and HCV and will be the main focus of this chapter, but HAV also has a few characteristics that should be noted. Hepatitis D, hepatitis E and hepatitis G viruses are less frequent and are not associated with any significant cutaneous manifestations [1 3].

tis, and cryoglobulinemia. The latter two have been seen in patients with the persistent cholestatic form of HAV infection. In these patients, evaluation of the cryoglobulins revealed IgM anti HAVantibodies [6,7]. In 1995, the FDA approved the first HAV vaccine, HAVRIX, by SmithKline Beecham. Following quickly, Merck was approved for another HAV vaccine, VAQTA. Both of these vaccines are inactivated. Current recommendations for the vaccine include children living in areas where there are 10 to 20 cases of HAV infection per 100,000 people per year [5].

Hepatitis A HAV is the most common type of hepatitis in the United States, making up for approximately 60% of the cases. HAV is prevalent among American Indians, Alaskan Indians, and Hispanics [3,4]. Transmission is through the fecal-oral route. The virus is shed in the feces 2 weeks before and 1 week after the onset of symptoms. HAV presents as a gastroenteritis or a viral respiratory infection, which worsens in severity with increasing age of the patient. Common symptoms include fever, hepatomegaly, jaundice, and dark urine. Jaundice is seen in approximately 70% of the cases [3 5]. Other case reports note symptoms such as urticaria, scarlatiniform eruption, cutaneous vasculi-

Hepatitis B Introduction The earliest outbreak of serum hepatitis (hepatitis B) was in Bremen shipyard workers in 1883, which manifested as jaundice [1]. Later, hepatitis B was accidentally discovered in 1966 through a reaction of an antigen found in an Australian Aborigine with an antibody found in a hemophiliac who underwent multiple blood transfusions [8 10]. Dr. Baruch Blumberg won the Nobel Prize in Physiology or Medicine in 1976 for this work. Today hepatitis B is the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma [10]. Virology Hepatitis B virus (HBV) is a partially double stranded DNA that belongs to the hepadnavirus fam-

* Corresponding author. 616 Memorial Heights # 7101, Houston, TX 77007. E-mail address: kristyn.a.warken@uth.tmc.edu (K. Warken).

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 1 0 - 9

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ily. The whole viron is called the Dane particle and measures 42 nm [10,11]. The Dane particle consists of an envelope surrounding a core containing the DNA, hepatitis B core antigen (HBcAg), DNA-dependent polymerase, and hepatitis B e antigen (HBeAg). The hepatitis surface antigen (HBsAg) is incorporated into the surrounding envelope [11]. The virus consists of approximately 3200 base pairs with 4 overlapping coding frames. The gene codes for structural proteins (pre-S, S, and core), replicative enzymes (polymerase and X), and regulatory factors [10,11]. Epidemiology Prevalence of HBV infection divides the world into three regions. The hyperendemic region or area of highest prevalence includes areas such as South East Asia, China, and sub-Saharan Africa. In this region 5% to 20% of the population are carriers. North Africa, the Middle East, Southern and Eastern Europe, and South America are considered intermediate endemic regions. The carrier rate of the general population in these areas ranges from 1% to 5%. The region of lowest prevalence includes Northern Europe, Western Europe, United States, Canada, Australia, and New Zealand. There is a carrier rate of less than 0.1% in these areas [10 12]. In areas of high prevalence, the infection is acquired more commonly in children and young adults, while in low prevalence areas the average age group is 20 to 40 years [12]. The World Health Organization estimated that 400 million people worldwide were infected with hepatitis B by the year 2000. Currently 1.25 million people in the United States are chronically infected. Annually, 140,000 to 320,000 people are infected with HBV in the United States [10,11]. Risk Factors Transmission of the virus is seen frequently in IV drug use, sexual activity, and occupational exposure. Other modes of transmission include organ transplant and vertical transmission to the fetus of a pregnant woman. The virus has been detected in bodily fluids such as blood, saliva, semen, and cervical secretions [11]. Sexual activity accounts for more than 50% of HBV transmission [13]. HBV has been associated with homosexual activity, prostitution, and sex under the influence of drugs [14 16]. In a study of heterosexual women, there was a 5% seroprevalence among participants who had 5 or fewer sexual partners in the past 4 months compared to a 30% seroprevalence in subjects with more than 5 sexual partners in 4 months

[14,15]. Transmission of HBV through homosexual activity is decreasing, while transmission through heterosexuals with multiple sex partners is increasing [13,16]. The Centers for Disease Control and Prevention announced in 1994 that 1012 healthcare workers were infected with HBV and 22 of those subjects died of hepatitis related illnesses. Healthcare workers have a 3 to 5 fold increased risk of being infected with HBV compared to the general population, although this risk is decreasing due to the mandatory HBV vaccine as well as universal precautions. There is a risk of infection in the range of 6% to 30% with each exposure [17]. Vertical transmission from the mother to the fetus occurs during the perinatal period and is the most important factor in areas of high prevalence such as Southeast Asia. The risk of transmission can be as high as 90% depending on the titers of HBeAg in the maternal serum and the ethnicity [12]. In the United States, vertical transmission has decreased due to the mandatory antepartum serum HBsAg. The sequelae of the infant can be reduced by the administration of HBV human hyperimmune globulin at delivery followed by the vaccination [18]. Clinical characteristics Acute HBV infection has an incubation period of 45 to 180 days. The prodromal period manifests as anorexia, nausea, jaundice, fatigue, and right upper quadrant pain. Approximately 15% of patients develop a serum sickness-like syndrome with fever, malaise, urticaria, and symmetric small joint pain [11,19]. Approximately 30% of the patients with acute HBV experience icteric hepatitis, while the other 70% develop anicteric hepatitis [19]. The icteric phase is characterized by a worsening of symptoms with dark urine, light stools, and jaundice. Some may also experience nausea, vomiting, and pruritus. The hallmark of acute hepatitis is elevated AST and ALT to levels exceeding 1000 2000 IU/L. In most cases, these symptoms disappear after 1 to 3 months [11,19,20]. During this time, HBsAg can be detected in the serum of the patient. If HBsAg does not disappear within 6 months, then the patient is diagnosed with chronic HBV infection. If the patient has active HBV replication (therefore active liver disease), HBeAg is detected in the serum [11,19]. A healthy carrier of HBV has no symptoms and normal values of AST and ALT. Patients have a 7% risk of relapsing within the first year and 2.9% risk in subsequent years. Healthy carriers who are 30 years old or older and have cleared the infection

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have an annual 1% probability of developing cirrhosis [11,21]. Only 10% of adults infected with HBV will become chronic carriers, yet 60% of elderly patients become chronic carriers due to decreasing cellular immunity [22]. The probability of developing chronic HBV infection highly depends on the age at which the patient first became infected with HBV. If infected in the perinatal period, the patient has almost 90% chance of developing chronic HBV. If infected during 1 to 5 years of age the chance declines to 20% 50%, and even further declines to less than 5% in adults who become infected [11,19,20,23]. Most of the patients with chronic HBV are asymptomatic unless the disease progresses to decompensated cirrhosis. Cirrhosis can manifest as ascites, splenomegaly, jaundice, peripheral edema, or encephalopathy [11,19,24]. These symptoms are accompanied by an increase in AST and ALT. Liver biopsy shows active inflammation with hepatocellular necrosis. Annually, 4000 deaths from cirrhosis and 8000 deaths from hepatocellular carcinoma can be attributed to chronic HBV infection [2,25]. Studies prove the risk of hepatocellular carcinoma in a patient with chronic HBV and in children with HBsAg is significant enough to routinely screen these patients with ultrasound and alpha-fetoprotein levels [26,27]. Full hepatic failure occurs in 0.1% to 0.5% [19].

Cutaneous manifestations Polyarteritis nodosa (PAN) PAN is one of the more serious and more common complications of HBV infection [1,19]. A viral hepatitis associated PAN was first suggested in the 1930s, but the idea was not proven until a serum test for HBsAg was invented [1]. PAN involves medial fibrinoid necrosis and inflammatory perivascular infiltration of small to medium arteries and arterioles [1,28]. The infiltrate is mainly composed of CD8 + T cells and macrophages, and eosinophils and plasma cells are seen in the adventitia [28]. The pathogenesis of HBV associated PAN is unclear, but it is thought to involve deposition of immune complexes in the vessel walls including IgM, complement factors (C3), and HBsAg [29,30]. In some cases HBsAg has been thought to be the triggering antigen [31 33]. Lesions of the arteries tend to be segmental and involve the bifurcation then spread circumferentially to involve adjacent veins [30]. The annual rate of people developing PAN in England is 4.6/1,000,000, while in hyperendemic HBV regions, such as Alaska, the rate increases to

77/1,000,000 [29,34,35]. Approximately 2/500 people with HBV develop PAN, but up to 50% of people with PAN test positive for HBsAg [14,30]. There is an increased rate of HBV associated PAN in the inner city population [34]. Symptoms arise weeks to months after an acute episode of HBV. Symptoms include fever, malaise, arthralgias, abdominal pain, mononeuritis, hypertension, polyarthritis, and weight loss [14,29,36]. PAN can progress to involve major organ systems such as the kidneys, gastrointestinal tract, and peripheral and central nervous system. In such cases hemorrhage, thrombosis, and infarction can occur [1,30]. Cutaneous involvement occurs in 10% 20% of individuals with PAN [6,37]. Skin manifestations include palpable purpura on lower extremities spreading to other dependent areas and then spreading centrally [36,37]. The purpura can progress to large cutaneous ulcers [37]. Tender, purple, subcutaneous nodules occur in some patients as well as extensive livedo reticularis. Urticaria and angioedema have also been reported in patients with HBV associated PAN [6,36,37]. In severe cases of PAN involving end arteries, distal gangrene may occur [14,28]. There is no correlation between the severity of PAN and the severity of the hepatitis, in fact, hepatic disease is often silent [1,6]. The mortality rates of people with PAN are equal between those with and without associated HBV infection. Prognostic factors take into account the severity of the PAN, the status of the liver, and renal, gastrointestinal, cardiac, and nervous system involvement [1]. Traditional treatments of PAN include corticosteroids, immunosuppressives (cyclophosphamide), and plasma exchange [1,11,29,36]. These treatments put the PAN into remission, decrease the risk of relapse, and increase the quality of life [30]. One pitfall in the treatment plan is that it promotes viral replication thus perpetuating the HBV infection [29,30,36]. Studies have shown that the HBV responds to antivirals after the PAN is under control [1,11,19]. Recent case reports show that HBV associated PAN may respond to interferon alpha following a successful treatment with immunosuppressives [38,39]. Studies show that the 10 year survival is the same for groups treated with corticosteroids and plasma exchange compared to a group treated with the same regimen with the addition of cyclophosphamide, but the long term survival is increased in the group with the cyclophosphamide [29]. Papular acrodermatitis of childhood (PAC) PAC is a syndrome first described by Fernando Gianotti in Milan in 1955. The syndrome is a mani-

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festation in children infected with HBV, which is not commonly seen in adults [40 43]. The disease is most commonly seen in children ages 2 to 6 years and has low infectivity. The main characteristics of the syndrome include a non-relapsing, erythemato-papular dermatitis localized to the face and limbs, lymphadenopathy, acute hepatitis (mostly anicteric), and HBsAg antigenaemia, subtype ayw [40]. Today HBV associated PAC is rarely seen in the United States, but is common in HBV hyperendemic regions such as Southern Europe and Japan [44]. PAC has also been associated with other viruses such as cytomegalovirus, Epstein-Barr virus, respiratory syncytial virus, coxsackie virus, and enterovirus [45 49]. The dermatitis is described as crowded lesions which are infiltrated, round, 2 3 mm in diameter, and sometimes purpuric. The non pruritic lesions are symmetrically spread over the face, limbs, and buttocks, sparing the trunk [40,50]. Eruption of the lesions ends in 2 to 3 days, but the dermatitis remains for 15 to 20 days [40,42]. The lesions do not affect mucus membranes or the antecubital and popliteal surfaces [40]. Infected infants have larger lesions measuring around 5 mm, while older children have smaller lesions measuring around 1 to 2 mm. The lesions include infiltrates of mononuclear cells and histiocytes in the upper dermis, especially around the capillaries. Koebnerization of papules frequently occurs. In the later stages of the dermatitis, the lesions are covered with a thin pityriasiform scale [40,44]. Paracortical hyperplasia of the inguinal and axillary lymph nodes, elevated liver enzymes, and hepatomegaly last 2 to 3 months. The hepatitis begins simultaneously or within 2 weeks of the onset of the dermatitis. A month later, the dermatitis begins to resolve as the hepatitis peaks. The hepatitis can progress to chronic liver disease [40,42]. In 1974 1975, an epidemic in Matsuyama City, Japan of HBV-associated PAC proved a relation between HBsAg and subtype ayw. The most common subtypes seen in Japan are adw and adr, but 93% of the patients in the epidemic were subtype ayw (the most common subtype in the Mediterranean) [50,51]. The study also showed that the parents were infected from their children through a non-parenteral route including through skin or mucous membranes [40,51].

associated with the prodromal phase of the disease [6,43]. The symptoms include urticaria, angioedema, arthropathy, proteinuria or hematuria, and rash. The syndrome occurs 6 weeks prior to the icterus and improves or disappears with the onset of jaundice [6,14,36,43,53]. The articular symptoms include an acute, nondeforming symmetric arthralgia of small joints of hands, shoulders, knees, and ankles. Symptoms also involve an edema and synovitis of the involved joints which can last for 20 days [43,55]. Immune complex deposition can also produce a mild focal or diffuse membraneous glomerulonephritis causing mild proteinemia or hematuria [43]. Dermatological manifestations include urticaria, angioedema, and various spectra of rashes [6,36,43]. The urticaria is a leukocytoclastic vasculitis (LCV) with endothelial edema, fibrinoid occlusion, and hemorrhage [14,43,56]. Approximately 4% of the patients experience angioedema [6,43]. Other rashes include palpable purpura, erythema multiforme, toxic erythema, and a lichenoid dermatitis [43,53,55]. The pathogenesis behind the syndrome includes deposition of immune complexes, which occurs due to antigen excess generating soluble antigen antibody complexes. The immune complexes are composed of HBsAg, IgG, IgM, and C3 [14,43]. SSLP is also associated with a hypocomplementemia [6,14,53]. Immune complexes produce lesions by producing anaphylatoxins C3a and C5a, which manifest as urticaria and vasculitis. As the antibody levels rise, the immune complexes become less soluble, therefore easier to clear. At this time clinical manifestations begin to subside [43]. Other cutaneous manifestations HBV infection has also been associated with erythema nodosum, urticaria, and lichen planus. Mixed cryoglobulinemia has also been associated with HBV, but since it is more frequently associated with HCV infection, it will be discussed in that section [6,57]. Hepatitis D virus (HDV) requires concurrent infection with HBV in order to replicate and is only seen in 5% of HBV infections. There is not an association between HBV coinfection with HDV and the occurrence of more frequent skin manifestations [2]. Prevention of HBV

Serum sickness-like syndrome (SSLP) SSLP was first described in 1843 by Graves and is now considered the most common dermatological manifestation associated with HBV [52 54]. SSLP occurs in 20% to 30% of patients with HBV and is

Currently, two methods of prevention are available including hepatitis B immunoglobin (HBIG) and hepatitis B vaccine. HBIG is only used in patients

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with recent exposure to the virus, preferably within 24 hours of exposure. HBIG is collected from donors with high titers of HBsAg. The dose is 0.06 mL/kg intramuscularly followed by the HBV vaccine series at a separate site [11,43]. The HBV vaccine was FDA approved in June of 1982 and now is a routine infant vaccine in the United States and other countries. The vaccine consists of recombinant HbsAg and is available from two pharmaceutical companies, Merck (Recombivax HB) and Smith Kline Beecham (Engerix-B). Three doses of the vaccine are given at time 0, 1, and 6 months intramuscularly. Approximately 96% of the patients have serodetection, defined as more than 10 mU/mL of HBsAb. Serodetection is decreased in patients that have end-stage renal disease, cirrhosis, liver transplants, and patients that are greater than 40 years of age [11,43,58,59]. Recently the FDA approved a new combination vaccine that protects adults against HAV and HBV. This vaccine, Twinrix, combines Havrix and Engerix and reduces the number of injections from 5 to 3, thus offering greater convenience and lower administration costs. Treatment of HBV Interferon alpha (IFN-a) is the standard treatment for chronic hepatitis B with evidence of decompensated liver disease. Indications for treatment require positive levels of HBeAg and HBV DNA, as well as evidence of chronic hepatitis. IFN-a has a dosage of 10 million units subcutaneously for one week, or 5 million units every day for 16 weeks. The conversion rate to HBeAb after the first year is 46%, compared to the 9% seen in the control group. After seroconversion there is evidence of decreased liver disease [60 62]. Nucleoside analogues are an alternative treatment for chronic hepatitis with evidence of active replication. Lamivudine is the only one FDA-approved and has a seroconversion rate of 17% 19%, which is comparable to IFN-a. The seroconversion doubles in percentage after 2 years. Lamivudine dose is only 100 mg/day orally making it a more convenient drug than IFN-a [62 64]. Famciclovir, which is only approved for treatment of herpes simplex virus and varicella zoster virus infections, is a less potent drug used in patients that are unresponsive to IFN-a and lamivudine [65]. Adefovir is another nucleoside analogue still being researched. In one study of 20 patients, the combination of IFN-a and lamivudine showed no difference compared to lamivudine alone. Research is currently being done on the combination of two nucleoside analogues [11,43].

Hepatitis C Introduction In 1989, HCV was discovered when its genome was first sequenced and cloned from the liver and plasma of an experimentally infected chimpanzee [66]. The subsequent development of diagnostic tests, including first and second generation serologic assays for antibody to hepatitis C virus (anti-HCV), has identified HCV as the cause of the majority of cases of community acquired non-A, non-B hepatitis [67,68]. Virology Hepatitis C is a single-stranded positive sense RNA virus that belongs to Hepacavirus, the third genus of the Flaviviridae family. The viral RNA is contained in a protein core which is wrapped in a lipid envelope in which two proteins (E1 and E2) are anchored as dimer complexes. The viral particle is small, measuring 55 65 nm in diameter [69]. The virus contains highly conserved 50 and 30 terminal regions which flank an open reading frame that codes for structural proteins (including the nucleocapsid core and two envelope proteins) and non-structural proteins vital for viral replication [70]. Epidemiology Found on all six continents, the hepatitis C virus is ubiquitous. It currently infects an estimated 2 3 million people in the United States and 175 million people worldwide [70]. Most estimates have separated three areas of endemicity. Canada, Northern Europe, Switzerland, and Australia are poorly endemic with an estimated prevalence below 0.5%. The United States and Southern and Western Europe have intermediate endemicity with a prevalence of HCV markers ranging from 0.5% 2%. The virus is highly endemic in Eastern Europe and Japan with a 2% 3% HCV marker prevalence [69]. Sixty to seventy percent of all cases of HCV are transmitted parenterally, through blood transfusion or intravenous (IV) drug use [71]. Risk factors Individuals with exposure to blood or blood products are at risk of infection with HCV. This includes IV drug users, organ transplant recipients, hemodialysis patients, and medical personnel through

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occupational exposure [72]. Blood products known to transmit the virus include red blood cells, white blood cells, platelet concentrates, fresh frozen plasma, and coagulation factor concentrates [69]. Vertical transmission from infected mothers to their infants, and sexual transmission through contact with an infected partner are other risks of infection in patients without direct exposure to blood products. Recently, poorly sterilized tattoo needles have been recognized as a source of HCV transmission. Still, an approximated 30% 40% of infected patients have no known risk factors suggesting some unknown mechanism of transmission [69]. The number of newly acquired infections per annum dropped from 180,000 in the mid-1980s to 28,000 in 1995 [73]. Factors contributing to the decline in the incidence of HCV over the past decade include the reduction of risk factors through changes in medical practices as well as education aimed at high risk groups [74]. In the past, blood transfusion was the major mode of HCV transmission. The implementation of blood screening procedures has reduced this risk from 6% in the early 1980s to 0.5% in 1995 [75,76]. A more recent estimate suggests that the risk of infection per unit of blood transfused is 0.01% 0.001%. Today, blood transfusion accounts for only 4% of all acute HCV infections [70]. Nevertheless, 85% 95% of post-transfusion hepatitis is caused by HCV suggesting this is still a viable mode of transmission [71]. Intravenous drug use has replaced blood transfusions as the most common risk factor for HCV transmission. Centers for Disease Control and Prevention (CDC) data on risk factors for reported episodes of acute HCV infection from 1991 1995 show that an excess of 40% of cases are secondary to IV drug use [70]. Because this is a poorly controlled mode of transmission, it is difficult to quantify the risk exactly. However, it is important to note that the longer the period of IV drug use the higher the risk. Users have more than 90% risk of infection after 6 years of regular drug use [69]. HCV is rapidly transmitted by the intravenous exposure and the majority of IV drug users will test positive for HCV infection within six months of starting injections [70]. Health care workers incur a threefold greater risk for infection with HCV than the general population due to their inadvertent exposure to blood products and bodily fluids. Occupational exposure currently accounts for 4% of all acute HCV infections [70]. The risk of infection from a single needlestick exposure is estimated to be 5% 15% depending on the size of the inoculum [77]. Sexual transmission is a documented mode of infection that accounts for a minority of cases of

HCV. The precise risk of transmission is debated but is generally accepted to be less than 5% [78,79]. One study that looked at regular sexual partners of hemophiliacs infected with HCV found that, in the absence of personal risk factors, only 3% 5% contracted the virus [80]. The low incidence of sexual transmission makes sense in light of the low levels of HCV RNA secreted in the saliva or semen of infected patients [81]. The potential for transmission is higher in patients with high-risk sexual behavior, namely those with sexually transmitted diseases such as herpes simplex virus-2 (HSV-2) or human immunodeficiency virus (HIV) [82,83]. The CDC currently recommends no change in sexual practice for couples in stable monogamous relationships [70]. The risk of vertical transmission has been proven but is also difficult to quantify with estimates in the range of 0% 10%. A recent study evaluating the prevalence of anti-HCV seroconversion in infants born to HCV infected mothers found that 5.1% of the newborns tested positive. The rate of infection was not affected by the type of delivery, feeding pattern, or the HIV status of the mother [84]. In contrast, another report documents a 3% risk of vertical transmission in HIV-negative women compared to a 20% risk in HIV-positive women, suggesting HIV may facilitate transmission [69]. Regardless of the mode of transmission, evidence suggests that the higher the viral load and rate of replication, the higher the risk of infection [85,86]. Clinical characteristics The vast majority of patients in the acute phase of HCV infection are asymptomatic. Symptoms occur in less than 25% of cases and are generally nonspecific including fatigue, anorexia, jaundice, weakness, and generalized malaise [70]. Despite the mild, often asymptomatic course, progression to chronic disease occurs in 70% 80% of those infected [87]. In most studies, chronicity is more frequent in cases associated with transfusion or percutaneous exposure (40% 60%) than in cases lacking an identifiable cause ( < 10%) [88]. In contrast, another article suggests that while the frequency of chronicity is independent of the risk factor for infection, severe disease in the form of chronic active hepatitis is more likely to be found in patients who acquired their infection through blood transfusion [71]. Cirrhosis complicates approximately 20% of chronic cases of HCV usually within 20 years of infection. Once the cirrhosis has begun, hepatocellular carcinoma develops in 1% 7% of patients over a 15 20 year period [70]. Factors that contribute to the severity of liver injury include

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excessive alcohol consumption, older age at initial infection, immunosuppression, and specific viral genotypes (type 1b) [89,87]. In contrast to hepatitis B virus (HBV), HCV is a rare cause of acute fulminant hepatic necrosis. In addition to a clinically benign course, the peak serum aminotransferase activity is lower in patients with HCV as compared with patients with HBV. A pattern of waxing and waning liver enzymes that is characteristic of HCV is rarely observed with other forms of hepatitis. Periods of elevated enzyme activity alternate with weeks to months of normal enzyme activity present in the face of active inflammation and ongoing fibrosis. The liver morphology is compatible with chronic active hepatitis on the basis of piecemeal necrosis, or erosion of the limiting plate of hepatocytes surrounding the portal tract [88]. Diagnosis of HCV often follows serendipitous discovery of elevated aminotransferases, an extrahepatic manifestation of the virus, or through screening of high risk groups [70]. Ninety percent of patients are identified by second generation serologic testing for anti-HCV. The other 10% are identified by techniques to detect HCV RNA [71]. Interestingly, HCV infection without seroconversion to anti-HCV has been found in infants born to HCV-infected mothers and in adults with clinical non-A, non-B hepatitis without obvious risk factors [90]. Given the high frequency of asymptomatic acute infection and carrier state, familiarity with the extrahepatic manifestations of the illness, particularly the visible cutaneous manifestations of the disease, is useful to help identify previously undiagnosed individuals. Cutaneous manifestations Mixed cryoglobulinemia Mixed cryoglobulinemia (MC) is the most documented extrahepatic manifestation of HCV infection. It presents cutaneously as inflammatory, palpable purpura which is usually confined to the lower extremities. Cryoglobulins are anti-immunoglobulin immunoglobulins (Igs) that precipitate at temperatures less than 37C. There are three types of cryoglobulins according to the classification system proposed by Brouet et al in 1974 [91]. Type I cryoglobulins are composed of single monoclonal immunoglobulins, usually IgG or IgM, without rheumatoid factor. Type II and type III cryoglobulins consist of rheumatoid factors (RF) (usually IgM) complexed with IgG which form immune complexes. Type II cryoglobulins are monoclonal IgM complexed with polyclonal IgG. In type III, both the IgM and the IgG are polyclonal. A new type II-III

variant (oligoclonal IgM complexed with polyclonal IgG) has recently been described [92,93]. Cryoglobulinemia, which is the existence of circulating cryoglobulins, is not always symptomatic. Cryoglobulinemic syndrome is the term used when patients with cryoglobulinemia develop clinical manifestations. The clinical triad associated with this syndrome includes purpura, arthralgia, and myalgia. Palpable purpura is the hallmark of the cryoglobulinemic syndrome. Arthralgias (50% 80%), renal involvement in the form of membranoproliferative glomerulonephritis (25%), and peripheral neuropathy (7% 60%) are additional disease manifestations [94]. Mixed cryoglobulinemia is considered essential if it is not associated with any disease other than Sjogrens syndrome. Because of the high prevalence of liver abnormalities seen in patients with MC, hepatotrophic viruses were suspected as causative agents. In early studies, HBV was implicated in the pathogenesis of MC [95]. Future studies revealed that evidence of ongoing HBV infection in patients with MC has rarely been found [96,97]. In 1990, the association between type II MC and HCV infection was first reported [98]. Since then, results from other studies have confirmed an association between MC and HCV infection [99,100]. Evidence in support of the association between MC and HCV includes: a high frequency of anti-HCV antibodies and HCV-RNA in the serum from patients with MC [99], anti-HCV antibodies and HCV-RNA concentrated in cryoprecipitate [101], and decreased serum aminotransferases and cryoglobulinemia during interferon-a administration [102]. It is established that the majority (80%) of what was previously known as essential MC is now known to be related to chronic HCV infection [94,103]. Despite a high prevalence of HCV markers in patients with MC, only an estimated 13% 54% of patients with chronic HCV will develop MC [94]. In a study by Lunel et al., only 14% of patients with HCV showed clinical signs of MC [104]. Furthermore, clinical signs of MC in HCV-infected individuals are rare in Mediterranean countries despite a high prevalence of HCV [104,105]. Although it is not clear why some patients infected with HCV develop MC, this finding suggests that there is some other factor besides HCV infection necessary for the development of cryoglobulinemia. To date, no significant association has been found between a specific HCV genotype and MC [106]. The high prevalence of genotypes 1b and 2a that has been reported mirrors the overall distribution of these genotypes in the same geographic location [107]. Similarly, attempts to associate specific host human leukocyte antigen

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(HLA) profiles and MC in patients with HCV have been controversial and inconclusive [108 111]. Although the pathogenesis of MC in HCV is unclear, recent evidence suggests that HCV-IgG and HCV-lipoprotein complexes may act as B cell superantigens inducing the synthesis of non-HCV reactive IgM with RF-like activity which leads to immunocomplex formation by means of a direct chronic stimulation of a specific population of B cells in the liver. Furthermore, it appears that HCV complexed to very low density lipoprotein (VLDL) containing apoE2 is poorly endocytosed by the low density lipoprotein (LDL) receptor and consequently persists in the circulation where it stimulates monoclonal RF production [45]. A study comparing the prevalence of apoE alleles in HCV-infected patients with and without MC found that the apo-E2 allele was significantly higher in HCV infected patients with MC. The risk of developing MC is three times higher in individuals carrying the apo-E2 allele [112]. Interferon-a (IFN-a) is the drug of choice for treatment of MC. Success of IFN-a treatment represents indirect proof for a pathogenetic link between MC and HCV infection. An estimated 42% 73% of those treated will respond. Unfortunately, there is a low long term response estimated at 0% 22% [94]. According to one study, factors predicting a response to IFN-a include male sex, viral genotype, and whether or not the disease is symptomatic [113]. Disappearance of cryoglobulins is usually associated with resolution of the cutaneous and joint symptoms of MC, not necessarily the neurological or renal abnormalities. Another recent study showed that ribavirin may have beneficial effects in patients who have not responded to IFN-a [114]. In patients who relapse after monotherapy with IFN-a, a combination of IFN-a and ribavirin has been shown to be effective and is another good option for treatment of recurrence [115]. Furthermore, the success of this modality is associated with decreased levels of circulating cryoglobulins and histologic improvement which further supports a direct role of HCV in the pathogenesis of MC [116]. Recently the FDA approved peginterferon alpha-2b for use in combination therapy with ribavirin for the treatment of HCV infection in patients with compensated liver disease who have not been previously treated with IFN-a. The effect of this combination therapy on MC or other mucocutaneous manifestation of HCV infection is not yet known. Porphyria cutanea tarda Porphyria cutanea tarda (PCT) is characterized by an abnormal porphyrin metabolism secondary to

decreased activity of uroporphyrinogen decarboxylase (URO-D). The cutaneous findings, including skin fragility, blister formation, hyperpigmentation and hypertrichosis, are caused by the photosensitizing action of accumulated porphyrins. Two forms of PCT have been described. The rare familial form is inherited as an autosomal dominant trait with incomplete penetrance. It is associated with a 50% reduction in URO-D activity throughout the whole body. The cause of the sporadic form, which accounts for most clinical cases of PCT, remains largely unknown. In this form, the 50% reduction in URO-D activity is confined to the liver. The enzymatic defect in sporadic PCT is necessary but not sufficient to account for the clinical manifestations of the disease. Alcohol, estrogens, hexachlorobenzene, and iron accumulation are several extrinsic factors known to trigger PCT in predisposed individuals [117,118]. Recent reports have documented a high but variable prevalence of HCV infection in patients with PCT [97,117,119 124]. The prevalence is higher in Southern Europe (67% 91%) and lower in Northern Europe (8% 10%) and New Zealand (4%) [120]. The prevalence in the United States is reported to be between 50% 75% [121,125]. The cause of this striking geographic divergence in prevalence is unclear and cannot be fully explained by variations in the prevalence of HCV in the general population in Northern as compared to Southern Europe. For example, in pooled blood donors, a sample that is presumably representative of the general population, the prevalence of HCV is 0.25% in Germany and 1% in Italy [126]. This small difference would not account for the 8% and 91% prevalence of HCV in PCT patients in Germany and Italy respectively [127]. Similarly, the regional variations in the prevalence of specific HCV genotypes does not account for the variation in the prevalence of HCV in PCT. The distribution of HCV genotypes in PCT patients is similar to nonporphyric HCV patients in Western Europe [128]. Interestingly, the prevalence of HCV infection is significantly higher in patients with the sporadic form of PCT as compared to the familial form, suggesting that HCV may play a permissive role in the modulation of the phenotypic expression of PCT [121]. Recently, an association between the hemochromatosis Cys282Tyr mutation and sporadic PCT has been found [129]. Inheritance of the Cys282Tyr mutation appears to be an important factor in determining an inherited predisposition to PCT. Interpretation of this association is unclear but it lends support to the theory that HCV may play a pathogenic role in the development of PCT in genetically predisposed individuals. Furthermore, the association between HIV and PCT supports

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the hypothesis suggesting a viral infection can reveal a porphyrin metabolism defect [119,123,130]. Although the link between HCV and PCT is well established, the mechanism of the interaction is unknown. In most cases, the HCV exposure and associated liver dysfunction precede the onset of PCT. It is reasonable to assume that the liver injury following HCV exposure triggers the pathogenic mechanism of the disease. Given that hepatic injury is almost always present in some form in clinically overt PCT, and that the known extrinsic factors that trigger this illness do so through effects on the liver, it is reasonable to assume that liver injury following HCV exposure unmasks the pathogenic mechanisms responsible for disease expression. Several hypotheses have been proposed to elucidate the role of HCV in the pathogenesis of PCT. It has been speculated that the increased prevalence of HCV in PCT patients is a result of HCV exposure during multiple therapeutic phlebotomies [127]. Lemoril et al. demonstrated no association between the frequency of phlebotomy and HCV status [120]. In their study, PCT patients infected with HCV had no more phlebotomy than non-HCV PCT patients. Other hypotheses include: (1) a decrease in uroporphyrinogen decarboxylase activity as a result of liver cell injury [117,121]; (2) an increased autoimmune response in the liver [131]; (3) an alteration in porphyrin metabolism through the cytochrome P-450 dependent mixed function oxidase system [121]; and (4) that HCV induces decompartmentalization of iron resulting in increased free iron and the formation of free radicals which are believed to alter cytochrome P-450 and cause a reduction in URO-D activity [119]. Lastly, an evolving area of investigation has been to determine whether HCV has a direct effect on porphyrin metabolism. Two European studies suggest that HCV has little direct effects on porphyrin metabolism [119,132]. In contrast, a study of 110 HCV patients found that 15% had elevated urinary porphyrins, mostly coproporphyrins [133]. Another recent study found that HCV infection was statistically significantly associated with elevated serum porphyrin levels after controlling for HIV [123]. Further study is needed in this area to clarify how HCV may contribute to pathogenesis of PCT. Interferon therapy is useful in the treatment of PCT associated with HCV, as evidenced by a decrease in urinary porphyrins and disappearance of skin lesions in patients treated with this modality [134,135]. According to a case report of a 61 year-old Japanese man with PCT associated with chronic HCV, initial laboratory results after the initiation of therapy may be misleading. In this particular case, urinary excretion of uroporphyrin and coproporphyrin initially increased

after an IV administration of interferon but then significantly decreased as did the HCV RNA titer after six weeks of continuous therapy [136]. Lichen planus Prior to the discovery of HCV, several well-documented studies reported an association between lichen planus (LP) and various liver diseases. In 1991, Monki et al. reported the first biopsy-confirmed case of LP in a patient with HCV-induced chronic active hepatitis, suggesting a clinical association between the two disorders [137]. Since then several studies have supported this proposed link with data demonstrating the prevalence of HCV ranging from 16% to 55% and 0.17% to 4.8% in LP patients and control groups respectively [138 143]. One case-report study from France found no significant difference between the 4.9% prevalence of HCV in LP patients as compared to 4.5% in control groups, casting doubt on the association between the two [144]. However, the control group in this study consisted of patients admitted to the hospital for surgery, a group thought to be at higher risk of HCV infection from the outset. Furthermore, a low prevalence of LP in the general population ( < 1%) makes a fortuitous association between LP and HCV unlikely [142]. Lichen planus is a chronic inflammatory mucocutaneous disease process. It usually presents as small, pruritic, purple, planar, polygonal papules with superimposed fine, reticulated white lines called Wickhams striae. The lesions are characteristically distributed on flexor wrists and forearms, extensor hands and ankles, lumbar region, shins, and genital area. Mucous membrane lesions are typically lacy white or ulcerative. The disease is slightly more common in women than in men and can occur at any age but is most common in the fifth decade. Histologically, LP is characterized by a subepidermal, band-like lymphocytic infiltrate that is associated with destruction of the basal layer of keratinocytes, sawtooth rete ridges, and pigmentary incontinence. Clinically, the lesions of HCV related LP are similar to those described for classic LP. The majority of reported LP cases in association with HCV have been the oral form of the disease. There has been some interest in determining whether a specific HCV genotype is responsible for the development of LP in some HCV infected patients. One study found that 83% of LP patients were infected with HCV-1b suggesting that HCV type 1b might play a role in the pathogenesis of HCV-induced LP. However, it has been determined that patients with HCV-1b tend to be significantly older. The mean age of patients in this study was 67.2 years suggesting that the higher prevalence of HCV-

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1b in LP patients is more likely related to age than an actual association between HCV-1b and LP [143]. Similarly, another study found that while HCV-1b was the most common subtype of HCV in LP patients, it was also the most common subtype in all HCV patients in that geographic area [141]. Although the association between LP and HCV is well documented, the pathogenesis remains unclear. One proposed theory is that HCV precipitates an autoimmune process [145]. The fact that LP is associated with other autoimmune diseases including alopecia areata, vitiligo, ulcerative colitis, myasthenia gravis, and diabetes mellitus supports this hypothesis [140]. In addition, one study demonstrated the presence of serum anti-nuclear and anti-thyroid antibodies in 54% of HCV-positive patients with LP [141]. In contrast, an immune-mediated mechanism has been suggested by the observation of three cases of LP after interferon gamma therapy [146]. Lastly, a case report of a patient who developed widespread, hypertrophic LP after a blood transfusion argues for a more direct role of HCV in the development of LP [147]. The efficacy of interferon therapy in the treatment of LP associated with HCV is somewhat unclear. Observation of the development and exacerbation of oral lichen planus in association with IFN therapy has been reported [148]. A more recent report suggests that during short-term follow-up oral lichen planus can persist even in the absence of serum HCV RNA during treatment with IFN. However, long-term follow-up at three years found resolution of macroscopic oral lichen planus lesions [149]. Thus, it appears that sustained improvement in liver function along with persistent absence of serum HCV RNA with long term IFN therapy contributes to the resolution of oral lichen planus lesions. Other cutaneous associations Several other skin conditions have been reported in association with HCV infection, including erythema multiforme [150], erythema nodosum [151], Henoch-Schonlein purpura [98], Bechets syndrome [152 154], necrolytic acral erythema [155,156], polyarteritis nodosa [157], prurigo nodularis [158], pyoderma gangrenosum [159], urticaria [160,161], and urticarial vasculitis [162 164]. Conclusion Viral hepatitis is a common disease with significant morbidity and mortality that is found throughout all parts of the world. It is a known cause of acute and

chronic liver disease. Because the disease can be asymptomatic in its acute stages, the diagnosis is often missed. The extrahepatic manifestations of the disease, in particular the visible cutaneous lesions, offer clues to the diagnosis of viral hepatitis. Familiarity with the most common skin lesions associated with each type of hepatitis virus will be useful in identifying previously undiagnosed individuals. This article serves as a review of the most widely published associations between skin diseases and specific subtypes of viral hepatitis.

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Lim HW, Harris HR, Fotiades J. Hepatitis C virus infection in patients with porphyria cutanea tarda evaluated in New York. NY Arch Dermatol 1995; 131(7):849. Koester G, Feldman J, Bigler C. Hepatitis C in patients with porphyria cutanea tarda. J Am Acad Dermatol 1994;31(6):1054. Stolzel U, Kostler E, Koszka C, et al. Low prevalence of hepatitis C virus infection in porphyria cutanea tarda in Germany. Hepatology 1995;21(6):1500 3. Chuang TY, Brashear R, Lewis C. Porphyria cutanea tarda and hepatitis C virus: a case-control study and meta-analysis of the literature. J Am Acad Dermatol 1999;41(1):31 6. Simmonds P, Mellor J, Craxi A, et al. Epidemiological, clinical, and therapeutic associations of hepatitis C types in Western European patients. J Hepatol 1996;24(5):517 24. Roberts AG, Whatley SD, Morgan RR, et al. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet 1997;349(9048):321 3. Blauvelt A, Harris HR, Hogan DJ, et al. Porphyria cutanea tarda and human immunodeficiency virus infection. Int J Dermatol 1992;31(7):474 9. Ferri C, Baicchi U, Ia Civita L, et al. Hepatitis C virus-related autoimmunity in patients with porphyria cutanea tarda. Eur J Clin Invest 1993;23(12):851 5. Cribier B, Rey D, Uhl G, et al. Abnormal urinary coproporphyrin levels in patients infected by hepatitis C virus with or without human immunodeficiency virus: a study of 177 patients. Arch Dermatol 1996; 132(12):1448 52. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 1998;27(6): 1661 9. Sheikh MY, Wright RA, Burruss JB. Dramatic resolution of skin lesions associated with porphyria cutanea tarda after interferon-a therapy in a case of chronic hepatitis C. Dig Dis Sci 1998;43(3):529 33. Takikawa H, Yamazaki R, Shoji S, et al. Normalization of urinary porphyrin level and diappearance of skin lesions after successful interferon therapy in a case of chronic hepatitis C complicated with porphyria cutanea tarda. J Hepatol 1995;22(2):249 50. Okano J, Horie Y, Kawasaki H, et al. Interferon treatment of porphyria cutanea tarda associated with chronic hepatitis C. Hepatogastroenterology 1997;44 (14):525 8. Mokni M, Rybojad M, Puppin Jr D, et al. Lichen planus and hepatitis C virus. J Am Acad Dermatol 1991;24:792. Bellman B, Reddy RK, Falanga V. Lichen planus associated with hepatitis C. Lancet 1995;346 (8984):1234. Chuang TY, Stitle L, Brashear R, et al. Hepatitis C virus and lichen planus: A case-control study of 340 patients. J Am Acad Dermatol 1999;41(5 Pt 1): 787 9. Bellman B, Reddy R, Falanga V. Generalized lichen planus associated with hepatitis C virus immunoreactivity. J Am Acad Dermatol 1996;35(5 Pt 1):770 2. Sanchez-Perez J, Moreno-Otero R, Borque MJ, et al. 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Dermatol Clin 20 (2002) 249 266

Herpes simplex viruses 1 and 2

Kimberly A. Yeung-Yue, MD a, Mathijs H. Brentjens, MD, MS a, Patricia C. Lee, MD a, Stephen K. Tyring, MD, PhD a,b,*
Departments of Dermatology, Microbiology/Immunology, and Internal Medicine, University of Texas Medical Branch Galveston, Galveston, TX 77555, USA b University of Texas Medical Branch Center for Clinical Studies, 2060 Space Park Drive, Suite 200, Houston, TX 77058, USA
a

Herpes simplex viruses (HSVs) are enveloped, linear, double-stranded DNA viruses, whose only known hosts are human beings [1]. Two types of the virus exist, HSV type 1 (HSV-1) and HSV type 2 (HSV-2), which are classified according to the antigenic differences in the envelope proteins. These types have different clinical manifestations and epidemiologies. Herpes labialis and herpes genitalis are the most common HSV-induced diseases.

Etiology and epidemiology The largest reservoir of HSV is associated with herpes labialis, most commonly resulting from primary infection with HSV-1 during childhood. In fact, more than 85% of the worlds population is seropositive for HSV-1 [2]. Incidence of HSV-1 infection is influenced largely by geographic location, socioeconomic status, and age. Individuals in developing countries and lower socioeconomic classes tend to acquire antibodies against HSV-1 at an earlier age than those in middle-class, industrialized populations. By the age of 5, more than one third of children in lower socioeconomic groups have seroconverted, compared with only 20% of children in middle-class groups. By early adolescence, 70% to 80% of lower socioeconomic populations are seropositive for HSV-1. In

contrast, middle-class populations increase to 40% to 60% seropositivity in the second and third decades of life. These differences in prevalence become less evident after the age of 40 [1]. Herpes genitalis is one of the most common sexually transmitted diseases in the world [3]. Seroconversion for HSV-2, the most common cause of genital herpes, rarely occurs before the onset of sexual activity. The strongest predictor for HSV-2 infection is the lifetime number of sexual partners. From 1988 to 1994, 22% of people 12 years of age or older in the United States were seropositive for HSV2, representing a 30% increase since 1976 to 1980. Seroprevalence was higher among women (26%) than men (18%) and higher among black people (50%) than white people (18%). White teenagers showed the largest increase in HSV-2 seroprevalence. Older age, greater lifetime number of sexual partners, Mexican-American heritage, less education, poverty, and cocaine use were associated with increased seroprevalence [4]. Transmission Among monogamous heterosexual couples, HSV-2 is acquired by the susceptible partner at a rate of 10% per year [5,6]. Susceptible women have a higher likelihood of contracting genital herpes from an infected man than a susceptible man becoming infected by a woman. Two studies demonstrated that women were approximately four times more likely to acquire HSV-2 than men [5,7]. There is increasing evidence that HSV-1 seropositivity in the susceptible partner is somewhat protective against HSV-2 infection. Of the women who

* Corresponding author. Departments of Dermatology, Microbiology/Immunology, and Internal Medicine, University of Texas Medical Branch Galveston, Galveston, TX 77555, USA. E-mail address: styring@utmb.edu (S.K. Tyring).

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 0 3 - 1

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developed HSV-2 antibodies in two studies, acquisition occurred at a higher annual rate in those who were seronegative for both HSV-1 and HSV-2 compared with those who were already seropositive for HSV-1 [5,6]. Only 10% to 25% of individuals who are HSV-2 seropositive report a history of genital herpes [8,9], suggesting that most subjects have unrecognized symptomatic infections or may lack symptoms altogether. After receiving proper education regarding the signs and symptoms of genital herpes, many individuals learn to recognize and report their disease more accurately [9 11]. At times, the virus may remain latent and not produce clinical disease in the host; however, the absence of clinical disease does not preclude the possibility of viral shedding and subsequent transmission of the virus [5,9,12,13]. Because many individuals abstain from sexual contact during the presence of clinically apparent, highly infectious lesions [14], it is reasonable to conclude that viral shedding in the absence of clinical disease is responsible for at least 70% of cases of HSV transmission [5]. Seropositivity for HSV-1 and HSV-2 (versus HSV-2 alone) in the source partner increases risk of HSV-2 transmission [7]. Prior infection with HSV-1 has been associated with increased asymptomatic shedding of HSV-2 [15], which may contribute to higher rates of transmission. The higher rates of asymptomatic infection in men (seroconversion without report of lesions) [15] and the 20% fewer number of outbreaks that occurs in women [10] also may account for increased transmission from men to women than from women to men. Herpes simplex and human immunodeficiency viruses Co-infection with HSV and HIV frequently occurs, probably because they potentiate each others transmission. In the United States, 68% of HIVpositive homosexual men [16], 63% of HIV-positive heterosexual men [17], and 78% of HIV-positive women [17] were seropositive for HSV-2. In London, 81% of heterosexual HIV-positive individuals (43% women and 38% men) had symptomatic genital disease caused by HSV-2 [18]. Individuals with genital herpes are more susceptible to infection with HIV type 1 (HIV-1) during sexual contact secondary to the ulcerative and inflammatory nature of HSV infection [16,19]. Intuitively, even microscopic ulcerative lesions provide a more accessible point of entry for HIV in susceptible hosts [16,17,20]. The inflammatory response associated with the herpetic lesions attracts activated CD4+

lymphocytes to the skin surface [21]. These lymphocytes in the HIV-negative host become more accessible and vulnerable to infection with HIV [20,22]. Individuals with concurrent HIV and HSV infection (versus persons seropositive for only one of these viruses) are at greater risk for transmitting both HIV and HSV to susceptible partners. HIV-positive individuals with genital herpes shed HSV-2 three to four times more frequently than those who are HIVnegative [23 25]. Most shedding (79%) is asymptomatic, and total HSV shedding increases as CD4 counts decline [23,24,26]. High titers of infectious HIV frequently can be detected in herpetic lesions, heightening exposure to susceptible partners and increasing risk for acquisition of the virus [17, 22,27]. In contrast to genital ulcers not associated with a sexually transmitted disease, herpetic lesions attract HIV-infected CD4+ lymphocytes [27]. It is postulated that HIV replication is increased on mucosal surfaces as well [27]. Keratinocytes and macrophages co-infected with HSV-1 and HIV-1 seem to enhance each others replication within the cell. HIV virions then are released at the skin surfaces when cell lysis occurs. Infection of epidermal cells that lack CD4 molecules seems to imply that HIV is capable of bypassing the need for this molecule to enter cells [20]. Active infection with HSV has been associated with increased HIV RNA in the plasma, possibly accelerating progression of HIV infection [28]. A more recent report, however, did not detect any fluctuation of HIV RNA with HSV shedding [29].

Pathogenesis Herpes simplex viruses are transmitted during close personal contact through the exchange of saliva, semen, cervical fluid, or vesicle fluid from active lesions. The virus must contact mucosal surfaces or abraded skin, where it first replicates and initiates infection [30]. The capsid then is transported within neurons through retrograde axonal flow to the dorsal root ganglia, where it replicates again to establish latency [1,31,32]. Initial replication of HSV-1 often occurs in the oropharyngeal mucosa and establishes latency in the trigeminal ganglia [14]. Herpes simplex type 2 often replicates in the genital mucosa, then establishes latency in the sacral sensory ganglia [14]. The virus remains in an apparently inactive state for varying durations. Even in the presence of intact humoral and cellmediated immunity, reactivation can occur with a proper stimulus [32]. The virus descends through

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the sensory nerve, then appears as vesicles or ulcers at the mucocutaneous sites. Recurrences are spontaneous, but there have been associations with physical or emotional stress, fever, exposure to ultraviolet light, nerve or tissue damage, immunosuppression, heat, cold, menses, concurrent infection, and fatigue [32,33]. Some studies have attempted to clarify the relationship between stress and herpes outbreaks. The investigators report that recurrences are associated with coping style, persistent stressors ( > 1 week), and high anxiety as opposed to transient episodes or intensity of stress [33,34]. The pathogenesis of herpes labialis seems to be more complicated than that of herpes genitalis. Spruance [35] observed the development of two types of herpetic lesions after ultraviolet radiation exposure to the orolabial area. The delayed lesions appear 3 to 7 days after the ultraviolet radiation exposure, respond well to antiviral therapy, and seem to be the result of typical HSV reactivation within the ganglia, as described previously. A subgroup of immediate lesions appears within the first 48 hours after irradiation, however, which occurs too quickly to follow this same pattern of reactivation. These lesions are rather resistant to antiviral therapy. It is postulated that HSV is present in the epithelium at the time of irradiation, allowing a more rapid development of cutaneous lesions. Primary infection refers to the first infection with either HSV-1 or HSV-2 in individuals who do not have antibodies against either HSV-1 or HSV-2. Recurrent infections or reactivated infections occur after the virus already has established latency in the sensory ganglia. When an individual who is seropositive for one of the two types of HSV develops an infection with the other HSV type for the first time, it is called a nonprimary infection. Although rare in immunocompetent hosts, a person also may be reinfected with a different strain of either HSV type, referred to as exogenous reinfection [36,37]. Reinfection with the same strain of HSV by autoinoculation [38,39] can occur (e.g., mouth to genital infection from scratching [40]) but usually is prevented by circulating antibodies [41]. This type of superinfection most likely occurs soon after primary infection, while antibody titers still are increasing. Occasionally during the primary infection, the virus can spread beyond the dorsal root ganglia to cause systemic infection. Examples include aseptic meningitis, disseminated neonatal HSV infection with multi-organ involvement, multi-organ disease of pregnancy, and dissemination in patients who are markedly immunocompromised.

Clinical manifestations During classic HSV outbreaks, a prodrome characterized by localized pain, tingling, burning, tenderness, paresthesia, lymphadenopathy, headache, fever, anorexia, or malaise precedes lesion formation [32]. Approximately 25% of recurrences fail to progress beyond this prodrome stage [2]. With disease progression, papules, vesicles on an erythematous base, and erosions appear over hours to days. These lesions usually crust then re-epithelialize, healing without scarring within 7 to 10 days. Other presentations include edema, fissures, ulcers, and pustules [42,43]. Mucocutaneous lesions are the most common manifestations of HSV infection, including herpes labialis and herpes genitalis. Both of these types of lesions frequently lack symptoms. Clinicians also should be aware that cystitis, meningitis, urethritis, and cervicitis can be the presenting conditions in some cases [15]. Herpes labialis Herpes labialis is the most common manifestation of HSV infection and often affects the buccal and gingival mucosa during primary infection. Termed gingivostomatitis, this disease is a common presentation in children. Swallowing may be difficult secondary to edema of the oropharynx and pain from ulceration. Most orolabial lesions are caused by HSV-1 but also may be caused by HSV-2 [14]. Recurrent disease tends to occur less frequently with HSV-2 than with HSV-1 in this location [44]. Lesions frequently appear at the vermilion border of the lip and usually consist of three to five vesicles. They often become pustular, ulcerative, or crusted within 72 to 96 hours, and pain resolves quickly afterward. The point of maximum lesion severity often occurs within 8 hours of onset, and most viral replication takes place within 48 hours. Most patients have approximately two outbreaks per year, but 5% to 10% have frequent recurrences (>6 outbreaks per year) [45]. Herpes genitalis Ninety-five percent of primary genital HSV infections occur between 3 days and 2 weeks after exposure [32,46], and 79% of infected individuals develop constitutional complaints [47]. Symptomatic genital disease may vary depending on the patients sex [48,49]. In women, lesions may involve the vulva, cervix, vagina, urethral or perianal skin, and

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extragenital areas such as the buttocks, thighs, or perineum. For unknown reasons, women have more severe disease and higher rates of complications during the primary infection (the first HSV infection in a seronegative patient) than men [48]. Lesions are painful and contain large quantities of infectious virus particles, which are excreted for an average of 3 weeks. Inguinal adenopathy and dysuria may result. Complications include urinary retention syndrome in 10% to 15% of women and aseptic meningitis in up to 25% of women. Men develop lesions most commonly on the glans penis or penile shaft, often six to ten vesicles. Perianal infection with associated proctitis is also common in homosexual men [13]. Similar to women, extragenital lesions may occur on the buttocks, perineum, or thighs. Although systemic complications are rare in men, aseptic meningitis has been reported. Nonprimary infection with a different HSV type causes fewer symptoms and heals more rapidly. Fewer lesions, shorter duration, diminished pain, and a decreased likelihood of complications prevail. Approximately 49% of patients experience constitutional symptoms [47]. Among symptomatic HSV infections, recurrent disease is the mildest form. Fewer lesions form, and viral shedding occurs at a lower concentration and shorter duration compared with primary infection. Women may experience only vulvar irritation, and men may develop only three to five vesicles on the penile shaft [50]. Viral shedding occurs for an average of 3 days, compared with 3 weeks during primary infection. Benedetti et al. [10] examined the recurrence rates of genital herpes after primary infection in men and women. Individuals had a median of four recurrences per year, although the frequency varied greatly. People with more severe primary infections (lasting 35 days or more) had recurrent episodes twice as often and with a shorter time to first recurrence than those with milder ones. After the primary episode of genital HSV-2 infection, 89% of patients had at least one recurrence during the first year. Thirty-eight percent of all patients had greater than six outbreaks per year, and 20% had greater than 10. Men had more frequent recurrences than women. Twenty-six percent of women and 8% of men had zero to one outbreak per year, whereas 14% of women and 26% of men had greater than 10 outbreaks per year. The serologic type of the virus causing genital infection affects the frequency of recurrence. The etiologic agent of herpes genitalis is usually HSV-2 but can be HSV-1 in up to one third of new cases [10,15,51,52]. Genital disease caused by HSV-1

tends to cause fewer recurrences and more mild disease than that caused by HSV-2 [12,44,51 53]. White race and insertive oral sex increase the incidence of primary genital infection with HSV-1; the highest risk occurs among white men who have sex with men [51]. The frequency of asymptomatic viral shedding varies greatly among individuals. Shedding without evidence of clinical disease occurs with greater frequency in women with more than 12 recurrent episodes per year [12], women with a recent primary episode [12,54,55], and in subjects who are seropositive for HSV-2 [12]. One study used viral cultures to determine that 51% of women shed virus in the absence of herpetic lesions on a mean of 2% of total days sampled. Eleven percent of these women, however, shed asymptomatically on greater than 5% of total days and probably present greater risk for transmission of the virus to sexual partners [12]. A more recent study involving men and women demonstrated a 3% rate of asymptomatic shedding, in which 39% shed asymptomatically on greater than 5% of days [9]. Asymptomatic viral shedding occurred in 55% of the women who were seropositive for HSV-2 alone, in 52% of those with both HSV-2 and HSV-1 antibodies, and in only 29% of subjects with HSV-1 seropositivity alone. Half of the episodes of asymptomatic shedding occurred within 7 days of a clinically apparent outbreak. Thirty percent of these episodes occurred before lesions appeared, and 20% of them occurred after the lesions had healed. Usually, asymptomatic shedding is captured in clusters of days, with a mean duration of 1.5 days [12]. Thirtytwo percent to 48% of all shedding occurred in the absence of lesions [9,12,55]. Men and women have similar rates of asymptomatic shedding [9]. Subsequent studies comparing different techniques of viral detection demonstrated that actual shedding may be approximately 3.5 times higher than can be detected by the conventional clinical methods (viral culture). Shedding was detected by viral culture on 9% to 10% of total days [54,55] and by polymerase chain reaction on 28% of total days [54]. Polymerase chain reaction also may detect viral DNA in culture-negative, symptom-free patients with genital herpes [9]. The most common complications of primary genital herpes include extragenital lesions (20%), aseptic meningitis (10%), sacral radiculomyelitis leading to urinary retention, neuralgia, and meningoencephalitis [56 58]. Herpes simplex virus also causes the most common sporadic form of encephalitis worldwide; if this complication is left untreated, mortality is 50% to 70%.

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Neonatal herpes Neonatal herpes simplex infections can have devastating consequences, especially if unrecognized or if treatment is delayed. The extent of the infection ranges from involvement of the skin, eyes, and mouth to encephalitis or disseminated disease [31]. Newborns may become ill with nonspecific signs and symptoms within 5 to 21 days, the incubation period for the infection. They often lack skin lesions. With the onset of seizures, neurologic and developmental deficiencies or death is inevitable [59]. Most cases of neonatal herpes are acquired during labor and delivery, with 60% to 70% attributed to maternal asymptomatic primary episode of genital herpes. Two percent to 3% of the obstetric population develops primary HSV infection during pregnancy, and 13% of HSV-seronegative pregnant women with HSV-2 seropositive partners become infected before labor. So long as maternal seroconversion occurs before labor, the fetus is at little risk; however, if seroconversion is not complete before the time of labor, the neonate has a 40% risk for infection [59]. Infants rarely acquire herpes infection owing to maternal viremia in utero, but it can occur in 5% of cases [59,60]. Recurrent genital herpes in the pregnant woman can mimic a primary infection. Many women (60% 70%) do not report a history of genital herpes but are seropositive for HSV-2. As a result of declining immunity during pregnancy, these women may experience their first symptomatic outbreak, which can be mild to severe. Similar to primary infection early in pregnancy, recurrent HSV-2 disease poses less risk to the fetus than primary HSV [59]. Herpes simplex type also has significant implications regarding the risk involved in a pregnant woman and her fetus. Primary or recurrent infection with HSV-1 during labor is transmitted more frequently to the neonate than HSV-2; however, disease usually is limited to the skin, eyes, and mucous membranes. Primary infection with HSV-2 (but not recurrent disease), on the other hand, likely disseminates to the central nervous system and causes serious neurologic sequelae or death [59]. Other cutaneous herpes simplex virus infections Herpes simplex virus infections are not limited to oral and genital areas and may affect many other cutaneous sites. Herpetic whitlow is an infection of the distal phalanx caused by HSV, characterized by pain, tingling, burning, swelling, erythema, and vesicles on an erythematous base [61,62]. Medical

personnel who contact oral or genital secretions frequently acquired whitlow before the routine use of gloves [61,62]. Although HSV-1 is the most common etiologic agent, the incidence of HSV-2 whitlow is increasing [62]. Herpes gladitorium may develop in athletes involved in contact sports, such as wrestling. This infection is usually a result of HSV-1 and commonly affects the head or eye. Cutaneous involvement of the extremities or trunk is also possible [63]. Herpetic sycosis (a viral folliculitis of the beard) and HSV folliculitis on other parts of the body present as painful, grouped, erythematous, perifollicular vesicles that do not respond to antibacterial or antifungal agents [64]. In the United States, keratoconjunctivitis caused by HSV is the number-one cause of corneal blindness [65]. The keratitis may be recurrent and can cause clouding or neovascularization of the cornea [66]. Eczema herpeticum, also known as Kaposis varicelliform eruption, is characterized by extensive vesicular lesions in patients with pre-existing dermatoses. Herpes simplex virus type 1 is the most frequent etiologic agent, and young patients with atopic dermatitis are the most frequently affected [63]. Older patients and individuals with various skin disorders, such as Dariers disease (keratosis follicularis), mycosis fungoides, pemphigus foliaceus, pityriasis rubra pilaris, Hailey-Hailey disease, congenital icthyosiform erythroderma, Sezarys syndrome, and patients with burns also have developed this condition. If diagnosis is overlooked and antiviral treatment is not initiated, the disease can be fatal. The most common etiologic agent of erythema multiforme is HSV (Fig. 1). Although relatively rare, erythema multiforme often develops in genetically susceptible persons soon after herpetic recurrences in orolabial or genital areas and extragenital cutaneous sites, such as the buttocks [67]. The characteristic erythematous papules usually develop into target lesions and mucosal ulcerations. Even without a history of HSV infection, HSV DNA can be detected by polymerase chain reaction in most skin lesions in erythema multiforme [68,69]. This finding supports the hypothesis that these lesions are caused by an immune-mediated response against HSV-specific antigens in the skin [68]. Herpes simplex virus in the immunocompromised individual Immunocompromised individuals often develop more severe HSV infections, similar to other opportunistic infections [22,70]. Recurrent outbreaks occur with greater frequency, and lesions may be extensive

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Fig. 1. Erythema multiforme (EM), characterized by the target lesions on this patients hands, most commonly is caused by herpes simplex infection even if the infection is unrecognized. In this case, EM occurred soon after an episode of herpes labialis.

or persistent. Multiple large, chronic, necrotic, or hyperkeratotic ulcers can form in atypical locations. Acyclovir-resistant HSV occasionally is isolated from such ulcers (Fig. 2) [22,52,70].

Diagnosis The patients history and physical examination are often sufficient for the diagnosis of HSV infection;

however, atypical presentations are common [42,43]. The differential diagnosis should include syphilitic chancre, fixed-drug eruption, chancroid, gonococcal erosion, folliculitis, pemphigus, pemphigoid, bullous impetigo, and contact dermatitis. The gold standard for diagnosis is a viral culture. The virus may be obtained from skin vesicles (up to 5 days), cerebrospinal fluid, stool, urine, throat, nasopharynx, conjunctivae, cervix, or cornea. Culture is a highly sensitive method for differentiating between

Fig. 2. Acyclovir-resistant herpes simplex virus was isolated from this patient during an outbreak of genital herpes. Treatment with foscarnet led to complete healing of the lesion.

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HSV-1 and HSV-2 [71]. Because the virus is cellassociated, an adequate sample requires vigorous swabbing of the base of the lesion with a Dacron (DuPont, Wilmington, DE; not cotton) swab. Unroofing the vesicles, scraping the base of the suspicious lesions, and examining the sample under the microscope using the Tzanck smear technique is a rapid and useful method of diagnosis. Although suggestive of HSV infection, however, multinucleated giant cells seen on the smear are not diagnostic because of their limited specificity. The Tzanck smear cannot distinguish among HSV-1, HSV-2, and varicella-zoster virus. Biopsy findings of multinucleated keratinocytes, intranuclear inclusions, and ballooning of the cells have a sensitivity and specificity similar to the Tzanck smear [72]. Although detection of viral DNA using polymerase chain reaction has demonstrated greater sensitivity for identifying herpes simplex than the traditional viral culture in the research setting [9,54], commercial use is generally only available for diagnosis of HSV encephalitis [73]. The technique is time-consuming and labor-intensive, but results are rapid relative to viral culture. Serologic testing for type-specific antibodies has additional benefits to the standard clinical methods of diagnosis (viral culture and Tzanck smear). It can be useful for confirming HSV infection in persons with a questionable history of herpetic disease and in those who have unrecognized or subclinical infection, so that they may be aware of their potential to transmit the virus. Equally important, serologic testing can rule out herpetic infection in symptomatic patients. The HSV serostatus of an HIV-seropositive person can be especially beneficial because suppressive therapy for HSV may decrease the transmission of HIV and help prevent accelerated progression of HIV disease [17,28]. Six commercially available HSV type-specific antibody tests currently are approved by the Food and Drug Administration (FDA) for use in adults. These tests are able to detect and distinguish between antibodies against the HSV-1 and HSV-2 type-specific proteins, gG-1 and gG-2. Two of the tests from Meridian Bioscience (Cincinnati, OH; an HSV-1 and an HSV-2 ELISA) have been discontinued; three of the tests offered by Focus Technologies (Cyprus, CA; an HSV-1 and an HSV-2 ELISA plus an immunoblot test for both HSV-1 and HSV-2 antibodies) are used in the laboratory [74]. The only point-of-care serologic test currently available is the POCkit HSV-2 Rapid Test made by Diagnology (Belfast, Northern Ireland). The test is simple to perform in 6 to 10 minutes, requiring cap-

illary blood from a fingerstick or serum sample and the provided reagent for detection of antibodies to HSV-2. Compared with Western blot (the goldstandard serologic test), the POCkit test had high (92% 96%) sensitivity and excellent (98% 100%) specificity [75,76]; however, interpretation of the results can vary by 5% to 10% [77]. Serologic tests for antibodies against HSV-2 alone are limited, because 30% of primary genital HSV infections are caused by HSV-1. A new point-of-care test manufactured by Quidel Corporation (San Diego, CA) is currently in trials for FDA approval [74]. Serologic testing in pregnant women and their partners to determine the risk of neonatal herpes in the unborn fetus is not widely used, but it has been recommended once more accurate tests become more widely available [59]. It can identify pregnant women with unrecognized infection who may shed HSV asymptomatically or help distinguish between a primary infection and a first clinically evident (but recurrent) episode of genital herpes. Testing also may identify discordant couples, allowing the source partner to consider taking oral suppressive therapy and alerting the physician to perform specific counseling about preventing transmission from the source partner to the pregnant woman. The current standard of care is delivery by cesarean section in women with symptomatic genital herpes [59]. Serologic testing for HSV antibodies has limitations. When used as the sole diagnostic test, the presence of type-specific antibodies cannot determine the location of the infection (e.g., orolabial or genital). Antibody detection gives limited information about the time of acquisition of the infection. For example, the presence of IgM antibodies against HSV would imply recent infection (occurring within approximately 1 month). Patients experiencing an episode of newly recognizable clinical disease tend to assume that they acquired the infection from a recent partner; however, seroconversion from a past primary episode may have preceded the current clinical outbreak [9,15,78]. The POCkit test has detected HSV-2 seroconversion a median of 2 weeks after symptomatic primary or nonprimary disease [74]. Serologic antibody tests should be used with caution in children younger than 14 because the currently available tests have not been evaluated for performance in this population. Pediatric sera accounted for most of the false-positive results with the former Meridian kits [74]. Type-specific results from serologic tests that use crude antigen preparations are inaccurate because of a high rate (82%) of cross-reactivity. At best, they can confirm infection with one or both of the HSV types, without definite indication of which type [74].

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Pathology Virus-induced cellular changes are indistinguishable among HSV-1, HSV-2, and varicella-zoster virus (the etiologic agent of chickenpox and shingles). The pathologic findings are similar for primary and recurrent episodes of HSV infection, except the extent of the changes is greater in primary infection. Evidence of cell death induced by viral replication within the epidermal layer includes ballooning of the cells, chromatin formation within the nuclei, and nucleus degeneration. Multinucleated giant cells form as the cells lyse. Vesicles also form as a result of the accumulation of clear fluid between epidermal and dermal layers. This fluid is rich with viral particles, cellular debris, inflammatory cells, and multinucleated giant cells. In the dermis, a varying degree of inflammatory cells are present. Mononuclear cells appear later as the host mounts its defense against the pathogen. Perivascular cuffing and hemorrhagic necrosis are most evident when infection extends beyond the skin. Lymphatics also can be infiltrated with inflammatory cells.

Treatment Early diagnosis and rapid initiation of antiviral therapy are essential for effective treatment of HSV, because the virus probably has undergone many cycles of replication by the time the host is symptomatic. An effective antiviral treatment ideally targets events that are unique to viral replication but does not disturb normal host cell function. Finding these events is difficult, because viruses use much of the host cells molecular machinery.

Acyclovir, valacyclovir, and famciclovir Acyclovir is an acyclic purine nucleoside analogue that is a competitive inhibitor of viral DNA polymerase. Acyclovir first must be phosphorylated by the herpes-specific thymidine kinase before it is phosphorylated two more times by host cell enzymes to its active form [79]. Therefore, HSV-infected cells have a 40 to 100 times higher concentration of acyclovir triphosphate than uninfected cells. The active drug competes with deoxyguanosine triphosphate for binding the viral DNA polymerase [80], which has a higher affinity for the drug than does the cellular DNA polymerase. Acyclovir completely and irreversibly inactivates the viral DNA polymerase and terminates DNA chain elongation because it lacks a

necessary 30 hydroxyl group [8]. Nucleoside analogue antiviral drugs, such as acyclovir, cannot prevent the death of cells that are already infected with the virus. Rather, the drugs limit replication and further spread of the virus to other cells [81]. Of the herpesviruses, the drug is most effective against HSV-1, HSV-2, and varicella-zoster virus. EpsteinBarr virus requires higher concentrations of acyclovir, and cytomegalovirus is resistant because it lacks the viral thymidine kinase. Acyclovir (Zovirax) is available in topical, intravenous, and oral preparations. Indications for its use include acute treatment for primary [82] or recurrent [83] HSV infections and chronic suppressive therapy [84] to reduce recurrent outbreaks and viral shedding. Orally administered acyclovir achieves a much lower plasma concentration than the intravenous form. It has an oral bioavailability of only 15% to 20% and a short intracellular half life (1 hour), necessitating a frequent dosing regimen [43]. Consequently, newer prodrug antiviral preparations such as valacyclovir (Valtrex) and famciclovir (Famvir) often are prescribed because of their more convenient dosing schedule and improved compliance. Regardless of the oral agent used, all of them have been shown to be equally effective. Valacyclovir is the L-valyl ester prodrug of acyclovir. After oral absorption, it is quickly and nearly completely metabolized to acyclovir by the liver and intestine [35,85]. Valacyclovir therefore has the same mechanism of action, safety profile, and efficacy as acyclovir. The oral bioavailability of valacyclovir is three to five times higher than that of acyclovir [85], approaching levels comparable with intravenous acyclovir. Valacyclovir is available only in an oral preparation. Similarly, famciclovir is the prodrug of penciclovir, which has a mechanism of action similar to acyclovir. Penciclovir (Denavir) is available only in a topical form because of its poor oral bioavailability, whereas famciclovir achieves a much higher (77%) oral bioavailability [43]. Famciclovir is converted rapidly to penciclovir by the gastrointestinal tract, blood, and liver. After entering infected cells, it is converted to its active form, penciclovir triphosphate, by viral and cellular enzymes. The active drug then inhibits viral DNA polymerase. Its safety profile and efficacy are comparable to that of acyclovir and valacyclovir. Acyclovir [86,87], valacyclovir [83,84], and famciclovir [88] all have excellent safety profiles and few adverse effects that are similar to placebo. Patients on daily suppressive acyclovir therapy have been followed up to 10 years without significant problems

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[89 91]. In healthy adults, 85% of acyclovir is excreted unchanged in the urine; however, patients with impaired renal function should receive reduced doses of acyclovir, valacyclovir, and famciclovir. A transient nephropathy and elevated creatinine can occur as a result of drug crystallization in the renal tubules and collecting ducts [92]. This problem can be minimized with adequate hydration and slow intravenous infusion of the drug for 1 hour. Renal dysfunction attributed to acyclovir is rare, usually reversible [93,94], and has not been reported with oral doses up to 800 mg five times a day [95]. Acyclovir is removed during hemodialysis but not peritoneal dialysis. Central nervous system disturbances such as agitation, hallucinations, disorientation, tremors, and myoclonus have been reported on rare occasions with intravenous acyclovir [96,97]. Treatment of herpes labialis As mentioned previously, orolabial herpes has been difficult to treat. Currently, topical 1% penciclovir cream applied every 2 hours for 4 days is the only FDA-approved treatment by prescription for recurrent episodes of herpes labialis. Adverse effects with penciclovir cream are similar to placebo. Self-initiated treatment within 1 hour of the onset of signs or symptoms of sunlight-induced recurrences decreases the time to lesion healing by up to a median of 2 days. Use of the cream also demonstrated a reduction in maximum lesion area, lesion-associated signs and symptoms, and daily assessments of pain, burning, and tenderness [98]. Approval for use of penciclovir was based on an earlier study, which showed faster lesion healing by 0.7 day, decreased pain, and reduced viral shedding relative to placebo. These results occurred not only in patients who initiated therapy early (during the prodrome or early erythema stage) but also in those who started therapy late (during the papule or vesicular stage). The frequency of aborted lesions was unaffected by the cream [99]. Topical 5% acyclovir cream initially seemed to be beneficial when used four times daily for herpes labialis, then later was shown to have limited efficacy. It is unknown whether its lack of efficacy despite frequent application of the drug (eight times a day) is attributed to a change in the delivery vehicle and reduced penetration of the drug to the site of viral replication [35]. Orally administered acyclovir for herpes labialis has mixed therapeutic value. For the treatment of primary herpetic gingivostomatitis, acyclovir suspension (15 mg/kg five times a day for 7 days) was effective at shortening the lesion duration from a

median of 10 to 4 days compared with placebo. Acyclovir also decreased the duration of fever, extraoral lesions, eating and drinking difficulties, and viral shedding. The ideal dose and length of treatment for primary infection still need investigation [100]. For sun-induced recurrent herpes labialis, acyclovir (200 mg five times a day for 5 days) decreases the time to loss of crust by 1 day but has little effect on pain or time to complete healing [101]. An increased dose of 400 mg five times a day, if started early during the prodrome or erythema-only stage, can modestly decrease the mean duration of pain by 36% and mean time to loss of crust by 27%. The frequency of aborted lesions and maximum lesion size are unaffected. On further examination of this study, Spruance [35] and Spruance et al. [102] determined that the subgroup of lesions with an identifiable prodrome benefited from therapy. In contrast, the subgroup of lesions lacking a prodrome (for which a papule was the presenting sign) did not. Famciclovir also has been investigated in the treatment of recurrent herpes labialis, although it is not FDA-approved for this indication (except in immunocompromised individuals). High doses of famciclovir (500 mg three times daily for 5 days) were more effective than lower doses, decreasing the median lesion healing time from 6 days in the placebo group to 4 days (48% reduction). The maximum lesion area also was reduced with famciclovir, but the number of lesions and frequency of aborted lesions were unaffected. Half the dose of famciclovir (250 mg three times daily for 5 days) showed only a minimal difference in efficacy than the higher dose. Patients may choose to use this lower dose at half the cost. Further studies on the optimal duration of treatment (5 days or shorter) are warranted [81]. The self-initiated combination of famciclovir (500 mg three times daily for 5 days) with the topical steroid, fluocinonide (0.05% Lidex Gel), three times daily for 5 days versus famciclovir alone showed promising results, with a greater number of aborted lesions (41% versus 8%), a reduction in the median maximum lesion size, and a decrease in the number of patients experiencing pain [103]. Suppressive therapy with acyclovir, although not FDA-approved, may have some therapeutic benefit in herpes labialis. Skiers, who are susceptible to suninduced orolabial herpes, were given 200 mg of acyclovir five times a day. In support of the difference between immediate and delayed groups of lesions, the frequency of reactivation was not affected, but fewer lesions developed and benefits of therapy were seen only at the end of the treatment period [71]. Skiers given 800 mg twice daily for

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sun-induced recurrences similarly healed slightly faster on days 5 and 6; most lesions healed by day 7 [101]. In the general population, individuals with frequent recurrences (six or more per year) can benefit from acyclovir 400 mg twice daily. Suppressive therapy at this dose delayed time to first recurrence from 46 to 118 days, reduced the mean number of recurrences by 53%, and decreased shedding by 71% [45]. Treatment of herpes genitalis Treatment is more aggressive for primary genital HSV infections compared with treatment for recurrent episodes. Oral acyclovir is effective when started within 24 hours of lesion formation [104,105], shortening the duration of viral shedding and time to lesion healing. Clinically, however, patients do not perceive a large benefit from treatment of recurrent episodes, and the duration of pain and pruritis is unaffected [106,107]. The previously recommended acyclovir dose of 200 mg five times a day has changed to a more convenient dosing schedule of 400 mg three times a day for 10 days during the primary episode. Acyclovir administered intravenously achieves high serum concentrations [108, 109]; it is an effective treatment for primary genital herpes, reducing viral shedding duration, pain, and time to complete healing (from an average of 10 days to 8 days) [110,111]. This route of delivery requires unnecessary hospitalization, however. The use of intravenous therapy should be reserved for patients with systemic complaints or extensive local symptoms. Valacyclovir is comparable to acyclovir for the treatment of first-episode genital herpes, but with more convenient dosing [82]. Valacyclovir should be given at a dose of 1 g twice daily for 10 days. Famciclovir (250 mg three times a day for 10 days), although not FDA-approved for this indication, can delay the time to first recurrence [112]. Acyclovir also is used for the treatment of recurrent genital herpes at a dose of 400 mg three times a day for 5 days. Although acyclovir seems to be more effective in the treatment of primary infection rather than recurrences, it is useful for recurrent episodes when started during the prodrome. Valacyclovir is as effective as acyclovir for recurrences [83]. The previously recommended dose of valacyclovir, 500 mg twice daily for 5 days [113], recently has been FDA-approved for a shortened 3-day course [114]. Famciclovir has been proven to delay the time to first recurrence as well [162]. A dose of 125 mg twice daily for 5 days is as effective as acyclovir [115], decreasing pain, burning, tenderness, and tingling [1].

Chronic suppressive therapy with acyclovir (400 mg twice daily) can decrease the frequency of genital recurrences by approximately 90% [90] and reduce asymptomatic shedding by greater than 90% [55]. Once-daily valacyclovir (500 mg) is effective for suppression in patients with fewer than 10 outbreaks per year, whereas 1000 mg once a day is more effective if patients have 10 or more episodes per year [84]. Famciclovir (250 mg twice daily) is also effective for individuals with frequent disease (six or more episodes per year) [88]. Evaluation of whether decreased viral shedding translates to reduced transmission is currently under way, but it is reasonable to believe that this is the case. Asymptomatic viral shedding is not prevented completely, however, and transmission may occur despite daily therapy [116]. Daily therapy should be discontinued every 1 to 2 years to reassess the frequency of recurrences and the need for pharmacologic suppression. If the primary purpose of chemoprophylaxis is to reduce the risk of transmission to susceptible partners, however, discontinuation of the drug may not be warranted [117]. A promising new topical gel, resiquimod (R-848) currently is being investigated in phase III clinical trials for the treatment of genital herpes. Previous trials show promising results indicating that resiquimod can reduce the number of genital herpes episodes in patients with a history of frequently recurrent disease. The median time to first recurrence was delayed from 57 days in the placebo group to 159 days in the resiquimod group; 32% of the patients in the resiquimod group compared with 6% of patients receiving placebo did not have any recurrences during the 6-month observation period [118]. Resiquimod does not have direct antiviral activity; rather, it is an immune response modifier from the same imidazoquinoline family as its analogue, imiquimod (Aldara), but it is approximately 100 times more potent in its ability to induce Th1 cytokine production. The gel should be applied directly to lesions, where it induces cytokines such as interferon-a, tumor necrosis factor-a, interleukin-6, and interleukin-12 [118,119]. Stimulation of the Th1 immune response, coupled with the HSV antigen already present in the host, mimics the effect of a therapeutic vaccine [118]. Treatment during pregnancy A pregnancy registry of more than 1000 women who were exposed to acyclovir during early pregnancy suggests that acyclovir is probably safe for use in pregnant women. There were no detectable increases in the number of congenital malformations in the offspring [59,120,121]; however, suppressive

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therapy with acyclovir during pregnancy is not recommended, and episodic therapy should be used with caution. Similar data for valacyclovir and famciclovir use during pregnancy do not exist. Treatment in the immunocompromised patient Immunocompromised patients have a high risk for developing frequent and severe symptoms from herpes infections. For example, renal transplant recipients have a 40% to 70% HSV reactivation rate in 1 year [122]. Topical acyclovir 5% ointment can be applied every 3 hours for 7 days to treat limited mucocutaneous HSV infections, such as herpes genitalis. More severe mucocutaneous involvement treated with intravenous acyclovir can decrease viral shedding and assist with lesion healing [123]. The combination of intravenous treatment followed by oral therapy for 3 to 6 months in patients who have received a transplant can help suppress symptomatic herpetic disease [124]. Famciclovir (500 mg twice daily for 7 days) has been effective for the treatment of recurrent oral or genital herpes in HIV-positive persons [125] and chronic suppression when used for 8 weeks (although the latter is not FDA-approved). Intravenous penciclovir seems promising for treatment of mucocutaneous infections in the immunocompromised patient. Recent investigations show efficacy similar to acyclovir with the added benefit of a less frequent, every-12hours regimen [126]. Herpes simplex virus resistance to antiviral therapy Resistance to acyclovir is infrequent, even in immunocompromised patients [127]. Resistant strains of the virus occur at rates of 4% to 10.9% in the immunosuppressed individual [128], compared with a rate of approximately 0.4% in the general immunocompetent population [128,129]. Although resistance usually develops after chronic exposure to a drug, HSV-resistant strains do not seem to correlate with acyclovir exposure [70]. Acyclovir-resistant HSV has been found in patients with no previous exposure to acyclovir [70,128,130]. The rates of resistance to acyclovir have not changed among patients on chronic suppressive therapy [131], and resistant strains are less common in patients receiving chronic suppression compared with episodic treatment with acyclovir [132]. Rather, increased replication caused by decreased immunity seems to cause the higher resistance rates [70]. Chronic suppressive therapy actually may decrease the incidence of resistant strains by limiting the amount of viral replication and therefore decreasing the probability of mutation [70].

Genomic mutations usually appear in the genes encoding the viral thymidine kinase [133 135]. The most common mutant form of HSV completely lacks thymidine kinase [136] and tends to be nonvirulent. Having no ability to reactivate from latency [128], however, mutants that do not recognize the active form of acyclovir also exist. Disseminated HSV infections [137] by resistant strains usually occur in immunocompromised hosts and include pneumonia [138], encephalitis [139], esophagitis [140], and mucocutaneous infections [141 143]. Foscarnet, an analogue of pyrophosphate, is the only drug approved by the FDA for the treatment of acyclovir-resistant HSV infections. Unlike acyclovir, foscarnet does not require thymidine kinase for phosphorylation [144]. The drug competitively binds viral DNA polymerase in the pyrophosphate binding site and prevents chain elongation [43,145]. Oral absorption is poor, so the drug must be delivered intravenously. Because of the possibility of renal toxicity, patients receiving therapy must have adequate hydration and close renal monitoring by way of serum creatinine. Other potential problems include electrolyte imbalances, nausea, vomiting, diarrhea, headache, fever, anemia, central nervous system disturbances, and penile ulceration (a contact dermatitis from the urine) [146]. Herpesvirus strains that are resistant to foscarnet [147] or foscarnet and acyclovir [148 150] also have been reported. Topical cidofovir (HPMPC) has potential usefulness for the treatment of acyclovir- and foscarnetresistant HSV. Case reports [150,151] and a small, randomized, double-blind, placebo-controlled trial [152] have shown improved lesion healing, decreased viral shedding, decreased lesion size, and reduced pain. Cidofovir is a monophosphonate molecule that is phosphorylated by cellular enzymes, incorporated into viral DNA by DNA polymerase, and then halts chain elongation. Similar to foscarnet, cidofovir can be used for thymidine kinase (TK) mutants and TKdeficient strains of HSV [153]. Intravenous cidofovir is dosed only weekly, but the complexity of administration and its nephrotoxic and neutropenic side effects can be limiting [154]. The promise of an effective topical preparation with less severe adverse effects is exciting.

Prevention Individuals with HSV infections frequently are plagued by the persistence of the infection and concerns about transmission to their sexual partners. With the proper education and adherence to recom-

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mended guidelines for safe sexual practices, the risk of transmission can be decreased. Patients should be taught how to recognize acute outbreaks in the source partner so that they may refrain from sexual activity when lesions are present. Ideally, condoms should be used during all sexual encounters because viral shedding occurs even in the absence of active lesions [12]. Areas of the skin that remain uncovered by the condom, such as the inguinal area, remain susceptible to infection, however. Women tend to shed virus over a greater area than men, whereas men usually shed the most from penile skin. Because condoms are able to cover this area of frequent shedding in men, it is reasonable that women are protected more effectively than men when condoms are used greater than 25% of the time (Fig. 3) [7]. Antiviral medication cannot eradicate latent infection by HSV; however, there are several vaccines under investigation for effectiveness in the prevention and treatment of HSV infection. The three types of vaccines currently in clinical trials include a replication-incompetent viral mutant vaccine (disabled infection single cycle [DISC]), adjuvant subunit vaccines, and DNA vaccines [155,156]. Evaluation of efficacy will depend on what is defined as the goal of the vaccine. Completely preventing infection and subsequent latency may be an unattainable standard; however, a reduction in the prevalence of HSV disease without preventing actual infection may prove to be a reasonable alternative [155,156]. A replication-incompetent mutant vaccine such as the DISC vaccine contains live viruses that are able to

infect cells but are incapable of spreading between cells [156]. The mutant virus is missing the glycoprotein H gene, which encodes a protein necessary for cell entry. This type of vaccine, administered directly to mucosal surfaces in an effort to increase local immunity, has been shown to be immunogenic and well tolerated in phase I trials [157,158]. Phase II trials are currently under way to test its efficacy in HSV-infected humans as a therapeutic (rather than preventive) modality. Recombinant subunit vaccines contain immunogenic proteins and lack viral DNA. In general, killed-virus vaccines are less immunogenic than the corresponding live-virus vaccines. Although the immunogenicity of a subunit vaccine can be enhanced with the addition of an adjuvant, a concominant increase in reactogenicity also can limit its usefulness [156]. One recombinant subunit vaccine developed by Chiron (Emeryville, CA) used surface glycoproteins from HSV-2 (gD2 and gB2) with the adjuvant MF59 to sufficiently induce HSV-2 specific neutralizing antibodies in humans [159]. It lacked overall efficacy in phase III trials, however. Phase III trials with a vaccine containing surface glycoprotein gD with the adjuvant monophosphoryl lipid A immunostimulant (MPL) afforded protection against clinically apparent HSV-2 disease in women who were seronegative for HSV-1 and HSV-2. This effect was not demonstrated in men or women with prior HSV-1 infection [160,161]. DNA vaccines consist of plasmid DNA that contains a limited number of genes. The resultant gene

Fig. 3. Condoms can help prevent transmission of herpes simplex virus, but areas not completely covered by the condom remain susceptible to infection.

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products are viral antigens, such as glycoproteins gB, gD, or gD2, which can induce humoral and cellmediated immunity responses. Phase I trials with these vaccines are in progress, in addition to others in preclinical development [156].

Summary An increased understanding of the pathogenesis and transmission of HSV infections and the development of sensitive type-specific diagnostic tests have helped develop effective prophylactic and therapeutic antiviral drug regimens. Effective medications have been available for quite some time, but the most optimal regimens are still under investigation. Advances in the treatment of atypical presentations of HSV infection (such as the use of cidofovir gel for the treatment of acyclovir-resistant HSV) are promising. Newer treatments, such as resiquimod, actually may alter the course of HSV infection, reducing the severity and frequency of recurrences. Vaccines are being explored as preventive and therapeutic measures against HSV.

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K.A. Yeung-Yue et al. / Dermatol Clin 20 (2002) 249266 DW. Recurrent genital herpes and suppressive oral acyclovir therapy. Ann Intern Med 1986;104:786 90. Christophers J, Clayton J, Craske J, et al. Survey of resistance of herpes simplex virus to acyclovir in northwest England. Antimicrob Agents Chemother 1998;42:868 72. Kost RG, Hill EL, Tigges M, Straus SE. Brief report: recurrent acyclovir-resistant genital herpes in an immunocompetent patient. N Engl J Med 1993;329: 1777 82. Balfour HH, Benson C, Braun J, et al. Management of acyclovir-resistant herpes simplex and varicellazoster virus infections. J Acquir Immune Defic Syndr 1994;7:254 60. Fife KH, Crumpacker CS, Mertz GJ, et al. Recurrence and resistance patterns of herpes simplex virus following cessation of > 6 years of chronic suppression with acyclovir. J Infect Dis 1994;169:1338 41. Englund JA, Zimmerman ME, Swierkosz EM, et al. Herpes simplex resistance to acyclovir: a study in a tertiary care centre. Ann Intern Med 1990;112: 416 22. Burns WH, Saral R, Santos GW, et al. Isolation and characterisation of resistant herpes simplex virus after acyclovir therapy. Lancet 1982;1:421 3. Crumpacker CS, Schnipper LE, Marlowe SI, et al. Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. N Engl J Med 1982;306:343 6. Pottage JC, Kessler HA. Herpes simplex virus resistance to acyclovir: clinical relevance. Infect Agents Dis 1995;4:115 24. Erlich KS, Mills J, Chatis P, et al. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989;320:293 6. Jones TJ, Paul R. Disseminated acyclovir-resistant herpes simplex virus type 2 treated successfully with foscarnet [letter]. J Infect Dis 1995;171:508 9. Ljungman P, Ellis MN, Hackman RC, et al. Acyclovir-resistant herpes simplex virus causing pneumonia after marrow transplantation. J Infect Dis 1990;162: 711 5. Gateley A, Gander RM, Jonson PC, et al. Herpes simplex virus type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS. J Infect Dis 1990;161:711 5. Sacks SL, Wanklin RJ, Reece DE, et al. Progressive esophagitis from acyclovir-resistant herpes simplex: clinical roles for DNA polymerase mutants and viral heterogeneity. Ann Intern Med 1989;111:893 9. Marks GL, Nolen PE, Erlich KS, Ellis MN. Mucocutaneous dissemination of acyclovir-resistant herpes simplex virus in a patient with AIDS. Rev Infect Dis 1989;11:474 6. Triebwasser J, Harris R, Bryant RE, Rhoades ER. Varicella pneumonia in adults: report of seven cases and review of the literature. Medicine (Baltimore) 1967;46:409 20.

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[143] Verdonck LF, Cornelissen JJ, Smit J, et al. Successful foscarnet therapy for acyclovir-resistant mucocutaneous infection with herpes simplex virus in a recipient of allogeneic BMT. Bone Marrow Transplant 1993; 11:177 9. [144] Crumpacker CS. Mechanism of action of foscarnet against viral polymerases. Am J Med 1992;92(Suppl 2A):3S 7S. [145] Oberg B. Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacol Ther 1989;40: 213 85. [146] Jacobson MA. Review of the toxicities of foscarnet. J Acquir Immun Def Syndrome 1992;5(Suppl 1): S11 17. [147] Safrin S, Kemmerly S, Plotkin B, et al. Foscarnetresistant herpes simplex virus infection in patients with AIDS. J Infect Dis 1994;169:193 6. [148] Birch CJ, Tyssen DP, Tachedjian G, et al. Clinical effects and in vitro studies of trifluorothymidine combined with interferon-alpha for treatment of drugresistant and -sensitive herpes simplex virus infection. J Infect Dis 1992;166:108 12. [149] Pelosi E, Hicks KA, Sacks SL, Coen DM. Heterogeneity of a herpes simplex virus clinical isolate exhibiting resistance to acyclovir and foscarnet. Adv Exp Med Biol 1992;312:151 8. rard M, et al. Successful [150] Snoeck R, Andrei G, Ge treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Clin Infect Dis 1994;18:570 8. [151] Lateef F, Don PC, Kaufmann M, et al. Treatment of acyclovir-resistant, foscarnet-unresponsive HSV infection with topical cidofovir in a child with AIDS. Arch Dermatol 1998;134:1169 70. [152] Lalezari J, Schacker T, Feinberg J, et al. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis 1997;176:892 8. [153] Snoeck R. Antiviral therapy of herpes simplex. Int J Antimicrob Agents 2000;16:157 9. [154] Martinez CM, Luks-Golger DB. Cidofovir use in acyclovir-resistant herpes infection. Ann Pharmacother 1997;31:1519 21. [155] Krause PR, Straus SE. Herpesvirus vaccines: development, controversies, and applications. Infect Dis Clin North Am 1999;13:61 81. [156] Stanberry LR, Cunningham AL, Mindel A, et al. Prospects for control of herpes simplex virus disease through immunization. Clin Infect Dis 2000;30: 549 66. [157] Boursnell ME, Entwisle C, Blakely D, et al. A genetically inactivated herpes simplex virus type 2 (HSV2) vaccine provides effective protection against primary and recurrent HSV-2 disease. J Infect Dis 1997; 175:16 25. [158] McLean CS, Ni Challanin D, Duncan I, et al. Induc-

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tion of a protective immune repsonse by mucosal vaccination with a DISC HSV-1 vaccine. Vaccine 1996;14:987 92. [159] Corey L, Langenber AG, Ashley R, et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. JAMA 1999;282:331 40. [160] Tyring SK. Virology for the dermatologist. Presented at the American Academy of Dermatology 59th Annual Meeting, Washington, DC March 30, 2001. [161] Leroux-Roels G, Moreau E, Desombere I, et al.

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Clinical manifestations of varicella-zoster virus infection

T. Minsue Chen, BS a, Saira George, BAa, Christy A. Woodruff, MD b, Sylvia Hsu, MD b,*
b a Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Department of Dermatology, FB-840, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

Varicella-zoster virus (VZV) is uniquely capable of producing varicella (chickenpox) and herpes zoster (shingles). The exact etymology of the word chickenpox is unknown, but its origin may be from the word chiche-pois, the French word for chickpea, describing the size of the vesicles. The association between varicella and herpes zoster was made first in 1888 when susceptible children developed primary varicella after exposure to individuals with acute zoster. Inoculation with vesicular fluid from herpes zoster lesions also was shown to produce varicella in susceptible persons. The relationship was confirmed by in vitro studies that recovered the same virus from patients with varicella and from patients with herpes zoster [1].

80% to 90%, making it one of the most infectious viral diseases of humans. Even limited contact, such as in a school or office setting, is associated with reported attack rates of approximately 10% to 35% [9]. Pathogenesis Varicella-zoster virus is an enveloped, doublestranded DNA virus that is classified within the subfamily Alphaherpesviridae [10]. With specific receptors, the virus attaches to and fuses with the host cell plasma membrane and gains entry to the cytoplasm. After the virus is uncoated, the nucleocapsid is transported to the nucleus, where the viral genome undergoes transcription and translation. Newly synthesized virions then are released from the cell. Varicella-zoster virus is acquired from patients with primary varicella or herpes zoster through either direct contact with infected vesicular fluid or inhalation of aerosolized respiratory secretions. The notion of airborne transmission of VZV had been suggested by epidemiologic evidence [11,12] but only recently confirmed by polymerase chain reaction detection of VZV DNA isolated from respiratory mucosa [13] and from air samples [14]. Molecular studies also suggest that the virus can be transmitted by the respiratory route as early as 24 to 48 hours before the manifestation of the rash [14]. The average incubation period is 14 days [15,16]. The virus presumably is inoculated at the conjunctival or upper respiratory tract mucosa. After invading and infecting host epithelial cells, the virus is engulfed by and replicates within mononuclear cells that carry it to regional lymph nodes [17]. Macro-

Varicella Although the disease is global in its distribution, varicella occurs more frequently in temperate than in tropical climates [2,3]. Varicella-zoster virus is endemic in the population at large but becomes epidemic during late winter and early spring [4,5]. Unlike zoster, varicella is primarily a disease of childhood; 90% of cases occur in children aged 14 years or younger [6]. Before widespread vaccination, the incidence of varicella in the United States approached the annual birth rate, averaging between 3.1 and 3.8 million cases per year [3,7,8]. The transmission rate of acute varicella to susceptible household contacts is estimated to be as high as

* Corresponding author. E-mail address: shsu@bcm.tmc.edu (S. Hsu).

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 1 2 - 2

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phages and monocytes may be infected, but recent experiments suggest the virus is lymphotropic, specifically for T cells [13,18]. Within 4 to 6 days after exposure, an initial mononuclear cell associated viremia develops and carries the virus to reticuloendothelial cells throughout the body [19,20]. After a period of viral replication, a second, higher-titer viremic phase ensues, resulting in widespread dissemination of the virus. This second stage of VZV viremia is detectable during the last 4 to 5 days of the incubation period and for a few days after the appearance of the characteristic rash [21]. The rash develops as VZV-infected mononuclear cells invade vascular endothelial cells, gaining access to cutaneous tissue. After the primary varicella infection resolves, the VZV travels centripetally and enters a latent phase in the dorsal root ganglia [22,23]. The hosts cell-mediated immune response, in particular T cells, is the chief defense against VZV infection and reactivation [17,24 26]. If the VZV-specific, cellmediated response is inadequate, uncontrolled viremia and severe varicella with visceral dissemination result [27]. Clinical manifestations Immunocompetent Acute varicella is generally a self-limited, benign infection characterized by fever (usually lower than 102F), malaise, and a generalized pruritic rash of approximately 5 days duration [15]. A prodrome of headache, malaise, and fever may occur 1 to 2 days before the development of the rash and is common among adolescents and adults. In children, the rash and fever generally occur simultaneously and without prodromal symptoms. The pruritic rash of chickenpox, the hallmark of the disease, typically begins on the head and spreads to the trunk and finally the extremities, where proximal involvement is greater than distal. Chickenpox lesions evolve from erythematous macules to papules and then to small vesicles on an irregular erythematous base, giving them their distinctive dewdrop-on-a-rosepetal appearance (Fig. 1). Within 24 to 48 hours of their formation, the vesicles transform into pustules that subsequently crust and scab. New lesions arise in successive crops during a 2- to 5-day period, producing the characteristic appearance of scattered lesions in various stages of evolution. Limited mucous membrane involvement of the conjunctivae, oropharynx, and vagina also can occur. Typically, varicella lesions heal without scarring as new epithelium forms at the base; however, hypopigmentation, skin pitting, and keloid forma-

Fig. 1. Chickenpox. Papules on an erythematous base, demonstrating the dewdrop-on-a-rose-petal appearance.

tion may result, especially among darker-skinned individuals [28]. The number of individual lesions during an acute infection generally indicates the severity of infection; the usual range in healthy children is 100 to 300 lesions [15]. In general, older children and adults develop more numerous lesions than young children. Secondary cases of varicella acquired from household contact are also typically more severe than the households primary case, presumably because of a higher inoculum from close contact with the affected person [9]. Individuals with previously traumatized skin, such as those with eczema or sunburn, also may be predisposed to the development of a more extensive rash [29,30]. Varicella in adults is generally associated with a greater number of skin lesions, more systemic complaints, and a higher risk of such serious complications as pneumonia [7], encephalitis [31], and death [31] than in children. Although they make up only 1.5% of all cases of primary varicella, adults account for 17% of hospitalizations for the disease [7]. Lower cell-mediated immune responses to the virus in adults compared with children may underlie this difference in clinical outcome [25,26]. Approximately three fourths of patients with no known clinical history of infection have detectable antibodies to VZV. Subclinical varicella, documented by increases in antibody titer after exposure to the virus, has been estimated to occur in as much as 5% of the population [9,32]. Immunocompromised Immunocompromised patients are at significantly higher risk of developing varicella-associated morbidity and mortality than their immunocompetent counterparts [33,34]. Individuals with impaired cellmediated immunity, such as leukemics and organ

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transplant recipients, are especially vulnerable. They develop more numerous and severe lesions that appear during a prolonged period and take longer to heal. Life-threatening secondary infection and disseminated varicella with visceral involvement are common and often fatal in these patients [33]. Progressive varicella with new lesion formation for more than 1 month after the onset of the illness also has been observed more frequently in immunocompromised patients, as has recurrent varicella, in which disseminated lesions reappear 1 month or more after the resolution of prior lesions and in the absence of reexposure [33,35,36]. Perhaps the largest group of immunocompromised patients at risk is HIV-seropositive patients. Most cases of varicella in HIV-infected patients follow a benign course, but persistent, acyclovir (ACV)resistant, verrucous lesions and fatal infection with severe organ involvement are more common in asymptomatic HIV-infected adults and children than among noninfected individuals [35 37]. Pregnancy and the neonatal period Acute varicella during pregnancy occurs in only 0.05% to 0.07% of pregnancies because a small percentage of women of childbearing age remain susceptible to VZV [38]. Risks to the mother, especially when infection occurs in the third trimester, include varicella pneumonia and its concomitant morbidity and mortality [39]. Mechanical ventilation and death in such cases is not uncommon [39]. Varicella-zoster virus infection during pregnancy also poses risks to the infant. Maternal varicella in the first trimester, weeks 8 to 12 in particular, carries a 2.2% risk of congenital varicella syndrome [40]. Cicatricial scarring of the skin is the most common manifestation of congenital varicella syndrome, but other reported abnormalities include chorioretinitis, microphthalmia, congenital cataracts, hypoplastic limbs, mental retardation, and early death [41]. Neonates of mothers who develop varicella in the immediate peripartum period (5 days before and up to 2 days after delivery) are at high risk for the development of disseminated varicella and death as a result of the intrauterine transmission of VZV before the transfer of protective maternal antibodies [42,43]. Severe varicella during any stage in pregnancy also can result in spontaneous abortion or zoster in early infancy [39,40,42]. Complications The risk of varicella complications is highest in immunocompromised patients, neonates, and

adults [6,31]. Most hospitalizations for varicella an estimated 4000 to 6000 a yearare attributed to complications in healthy children, however [5,7,31]. Bacterial infection One to four percent of otherwise healthy children with varicella develop superinfection of the skin and soft tissues, making it the most common complication of varicella among healthy children [4,7,34,44,45]. Staphylococcus aureus or Streptococcus pyogenes infections such as impetigo, furunculosis, cellulitis, erysipelas, and lymphadenitis are the most frequently encountered [4,44,45]. Necrotizing fasciitis, a life-threatening and rapidly progressive infection of the skin and subcutaneous tissues, also has been reported as a complication of chickenpox in children [44,46]. Children with varicella who develop bacteremia are at risk of developing bacterial pneumonia, meningitis, arthritis, and osteomyelitis [44,47 50]. Bacterial sepsis, shock, and disseminated intravascular coagulation also may occur [4,44,45,48,51]. Neurologic Neurologic complications, namely acute cerebellar ataxia and meningoencephalitis, are the second most common cause of varicella-related morbidity in healthy children [4,7,34,45,48,52]. Symptoms of cerebellar ataxia include gradually progressive irritability, ataxia, nystagmus, and speech disturbances that persist for days or weeks but normally clear completely over time. Varicella meningoencephalitis, or cerebritis, presents with sudden but transient neurologic changes such as alterations in sensorium, seizures, or meningeal signs that usually resolve in 24 to 72 hours [52]. Other rare complications involving the central nervous system include transverse my syndrome elitis, optic neuritis, and Guillain-Barre [45,52]. Respiratory Hematogenous spread of the virus to the lungs can result in varicella pneumonia, an infrequent complication in children but the leading cause of varicella-associated morbidity and mortality among adult, pregnant, and immunocompromised individuals [7,53]. Approximately 1 in 400 adults with varicella requires hospitalization for VZV pneumonia [7]. Risk factors for VZVpneumonia include older age, extent of the cutaneous rash, immunosuppression, pregnancy (especially third trimester), smoking, and chronic obstructive pulmonary disease [54].

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Hepatic Asymptomatic transient hepatitis, with mild elevations of liver transaminases, commonly is seen in healthy people with varicella infection [55,56]. Fulminant hepatic failure caused by extensive viral destruction of the hepatocytes is uncommon and usually associated with progressive varicella [57]. The differential diagnosis of hepatic failure in children with varicella also must include Reyes syndrome, a hepatic encephalopathy associated with salicylate administration and febrile viral illnesses. After reports of the association between aspirin and Reyes syndrome were published, a dramatic decrease in the incidence of the syndrome has occurred [7,58]. Hematology Postinfectious, immune-mediated thrombocytopenia may result in bleeding complications 1 to 2 weeks after a case of chickenpox [59]. Purpura fulminans, or varicella gangrenosa, is a rare but life-threatening complication of varicella in children that results from disseminated intravascular coagulation caused by autoimmune protein S deficiency [60,61]. The first sign is often an enlarging subcutaneous ecchymosis at the end of the first week of an otherwise uncomplicated case of chickenpox that then becomes tender and gangrenous; within hours, shock develops. Other reported complications Chickenpox lesions may occur on the conjunctivae but usually heal without complications. Serious ophthalmologic complications caused by primary varicella infection, such as keratitis or anterior uveitis, are rare. Viral arthritis, myocarditis, pericarditis, pancreatitis, orchitis, and glomerulonephritis also have been reported. Mortality Approximately 100 people die of chickenpox annually [62]. More than half are children, but the case-fatality rate is highest among adults and infants [31,53]. The most common cause of lethal varicella infection is pneumonia, followed by secondary infection, central nervous system complications, and hemorrhagic complications [53].

of VZV-induced skin manifestations. These manifestations include acute herpes zoster, zoster sine herpete, chronic zoster, and disseminated zoster. The clinical polymorphism of herpes zoster reactivation may be dependent on the patients age, fluctuations in immune status, prior treatment, and VZV gene expression [64]. Pathogenesis After resolution of primary varicella, the neurotropic virus spreads centripetally from infected skin and mucosal lesions along adjacent sensory nerve endings to dorsal root and cranial nerve ganglia, where it enters the latent state. Clinical manifestations result when the virus is reactivated. Newly synthesized VZV virions are transported along the sensory nerve and released into the skin, where a unilateral, vesicular eruption involving one or two dermatomes forms along the distribution of the sensory nerve. The latent period may seem to last for many years after the primary infection; on the contrary, latency rarely is maintained for prolonged periods [65]. Subclinical reactivation and viremia occur frequently in immunocompromised patients [66]. Fortunately, herpes zoster is less contagious to others than primary varicella. The patients immunity, particularly the VZVspecific, cell-mediated immunity, is instrumental in preventing symptomatic recurrences [24]. Other reported trigger mechanisms include trauma, sunburn, stress, and old age with its concomitant immune dysregulation or immunosuppression [67]. Acute zoster Immunocompetent The incidence of herpes zoster (shingles) increases with age [63]. Children who contract varicella during infancy, however, have a much higher incidence of zoster than those who do not contract the primary infection until they are older [68]. A prodrome of symptoms, similar to primary varicella, is common in children. Fever, malaise, paresthesia, or dysesthesia in the affected dermatome may appear before skin lesions erupt. The pain is subject to a wide array of misdiagnoses, especially if the thoracic region is involved (ie, peptic ulcer disease, gallbladder disease, renal colic, myocardial infarction). The most common places of involvement include the thoracolumbar (T3-L2) and facial (V1) dermatomes. The rash begins as unilateral, grouped, erythematous macules and papules on edematous bases, which then progress to vesicles, then to pustules, and finally to

Zoster Herpes zoster classically presents in a dermatomal distribution with associated paresthesia in approximately 15% to 20% of the seropositive population [63]. An increasing number of atypical presentations have been reported, demonstrating the wide spectrum

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crusts along a dermatomal distribution during a 2-week period (Fig. 2). Skin involvement is often greatest at the site that was affected most severely by primary varicella. Regional lymphadenopathy also may be present [63,69]. Severe neuritis with substantial acute pain, dysesthesia, and skin hypersensitivity is often more severe in people older than 50 and in immunocompromised patients [70]. Immunocompromised Because of their decreased cell-mediated immunity and immune dysregulation, immunocompromised patients are at an approximately 20-fold increased risk for zoster than age-matched control patients [71]. Among patients with cancer, the highest risk of herpes zoster occurs in those with leukemia or lymphoma, in particular Hodgkins disease, or after chemotherapy or radiotherapy [72]. A strong relationship has been reported between primary gynecologic tumors and the subsequent development of zoster in lumbar or sacral dermatomes, as well as between primary breast or respiratory cancer and zoster in thoracic dermatomes [73]. Previously irradiated dermatomes are observed to have nearly twice the frequency of zoster than other dermatomes [73].

Herpes zoster typically pursues a benign course in immunocompromised patients, with resolution of cutaneous lesions typically occurring in 2 to 3 weeks, often without specific antiviral chemotherapy [74]. Immunocompromised patients, however, may develop several episodes of, atypical manifestations of, or increased severity of herpes zoster. Disseminated visceral disease, diffuse cutaneous dissemination (varicelliform zoster), chronic hyperkeratotic skin lesions, ACV resistance, bullous ecthymatous zoster, lichenoid reactions, and follicular herpes zoster have been reported in immunocompromised persons [37,75 78]. Contrary to previous belief, zoster is not a marker for occult malignancy. An acute episode of zoster can occur in an immunocompetent person and does not warrant a search for a malignancy [79]. The risk of herpes zoster in HIV-infected patients is not correlated with the duration of HIV infection, nor is it predictive of a rapid progression to AIDS [71]. Depletion of CD4 lymphocytes, however, is associated with more severe, chronic, recurrent, and more prolonged VSV infections, leading to scarring and subsequent dissemination. The diagnosis of multidermatomal zoster in HIV-positive patients, which occurs at a lower CD4 level than zoster involving a single dermatome, is included as an AIDS-defining illness [69,80]. Pregnancy and the infant Herpes zoster during pregnancy is not as serious a problem as primary varicella during pregnancy [41]; it does not result in serious morbidity or intrauterine varicella infection. Transplacental transmission of the virus does not occur with maternal herpes zoster; preexisting maternal immunity is postulated to protect the fetus by preventing viremia. If, however, maternal zoster develops just a few days before delivery, the infant may acquire varicella. Passively acquired varicella virus-specific IgG antibody may not have had time to accumulate within the infant, thereby decreasing the protective effect of maternal immunity [81]. Infants who were exposed to varicella in utero may develop herpes zoster early in life without having had previous varicella [82]. When the infants level of maternal antibody wanes, the relative immunosuppression may lead to early viral reactivation and herpes zoster in the infant [8]. Other manifestations Chronic zoster In the 1980s, the first reports of longstanding or chronic VZV infections appeared. Typical clinical

Fig. 2. Herpes zoster. Dermatomal distribution of coalescing, grouped vesicles on an erythematous base.

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presentation consists of single or multiple pox-like or wart-like (verrucous) hyperkeratotic and well-demarcated lesions rather than the classic vesicles. Lesions usually persist from several weeks to months, with periods of extension or regression without healing completely. Rarely, some patients may experience pain. These lesions may follow an episode of primary varicella or an episode of dermatomal or disseminated cutaneous zoster. The verrucous lesions may resolve with scarring in 2 to 3 weeks; relapses after successful therapy, however, are possible and may affect either the same or another site. Because chronic zoster often is associated with ACV resistance, tissue biopsy and culture should be performed to document antiviral resistance [64]. Currently, most chronic zoster cases are found in HIV-infected patients with profound immune suppression and CD4 cell counts less than 200 and in organ transplant recipients. Most patients have had previous episodes of zoster and prolonged low-dose ACV prophylaxis. Chronic zoster often is unrecognized because of its atypical presentation, which mimics molluscum contagiosum, basal cell carcinoma, ecthyma gangrenosum, and disseminated deep fungal infection [64]. The presence of other viruses in chronic verrucous lesions, however, suggests that this morphology is not virus-specific [83]. Cutaneous and visceral dissemination Dissemination probably results from hematogenous spread of the virus and is defined by the number of lesions outside the primary and immediately adjacent dermatomes. Lesions disseminate more commonly in immunocompromised patients, often mimicking acute varicella, and may be a marker for visceral involvement, most commonly of the lung, liver, and brain. Disseminated zoster can be potentially fatal, especially in immunocompromised patients [65,69]. Other reported organ system involvement includes direct VZV infection of the heart, gastrointestinal tract, and joint spaces [84 87]. Zoster sine herpete Zoster sine herpete, or pain without the rash, is a rare presentation of herpes zoster; dermatomal pain is present with failure to develop a rash, likely because of neural inflammation and damage from viral reactivation. Increased IgG antibody titers between the acute and convalescent phases confirm the diagnosis. Zoster sine herpete frequently is misdiagnosed as other conditions that can present with pain in the affected areas [88].

Complications Most healthy patients recover without sequelae from an attack of herpes zoster. In general, complications are more common among elderly or immunesuppressed patients [89,90]. Postherpetic neuralgia is the most common complication in otherwise healthy patients, but neurologic, dermatologic, and ocular complications can occur as well. Multidermatomal, disseminated, or trigeminal zoster tends to have a higher complication rate [91]. Postherpetic neuralgia One of the most debilitating complications of herpes zoster is postherpetic neuralgia, defined as pain that persists in an affected area for more than 1 month after the lesions have healed [92]. The incidence of postherpetic neuralgia is age related, affecting approximately half of zoster patients older than 60 years and only approximately 15% of younger patients with zoster [89]. Patients usually describe a burning ache and hypesthesia so severe that any contact with the skin is intolerable. Other abnormal sensations may persist, such as pruritis, paresthesia, dysesthesia, or anesthesia lasting for months to years. In most cases, patients are free of pain at the end of 1 year without treatment [92]. The symptoms represent a neurodestructive process caused by viral invasion and a local inflammatory response with active ganglionitis and radiculoneuritis. Extensive death of primary neurons may result in chronic pain caused by the irreversible damage [93]. Other neurologic complications Muscle weakness and motor nerve paralysis are transient complications of zoster that result from direct extension of the inflammatory response from the sensory ganglion to adjacent anterior horn cells in the spinal cord. Symptoms usually occur in the first 2 to 3 weeks after the onset of the rash and persist for several weeks. Motor difficulties or paralysis may be found when the trigeminal or facial nerve is involved (Bells palsy). Zoster also may involve the geniculate ganglion, with auditory neuritis and a vesicular rash on the auricle (RamsayHunt syndrome) that may progress to permanent damage of the nerves, resulting in tinnitus, vertigo, deafness, otalgia, or loss of taste. Cardiac arrhythmia, dysphagia, urinary retention, constipation, diaphragmatic paralysis, and ocular palsies can occur when innervating nerves are infected by the virus. Meningoencephalitis also has been associated with herpes zoster [92].

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Ocular Viral invasion and local inflammation involving, most commonly, the nasociliary branch of the fifth cranial nerve may lead to ocular complications that can occur in up to 2% of immunocompetent patients with herpes zoster [67,89]. Zoster involving the tip or side of the nose (Hutchinsons sign) requires ophthalmologic consultation to exclude ocular involvement [67]. Corneal damage accompanied by visual impairment is the most feared complication. Ocular palsy, lid ptosis, conjunctivitis, panophthalmitis, retinal vasculitis, retinal artery occlusion, optic neuritis, and choriodal detachment also have been reported. Horners syndrome and Argyll Robertson pupil also can be seen [67,94,95]. Acute retinal necrosis may be associated with VZV reactivation without cutaneous findings, manifesting as retinal arteritis, necrotizing retinitis, vitreitis, and retinal detachment [96]. Dermatologic Similar to chickenpox, secondary infection is the most common dermatologic complication of herpes zoster, especially impetigo and cellulitis [92]. It is hypothesized that the herpes zoster lesions serve as portals of entry for staphylococcal or streptococcal microorganisms [75]. Necrotizing faciitis [97] and herpes gangrenosa [92] (a superficial gangrene with cellulitis) also have been observed with zoster infection. Disfiguring cutaneous pits and keloidal scars with pigmentary changes may develop with healing of varicella skin lesions, particularly in darkly pigmented skin [28,98]. Rarely, granuloma annulare [99] and leukocytoclastic vasculitis [100] may occur. Mortality The most frequent causes of death are related to visceral complications of zoster: pneumonia, hepatitis, encephalomyelitis, and disseminated intravascular coagulopathy [101].

pathognomonic for acute herpes zoster. Clinical manifestations of, differential diagnoses for, and methods for diagnosis of VZV infections are summarized in Fig. 3. Mimickers of varicella include disseminated herpes zoster, other viral exanthems (Coxsackievirus and Echovirus infections), impetigo, insect bites, scabies, erythema multiforme, papular urticaria, drug eruption, or other vesicular dermatoses such as dermatitis herpetiformis [69,102]. The differential diagnosis of herpes zoster includes zosteriform herpes simplex virus infection that, unlike zoster, often recurs. Other diagnostic possibilities include burns, arthropod reactions, localized bacterial or viral skin infections, or even vaccinal autoinoculation [69]. Cultures remain the gold standard for virologic confirmation [103], and the virus can be cultured easily from vesicular fluid within 5 days of the onset of symptoms or before the crusting of lesions. Viral cultures, however, are positive in only 30% to 60% of all varicella and herpes zoster cases and do not provide immediate diagnostic support [24]. Alternatively, the traditional Tzanck smear is easy to perform but will not differentiate between herpes simplex virus and VZV [102]. In more difficult cases, additional studies may be necessary, including VZV IgM or IgG acute-phase and convalescent-phase antibody titers, direct immunofluorescence, dot-blot hybridization, and polymerase chain reaction [43,69,104].

Treatment Varicella Varicella is typically a benign, self-limited infection in healthy children. Treatment, therefore, has been traditionally directed at relieving pruritus and maintaining skin hygiene to prevent bacterial superinfection. Antipyretics may be administered for fever; aspirin, however, is contraindicated during acute varicella because of the risk of Reyes syndrome [105]. Because of its disease-modifying effects and low risk of adverse reactions, oral ACV is currently the only Food and Drug Administration (FDA) approved drug for varicella in otherwise healthy children. Treatment with ACV, a guanosine analogue, results in shorter periods of new lesion formation, fewer overall lesions, and more rapid healing but only if administered within 24 to 48 hours of rash onset because VZV replication occurs primarily during the first few days of the rash [106,107]. Constitutional symptoms such as fatigue, anorexia, and lethargy also are reduced, and defervescence of

Diagnosis Typically, the clinical presentation is classic and sufficient to establish the diagnosis of chickenpox or herpes zoster. Virologic confirmation is necessary when the clinical presentation is atypical, drug resistance is suspected, or diagnosis of VZV infection from a purely clinical perspective is not possible. In an individual with a diffuse rash consistent with chickenpox, a history of recent VZV exposure, and no history of varicella or vaccination, the diagnosis of varicella can be made without further workup. The characteristic dermatomal, vesicular rash is, likewise,

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Fig. 3. Clinical manifestations of, differential diagnoses for, and methods for diagnosis of VZV infection. (Data from McCrary M, Severson J, Tyring SK. Varicella zoster virus. J Am Acad Dermatol 1999;41:1 14; Nikkels AF, Snoeck R, Rentiert B, et al. Chronic verrucous varicella zoster virus skin lesions: clinical, histological, molecular and therapeutic aspects. Clin Exp Dermatol 1999; 24:346 53; and Oranje AP, Folkers E. The Tzanck smear: old, but still of inestimable value. Pediatr Dermatol 1988; 5:127 9.)

fever generally occurs 1 day earlier with ACV treatment [106 108]. An increase in ACV resistance, as initially feared, has not occurred with short-term therapy for varicella. In uncomplicated cases of varicella in healthy children, ACV treatment has clinical and economic benefits [82,109]. Acyclovir, however, has not been shown definitively to decrease the rate of complications in this group [16,106,108]. Because of their higher risk of complications, oral ACV administered within 24 hours of rash onset is believed to be even more cost-effective and beneficial for newborns (younger than 2 weeks), preterm infants in the nursery, children (older than 13 years), and adults (including pregnant women) who develop uncomplicated varicella [82,108,109]. Oral ACV also is indicated for children with chronic skin diseases who are especially susceptible to skin superinfection and those with pulmonary disorders whose underlying disease may be exacerbated significantly [82]. Intravenous ACV is indicated in the treatment of varicella in the immunocompromised patient because it shortens the course of the cutaneous disease and

helps to prevent VZV dissemination [110 112]. Therapy should be initiated as early as possible but still may be of benefit in the immunocompromised patient when started as late as 3 days after the rash and before organ dissemination develops [110]. Several large clinical trials with herpes zoster have reported better efficacy, better oral bioavailability, and decreased dosing regimen with valacyclovir (a prodrug of ACV) and famciclovir (a prodrug of penciclovir) than ACV. Like ACV, both drugs inhibit viral DNA synthesis and replication by targeting viral DNA polymerase [113 115]. Although these prodrugs are used widely (at herpes zoster doses) to treat primary varicella in older teenagers and adults, controlled trials with valacyclovir or famciclovir for chickenpox are lacking. Table 1 summarizes treatment recommendations for varicella.

Herpes zoster and postherpetic neuralgia Antiviral agents should be administered as soon as the classic zoster eruption is noted, ideally within the

T.M. Chen et al. / Dermatol Clin 20 (2002) 267282 Table 1 Varicella and herpes zoster treatment recommendationsa Varicella Children (weighing less than 40 kg) Immunocompetent Acyclovir 20 mg/kg (maximum, 800 mg) po qid 5 daysb Immunocompromisedc Acyclovir 500 mg/m2/d iv q 8 hours 7 10 daysb Adults Immunocompetent Acyclovir 800 mg po 5 per day 7 daysb Valacyclovir 1000 mg po tid 5 7 days Famciclovir 500 mg po tid 5 7 days Immunocompromisedc Acyclovir 10 12 mg/kg iv q 8 hours 7 10 daysb Zoster Children Immunocompetent/immunocompromisedc Acyclovir 1500 mg/m2/d iv divided into three doses 5 10 daysb, or Acyclovir 10 mg/kg iv q 8 hours 5 10 daysb Adults Immunocompetent Acyclovir 800 mg po 5 per day 7 daysb Acyclovir 500 mg/m2 iv q 8 hours 5 7 daysb Valacyclovir 1000 mg po tid 7 daysb Famciclovir 500 mg po tid 7 daysb Immunocompromisedc Acyclovir 10 mg/kg/dose iv q 8 hours 7 10 days (including disseminated zoster) Foscarnet 40 mg/kg/ q 8 hours 14 days

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Treatment recommended for 5 to 10 days, or until no new lesions have appeared for 48 hours. Consider changing the dosage, choice of antiviral agent, or route of administration if there is no clinical response. b Approved by the FDA. c Immunocompromised/high-risk patients include those who are nonimmune, immunocompromised, neonates with history of maternal varicella (5 days before to 2 days after delivery), preterm infants (< 28 weeks gestation, < 1000 g; hospitalized, no maternal history of varicella, or titers negative for VZV), and immunosuppressive therapy (steroids > 1 mg/kg/d for >1 month; chemotherapy). Abbreviations: iv, intravenously; po, by mouth; q, every; qid, four times a day; tid, three times a day. Data from Arvin AM. Varicella-zoster virus. Clin Microbiol Rev 1996;9:361 81; and Cohen JI, Brunell PA, Straus SE, et al. Recent advances in varicella-zoster virus infection. Ann Intern Med 1999:130:922 32; and Trizna Z, Tyring SK. Antiviral treatment of diseases in pediatric dermatology. Dermatol Clin 1998;16(3):539 52

first 48 to 72 hours [116]. If, however, 3 days have passed since the onset of the rash, a select group of patients benefits from antiviral therapy [24]. This group includes patients older than 50, those in an immunosuppressed state, those with involvement of a trigeminal dermatome (V1-V3), or patients with lesions that have not crusted and are still evolving. Otherwise, treatment should be aimed at controlling pain and pruritus [117] and minimizing the risk of a secondary infection [118]. Acyclovir, valacyclovir, and famciclovir are the primary medications used in the treatment of zoster. For adults with herpes zoster, ACV and valacyclovir are equivalent at decreasing the time needed for

healing and crusting, but valacyclovir and famciclovir decrease the duration of postherpetic neuralgia [115]. One double-blind study showed that patients taking oral valacyclovir had accelerated resolution of herpes-associated pain by approximately 10 days when compared with patients taking acyclovir [113]. When compared with ACV, famciclovir provided quicker dissipation of pain when treatment was initiated within 48 hours of the appearance of the rash [114]. The list above summarizes treatment recommendations for herpes zoster. The use of steroids in conjunction with an antiviral agent for the treatment of herpes zoster remains controversial. Recent studies reported that the addi-

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tion of steroids to ACV treatment for herpes zoster did not decrease the incidence of postherpetic neuralgia and actually led to more side effects [119]. On the other hand, acyclovir plus prednisone may increase the quality of life during the acute zoster episode in healthy patients older than 50 [120]. A retrospective study of patients with Ramsay-Hunt syndrome who were given ACV and prednisone early in the illness found that the facial nerve paralysis resolved completely in a higher percentage of patients [121]; patients treated with ACV alone were not evaluated in this study. A meta-analysis of the literature regarding the treatment of postherpetic neuralgia found that both tricyclic antidepressants and anticonvulsants are helpful in decreasing the pain by approximately 50%. Gabapentin was not significantly more helpful than other anticonvulsants, and selective serotonin reuptake inhibitors did not offer a significant advantage compared with placebo [122]. Other treatments include topical capsaicin or lidocaine, regional nerve blocks, transcutaneous electrical stimulation, acupuncture, and gamma knife radiosurgery [24,123].

Prevention Varicella vaccine Currently, it is estimated that 4 million cases of chickenpox, 9900 serious complications, and 100 deaths occur annually, with an economic impact of $530 million a year; the vaccination program is projected to save $384 million annually in the first 30 years [126]. In the mid-1990s, VZV vaccination was first recommended for all susceptible individuals 12 months of age or older [127]. Widespread vaccination since the mid-1990s has resulted in drastic changes in the epidemiology and incidence of varicella. Current literature suggests that the vaccine is clearly on its way to preventing the projected estimates of more than 94% of primary varicella cases [126]. Early studies in children with leukemia and pre-organ transplant recipients also suggest that the incidence of herpes zoster is decreased markedly in vaccine recipients [128,129]. The vaccine provides active immunization by way of the live attenuated virus, known as the Oka strain. Vaccinees may develop viremia and should therefore avoid nonimmune and high-risk persons because of the theoretical risk of transmitting the live, attenuated vaccine strain virus [24]. Serology before vaccination is recommended in persons older than 12 years who have a questionable history of varicella because subclinical infection may have occurred; three fourths of patients who report a negative clinical history have VZV-specific antibodies [127]. Vaccine indications and contraindications are listed in Fig. 4. Side effects are minimal but include low-grade fever, mild discomfort at the injection site, and a limited maculopapular or varicelliform rash (approximately three to five lesions) at the injection site within a month of vaccination [24,130,131]. If a rash does occur, exposure to the wild-type VZV strain should be traced because the vaccine strain has rarely been recovered from the skin lesions [132]. Additionally, widespread vaccination has resulted in the emergence of a new variant of chickenpox that occurs in 20% of vaccinees exposed to wild-type strain of VZV [133 135]. Modified varicella-like syndrome, or breakthrough varicella, is typically mild, with few to no systemic complaints, complications, and skin lesions (approximately 30) that resolve rapidly. Vesicles rarely form [136]. Modified varicella-like syndrome is less infectious than classic varicella (transmission rate 12.2% versus 80% to 90%), with mild secondary cases [135,136]. Vaccination of infants and booster shots in older persons continue to be controversial. Currently, there

Treatment failure Antiviral therapy usually is recommended for 5 to 10 days (ie, primary varicella). If, however, cutaneous lesions continue to appear after 48 hours of initiating therapy, the patient may not be responding to the treatment. The dosage may need to be increased, the route of administration changed, or an alternative antiviral agent regimen selected. Suboptimal ACV blood concentrations in HIV-infected persons may be related to decreased gastrointestinal function and poor absorption [64,124]. Resistance to ACV is encountered most commonly in immunosuppressed patients on prolonged low-dose ACV prophylaxis [36]. Lyall et al [76] proposed that viral replication in the presence of low-dose ACV may encourage the emergence of ACV-resistant mutant strains. Resistance usually develops at the level of the viral thymidine kinase and should be confirmed with viral culture and sensitivity studies. Intravenous foscarnet, a pyrophosphate antagonist, is the drug of choice when ACV resistance has developed and should be continued until the lesions have healed completely. In the rare case of ACV and foscarnet resistance, treatment efficacy with cidofovir has been reported in several case reports and small series [125]. In view of current HIV and tuberculosis treatment strategies, multidrug regimens may be necessary to prevent the development of resistance.

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Fig. 4. Indications for varicella vaccination. * Varicella vaccine is contraindicated if any of the following conditions are present: history of varicella, congenital immunodeficiency, blood dyscrasia, leukemia (not in remission), lymphoma, other malignancy, high-dose steroids (> 2 mg/kg/d >1 month), pregnancy, exposure to varicella or zoster less than 21 days previously, allergy to neomycin, intercurrent illness, transfusion of IgG or other blood product (within < 5 months), and administration of salicylates (within < 6 weeks). **Measles, mumps, and rubella vaccine can be administered simultaneously if given with a different syringe and at a different injection site. ***Vaccination in older patients (with history of chickenpox) has not been FDA-approved. **** High-risk patients include those who are nonimmune immunocompromised, neonates with history of maternal varicella (5 days before to 2 days after delivery), preterm infants (< 28 weeks gestation, weight < 1000 g; hospitalized, no maternal history of varicella or titers negative for VZV), and those who are receiving immunosuppressive therapy (steroids > 1 mg/kg/d for > 1 month; chemotherapy). (Data from Arvin AM. Varicella-zoster virus. Clin Microbiol Rev 1996;9:361 81; and Cohen JI, Brunell PA, Straus SE, et al. Recent advances in varicella-zoster virus infection. Ann Intern Med 1999:130:922 32.)

are no recommendations or studies on infants who develop varicella during the first year of life. These infants may require vaccination because their VZVspecific immunity may not be protective: their immune system is immature, and maternal IgG antibodies are still present when they developed varicella. In older patients, booster shots may provide intermittent antigenic stimulation to maintain adequate levels of VZV-specific immunity to prevent herpes zoster; however, they have not been FDA-approved. It is well known that the immune senescence develops (immune dysregulation) with age [137], and the incidence of herpes zoster increases. Recent studies also suggest that continuous exposure to patients infected with VZV has been associated with a

decreased incidence of herpes zoster [138] and that VZV vaccination enhances VZV-specific, cell-mediated immunity in the elderly [139,140]. Postexposure prophylaxis In view of its highly contagious nature and the risk of associated complications with VZV infection, postexposure prophylaxis is recommended in select patients. Risk assessment and prophylaxis recommendations are based on the type of exposure, patient immune status, and time lapsed since exposure. The likelihood of VZV transmission is increased with indoor, face-to-face contact with an infected person. Individuals at high risk of VZV-

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Fig. 5. Varicella-zoster virus postexposure prophylaxis. * Varicella is considered more contagious than herpes zoster. ** See Fig. 4 for a list of persons at high risk for VZV infection complications. *** See Fig. 3 for a list of treatment recommendations. (Data from Arvin AM. Varicella-zoster virus. Clin Microbiol Rev 1996;9:361 81; and Cohen JI, Brunell PA, Straus SE, et al. Recent advances in varicella-zoster virus infection. Ann Intern Med 1999:130:922 32.)

associated morbidity include immunocompromised patients, neonates, preterm infants, and individuals receiving chronic steroid therapy or chemotherapy. Otherwise healthy individuals are considered to be at low risk [24]. High-risk individuals should receive passive immunization with VZV-specific immune globulin within 96 hours of exposure [127]. Studies have shown that 30% to 50% of patients who receive VZV-specific immune globulin develop a clinical infection; the infection, however, may be less severe with fewer complications than if the patient had not received VZV-specific immune globulin prophylaxis [71,141]. Low-risk patients should be vaccinated within 3 days of VZV exposure to provide for active immunization [142]. For patients who have missed the 96-hour window for VZV-specific immune globulin, high-dose ACV (40 80 mg/kg for 7 days, starting 7 9 days after the exposure) is recommended for otherwise healthy patients in whom vaccination is contraindicated [24]. Neither vaccination nor highdose ACV has been FDA-approved for VZV postexposure prophylaxis. Additional studies are recommended. Postexposure prophylaxis is summarized in Fig. 5.

classic clinical presentations. In immunocompromised patients, however, the atypical presentation can make the diagnosis more challenging. Although varicella typically follows an uncomplicated course in children, adults and immunocompromised patients can develop complications involving several organs; some complications may be fatal. Prevention of disease with the vaccine is ideal. When varicella or zoster infection does occur, proper treatment should be initiated, depending on the age and immune status of the patient.

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Summary Infections by VZV, the virus that causes chickenpox and herpes zoster, usually are diagnosed by the

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T.M. Chen et al. / Dermatol Clin 20 (2002) 267282 recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1996;45:1 37. Broyer M, Tete MJ, Guest G, et al. Varicella and zoster in children after kidney transplantation: longterm results of vaccination. Pediatrics 1997;99:35 9. Hardy I, Gershon AA, Steinberg SP, et al. The incidence of zoster after immunization with live attenuated varicella vaccine. N Engl J Med 1991;325:1545 50. Gershon AA, Steinberg SP, LaRussa P, et al. Immunization of healthy adults with live attenuated varicella vaccine. J Infect Dis 1988;158:132 7. White CJ, Kuter BJ, Hildebrand CS, et al. Varicella vaccine (VARIVAX) in healthy children and adolescents: results from clinical trials, 1987 to 1989. Pediatrics 1991;87:604 10. White CJ. Clinical trials of varicella vaccine in healthy children. Infect Dis Clin North Am 1996; 10:595 608. Krause PR, Klinman DM. Efficacy, immunogenicity, safety, and use of live attenuated chickenpox vaccine. J Pediatr 1995;127:518 25. Larussa P, Steinberg SP, Shapiro E. Viral strain identification in varicella vaccinees with disseminated rashes. Pediatr Infect Dis J 2000;19:1037 9. Lim YJ, Chew FT, Tan AY, et al. Risk factors for breakthrough varicella in healthy children. Arch Dis Child 1998;79:478 80. Watson BM, Piercy SA, Plotkin SA. Modified chickenpox in children immunized with the Oka/Merck varicella vaccine. Pediatrics 1993;91:17 22. Weksler ME. Immune senescence. Ann Neurol 1994; 35(Suppl):S35 7. Solomon BA, Kaporis AG, Glass AT, et al. Lasting immunity to varicella in doctors study (L.I.V.I.D. study). J Am Acad Dermatol 1998;38:763 5. Levine MJ, Ellison MC, Zerbe GO, et al. Comparison of a live attenuated and an inactivated varicella vaccine to boost the varicella-specific immune response in seropositive people 55 years of age and older. Vaccine 2000;18:2915 20. Raeder CK, Hayney MS. Immunology of varicella immunization in the elderly. Ann Pharmacother 2000;34:228 34. Takahashi M, Otsuka T, Okuno Y, et al. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet 1974;2:1288 90. Salzman MB, Garcia C. Postexposure varicella vaccination in siblings of children with active varicella. Pediatr Infect Dis J 1998;17:256 7.

[115] Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgiaa randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med 1995;123:89 96. [116] Wood JM, Shukla S, Fiddian AP, et al. Treatment of acute herpes zoster: effect on early (< 48 h) versus late (48 72 h) therapy with acyclovir and valaciclovir on prolonged pain. J Infect Dis 1998;178(Suppl 1): S81 4. [117] Kost RG, Straus SE. Postherpetic neuralgia: pathogenesis, treatment, and prevention. N Engl J Med 1996;335:32 42. [118] Carrasco DA, Vander Straten M, Tyring SK. Treatment of varicella-zoster virus and postherpetic neuralgia. Dermatologic Therapy 2000;13:258 68. [119] Wood MJ, Johnson RW, McKendrick MW, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 1994;330:896 900. [120] Whitley RJ, Weiss H, Gnann JW, et al. Acyclovir with and without prednisone for the treatment of herpes zoster: a randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann Intern Med 1996;125:376 83. [121] Murakami S, Hato N, Horiuchi J, et al. Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol 1997;41:353 7. [122] Collins SL, Moore A, McQuay HJ, et al. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 2000;20:449 58. [123] Urgosik D, Vymazal J, Vladyka V, et al. Treatment of postherpetic trigeminal neuralgia with the gamma knife. J Neurosurg 2000;93(Suppl 3):165 8. [124] Jacobson MA, Berger TG, Fikrig S, et al. Acyclovirresistant varicella zoster virus infection after chronic and acyclovir therapy in patients with acquired immunodeficiency virus (AIDS). Ann Int Med 1990; 112:187 91. [125] Snoeck R, Andrei G, Clercq ED. Novel agents for the therapy of varicella-zoster virus infections. Expert Opin Investig Drugs 2000;9:1743 51. [126] Lieu TA, Cochi SL, Black SB, et al. Cost-effectiveness of a routine varicella vaccination program for US children. JAMA 1994;271:375 81. [127] Centers for Disease Control. Prevention of varicella:

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Cutaneous manifestations of Epstein-Barr virus infection

Nneka I. Ikediobi, MDa,*, Stephen K. Tyring, MD, PhDb
b a Mayo Medical School, Rochester, MN 55905, USA Departments of Dermatology, Microbiology / Immunology and Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA

History of Epstein-Barr virus In 1964, Epstein et al [1] first identified EpsteinBarr virus (EBV) as a virus when cultured lymphoblasts from Burkitts lymphoma examined with electron microscopy were shown to contain immature and mature forms of virus particles similar in structure to the herpes simplex virus. In 1968, it was shown that EBV, a herpes virus, was probably the causative agent of infectious mononucleosis [2]. Further study performed in 1970, which involved the analysis of biopsy samples of Burkitts tumors and anaplastic carcinomas of the nasopharynx for the presence of EBV DNA, demonstrated evidence for the presence of EBV genomic material in these tumors [3]. Epstein-Barr virus is a member of the herpesvirus family. Its genome consists of a linear DNA molecule that encodes various proteins necessary for gene regulation, viral replication, and modulation of the host immune response [3,4].

Infectious mononucleosis Infectious mononucleosis (IM) is a self-limited viral illness caused by infection of B cells by EBV. Infection of B cells occurs either by direct contact with EBV present in oral secretions or indirectly by infected oropharyngeal epithelial cells with which the B cells

Manuscript prepared as fourth year medical student. * Corresponding author. Current address: 415 15th St. SW, Rochester, MN 55902, USA. E-mail address: ikediobi.nneka@mayo.edu (N.I. Ikediobi).

come into contact. Some studies indicate that the primary site of infection is oropharyngeal epithelial cells, which subsequently infect B cells [5,6]; however, other studies state that the primary site of infection is the B cell [7,8]. After infection, B cells undergo proliferation within lymphoid tissues, which stimulates a T-cell response consisting of activation and replication, resulting in the typical manifestations of IM. The symptomatic phase of IM lasts 2 to 4 weeks [9]. The main route of transmission of EBV is through saliva, because the virus is shed continually from the oropharynx for approximately 18 months after primary infection and is shed intermittently in 15% to 25% of healthy EBV-positive individuals [10]. The characteristic symptoms of IM, seen in greater than 50% of patients, include the triad of fever, pharyngitis, and lymphadenopathy. Accompanying symptoms of malaise, fatigue, shaking chills, and headache are also common. Other identified symptoms include hepatosplenomegaly, palatal petechiae, hemolytic anemia, aplastic anemia, thrombocytopenia, genital ulcers, hepatitis, splenic rupture, and neurologic problems [4]. Approximately 5% of patients with IM who are not receiving antibiotic therapy develop a cutaneous eruption. This eruption is nonspecific and not diagnostic of IM. This rash has been described as a macular, erythematous, scarlatiniform, urticarial, petechial, erythema multiforme-like or herpetiform eruption [10,11]. Laboratory findings include an absolute lymphocytosis with greater than 50% lymphocytes, which peaks during the second and third weeks of illness, and an absolute leukopenia count of less than 5000 leukocytes/mm3. Atypical lymphocytes compose approximately 10% or more of the white cell count and represent activated T cells responding to infected

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B cells. Other findings include neutropenia, thrombocytopenia, and elevated transaminases [4,9,10]. An erythematous, maculopapular eruption occurs in approximately 70% to 100% of patients with IM when antibiotics, specifically ampicillin, are administered during the acute stage of IM [12]. Ampicillin produces a rash in approximately 3% to 22% of normal, healthy individuals without EBV [13]. The increased incidence of the maculopapular rash that occurs in patients with IM treated with ampicillin suggests that there are specific factors associated with IM that result in this predisposition. Reactions with rash development of similar morphology have been observed with other antibiotics, including amoxicillin, methicillin, erythromycin, ampicillin derivatives, levofloxacin, acetaminophen, and cephalexin [14 19]. The mechanism underlying the development of this rash is unknown; however, various theories have been postulated to describe the pathogenesis of the reaction. The rash associated with antibiotic hypersensitivity in patients with IM is typically an erythematous, pruritic, maculopapular eruption predominantly involving the upper extremities and trunk. The palms, soles, and oral mucosa also have been reported to be occasionally involved. The rash usually is accompanied by fever and pruritus, and in severe cases, edema of the lips and eyelids, diarrhea, or arthralgias may occur. The reaction usually begins 7 to 10 days after initiation of antibiotic therapy [10,13,17]. The pathogenesis of the rash is believed to be secondary to polyclonal B-cell activation that occurs during EBV infection with production of polyclonal antibodies that form immune complexes capable of fixing complement [9]. The temporary appearance of circulating cryoprotein immune complexes consisting of IgG, IgM, IgA, C3, C4, C5, and EBV viral particles has been demonstrated. These factors were present only during the acute urticarial phase of IM and disappeared during recovery, suggesting that the previously mentioned factors may be key components in the development of the rash that occurs in IM [20]. The transient nature of hypersensitivity reactions to antibiotics was supported by a study showing that in two thirds of patients with IM who reacted to ampicillin during the acute stage of illness, there was noted disappearance of this reactivity after the acute phase of IM. In this study, a reaction greater than 3 mm in diameter with wheal formation to test doses of intracutaneous ampicillin was considered a positive response [21]. Only 2 of 20 patients with IM and an ampicillin rash showed a positive reaction to subsequent ampicillin skin tests. One of them had a prior penicillin

hypersensitivity, and the other patient had a history of atopy. This finding suggests that the rash that occurs is not permanent and is not a marker for future reactivity to penicillins, except in patients with a prior penicillin hypersensitivity or history of atopy [22]. Infectious mononucleosis also has been associated less commonly ( $5%) with the development of transient cold urticarias and in severe cases, anaphylaxis [23,24]. It has been demonstrated that certain cold-related factors, such as cryoglobulins, cryofibrinogens, and cold hemolysins may play a role in inducing complement activation with subsequent mast-cell degranulation and resultant urticarial formation. A review of the literature on the incidence of cold urticaria in patients with IM performed by Wu et al [25] did not show consistency in terms of the presence or absence of all the known cold-related factors. Overall, reports have failed to show a definite link between cold urticaria and the previously mentioned cold-related factors [25,26]. A 1998 report by Lande et al [27] describes the development of oral and nasal ulcerations, leukocytoclastic vasculitis, and an immune complex mediated glomerulonephritis in the setting of IM with diagnostic IgM viral capsid antigen antibodies indicative of acute EBV infection. Immunohistochemical staining of sections failed to show EBV-latent membrane proteins within the glomeruli, renal parenchymal cells, and skin. Despite this observation, it was speculated that the most likely pathogenetic mechanism to explain the previously mentioned clinical and histologic findings is based on stimulation of the immune system in response to other EBV antigens not detectable by the immunohistochemical stains used in this report. Erythema nodosum, which presents as multiple, painful, red nodules on the lower extremities, has been reported to occur in association with IM. It has been theorized that the mechanism of this phenomenon is immunologic and secondary to the activation of the cell-mediated and humoral arms of the immune system [28]. Exacerbation of pre-existing mild acne vulgaris has been reported as a response to clinically and serologically confirmed acute EBV infection. Inflammatory nodulocystic lesions were noted to involve the face, neck, chest, and back. A combination of isotretinoin, methylprednisolone, and antibiotic therapy resulted in resolution of the lesions. It was suggested that the EBV infection could have caused a depression of immune functioning, leading to an exacerbation of an already existing skin problem, namely, acne vulgaris [29]. Infectious mononucleosis has been linked to the development of genital ulcers after all other causes have been excluded. Portnoy et al [30] reported on a

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patient who developed bluish-black lesions on the labia minora that eventually developed into ulcers during a confirmed episode of IM. These lesions were reminiscent of small-vessel vasculitis lesions that previously had been reported to occur in association with IM. It was postulated that free EBV was produced and released by cells within the ulcerated lesions, causing cytolysis. Speculations about the mode of transmission in genital ulcerations include the introduction of virus into the genital area through orogenital contact, suggested by the recovery of EBV in culture samples from the genital ulcers, congregation of circulating EBV-infected B lymphocytes within the ulcers as an exudate, and immune complex deposition within lesions, with complement fixation and resultant ulceration [30 32]. Diagnosis and management The heterophile antibody test (Monospot) is used in conjunction with clinical and laboratory findings of IM to diagnose acute EBV infection. The tests of choice for determining acute versus past EBV infection in immunocompetent hosts and monitoring disease progression over time are the viral-specific antibody serologic tests. These tests detect IgM and IgG antibodies to viral capsid antigen, early antigen, and EBV nuclear antigens. In immunocompromised hosts, caution must be exercised in interpreting these serologic tests because the immunologic response is diminished in these individuals. In individuals with a depressed immune response, the detection of viral genomic material using polymerase chain reaction (PCR) or in situ hybridization (ISH) is a more reliable test for diagnosis [9,10,33]. The management of IM is mainly supportive and consists of symptomatic treatment approaches. Nonsteroidal anti-inflammatory agents and acetaminophen may be used to alleviate the fever and discomfort associated with pharyngitis associated with IM. Superimposed bacterial infection of the oropharynx with streptococcal sp. should be treated with penicillin or erythromycin for 10 days [9,10]. A meta-analysis of five randomized, controlled trials consisting of 339 patients with acute EBV infection was performed by Torre et al [34] to determine the benefit of antiviral therapy with acyclovir. It showed a small, nonsignificant reduction of symptoms and duration of illness but a significant reduction of oropharyngeal shedding of EBV. It was concluded that there was no indication for the use of acyclovir in the treatment of acute IM [34,35]. Corticosteroids (1 mg/kg/d prednisone 2 3 days with 2-week taper) are indicated for individuals with

acute IM and severe complications of airway obstruction secondary to hypertrophied lymphoid tissue of Walderyers ring, hemolytic anemia, thrombocytopenia, myocarditis, or pericarditis. Reports have demonstrated that corticosteroids are not indicated for uncomplicated IM, however, and may even predispose to development of complications [9,10,36 38].

Oral hairy leukoplakia Oral hairy leukoplakia (OHL) has emerged as an established disease entity secondary to the epidemic of HIV infection. Oral hairy leukoplakia first was recognized as a clinical entity among homosexual men in 1984 [39,40]. It serves as a marker for severity of disease and early progression to AIDS in HIVinfected patients. Numerous reports in the literature describe the occurrence of OHL in patients who are immunosuppressed for reasons other than that associated with HIV infection and AIDS [41 44]. Active replication of EBV and expression of lytic viral proteins occur within this lesion in affected individuals, unlike all other EBV-associated lesions, within which only EBV-latent proteins are detected [4,45]. Oral hairy leukoplakia lesions characteristically resemble whitish patches with a verrucous or filiform, irregular surface that cannot be scraped off. These asymptomatic, nonmalignant lesions are located primarily on the lateral surfaces of the tongue unilaterally or bilaterally and occasionally have been observed on the dorsal and ventral surfaces of the tongue, palatal mucosa, floor of the mouth, buccal mucosa, and oropharynx [45]. A burning sensation, which is most likely secondary to coinfection by Candida sp., may be associated with these lesions [46]. The lesions typically are associated with a waxing-and-waning course [41]. The histologic features that typify OHL include irregular epithelial hyperplasia with associated parakeratosis and acanthosis. Ballooning of keratinocytes occurs, and there are small, pyknotic nuclei with intranuclear inclusions and a clear perinuclear halo. The cytoplasm may adopt a ground-glass appearance [9,45]. There is also a mild inflammatory infiltrate observed within the subepidermal layers [45]. Langerhans cells are noted to be absent in the epithelium [47]. Hyphae of Candida sp. also have been observed within the superficial epithelium of approximately 43% to 100% of patients with OHL and may play a role in production of the epithelial hyperplasia observed in OHL [42]. A recent study by Webster-Cyriaque et al [48] delineated two main types of infection by EBV that

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have been observed in OHL lesions. The predominant state, which is characterized by viral replication and cytolysis, is known as the permissive type. The second state of infection, characterized by the production of proteins responsible for inducing cell growth, is called the latent transforming type. Latent transforming and lytic viral proteins were detected at the same time within the same cells in the middle upper stratum spinosum layer in this study. This finding suggests that the latent transforming proteins might be responsible for creating a suitable environment for continued cell survival and the viral replication that is manifest in the permissive state of infection. These observations explain the typical histologic manifestations of OHL, including acanthosis and epithelial hyperplasia, as already described. There are conflicting reports in the literature about the pathogenesis of OHL. Some reports support a mechanism based on superficial viral infection of cells in the spinous layer because viral replicative and latent proteins have been detected predominantly in the superficial epidermal layers by ISH and not in the basal layers. In addition, EBV-RNAs specific for latent infection have not been detected in OHL lesions [49 51]. Other reports support the viral reactivation mechanistic model because they have demonstrated the presence of viral lytic proteins in the basal epithelial cells of HIV-positive and healthy HIV-negative, EBV-positive individuals. These proteins were detected by PCR analysis but not by ISH, suggesting that the failure of previous studies to detect the presence of these proteins in the basal epidermal layers might be secondary to the low sensitivity of ISH compared with PCR [52,53]. The concept of a primary EBV infection also being associated or causative of OHL was supported by a 1999 case report describing the occurrence of OHL in an HIV-negative individual with clinical and laboratory findings suggestive of an acute EBV infection [32]. Epstein-Barr virus DNA has been demonstrated within OHL lesions, further confirming the intimate relationship between OHL and EBV [4,45]. Oral hairy leukoplakia lesions also usually contain more than one EBV strain or type [4]. The differential diagnoses of white lesions in the oral mucosa include hyperplastic candidiasis, lichen planus, idiopathic leukoplakia, traumatic keratosis, white sponge nevus, and oral graft-versus-host disease [41,43,45]. Diagnosis and management The clinical significance of OHL lies in its association with immunosuppression, secondary to any

cause, and so its appearance should prompt the clinician to initiate a thorough history-taking and search for causes of immunosuppression. The diagnosis of OHL is accomplished through clinical and histologic means. The clinical diagnosis is made by observance of the gross appearance of the typical lesions as described in the preceding paragraphs. The histologic diagnosis is made by visualizing specimen sections under light microscopy and identifying the typical characteristics, including hyperplasia, parakeratosis, acanthosis, and mild to absent inflammatory cell infiltrates [45]. The molecular gold standard for confirmation is the detection of EBV-encoded RNA transcripts by in situ hybridization of biopsy specimens [33]. Electron microscopy, revealing the presence of herpes-like particles, also provides definitive diagnosis of EBV-related OHL [45]. Studies to determine the reliability of EBV-DNA PCR, which is a less invasive, simple, and quick test for diagnosing OHL, have shown that it has certain limitations, including a low specificity. It has been suggested that although it is a more attractive test, it should be used only as a guide and should not be viewed as conclusive for the diagnosis of OHL [54]. Other less invasive technologies, such as exfoliative cytology and electron microscopy, have not been shown to accurately differentiate between OHL and other lesions [55]. Treatment of OHL has included topical or systemic antifungals, topical retinoids, acyclovir, azidothymidine, and podophyllin; however, lesions still can recur after therapy is discontinued. Surgical excision and cryotherapy are also means of removal of lesions, but more lesions still can appear on other areas of the tongue [56 60].

Cutaneous lymphomas Lymphoproliferative disorders associated with EBV are well documented in the literature. Individuals who are most susceptible to EBV-associated lymphoproliferative disorders have either a congenital or acquired immune deficiency, including severe combined immunodeficiency disorder, solid or bone marrow transplantation, and AIDS [4]. Cutaneous lymphomas also have been associated with EBV. Su et al [61] identified three main subtypes of cutaneous T-cell lymphomas (CTCLs) within which EBV genomic material was detected. The subtypes emerged on the basis of clinical and histologic features and included angiocentric T-cell lymphoma/lymphomatoid granulomatosis with common presentations of chronic ulcerations and reddish-purple papules,

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T large cell lymphoma (with three of four cases presenting with an aggressive course), and secondary CTCL involving the skin, with a dismal prognosis. The course of T large cell lymphoma was characterized by constitutional symptoms of fever, hepatosplenomegaly, jaundice, pancytopenia, and coagulopathy. Numerous studies in the literature that involved the use of molecular techniques describe the detection of EBV genomic material within lesional tissues of patients with primary cutaneous angiocentric T-cell lymphoma, mycosis fungoides, Sezary syndrome (epidermotrophic CTCL), and pleomorphic T-cell lymphoma (PMTCL) [62 66]. A study performed by Peris et al [67] in 1994, however, came to the conclusion that EBV did not play a significant role in the development of cutaneous lymphoproliferative disorders. Analysis of skin specimens from 24 patients with primary cutaneous lymphoproliferative disorders and 22 control patients for the presence or absence of EBV genomic material was performed using PCR and ISH techniques. Results revealed that only one of two cases of mycosis fungoides (MF), one of seven cases of PMTCL, one of six cases of cutaneous B cell lymphoma (CBCL), three of eight cases of pseudolymphoma, and 2 of 22 control cases demonstrated the presence of EBV DNA by PCR. The clinical manifestations of these lymphoproliferative disorders included multiple nodules, violaceous papules, and chronic necrotic skin lesions and masses [61,68]. Common histologic findings for cutaneous angiocentric T-cell lymphomas are dermal blood vessel infiltration and destruction by atypical lymphocytes of a clonal population [63,68]. There have been reports on the occurrence of a lesion called recurrent necrotic papulovesicles of the face, with postulations not only of its association with EBV but also that it might represent a new subtype of peripheral T-cell lymphoma with a predilection for the skin. Latent EBV infection of lymphoid cells in lesional tissue confirmed by ISH and the progression of these lesions to T-cell lymphoma in most patients who were studied support these postulations [69,70]. In 1993, McGregor et al [71] reported on four cases of post-renal transplant cutaneous lymphoma, three of which were EBV-associated primary CBCLs and one of which was CTCL without evidence of EBV infection. Clinical presentations included single or multiple ulcerated nodules and hemorrhagic plaques. The presence of EBV was detected using EBV PCR and in situ hybridization techniques. This report lends support to the association between EBV and the development of post-transplant cutaneous lymphoma.

Summary The most common cutaneous manifestations of EBV include IM, OHL, and cutaneous lymphoproliferative disorders. Infectious mononucleosis is a self-limited manifestation of acute EBV infection. The transient rash that occurs quite commonly in patients with IM who have received antibiotic therapy is an erythematous, maculopapular eruption, usually located on the trunk and upper extremities. Oral hairy leukoplakia occurs in immunosuppressed HIV-positive and HIV-negative individuals. In HIVpositive individuals, it serves as an indicator of disease severity and rapid progression to AIDS. The presence of OHL in an individual should prompt the clinician to perform a through history-taking and investigation of immune status. Cutaneous lymphoproliferative disorders associated with EBV occur in individuals with congenital or acquired immunodeficiency syndromes.

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Cytomegalovirus infections
Mohamad Khoshnevis, MDa, Stephen K. Tyring, MD, PhDb,*
a

Department of Internal Medicine, Baylor College of Medicine, Houston, TX 79030, USA b University of Texas Medical Branch, Route 1070, Galveston, TX 77555, USA

Human cytomegalovirus (HCMV) is a highly species-specific DNA virus that belongs to the Betaherpesvirinae subfamily of the Herpesviridae family [1]. Like other DNA viruses in this familyherpes simplex, varicella-zoster, Epstein-Barr virus, and human herpesviruses 6, 7, and 8HCMV can cause irreversible destruction of the infected cells in the productive cycle [2]. Interestingly, these viruses are capable of remaining latent in the host after initial infection and cause overt disease in different situations of waning immunity. Infection with HCMV is common. In most developed countries, HCMV seroprevalence steadily increases after infancy, and 10% to 20% of children are infected before puberty [1]. In adults, the prevalence of antibodies ranges from 40% to 100% [1]. Today it is known that approximately 70% to 100% of the population worldwide are carriers of the virus [3]. Epidemiologically, humans are the only reservoir of HCMV, and transmission occurs by person-toperson contact [1]. Despite its worldwide distribution, infection with HCMV is more common in the developing countries and in areas of low socioeconomic conditions [1]. Human cytomegalovirus infection primarily occurs in childhood and remains the leading cause of congenital viral infections in humans, with an incidence of 0.2% to 2.2% of live births [4]. On the other hand, whereas 50% to 90% of bone marrow and organ transplant patients experience HCMV infections in the post-transplantation period, the prevalence of HCMV approaches 100% in most HIV-infected groups of patients [4]. In this article, the authors focus mainly on the effect

of HCMV infection on immunocompetent and immunocompromised adults.

Structure of the virion The virion of cytomegalovirus has the hallmark structural feature characteristics of the herpesvirus family [5,6]. Its comparatively large DNA genome (230 Kb) [7,8] is located in the central core of the particle. Its capsid is estimated to be 116 nm in diameter; it is composed of 162 capsomeres and is icosahedral in shape [9]. The capsomeres are approximately 15 nm in diameter, 20 nm long, and have a central channel approximately 3 nm in diameter [9]. There is evidence of pinwheel-like projections radiating out symmetrically from the capsomeres [9]. These projections are believed to interlink the capsomeres. The nucleocapsid is embedded in a layer called the tegument that fills the space between the nucleocapsid and the trilaminate envelope. The large genome of HCMV encodes more than 65 unique glycoproteins [10]. Interestingly, although several of the envelope glycoproteins elicit strong host immune responses (including the production of virus-neutralizing antibodies), others may contribute to evasion of host cellular immune responses by limiting viral antigen presentation [10]. Glycoprotein 65 is one of the abundant virion envelope glycoproteins, with an estimated molecular weight of 65 kD that was detected initially with murine monoclonal antibodies [11]. Antibodies reactive to this protein were shown to have potent virus-neutralizing activity in the presence of complement and to react strongly with the surface of infected cells [11]. Human antibody responses to glycoprotein 65 have not been studied [10]. P65 antigenemia is one of the methods of detecting HCMV.

* Corresponding author. E-mail address: styring@utmb.edu (S.K. Tyring).

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 0 7 - 9

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Virus binding and entry Infection of cells with HCMV is a finely tuned process in which the virus subverts the host cell machinery at multiple levels, beginning with the initial contact of the virus and culminating in its evasion of immune surveillance. The initial interaction of the cytomegalovirus with the host cell is adsorption and is mediated through interactions among several viral glycoprotein complexes, cellsurface proteoglycans, and at least two to three different cellular receptors [12]. After adsorption, penetration happens. Penetration includes the fusion of the viral envelope with the cell membrane and, unlike adsorption, which can happen at 4C, fusion occurs only at 37C [13]. Subsequently, a cascade of physiologic responses takes place within minutes of binding, leading to hydrolysis of phosphatidylinositol(4,5)-biphosphate and stimulation of arachidonic acid metabolism. Arachidonic acid then is converted into prostaglandin H2 in a reaction that includes byproducts such as reactive oxygen intermediates. These intermediates are believed to activate transcription factor nuclear factor kB. Speir et al. [14] initially reported that infection of smooth muscle cells with HCMV resulted in an increase in reactive oxygen intermediates as early as 30 minutes after infection and an increase in sequence-specific DNA binding by nuclear factor kB. On the other hand, G-protein coupled receptors also activate phospholipase C, leading to production of the second messengers, inositol triphosphate and diacylglycerol, which in turn go on to activate calcium release from the endoplasmic reticulum and protein kinase C, respectively; hence, viral protein synthesis and replication begin [15]. It has been shown that infection of primary fibroblasts with HCMV inhibits cell cycle progression and alters the expression of several key regulatory proteins, including cyclins A, B, D, and E and the tumor-suppressor proteins P53 and retinoblastoma [16 19]. Infection with HCMV leads to specific alterations in the factors that regulate progression in cell cycle. Unlike the herpes simplex virus, the growth cycle of HCMV is relatively slow; although viral DNA synthesis begins in the nucleus at 16 to 24 hours after infection, no virus is released until 72 to 96 hours have passed [20]. The initial site of infection and how the virus enters the bloodstream are unknown [21]. After infection, cytomegalovirus spreads by way of the bloodstream to various organs, including the kidneys, liver, spleen, brain, retina, esophagus, inner ear, lungs, and colon as well as salivary glands [22]. During viremia, HCMV DNA is detectable in monocytes, lymphocytes, and neutro-

phils [23]. Although polymorphonuclear (PMN) cells are positive for viral DNA more frequently than mononuclear cells [24 27], it is likely that this positivity represents phagocytosis of intact virions rather than viral replication within the cells [21]. Although the virus does not replicate within them, these leukocytes play an important role in dissemination of virus throughout the body [21]. As for polymorphonuclear cells, infection of monocytes is abortive [28 30], but a productive infection ensues when they are stimulated to differentiate into macrophages [31 34]. The infection of such monocytederived macrophages is nonlytic and cell-associated [21]. Large amounts of intracellular virus are produced, but no detectable extracellular virus is released. The virus disrupts microtubules and fails to enter the endosomal-lysosomal pathway [35], so the virus accumulates in large cytoplasmic vacuoles that fail to fuse with the plasma membrane. This immune evasion mechanism does not, however, prevent virus from spreading, because these monocytes/macrophages are able to infect endothelial and fibroblast cells. In turn, this endothelial cell infection can infect more phagocytes [36]. Indeed, endothelial cells acutely infected with cytomegalovirus enlarge and detach from the vessel wall to enter the bloodstream and disseminate virus [37,38]. Although most infected cells lyse, a surviving population becomes trapped in the capillary beds, initiating organ infection [21].

Natural history The natural history of HCMV infection can be divided into the primary infection, latent infection, and reinfection [2]. In the primary infection, the host contracts the virus prenatally by either transplacental transmission [39] or intrauterine transfusion [40]. Perinatally, infected cervical secretions are often the culprit, whereas postnatally infected urine, saliva, or breast milk and blood transfusion and organ transplantation are the major sources of virus [39,41 43]. Saliva is believed to be particularly important, because the virus has a tropism for the salivary gland and is shed persistently in saliva [44]. In immunocompetent adults, HCMV infection, when clinically present, mostly presents as a mononucleosis-like syndrome [45] consisting of a febrile pharyngotonsillitis with lymphadenopathy and, at times, arthralgias [46]. Although a fatal fulminant hepatitis has been reported by Rustgi et al. [47], the most common scenario is a mild increase in transaminases. Other investigators have reported meningitis, encephalitis, syndrome, myocarditis, pericarditis, Guillain-Barre

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pneumonia, retinitis, and hematologic abnormalities [45,48]. Owing to its ability to remain latent in peripheral leukocytes, HCMV can be transmitted through transfusion [2]. Although HCMV rarely causes any symptoms in immunocompetent subjects, immunocompromised patients, particularly patients with AIDS and recipients of organ transplants, are considered at high risk, with the likelihood of developing cytomegalovirus disease dictated mainly by the degree of immune suppression [49]. These patients often develop viremia with bouts of fever and variable liver, lung, gastrointestinal, or retinal involvement [2]. Interestingly, the major disease manifestations of HCMV infection are retinitis in HIV-infected patients and pneumonitis in patients who have undergone bone marrow and solid-organ transplantation [49]. In AIDS, HCMV infection predominantly occurs in patients with CD4 counts of less than 50. In these patients, the most common and debilitating manifestation of HCMV disease is retinitis, occurring in up to 30% of patients with CD4 counts of less than 100 and accounting for approximately 80% to 90% of HCMV end-organ disease in patients with HIV.

Cutaneous manifestations of human cytomegalovirus In 1989, Lee [50] stated that cutaneous eruptions develop in 10% to 25% of patients with HCMV infections and that pathologically proven cytomegalovirus skin infections are rare. This number is likely to have changed, however, after the institution of efficient highly active antiretroviral therapy (HAART) therapy in patients with AIDS and effective prophylaxis in organ transplant recipients. Pariser [51] described two clinical patterns of specific cutaneous involvement in disseminated cytomegalovirus infection. One type consisted of relatively localized, ulcerative lesions and the other of a more widespread, exanthematous eruption of macules and papules that may become pruritic. The histopathologic finding common to all cases of localized cytomegalovirus ulcers was described as a cytomegalic vasculitis of small blood vessels in the dermis. The affected endothelial cells were described as large and atypical. Some cells showed the nuclear change considered diagnostic of cytomegalovirus infection, namely a large homogeneous intranuclear inclusion surrounded by a clear halo, which is in turn surrounded by a rim of nuclear material [52]. Drago et al. [2] classified the dermatologic manifestations of HCMV as specific or nonspecific. Nonspecific lesions are mostly second-

ary to postinfection immune derangements or hypersensitivity reactions arising from medical therapy (such as ampicillin) [40,53] and include generalized maculopapular rashes and urticarial and scarlatiniform eruptions. The petechiae, purpura, and jaundice that are seen in neonates with cytomegalovirus inclusion disease also are included. Specific lesions, on the other hand, are dependent on the immune status of the patient. Cutaneous lesions reported in the immunocompromised patient vary from localized genital ulcerations to cutaneous ulceration of the chest [50], verrucous plaques of the heel [54], and crusted papules of the face [55]. It is worth mentioning that cytomegalovirus has been reported in the biopsy samples from immunocompromised patients with erythematous and purpuric morbilliform rash [50], scattered verrucous lesions [54], and perifollicular papulopustules [55]. A generalized urticaria during disseminated cytomegalovirus infection and a vesiculobullous eruption with histologic evidence of intraepidermal multinucleate giant cells consistent with the cytopathic damage usually produced by herpes group viruses also have been reported [51,56]. Unlike immunocompromised patients, patients with intact immune systems rarely have cutaneous cytomegalovirus presentations [2]. Weigand et al. [46] reported erythematous, edematous, purpuric papules and plaques over a livedo pattern on the lower extremities of a 7-year-old girl. Other investigators have attributed a purpuric rash with bullae on the legs of an adult woman to cytomegalovirus [57]. A case of an acute papular purpuric dermatosis in the characteristic gloves-and-socks distribution also has been reported [58]. Interestingly, cytomegalovirus has been found in the ulcerated nodules of two patients with systemic lupus erythematosus and in skin lesions of patients with vitiligo [59 61].

Detection methods Although antiviral prophylaxis has led to a reduction in mortality and morbidity caused by HCMV disease in recent years, the toxicity associated with the antiviral agents remains a significant problem [62]. This toxicity has prompted efforts aimed at the development of highly sensitive and quantitative detection methods to identify high-risk patients before the onset of the disease. This strategy has been termed pre-emptive or early therapy [63 65]. Owing to the high sensitivity of these methods, cytomegalovirus is detectable in a substantial number of patients with asymptomatic infection who never progress to disease [14,66], although patients with

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disease often have a higher viral load than those who remain asymptomatic [67 69]. Studies with allogenic marrow transplant recipients showed that viremia is highly predictive of the development of cytomegalovirus disease. The same is true for solidorgan transplant patients; however, viremia in this group of patients is somewhat less predictive of disease [70 73]. There are several techniques for detecting cytomegalovirus, and often, concordant results of several methods are needed to establish a pathogenic relationship [2]. These techniques are based on either direct detection of the virus or indirect evaluation of the specific immune response [2].

have been largely replaced by direct antigen or detection methods [62]. PP65 antigenemia assay This assay consists of direct staining of PMNs with monoclonal antibodies directed against the lower matrix protein PP65 [76 78]. PP65 is present in the cytomegalovirus virion and is detectable in infected peripheral mononuclear cells. The results are expressed as the number of antigen-positive cells relative to the number of the cells used to prepare the slide [62]. This assay is a sensitive method of estimating the systemic cytomegalovirus load. Its advantages include a short processing time (less than 6 hours) and the lack of requirement of a highly specialized laboratory. It is a good choice for laboratories with low-to-medium volume testing; however, it needs to be processed immediately, and the results are subject to personal skills in slide interpretation [62]. A longitudinal study performed with patients who had received a kidney transplant found that high initial levels of antigenemia correlated with higher positive predictive values for disease. This study suggested that patients with antigenemia of greater than 10 positive cells per slide are at high risk for the development of cytomegalovirus-related symptoms, so these patients might benefit from antiviral treatment [79]. In situ hybridization The DNA hybridization technology is based on the detection of particular nucleic acid sequences in biologic material and can be performed even on formalin-fixed or paraffin-embedded tissues. A labeled, single strand of DNA with sequences complementary to the target nucleic acid (DNA probe) is used to seek and hybridize the viral genome in the test specimen. This method specifically localizes the viral genomes in a particular cell type [80]. Polymerase chain reaction In the past decade, polymerase chain reaction (PCR) technology has become an invaluable diagnostic tool in virology because of its ability to detect minute amounts of viral nucleic acids in clinical specimens. Major progress has been made in developing quantitative assays for cytomegalovirus DNA. Quantitative PCR accurately and reproducibly can determine the systemic and site-specific cytomegalovirus load [62]. Cytomegalovirus quantification can

Viral culture Cytomegalovirus grows only in human fibroblast cell cultures [2]. Samples may be collected from saliva, blood, urine, feces, semen, cervical secretions, and bronchoalveolar lavage fluid, and tissue biopsies may be obtained from target organs such as skin, lung, liver, and kidney. Owing to the slow-growing characteristics of cytomegalovirus, cultures should be observed at least twice weekly to detect any focal cytopathic effect [2]. Culture of HCMV from oral lesions is considered to be not specific because the virus can be extracted from other sites of the upper gastrointestinal tract [74]. Cytomegalovirus also is commonly excreted in the saliva and urine of allograft recipients, and urine detection of cytomegalovirus might be a mere coincidence [2]. Using Kaplan-Meier analysis, Emery [75] showed that elevated baseline HCMV loads in blood also were significantly associated with a shorter time to death. The time to reach 40% mortality was 224 days in patients with greater than 10,000 genomes/mL, compared with 642 days for patients with undetectable viral loads at baseline [75]. Interestingly, there was no relationship between baseline urine load and survival [75]. Detection of cytomegalovirus in peripheral blood mononuclear cells does not indicate that the virus has caused the disease [2]. The detection of free virus in plasma is more important, because viremia is more specific and indicative of a poor prognosis [2], and recent prospective studies have shown that the detection of cytomegalovirus in blood is predictive of the development of cytomegalovirus disease [67,72]. On the other hand, although culture-based assays can provide an estimate of cytomegalovirus quantity, the practical significance of these assays has been limited by the relatively low sensitivity, the time-consuming nature of the methods, and the rapid loss of viability in stored specimens [62]. Therefore, these methods

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be performed in different fractions of the blood (i.e., plasma and cells) and organ fluids, including cerebrospinal fluid, urine, throat wash, and semen. Polymerase chain reaction does not provide information about the specific cellular localization of the virus [80], nor does it permit firm conclusions about the etiopathogenic role of the detected virus, because it might be an innocent bystander [2]. Polymerase chain reaction cannot distinguish between latent and productive infection or latently infected cells and active replication [2]. Other methods Other diagnostic methods include light microscopy, electron microscopy, and serologic methods. Histologic examination under light microscopy, in which hematoxylin and eosin stained sections may show enlarged, irregularly shaped endothelial cells containing intracytoplasmic and intranuclear inclusions, is the most available method for diagnosing cytomegalovirus infection [51]. Obviously, this method, although specific, is less sensitive than cultures [2]. By using ELISA or complement fixation, cytomegalovirus antibody titers can be measured. Although IgG antibodies against cytomegalovirus indicate a past infection [2], rising titers of IgG often indicate acute infection. In acutely ill patients, detection of IgM antibody is highly indicative of primary or recurrent cytomegalovirus infection [2]. Although cytomegalovirus DNA is detectable in cell-free plasma or serum by PCR [66,68,81 83], isolation of cytomegalovirus from plasma in cell culture is extremely infrequent [62]. Currently, the use of leukocytes seems to be more appropriate in situations in which the viral DNA load is low (such as during antiviral therapy) [68] or when pre-emptive therapy is envisaged in a setting where there is rapid progression from first detection to cytomegalovirus disease, such as after allogenic marrow transplantation [66,84].

Treatment There are four different therapeutic strategies for the management of HCMV disease, including treatment of the manifest disease, prophylaxis, suppressive therapy, and pre-emptive therapy. In prophylaxis, treatment is started in the absence of detectable virus or disease and is aimed at prevention of cytomegalovirus infection or reactivation in high-risk patients. In suppressive and pre-emptive strategies, treatment is

started in the absence of manifest disease but in the presence of detectable virus. Suppressive therapy is started when the virus is detectable in peripheral sites, such as urine, whereas pre-emptive treatment is based on the detection of virus systemically, such as in blood [1]. The strategy of choice depends on the balance between the risk of cytomegalovirus disease and the toxicity of the drug. For example, in view of the relatively low predictive value of peripheral virus detection for cytomegalovirus disease, acceptable toxicity should be low in the case of suppressive treatment, whereas higher degrees of toxicity may be acceptable in the case of pre-emptive treatment [1]. Ganciclovir, foscarnet, and cidofovir are among the most well-known cytomegalovirus DNA polymerase inhibitors. Despite inhibition of cytomegalovirus replication, these drugs exhibit toxicity and require intravenous administration to obtain therapeutic drug levels, both of which limit their use for long-term treatment. The first antiviral drug approved for the treatment of cytomegalovirus disease was ganciclovir [43], followed by foscarnet. Ganciclovir triphosphate inhibits cytomegalovirus DNA polymerase and can be incorporated into cytomegalovirus DNA, eventually terminating elongation. In cytomegalovirus-infected cells, ganciclovir is phosphorylated by a viral kinase encoded by the UL 97 gene. Ganciclovir is virustatic, and on discontinuation of treatment, viral spread and progression of the disease characteristically recur [85]. In uncontrolled trials, treatment with ganciclovir resulted in the improvement or stabilization of cytomegalovirus retinitis in 80% to 90% of patients [86]. The oral form of ganciclovir has a low bioavailability [87] and is used mainly for prevention purposes and maintenance treatment of cytomegalovirus retinitis in HIV-infected patients [88]; its oral prodrug, valganciclovir, however, has a much higher bioavailability of the metabolite, ganciclovir. Ganciclovir is concentrated 10 times more in infected cells compared with uninfected ones. Bone marrow toxicity, particularly neutropenia, has significantly limited the use of ganciclovir in many patients. This bone marrow toxicity is increased with other marrow suppressants, particularly zidovudine [89]. Although inhibiting DNA polymerase and preventing chain elongation by blocking nucleoside binding sites, foscarnet does not require phosphorylation for activation [85] and is effective against ganciclovir-resistant cytomegalovirus isolates. Nephrotoxicity is a well-known side effect of foscarnet, and approximately 50% of patients experience a two- to threefold increase in serum creatinine that is usually reversible in patients with no history of renal impair-

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M. Khoshnevis, S.K. Tyring / Dermatol Clin 20 (2002) 291299 Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott-Raven; 1996. p. 2493 2523. Kanich RE, Craighead JE. Human cytomegalovirus infection of cultured fibroblasts, II: viral replicative sequence of a wild and an adapted strain. Lab Invest 1972;27:273 82. Roizman B. Herpes simplex viruses and their replication. In: Fields BN, Knipe DM, Howley PM, editors. Fields virology, vol. 2. Philadelphia: Lippincott-Raven; 1996. p. 2231 95. Cha T, Tom E, Kemble GW, Duke GM, Mocarski ES, Spaete R. Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol 1996;70:78 83. Chee MS, Bankier AT, Beck S, Bohni R, Brown CM, Cerny R, et al. Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr Top Microbiol Immunol 1990;154:125 69. Irmiere A, Gibson W. Isolation and characterization of a noninfectious virion-like particle released from cells infected with human strains of cytomegalovirus. Virology 1983;130:118 33. Britt WJ, Mach M. Human cytomegalovirus glycoproteins. Intervirology 1996;39:401 12. Britt WJ, Auger D. Identification of a 65000 dalton virion envelope of human cytomegalovirus. Virus Res 1985;4:31 6. Fortunato EA, Spector DH. Regulation of human cytomegalovirus gene expression. Adv Virus Res 1999; 54:61 128. Topilko A, Michelson S. Hyperimmediate entry of human cytomegalovirus virions and dense bodies into human fibroblasts. Res Virol 1994;145:75 82. Speir E, et al. Role of reactive oxygen intermediates in cytomegalovirus gene expression and in the response of human smooth muscle cells to viral infection. Circ Res 1996;79:1143 52. Fortunato EA, McElroy AK, Sanchez V, Spector D. Exploitation of cellular signaling and regulatory pathways by human cytomegalovirus. Trends Microbiol 2000;8:111 19. Bresnahan WA, et al. Human cytomegalovirus inhibits cellular DNA synthesis and arrests productively infected cells in late G1. Virology 1996;224:150 60. Dittmer D, Mocarski ES. Human cytomegalovirus infection inhibits G1/S transition. J Virol 1997;71: 1629 34. Jault FM, et al. Cytomegalovirus infection induces high levels of cyclins, phosphorylated Rb and p53, leading to cell cycle arrest. J Virol 1995;69:6697 704. Lu M, Shenk T. Human cytomegalovirus infection inhibits cell cycle progression at multiple points, including the transition from G-1 to S. Virol 1996;70:8850 7. Mocarski ES. Cytomegalovirus and their replication. In: Fields BN, Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott-Raven; 1996. p. 2447 92. Sweet C. The pathogenecity of cytomegalovirus. FEMS Microbiol Rev 1999;23:457 82.

ment [90]. Although electrolyte imbalances (especially calcium) [91], elevated transaminases, nausea, vomiting, nephrogenic diabetes insipidus, and pancytopenia have been reported as side effects of foscarnet, skin involvement can occur. Ulcers and erosions in the esophagus, penis, and vulva have been cited to be the most common cutaneous reactions with foscarnet therapy [92]. A case of toxic epidermal necrolysis also has been reported as a side effect of treatment with foscarnet [92]. Cidofovir is a nucleotide analogue with broad in vitro antiviral activity against adenoviruses and cytomegalovirus [93]. Its pharmacokinetic profile allows a once-a-week dosing regimen. Studies have shown its efficacy against cytomegalovirus retinitis in HIVinfected patients. It can cause nephrotoxicity, in particular, tubular toxicity. Prehydration and concomitant use of probenecid can reduce the risk of nephrotoxicity [93]. Other side effects include bone marrow suppression and ophthalmic effects that include uveitis, iritis, and ocular hypotonia [93]. Increased serum creatinine and diabetes mellitus have been reported as risk factors for developing ophthalmic side effects, whereas the use of probenecid seems to be protective [93]. Fomivirsen is the first in a new class of antiviral agents. It is an antisense drug that is given intravitrally to treat cytomegalovirus retinitis. Ideally, for prophylactic purposes, oral agents with minimal toxicity clearly are desirable. Acyclovir, although not sufficient for treatment of manifest disease, has been shown to confer some benefit in select patient groups in high doses [64]; however, the valine ester of acyclovir-valacyclovir may improve the prophylactic or pre-emptive efficacy of acyclovir. Currently, there are several new antiviral agents in clinical development. There is still more room for novel drugs with improved efficacy and less toxicity that may change future treatment strategies.

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Schmidt GM, Horak DA, Niland JC, Duncan SR, Forman SJ, Zaia JA. A randomized controlled trial of prophylactic gancyclovir for cytomegalovirus pulmonary infection in recipients of allogenic bone marrow transplants. The City of Hope-Stanford-Syntex CMV study group. N Engl J Med 1990;324:1005 1111. Boeckh M, Hawkins G, Myerson D, Zaia J, Bowden RA. Plasma PCR for cytomegalovirus DNA after allogenic marrow transplantation: comparison with PCR using peripheral blood leucocytes, pp65 antigenemia and viral culture. Transplantation 1997;64:108 13. Bowen EF, Sabin CA, Wilson P, Griffiths PD, Davey CC, Johnson MA, et al. Cytomegalovirus (CMV) viremia detected by polymerase chain reaction identifies a group of HIV-positive patients at high risk of CMV disease. AIDS 1997;11:889 93. Gerna G, Furione M, Baldanti F, Sarasini A. Comparative quantitation of human cytomegalovirus DNA in blood leucocytes and plasma of transplant and AIDS patients. J Clin Microbiol 1994;32:2709 17. 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Dermatol Clin 20 (2002) 301 306

Human herpesviruses 6 and 7

Tami De Araujo, MDa, Brian Berman, MD, PhDb,*, Andrew Weinstein, MD, MPH a
a b

Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, FL 33136, USA Departments of Dermatology and Cutaneous Surgery, and Internal Medicine, University of Miami School of Medicine, 1600 NW 10th Avenue, Room 2023-A, Miami, FL 33136, USA

Human herpesvirus 6 First isolated in 1986 by Salahuddin et al [1] from peripheral blood mononuclear cells of patients with lymphoproliferative disorders and AIDS, this herpesvirus initially was believed to preferably infect B cells and therefore was named human b-lymphotropic virus. Its predominant tropism subsequently was defined to be the human T cell, and the virus was renamed human herpesvirus 6 (HHV-6). Recently, CD46 has been identified as a cellular receptor for HHV-6 [2]. Human herpesvirus 6 belongs to the Roseolavirus genus of the Betaherpesvirinae subfamily and is more closely homologous with human herpesvirus 7 (HHV-7) than with cytomegalovirus, another member of this subfamily (Box 1).

The virus is ubiquitous in the population, with greater than 90% seropositivity in adults, and it has a worldwide distribution [3]. Infection usually occurs within the first 2 years of life as a febrile illness. Like other herpesviruses, HHV-6 persists in the host, in a latent state in monocytes and bone marrow progenitor cells, and as a chronic infection of the salivary glands, which is the likely mode of transmission [4]. Human herpesvirus 6 is pathogenic in the immunosuppressive periods after organ transplantation and may be a cofactor in the progression of HIV disease [4 6]. Recently, its role in the pathogenesis of multiple sclerosis has been investigated extensively because of the marked neurotropism of the virus and its detection in oligodendrocytes in plaque regions [7,8]. Additional investigations, however, are necessary to definitely establish the role played by HHV-6 in these diseases.

Box 1. Classification of the human herpesviruses and common disease associations Human Human Human Human Human Human Human Human herpesvirus herpesvirus herpesvirus herpesvirus herpesvirus herpesvirus herpesvirus herpesvirus 1 2 3 4 5 6 7 8 Herpes simplex virus 1 Herpes simplex virus 2 Varicella-zoster virus Epstein-Barr virus Cytomegalovirus Orolabial ulcerations Genital ulcers Varicella, herpes zoster Mononucleosis, oral hairy leukoplakia Most often clinically inapparent Exanthema subitum Unknown Kaposis sarcoma

* Corresponding author. E-mail address: Bberman@med.miami.edu (B. Berman). 0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 0 8 - 0

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Biology Human herpesvirus 6 is an enveloped virus 160 to 200 nm in diameter with a naked nucleocapsid approximately 90 to 110 nm in diameter. The virus genome is a double-stranded DNA sequence of 167 kbp in length [3]. The envelope contains lipoprotein and glycoproteins that are responsible for biologic functions, such as binding to the host cell receptors or acting as targets for neutralizing antibodies. Two variants have been identified, HHV-6A and HHV-6B, with their genomic sequence differing by less than 10% [9]. Despite the close homology, these two variants have distinctive biologic (ie, growth properties, restriction enzyme patterns, antigenic profiles) and epidemiologic characteristics (see following discussion). The main cellular tropism of HHV-6 is directed toward CD4+ T cells; however, other sites of replication include CD8+ and gd-T lymphocytes, macrophages, natural killer cells, and epithelial and neural cells [3,10,11]. Human herpesvirus 6 establishes persistent infection in cells of the monocyte/macrophage lineage and chronic replication with continuous or frequent production of infectious virus in the salivary glands. Several genes encoded by HHV-6 show homology to those of human cytomegalovirus [3]. In peripheral blood, the expression of the U94 immediate early gene, characteristic of HHV-6, seems to be critical in the establishment and maintenance of virus latency and restricts the lytic replication cycle of the virus [12]. It has been reported that infection with HHV-7 can lead to reactivation of HHV-6 from latency and that HHV-6 may interact with HIV, causing an increased HIV replication and pathogenicity [11]. Some investigators, however, have demonstrated that HHV-6 can inhibit HIV replication in vitro in certain circumstances [13]. Recently, CD46, a glycoprotein expressed on the surface of all nucleated cells, has been shown to be a cellular receptor for HHV-6A and HHV-6B [2,3]. The mechanisms by which HHV-6 causes disease, how-

ever, are not fully understood. The virus causes ballooning and has been demonstrated to induce apoptosis in uninfected bystander CD4+ T cells [3]. Human herpesvirus 6 also exerts multiple effects on the immune system, such as enhancement of natural killer T-cell activity, suppression of peripheral blood mononuclear cell proliferation, and induction of numerous cytokines (interferon-a, interferon-g, interleukin-1b, tumor necrosis factor-a, and interleukin15) [3]. Interestingly, HHV-6 genome encodes for proteins that are homologous to immune mediators in the chemokine family, which may contribute to the pathogenesis of the virus. Epidemiology The virus is ubiquitous and found worldwide. Approximately 95% of the human population is seropositive for HHV-6, and infection, transmitted most likely by means of saliva, usually occurs during the first 2 years of life [14,15]. The peak age of acquisition in the United States is 6 to 12 months, probably reflecting initial protection by maternal antibodies, but it may be acquired as early as 2 weeks of age [16], and infrequently, infection in utero also may occur [17]. The role of breast milk in transmission of HHV-6 infection has not been determined. One epidemiologic study found the prevalence of HHV-6A in healthy children in peripheral blood leukocytes and saliva to be 3% and 2%, respectively, whereas the prevalence for variant B in peripheral blood leukocytes and saliva was 71% and 50%, respectively [18]. The HHV-6B variant is believed to be responsible for clinical disease, whereas the pathogenicity of the HHV-6A variant has been incompletely determined. Immunocompromised patients, especially those who have undergone solid-organ transplant, are at greater risk of HHV-6 infection [4,7,19]. Whether this infection represents a superinfection or is the result of reactivation of a latent infection remains unclear.

Box 2. Diseases associated with HHV-6 Inflammatory diseases: exanthema subitum, febrile illnesses of infancy, chronic fatigue syndrome, gloves-and-socks syndrome, hypersensitivity drug reactions, Gianotti-Crosti syndrome Malignant diseases: oral carcinoma, lymphomas, leukemia, cervical carcinoma Neurologic diseases: multiple sclerosis, demyelinating diseases in AIDS Post-transplant disorders: graft-versus-host disease, skin eruptions, encephalitis, pneumonitis

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Disease associations Several diseases have been associated with HHV6 infection since its discovery and characterization (Box 2) [2,4 8]. Dermatologically, a definite association has been established between HHV-6 and exanthema subitum. Exanthema subitum (roseola infantum) In 1988, on the basis of seroconversion and concurrent viral isolation from peripheral blood lymphocytes (PBL), Yamanishi et al [20] concluded that HHV-6B causes exanthema subitum (roseola infantum). Exanthema subitum is characterized by 3 to 5 days of high fever (39C 40C), followed by a maculopapular rash on defervescence. It may be accompanied by upper respiratory tract symptoms and cervical lymphadenopathy. A variable clinical presentation in which no rash develops has been described [15]. Other possible causes of exanthema subitum include HHV-7 and enterovirus and parvovirus infections. Most children recover from exanthema subitum without sequelae; however, liver dysfunction and convulsions are the most frequent complications [14,15]. Other skin diseases Other diseases such as gloves-and-socks syndrome, hypersensitivity drug reactions, GianottiCrosti syndrome, pityriasis rosea, and lymphoproliferative malignancies also have been linked to HHV-6 [19,21 25]. Human herpesvirus 6 has been detected in skin biopsy samples of patients with graft-versus-host disease, and one study documented an increased prevalence of HHV-6 DNA in skin and rectal biopsy samples and with the severity of graft-versus-host disease (GVHD) [19]. Infection with HHV-6 has been associated with drug-induced eruptions in several reports [21,22] because skin biopsies have demonstrated viral components by immunohistology or polymerase chain reaction, and viral culture of peripheral blood leukocytes has correlated with the evolution of skin lesions. A pilot study performed by one of the authors of this article (B.B.) failed to demonstrate an association between HHV-6 and cutaneous drug-induced eruptions, however (unpublished data, 1999). Diagnosis Laboratory diagnosis often is confounded by the ubiquitous and persistent nature of the virus and lack of a specific, accepted test to detect HHV-6. Differentiation of active infection from chronic persistence

or latency may be difficult to demonstrate. Human herpesvirus 6 can be cultured in lymphocytes stimulated by phytohemagglutinin and interleukin-2 [3]. Because most individuals are nonsymptomatic carriers, a positive viral culture does not necessarily mean a clinically relevant infection. ELISA immunoassay may be used but has the drawback that it does not differentiate between variants A and B, and there may be cross-reactivity with other herpesviruses [3 5]. Anti HHV-6 IgM can be found in 5% of healthy adults and therefore is not a reliable method to diagnose HHV-6 pathologic infection [4]. Serologic evidence is defined as a fourfold or greater rise in IgG titer; however, this measure does not differentiate between primary or reactivation infection. Plasma polymerase chain reaction has shown sensitivity and specificity of 90% and 100%, respectively, for diagnosing primary HHV-6 infection in immunocompetent children and therefore seems to be a good diagnostic tool [3].Viral antigen or nucleic acid detection in tissues by immunohistology and nucleic acid hybridization, respectively, also may be helpful in the diagnosis. Treatment In most cases, HHV-6 causes a benign and selflimited illness in which antiviral therapy is not indicated. To date, there have been no controlled trials of antiviral therapy against infection with HHV-6 [3,5]; however, several reports attest to the ability of existing viral agents, presently used in cytomegalovirus (CMV) infections, to suppress HHV-6 replication in vitro [26,27], and it seems that ganciclovir and foscarnet are effective inhibitors of replication. One study has shown that the U69 HHV-6 viral protein (similar to the UL97 phosphotransferase of CMV) is able to phosphorylate ganciclovir with comparable efficiency to the CMV (UL97) gene product [27]. Because HHV-6 lacks a viral thymidine kinase, acyclovir has relatively low activity against HHV-6, as shown by in vitro studies, and it is not indicated as the first line of treatment [26].

Human herpesvirus 7 The seventh member of the Herpesvirus family, HHV-7, was isolated first in 1990 by Frenkel et al [28] from CD4+ T cells of a healthy adult. DNA analyses have shown that HHV-7 is related closely to HHV-6 and CMV, and therefore it is included in the Roseolavirus genus of the Betaherpesvirinae subfamily (see Box 1). Human herpesviruses 6 and 7 share

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similar cell tropisms, disease associations, and some antigenic epitopes. Human herpesvirus 7 is highly seroprevalent worldwide, and primary infection usually occurs during childhood but later than that caused by HHV-6. Similar to HHV-6, latency is established in peripheral blood T cells, and a persistent infection in the salivary glands is believed to be the most likely mode of transmission [29]. Little is known about the pathogenicity of HHV-7. Recently, it has been proposed as the causative agent of pityriasis rosea; however, a definite causality has not yet been proved. Biology The virus genome of HHV-7 is approximately 144.8 kbp in size and is co-linear with HHV-6 for most of its length, which explains the serologic crossreaction between the two viruses [29]. The virus attaches to and penetrates host cells through specific interactions of virion envelope glycoproteins with cell surface molecules, specifically CD4. Indeed, blockage of the CD4 molecule with anti-CD4 antibodies inhibits HHV-7 infection [30]. Although HHV-7 is lymphotropic, it cannot, however, establish a productive infection in T cells. A role for HHV-7 has been suggested in the transactivation of HHV-6 infection and inhibition of HIV replication, viruses that share the same cellular receptor [31,32]. The ability to isolate HHV-7 from activated but not resting PBL suggests that the virus may adopt a true state of latency in T cells. Infection by HHV-7 results in changes in host cell morphology and phenotype, gene expression, and cell function [29]. Factors secreted from infected cells may affect nearby uninfected cells to recruit susceptible cells or to induce apoptosis. Additionally, HHV-7 infection induces host cell upregulation of interleukin-15 and down-modulation of the cell surface molecule CD4 [33]. Epidemiology Infectious HHV-7 has been isolated from the saliva of as many as 90% of healthy individuals in different parts of the world, and saliva is the most likely means of transmission. Primary infection occurs in childhood, usually in children 26 months old, with prevalence greater than 90% reached by the ages of 6 to 10 years [16,33]. Molecular epidemiologic evidence for horizontal transmission of HHV-7 was presented by Takahashi et al [34], who found similar restriction endonuclease patterns of viral DNA purified from saliva isolates of

family members living in the same household. Fortyeight percent of the isolates from children had restriction profiles similar to the mother, and 28% of the isolates were similar to the father. Disease associations Little is known about the pathogenicity of HHV-7. It has been associated with febrile illness in children and exanthema subitum, and more recently, it has been implicated as the causative agent of pityriasis rosea (Box 3) [4,5,33,35 37].

Box 3. Diseases attributed to HHV-7 infection Pityriasis rosea Exanthema subitum Febrile illnesses of infancy Chronic fatigue syndrome Reactivation of HHV-6 infection Post-transplantation skin eruptions

Human herpesvirus 7 infection is proposed to predispose the host to CMV disease, as demonstrated in several reports by the detection of increasing antibody titers to HHV-7 in patients with CMV disease [29]. The possibility of HHV-7 affecting the replication of other Betaherpesviruses is supported by a report that HHV-7 infection can reactivate latent HHV-6 in children with a history of exanthema subitum [29]. Pityriasis rosea and human herpesvirus 7 Pityriasis rosea is an inflammatory disease of unknown origin. Clinical and epidemiologic features of pityriasis rosea have long led to speculation that it has a viral etiology [35]. Clinical evidence supporting a viral etiology includes the following findings: the disease has fever as a prodrome, it presents as a characteristic exanthem with a pattern of distribution, and it shows spontaneous resolution without treatment and recurrence in immunocompromised states. Epidemiologic aspects that point to a viral etiology include a peak occurrence in spring and fall and the bunching of cases in communities. Several viruses have been postulated to be causative agents, but none has been proven. A recent controversy has developed regarding Drago et als [36] assertion that pityriasis rosea represents a reactivation of latent HHV-7. In this study, high levels of interferon-a in the serum and

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a cytopathic effect in co-cultured mononuclear cells were observed in patients with pityriasis rosea. These same effects were not observed in control patients or in patients who were cured, and the effects reappeared in the patient who had a relapse. Etiologic evidence also was supported by HHV-7 DNA sequences isolated from peripheral blood mononuclear cells, skin, and plasma of patients with acute pityriasis rosea and by their absence in the plasma of cured patients and control patients. Also, cell-free viral DNA in body fluids, possibly reflecting viral replication and virulence, was an additional finding that corroborated the causative role, because there have been no reports of HHV-7 detected in plasma of healthy people or patients with other illnesses. Drago et al [36], based on their results, concluded that pityriasis rosea may be a manifestation of late primary HHV-7 infection. These results, however, could not be reproduced by others. In 1999, Kempf et al [37] studied skin biopsy specimens from 13 patients with pityriasis rosea and compared them to skin biopsy specimens from 14 patients with no known skin disease. All samples were paraffin-embedded sections. DNA was amplified using nested polymerase chain reaction and controlling for contamination and was examined for the presence of HHV-7. Immunohistochemistry, using HHV-7 antibody, also was performed. The results elicited HHV-7 DNA positivity in 1 of 13 pityriasis rosea skin samples (which were also antibody positive in immunohistochemistry) and in 2 of 14 control skin samples (with one sample also being antibody positive). Based on these results, Kempf et al [37] concluded that there is no association between HHV-7 and pityriasis rosea. Also, these investigators criticized Drago et als initial report, alleging that it was based on faulty methodology. Diagnosis Diagnosis of HHV-7 infection can be complicated by the nucleic acid and amino acid similarities between HHV-6 and HHV-7 and by the lack of a standardized routine assay for HHV-7 [38]. The same diagnostic tools discussed for HHV-6 infection may be used in the diagnosis of HHV-7 infections (see Diagnosis section for HHV-6) [29]. Viral isolation can be obtained using fresh cord blood lymphocytes and peripheral blood lymphocytes, especially the Sup-T1 cell line. Human herpesvirus 7 specific antibodies are commercially available and can be helpful in differentiating both viruses. In children, demonstration of IgG seroconversion probably indicates primary infection. Serologic assays are less

useful for associating HHV-7 with disease in immunocompetent adults, because virtually all adults are IgG positive, although a significant rise in titer (fourfold or greater) may be a useful indicator of activity. Treatment of human herpesvirus 7 No defined circumstances warrant specific treatment for HHV-7 infection. In vitro studies revealed the virus to have little or no sensitivity to the thymidine kinase dependent anti-herpetic drugs, such as acyclovir [39]. Other investigators have reported that HHV-7 shows a similar degree of susceptibility to ganciclovir as HHV-6 in vitro, but the results have not been uniform [40].

Summary Human herpesviruses 6 and 7 are newly discovered viruses that belong to the genus Roseolavirus within the subfamily Betaherpesvirinae. These ubiquitous viruses may cause primary or chronic persistent infection or remain in a state of latency for many years, until a decrease in the immunologic state of the host leads to reactivation of infection. Several diseases have been linked with HHV-6 and HHV-7. In the dermatologic arena, a definite association has been proven only for HHV-6 and exanthema subitum (roseola infantum), whereas the role of HHV-7 in the pathogenesis of pityriasis rosea remains a matter of debate.

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[1] Salahuddin SZ, Ablashi DV, Markham PD, et al. Isolation of a new virus, HBVL, in patients with lymphoproliferative disorders. Science 1986;243:596 601. [2] Santoro F, Kennedy PE, Locatelli G, et al. CD46 is a cellular receptor for human herpesvirus 6. Cell 1999; 99:817 27. [3] Clark DA. Human herpesvirus 6. Rev Med Virol 2000; 10:155 73. [4] Emery VC. Human herpesvirus 6 and 7 in solid organ transplant recipients. CID 2001;32:1357 60. [5] Kosuge H. HHV-6,7 and their related diseases. J Dermatol Sci 2000;22:205 12. [6] Lusso P, Gallo RC. Human herpesvirus 6 in AIDS. Immunol Today 1995;16:67 71. [7] Challoner PB, Smith KT, Parker JD, et al. Plaqueassociated expression of human herpesvirus in multiple sclerosis. Proc Natl Acad Sci USA 1995;92:744 93. [8] Soldan SS, Berti R, Salem N, et al. Association of human herpesvirus 6 (HHV-6) with multiple sclerosis:

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T. De Araujo et al. / Dermatol Clin 20 (2002) 301306 increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nat Med 1997;3: 1394 7. Gompels UA, Nicholas J, Lawrence G, et al. The DNA sequence of human herpesvirus 6: structure, coding content, and genome evolution. Virology 1995;209: 29 51. Lusso P, Malnati MS, Garzino-Demo A, et al. Infection of natural killer cells by human herpesvirus 6. Nature 1993;362:458 62. Lusso P, Garzino-Demo A, Crowley RW, et al. Infection of g/d T lymphocytes by human herpesvirus 6: trascriptional induction of CD4 and susceptibility to HIV infection. J Exp Med 1995;181:1303 10. Rotola A, Ravaioli T, Gonelli A, et al. U94 of human herpesvirus 6 is expressed in latently infected peripheral blood mononuclear cells and blocks viral gene expression in transformed lymphocytes in culture. Proc Natl Acad Sci USA 1998;95:13911 6. Levy JA, Landay A, Lennette ET. Human herpesvirus 6 inhibits human immunodeficiency virus type 1 replication in cell culture. J Clin Microbiol 1990;28: 2362 4. Bernstein DI. Human herpesvirus-6 and exanthem subitum. Progress Ped Infect Dis 1991;179 92. Stoeckle MY. The spectrum of human herpesvirus 6 infection: from roseola infantum to adult disease. Annu Rev Med 2000;51:423 30. Huang LM, Lee CY, Liu MY, et al. Primary infections of human herpesvirus 7 and human herpesvirus 6: a comparative, longitudinal study up to 6 years of age. Acta Pediatr 1997;86:604 8. Aubin JT, Poirel L, Agut H, et al. Intrauterine transmission of human herpesvirus 6. Lancet 1992;340: 482 3. DiLuca D, Mirandola P, Ravaioli T, et al. Distribution of HHV-6 variants in human tissues. Inf Ag Dis 1996; 5:203 14. Al A, Sviland L. Pathogenesis of GVHD: role of herpes viruses. Bone Marrow Transplant 1993;11:349 55. Yamanishi K, Okuno T, Shiraki K, et al. Identification of human herpesvirus 6 as causal agent for exanthema subitum. Lancet 1988;1:1065 7. Suzuki Y, Inagi R, Aono T, et al. Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome. Arch Dermatol 1998;134:1108 12. Tobyama M, Yahata Y, Yasukawa M, et al. Severe hypersensitivity syndrome due to sulfasalazine associated with reactivation of human herpesvirus 6. Arch Dermatol 1998;134:1113 7. Ruzicka T, Kalka K, Diercks K, et al. Papular pruritic gloves and socks syndrome associated with human herpesvirus 6 infection. Arch Dermatol 1998;134: 242 4. [24] Yasumoto S, Tsujita J, Imayama S, et al. Case report: Gianotti-Crosti syndrome associated with human herpesvirus 6 infection. J Dermatol 1996;23:499 501. [25] Drago F, Rebora A. The new herpesviruses: emerging pathogens of dermatological interest. Arch Dermatol 1999;135:71 5. [26] Takahashi K, Suzuki M, Iwata Y, et al. Selective activity of various nucleoside analogues against human herpesvirus 6 and 7. Antivir Chem Chemo 1997;8: 24 31. [27] Yoshida M, Yamada M, Tsukazaki T, et al. Comparison of antiviral compounds against human herpesvirus 6 and 7. Antiviral Res 1998;40:73 84. [28] Frenkel N, Schirmer EC, Wyatt LS, et al. Isolation of new herpesvirus from CD4+ T cells. Proc Natl Acad Sci USA 1990;87:748 52. [29] Black J, Pellett P. Human herpesvirus 7. Rev Med Virol 1999;9:245 62. [30] Yasukawa M, Hatta N, Sada E, et al. Human herpesvirus infection of CD4+ T cells does not require expression of the OKT4 epitope. J Gen Virol 1996;77:3103 6. [31] Fabio G, Knight SN, Kidd IM, et al. Prospective study of HHV-6 and HHV-7 and cytomegalovirus infection in human immunodeficiency virus-positive patients. J Clin Microbiol 1997;35:2657 9. [32] Lusso P, Secchiero P, Crowley R, et al. CD4 is a critical component of the receptor for human herpesvirus 7 interference with human immunodeficiency virus. Proc Natl Acad Sci USA 1994;91:3872 6. [33] Leach CT. Human herpesvirus 6 and 7 infections in children: agents of roseola and other syndromes. Curr Opin Pediatr 2000;12:269 74. [34] Takahashi Y, Yamada M, Nakamura J, et al. Transmission of HHV-7 through multigenerational families in the same household. Ped Infect Dis 1997;16: 975 8. [35] Aoshima T, et al. Virus like particles in the herald patch of pityriasis rosea [letter]. Dermatologica 1981; 162:64 5. [36] Drago F, Ranieri E, Malaguti F, Battifoglio MC, Losi E, Rebora A. Human herpes virus in patients with pityriasis rosea. Dermatology 1997;195:374 8. [37] Kempf W, et al. Pityriasis rosea not associated with human herpes 7. Arch Dermatol 1999;135:1070 2. [38] Tsukazaki T, Yoshida M, Namba H, et al. Development of a dot blot neutralizing assay for HHV-6 and HHV-7 using specific monoclonal antibodies. J Virol Methods 1998;73:141 9. [39] Kimberlin DW. Human herpesviruses 6 and 7: identification of newly recognized viral pathogens and their association with human disease. Pediatr Infect Dis J 1998;17:59 68. [40] Zhang Y, et al. Selective activity of various antiviral compounds against HHV-7 infection. Antiviral Res 1999;43:23 35.

[9]

[10]

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[14] [15]

[16]

[17]

[18]

[19] [20]

[21]

[22]

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Human herpesvirus 8
Paul T. Martinelli, MDa, Stephen K. Tyring, MD, PhDb,*
a

Department of Dermatology, University of Texas Houston Health Science Center, Houston, TX 79030, USA b Department of Dermatology, University of Texas Medical Branch, Route 1070, Galveston, TX 77555, USA

Kaposis sarcoma Kaposis sarcoma was described first in 1872 by Moritz Kaposi, a Hungarian dermatologist working in Vienna at the time. Kaposi reported on five men with idiopathic multiple pigmented sarcomas of the skin, including one patient who developed visceral disease in the lungs and gastrointestinal tract [1]. Since its original description one century ago, four clinical, although histologically similar, variants of Kaposis sarcoma have been reported and well characterized. Substantial evidence now exists for a viral pathogenesis of Kaposis sarcoma. Clinical variants The classic variant of Kaposis sarcoma predominantly affects elderly men of Mediterranean and Eastern European origin, with a male-to-female ratio of nearly 15 to 1 [1]. The disease generally presents with multiple, firm, reddish-brown to purple-blue plaques and nodules, usually on the hands and feet and progressing for years and decades to the arms and legs, ultimately involving the viscera or mucosa in approximately 10% of patients. The classic form of the disease is generally the most indolent variant, with most patients developing paranodular skin disease without visceral invasion [2]. Left untreated, the lesions of classic Kaposis sarcoma may progress from macules and patches to confluent nodules, which may sometimes occur in the presence of

* Corresponding author. University of Texas Medical Branch, 2060 Space Park Drive, Suite 200, Houston, TX 77058, USA. E-mail address: styring@utmb.edu (S.K. Tyring).

lymphedema. The histologic appearance of the lesions is similar to that seen with all other clinical variants; spindle-shaped tumor cells characteristically surround hyperemic vascular slits, usually accompanied by extravasated hemosiderin, erythrocytes, and fibrosis. The median age of histologic diagnosis, according to the results of one study of 90 patients, is 64 years [3]. An increased risk of lymphoma has been noted inconsistently in some studies, and although classic Kaposis may occur without overt immunosuppression, homosexual men may be at an increased risk for development of the disease [1]. Endemic Kaposis sarcoma is a clinically and epidemiologically distinct variant occurring in Africa. This form of the disease has risen in reported incidence during the past few decades. In 1971, Kaposis sarcoma accounted for only 3% to 9% of all reported cancers in Uganda [4], but in a study published in 1993, Kaposis sarcoma in HIV-negative and HIV-positive patients was found to be the most frequently occurring tumor in central Africa, accounting for approximately 50% of all tumors diagnosed in men in some countries [5]. Endemic Kaposis generally is observed in patients older than 20 years [6] and may present in a localized and indolent manner as nodules or plaques on edematous limbs, with rare lymph node or systemic involvement; however, a more clinically aggressive lymphadenopathic form exists and characteristically affects children [7]. In children, the disease often has a more fulminant and sometimes fatal course [8,9], with massive nodal involvement expected. Kaposis sarcoma also occurs in the setting of iatrogenic immunosuppression. Numerous studies have documented the risk of developing Kaposis sarcoma among organ-transplant recipients and patients taking immunosuppressive therapy [10 13].

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Incidence rates of Kaposis sarcoma developing after transplantation vary between 0.5% and 5.3% [10 14], with a median interval from surgery to the diagnosis of Kaposis of approximately 30 months [14,15]. In addition to solid-organ transplantation, the development of Kaposis sarcoma has been noted with immunosuppressive agents in numerous other disease states, including systemic lupus erythematosus, rheumatoid arthritis, polymyositis, and temporal arteritis, to name a few [6]. Immunosuppression-associated Kaposis sarcoma has been reported to occur, although rarely, after allogeneic or autologous stem cell transplantation, and the five cases in the literature have been reviewed recently [16]. This variant of Kaposis tends to have a relatively aggressive nature, involving lymph nodes, mucosa, and the viscera in approximately half of all affected patients, even in the absence of detectable skin lesions. The final clinical variant is the epidemic, or AIDS-associated, type of Kaposis sarcoma. This variant was first reported 20 years ago in 50 young homosexual men with AIDS who were found to have an aggressive form of Kaposis sarcoma. This variant is typically lymphadenopathic and tends to involve visceral organs and mucosa as well as the skin. The disease is frequently fatal, and interestingly, affects homosexual men with AIDS 20 times more commonly than men with hemophilia and AIDS with similar degrees of immunosuppression [17], implicating its potential for transmission through various high-risk sexual routes [18,19]. Despite a decrease in the incidence of Kaposis sarcoma in American men with AIDS after the introduction of highly active antiretroviral therapy, Kaposis sarcoma remains the most common AIDS-associated neoplasm in the United States. Reynolds et al. [20] found that among 1756 newly diagnosed malignancies in a cohort of patients with AIDS, approximately 83% of the malignancies were Kaposis sarcoma, with non-Hodgkins and Hodgkins lymphoma constituting 13% and 1%, respectively, of all cases analyzed. Furthermore, there is also some evidence to suggest that patients with AIDS-related Kaposis sarcoma may be at an increased risk of developing a second malignancy, most commonly non-Hodgkins lymphoma [21].

Role of human herpesvirus 8 Even before the isolation of human herpesvirus 8 (HHV 8) from Kaposis sarcoma lesions, there was growing epidemiologic evidence pointing to an infectious etiology for the neoplasm [22]. Studies performed in the 1960s and 1970s reported ultrastruc-

tural evidence for a herpesvirus in Kaposis sarcoma lesions [23]. Furthermore, there seemed to be a clustering of the disease in well-defined segments of the population. For example, a larger number of sexual partners among homosexual men was the variable most strongly associated with the development of Kaposis sarcoma in a large, multicenter, case-control study [24]. Confirming this finding, Beral et al. [17] , using surveillance data from patients with AIDS, found that Kaposis sarcoma was 20,000 times more common in persons with AIDS than in the general population. In addition, they reported that the occurrence of Kaposis sarcoma was much more frequent in homosexual patients with AIDS (21%) than in hemophilic patients with AIDS (1%), implicating a potential sexual, and hence, infectious origin of the tumor. This report was critical because it provided strong support for the presence of an infectious cofactor, other than HIV type 1 (HIV-1), as integral to the development of Kaposis sarcoma. It was against this historic background in which Chang et al. [25], in 1994, using the technique of representation difference analysis, identified unique DNA sequences associated with AIDS-related Kaposis sarcoma lesions. These sequences were shown to be of nonhuman origin and were found to be closely homologous to genes of members of the gammaherpesvirus subfamily, including Epstein-Barr virus and Herpesvirus samirii, both of which are notable for causing tumors, especially lymphoproliferative disorders in humans and animals. Because these DNA sequences represented a novel human herpesvirus, Chang et al. coined the name HHV 8, or Kaposis sarcoma associated herpesvirus, for the infectious agent. Within 2 years of its discovery, the 165-kb HHV 8 genome was sequenced [26], providing important clues about its mechanisms of oncogenesis at the molecular level. Since the time of its discovery, HHV 8 sequences, with the aid of polymerase chain reaction (PCR), have been found in all clinical variants of Kaposis sarcoma [27 34], strengthening the virus association with the pathogenesis of the disease. The virus is found in HIV-positive and HIVnegative patients with Kaposis sarcoma [35]. Several other observations support the etiologic role of HHV 8 in Kaposis sarcoma. Human herpesvirus 8 sequences can be detected before the onset of Kaposis sarcoma lesions [36,37], strengthening the virus association with the disease. In addition, HHV 8 seropositivity in peripheral blood mononuclear cells strongly predicts subsequent development of Kaposis sarcoma [38]. Like most other human herpesviruses, HHV 8 may be in a latent stage of infection early in the course of the clinical disease [39],

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infecting a smaller percentage of spindle cells than later in its course.

Molecular biology of human herpesvirus 8 Sequencing of the HHV 8 genome provided important insights into the ways that the virus can support uncontrolled neoplastic growth. As mentioned previously, the full genome was originally mapped by Russo et al. [26] using a genomic library made from a primary effusion cell line. Human herpesvirus 8 also was sequenced independently from a Kaposis sarcoma biopsy specimen, and the genome was found to be nearly identical [40]. In the virion, the HHV 8 genome is a linear, doublestranded, 165-kb DNA molecule, which is maintained stably in latently infected B cells as episomal monomeric circles [41]. The genomic structure contains a central unique segment approximately 140.5 kb long, flanked by numerous noncoding tandem repeat stretches of GC-rich DNA. The long unique region contains approximately 80 potential open reading frames. Unlike many other viruses, HHV 8 incorporated several recognizable host genes during its evolution and uses this molecular piracy in the pathogenesis of neoplastic growth. For example, the virus encodes proteins that are homologues to human oncoproteins, including a cyclin that can directly trigger the initiation of DNA synthesis by way of inhibition of the retinoblastoma protein, which governs progression from the G1 to S phase of the cell cycle [42 47], and a Bcl-2 like protein that inhibits apoptosis [48]. Other putative genetic mechanisms of deregulating normal cellular proliferation include the virus expression of a G-protein coupled receptor [49], constitutionally active immunoreceptor [50], and an inhibitor of apoptosis mediated by the FLICE (Fasassociated death domain-like interleukin-1b-converting enzyme) pathway [51]. Also noteworthy is the finding that HHV 8 encodes an interleukin-6 that can affect the replication and migration of uninfected cells [52], thereby acting in a paracrine fashion. Human herpesvirus 8 encodes inhibitors of the interferon signaling pathway [53], and in a recent study, one of these inhibitors (vIRF-2) was further characterized and shown to be a nuclear protein that inhibits RNA-activated protein kinase [54]. There are also reports that a latency-associated nuclear antigen in HHV 8 may inhibit the tumor suppressor gene p53, thereby enhancing tumorigenesis [55,56]. There are, therefore, various different molecular mechanisms that may enable the virus to subvert normal cellular

proliferation. As the genotyping of Kaposis sarcoma lesions has progressed through the years, some investigators have noted regional variations of some genotypes of HHV 8 based on sequence variability among the open reading frames. One group of researchers reported that one genotype in particular was more prevalent in South Texas than in any other region studied [57]. There is also evidence that suggests that the role of HIV-1 infection in the development of Kaposis sarcoma may be more important than merely providing a state of immunodeficiency. Instead, there may be a synergistic relationship between the HIV-1 Tat protein and HHV 8 infection. Tat promotes the growth of the Kaposis sarcoma spindle cells, by way of its binding to heparan sulfate and the displacement of basic fibroblast growth factor into the matrix [39,58]. The spindle cells then acquire Tat from the extracellular fluid. In addition, Tat augments the angiogenic activities of basic fibroblast growth factor, interferon-gamma, and vascular endothelial growth factor, in addition to augmenting the extracellular matrix [59]. Therefore, HIV infection may play a more active role in the development of Kaposis sarcoma by generating inflammatory cytokines and by providing Tat. Epidemiology and transmission of human herpesvirus 8 Serologic studies [1] have demonstrated that, unlike other human herpesviruses, HHV 8 is not ubiquitous; instead, its infection rates parallel the incidence of Kaposis sarcoma in the region analyzed. The seroprevalence of HHV 8 tends to be lowest in Asia, with 0.2% of blood donors in Japan testing positive [60]; it is 10% in the United States, and quite high (approximately 50%) in some African nations [61,62], with intermediate rates in Italy and the Mediterranean. As mentioned previously, homosexual men have a higher rate of Kaposis sarcoma than the general male population and can have relatively high rates of asymptomatic infection [63]. Studies have shown that viremia is not a prominent component of HHV 8 infection, because only approximately 50% of patients with Kaposis sarcoma have detectable HHV 8 in their peripheral blood mononuclear cells using PCR [37]. Serologic assays to detect antibodies to HHV 8, which are often lifelong after infection, are more sensitive than PCR. A commonly used serologic test detects the antibody generated to HHV 8 latency-associated nuclear antigen. These assays confirm that HHV 8 consistently is found in association with Kaposis sarcoma and is

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detectable in 70% to 100% of patients with the disease [64,65]. Although the etiology and pathogenesis of Kaposis sarcoma are described extensively in the literature, finding the exact mode of transmission of HHV 8 has been more controversial. Human herpesvirus 8 predominantly is spread sexually, and it seems to be more readily transmissible through homosexual activities, such as through increased exposure to fecal-oral contact [18]. As mentioned previously, the number of sexual partners was the largest risk factor for the development of Kaposis sarcoma among a large cohort of patients with AIDS [24]. Similarly, an epidemiologic study on the transmission of HHV 8 in women confirmed that sexual activity was a significant independent risk factor for the development of Kaposis sarcoma [66]. This study also documented that injection drug use was another significant risk factor, indicating that HHV 8 can be spread parenterally, although less efficiently than hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV. Given the incidence of Kaposis sarcoma in children in Africa [61,62], however, other modes, such as transplacental transmission, must play a role. The exact route of transmission of HHV 8 is still being investigated. One group of investigators [67] documented a high rate of HHV 8 presence in the semen and prostate (91% and 44%, respectively) of HIV-negative men undergoing varicocele repairs. Another study documented that, using nested PCR, 91% of homosexual HIV-positive men had detectable HHV 8 in their semen [68]. Other studies have not been able to confirm these findings, however [69]. Several investigators have examined mucosal spread of HHV 8, particularly through the saliva [70,71]. One study [71] examined a cohort of HHV 8-seropositive homosexual men and documented the presence of HHV 8 DNA in 30% of oropharyngeal samples, compared with 1% of anal and genital samples, suggesting that oral transmission through deep kissing may be a more common mode of transmission than intercourse. These results are difficult to explain, given the much greater incidence of open-mouthed kissing than HHV 8 infection in the heterosexual community, suggesting that transmission may be related not only to the presence of the virus but also to the amount of infectious virus shed [70]. Treatment of Kaposis sarcoma In patients with classic Kaposis sarcoma who present with single lesions, simple excision is typically adequate and also can be used to treat recur-

rences without unacceptably high recurrence rates [72]. Patients with several lesions often are treated best with single doses of radiation (8 12 Gy) delivered to an extended field [1]. In extensive or recurrent disease, patients can undergo a combination of surgery, radiotherapy, and chemotherapy. Complete remissions have occurred with chemotherapy alone, and responses can last several years; responses have been obtained consistently with vinblastine, bleomycin, doxorubicin, and dacarbazine, alone or in combination [1,72 74]. Intralesional interferon alfa-2b is also effective in clearing lesions and has the advantage of little systemic toxicity. One case series examined the effect of hyperthermic (40C) perfusion of an affected limb with tumor necrosis factor-alpha and melphalan, and a response was found in all patients examined [75]. Endemic Kaposis sarcoma usually is treated with the same drugs as the classic variant. In patients with immunosuppression-associated Kaposis sarcoma, the lesions typically regress with the reduction, modification, or cessation of the immunosuppressive chemotherapeutic regimen. Again, similar chemotherapeutic agents can be used with reasonable efficacy. In the epidemic variant, excellent responses have been noted with the initiation of highly active antiretroviral therapy (HAART), with complete and lasting remissions reported [76]. Radiation is another therapeutic option, but patients with this form of the disease typically require total higher doses to achieve lasting success [77]. Patients exhibiting extensive disease with widespread mucocutaneous involvement, visceral disease, or lymphedema are treated best with cytotoxic chemotherapy; the drugs most frequently used include the liposomal anthracyclines, paclitaxel, vinca alkaloids, and bleomycin [1,78 80]. One small, randomized study found a 40% response rate to liposomal daunorubicin and a delay in the progression of the disease [79], but as noted by White [80], owing to the potential harmful effects of this treatment in patients with AIDS, it should be reserved for advanced HIV-related Kaposis sarcoma. Biologic agents such as interferon-alpha may be used alone or in conjunction with HAART in patients with epidemic Kaposis sarcoma.

Other human herpesvirus 8 associated conditions Multicentric Castlemans disease Multicentic Castlemans disease (MCD), also called multicentric angiofollicular lymphoid hyperplasia, is an atypical lymphoproliferative disorder that

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may be related to immune dysregulation [81]. It usually occurs in older men and typically presents with multiple lymphadenopathies and a variety of constitutional complaints. Patients may progress to multisystem disease, including skin rashes, cytopenias, autoimmune disorders, and infections, and frequently will develop malignancies, most commonly Kaposis sarcoma and non-Hodgkins lymphoma [82]. Follicular hyperplasia with proliferation of plasma cells and hyaline vascular alterations in lymph nodes are the key histopathologic findings in MCD [83]. As in Kaposis sarcoma, there has been a consistent association between HHV 8 infection and the development of MCD. In one study of 31 patients with MCD, HHV 8 DNA was found in 14 of 14 HIVpositive patients and 7 of 17 HIV-negative patients [82]. These data suggest that HHV 8 may be an etiologic factor in the development of MCD, especially with concurrent HIV infection. Another group of investigators hypothesized that HHV 8 may express both latent and lytic proteins in MCD, as opposed to the predominantly latent gene expression pattern seen in association with Kaposis sarcoma and primary effusion lymphomas [83]. Primary effusion lymphoma Primary effusion lymphomas (PELs), also known as body cavity based lymphomas, are a type of highgrade non-Hodgkins lymphoma that grow nearly exclusively in the pericardial, peritoneal, and pleural cavities as lymphomatous effusions, usually in the absence of any identifiable tumor mass. Similar to Kaposis sarcoma, the disease generally presents in men who are frequently, but not exclusively, homosexual, and it is diagnosed at a median age of 42 when associated with HIV infection and at 73 when HIV is not involved [84]. Primary effusion lymphomas have indeterminate immunophenotypes but Bcell genotypes with clonal rearrangement of their immunoglobulin genes. In contrast to many AIDSrelated B-cell non-Hodgkins lymphomas, the PELs reported in the literature often contained the EpsteinBarr viral genome and had no rearrangements of the c-myc gene [85,86]. The disease represents a distinct clinicopathologic entity [84], and a strong association between HHV 8 infection and PELs has been identified. Cesarman et al. [81] used PCR to examine the DNA of 193 lymphomas from 42 patients with and 151 patients without AIDS. They found that HHV 8 sequences were identified in eight of the lymphomas in the AIDS population, and all eight, and only those eight, were PELs. In addition, they noted that viral DNA was 40 to 80 times more abundant in the

lymphomas than in the Kaposis sarcoma lesions. Other case series [87,88] have confirmed these results, demonstrating HHV 8 sequences within the PELs and strongly suggesting that the herpesvirus has a pathogenic role in the development of this AIDSrelated lymphoma.

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Dermatol Clin 20 (2002) 315 331

Human papillomavirus: a review

Mathijs H. Brentjens, MD, MS, Kimberly A. Yeung-Yue, MD, Patricia C. Lee, MD, Stephen K. Tyring, MD, PhD*
Departments of Dermatology, Microbiology/Immunology, and Internal Medicine, University of Texas Medical Branch Galveston, Galveston, TX, USA

Genital warts (condyloma acuminata) have been documented since the time of Hippocrates, and cutaneous warts were reported by the first century AD. It was not until the late eighteenth century, however, that the infectious nature of warts became known. In 1891, Payne first recognized that cutaneous warts were transmissible. In 1901, Heidingsfeld described the transmission of condyloma acuminata through sexual contact. In 1949, Strauss et al isolated the agent responsible for warts, the human papillomavirus (HPV) [1]. Since then, HPV has become recognized widely as a significant human pathogen. Human papillomavirus infection has been associated with benign and malignant lesions. Benign lesions include common warts (verruca vulgaris); plantar warts; genital warts (condyloma acuminata); lesions of the mouth, nose, and throat; conjunctival papillomatosis; and cervical intraepithelial neoplasias. Human papillomavirus also is associated with epidermodysplasia verruciformis, an inherited disease in which patients develop skin cancer after exposure to sunlight. Malignant lesions associated with HPV include oral and respiratory squamous cell carcinomas, anogenital cancers, and cervical cancer. Currently, there is no definitive therapy for HPV infection. Treatment modalities used at present include tissue ablation, chemotherapy, and immunomodulation. Recent advances focus on prevention of HPV infection, with several vaccine candidates undergoing clinical trials. This article reviews the structure

of HPV and its pathogenesis, clinical manifestations, epidemiology, and treatment as well as prevention of HPV infection.

Structure Human papillomaviruses belong to the family papillomaviridae, which includes papillomaviruses affecting other species. Until recently papillomaviruses were classified as belonging to the family papovaviridae, along with polyomaviruses [2]. Papillomaviruses show remarkable specificity and are not known to infect species other than their natural hosts. They have been found in numerous animals, including cows and rabbits [3]. Human papillomaviruses are nonenveloped and have icosahedral symmetry, with 72 capsomeres forming the outer coat. This coat consists of a major capsid protein and a minor capsid protein. The genome consists of circular double-stranded DNA approximately 8 Kb in length. The DNA encodes nine overlapping genes and contains a single control region (incorporating promoter regions and regulatory regions) (Fig. 1). The genes are distributed into early (E1 E7) and late regions (L1 and L2). Early genes encode proteins that are involved with regulation of viral DNA replication and transcription. Early genes also are involved with oncogenic transformation in high-risk HPV types. The L1 and L2 genes encode the major and minor capsid proteins, respectively. The papillomavirus E1 protein demonstrates ATPase and helicase activity: it functions both to promote viral replication and to inhibit viral integration into the host genome [4 11].

* Corresponding author. University of Texas Medical Branch, Center for Clinical Studies, 2060 Space Park Drive, Suite 200, Houston, TX 77058, USA. E-mail address: styring@utmb.edu (S.K. Tyring).

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 2 8 - 6

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Fig. 1. Map of HPV type 16 genome. E1 E7 = early regions; L1 and L2 = late regions; kbp = kilobase pairs; NCR = Non-coding region. (From Baron S, editor. Medical microbiology. Galveston [TX]: The University of Texas Medical Branch at Galveston; 1996. p. 803; with permission.)

The papillomavirus E2 protein significantly increases the affinity of E1 binding to the viral replication origin [4,12]. In fact, it has been demonstrated that the presence of both E1 and E2 is necessary and sufficient to induce viral DNA replication [10,13]. In addition to its role in viral replication, E2 also has a role in viral transcription. The E2 open reading frame has been studied extensively in bovine papillomavirus: it encodes three separate proteins that function either to enhance or repress viral transcription [14]. Dowhanick et al [15] demonstrated that the full-length E2 protein inhibits cell growth in vitro in cells containing the DNA of high-risk HPV types 16 and 18. These data suggest that E2 proteins play a large role in preventing oncogenic transformation of HPV-infected cells. Not much is known about HPV E4 proteins. They are associated with collapse of the cellular cytokeratin network, perhaps enhancing virus exit from the cell [16]. E4 proteins do not seem to be necessary for oncogenic transformation. The E5 protein independently can cause tumorigenic transformation in vitro, likely secondary to modification of growth factor pathways [17]. This protein forms complexes with platelet-derived growth factor receptors and epidermal growth factor receptors, thereby constitutively activating them [18]. E5 also may work together with the E7 protein to promote malignant transformation in cell lines, again possibly secondary to E5 protein stimulation of growth factor pathways [19]. The oncogenic potential of high-risk HPV types most likely is related to the E6 and E7 proteins. Terminally differentiated keratinocytes lack the ability to replicate DNA. E6 and E7 enable HPV to use

cellular proteins for continued viral replication by arresting the process of keratinocyte differentiation [20]. In particular, these proteins have been shown to inhibit the function of tumor suppressor proteins p53 and Rb, respectively [21 23]. Studies suggest that E6 (particularly in high-risk types) is able to bind to p53 with great affinity, thereby significantly enhancing its degradation [24]. Like p53, Rb plays an important regulatory role in cell division. In its hypophosphorylated form, Rb releases E2F, which stimulates cell cycle progression [25]. The binding of E7 to Rb acts in a manner similar to hypophosphorylation [26]. Additionally, HPV type 16 E7 acts to promote the degradation of Rb [27]. Studies also show that E6 and E7 together effectively downregulate the expression of interferon (IFN)-responsive genes and IFN itself, thereby limiting host immune response to HPV infection [28,29]. Numerous other mechanisms have been proposed to explain the role of E6 and E7 proteins in the pathogenesis of HPVrelated disease [30].

Pathogenesis All HPV types target squamous epithelial cells. Infection begins with viral entry through traumatized epithelium and then may follow one of three paths: latent infection, in which there is no gross or microscopic evidence of disease; subclinical infection, in which colposcopy or microscopy reveals evidence of infection in the absence of clinical disease; and clinical disease. Most genital HPV infections are latent or subclinical [31]. In subclinical and clinical

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infections, early HPV genes are expressed in basal epithelial cells. Translation of capsid proteins L1 and L2 occurs in terminally differentiated keratinocytes, whereas early proteins act to maintain cellular transcription and translation [5]. Clinical and histopathologic evidence of HPV infection usually develops 1 to 8 months after initial exposure [32]. In the absence of transformation, HPV follows the normal cycle of viral reproduction: attachment, penetration, transcription and translation of viral genes, replication of the viral genome, assembly, and release [33]. Physical manifestations of infection include epidermal thickening, hyperplasia of the stratum spinosum, and some degree of hyperkeratosis [2]. Untreated, these lesions may regress spontaneously, persist as benign lesions, or progress to precancerous lesions and eventually, cancer [34 37]. One study suggests that persistence of disease may be attributable to a lack of Langerhans cells at the site of the lesion, leading to decreased stimulation of cell-mediated immune response [38]. The methods by which high-risk HPV types lead to oncogenic transformation are not yet completely understood. Current evidence indicates that oncogenic transformation requires viral genome integration into the host DNA [39 41]. Although the host locus of integration is nonspecific, the circular HPV genome most often breaks in the E1 E2 region, resulting in a loss of transcriptional control of early genes E6 and E7 [42]. As mentioned previously, E6 and E7 proteins promote degradation of p53 and Rb.

Carcinogenic potential is enhanced considerably with depletion of these regulatory proteins, but other factors are necessary for the formation of carcinoma in HPV-infected cells [43].

Classification and clinical manifestations Human papillomaviruses are classified according to genetic similarity with previously identified types. At the International Papillomavirus Conference in 1995, novel HPV types were defined as having less than 90% homology with known types in the L1 open reading frame. To date, more than 100 HPV types have been identified [44]. Human papillomaviruses also are grouped according to their tissue tropism (dermatotropic or mucosotropic) or potential for malignant transformation (high risk and low risk). Human papillomaviruses cause a wide range of disease processes, depending on HPV type (Table 1). Just as HPV types can be described as dermatotropic or genital-mucosotropic, manifestations of these infections can be described as nongenital cutaneous and genital-mucosal. Nongenital cutaneous manifestations Benign cutaneous lesions associated with HPV include common warts (verruca vulgaris, Fig. 2), plantar warts, and flat warts. Human papillomavirus also has been linked to keratoacanthomas, actinic

Table 1 Manifestations of various HPV types Manifestation Nongenital Plantar warts Common warts Flat warts Keratoacanthomas Cutaneous squamous cell carcinomas Oral lesions Other nongenital lesions Epidermodysplasia verruciformis (EV) (also found in immunocompromised individuals) Anogenital Condyloma acuminata Anogenital dysplasias and neoplasias Other anogenital lesions Immunocompromised hosts HPV types 1 2, 4, 49 3, 10, 28, 49 37 38, 41, 48 13, 32, 57 6, 7, 11, 60, 63, 65, 78 5, 8, 9, 12, 14, 15, 17, 19, 20 25, 36, 47, 50

6, 11, 16, 18, 70 16, 18, 26, 27, 30, 31, 33 35, 40, 42 45, 51 59, 61, 62, 64, 66 69, 71 74 6, 11, 16, 18, 33, 39 72 77 (also types seen in EV)

Abbreviation: HPV; human papillomavirus. Adapted from Tyring SK. Human papillomavirus infections: epidemiology, pathogenesis, and host immune response. J Am Acad Dermatol 2000;43;S18 S26; with permission.

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Fig. 2. Common warts (verruca vulgaris).

keratoses, stucco keratoses, and seborrheic keratoses, although there is no firm evidence to support a causal role for HPV in these lesions [45 48]. The most common HPV types found in benign skin lesions are types 1 to 4 [49]. Malignant skin tumors associated with HPV include cutaneous squamous cell carcinoma and possibly basal cell carcinoma. The etiologic role of HPV is defined better in squamous cell carcinoma, especially in immunocompromised patients [50]. Human papillomavirus type 16 seems to be associated most strongly with squamous cell carcinoma, especially when located on the fingers [51]. The role of HPV in basal cell carcinoma is less certain, although HPV DNA also has been detected in these lesions [52]. Human papillomavirus infection has been associated with benign and malignant mucosal lesions of the oral cavity, respiratory tract, esophagus, and eyes. Types 6 and 11 often are found in benign lesions, whereas types 16 and 18 occur frequently in cancers [2]. Syrjanen and Syrjanens Papillomavirus Infections in Human Pathology contains a comprehensive review of the role of HPV in these lesions [53]. Epidermodysplasia verruciformis Epidermodysplasia verruciformis (EV) is a genetic disease characterized by HPV infection with multiple types not seen in otherwise healthy individuals (Table 1, Fig. 3). Susceptibility to these HPV types is believed to be secondary to a defect in cellmediated immunity [54]. Epidermodysplasia verruciformis manifests in childhood with lesions on the

back, chest, and limbs [55]. These lesions undergo oncogenesis in 25% to 63% of cases, especially on areas of the skin exposed to sunlight [56,57]. Only a few EV-related types (most notably 5 and 8) seem to have oncogenic potential, however [56]. Most EVrelated HPV types also have been found to cause lesions in immunocompromised hosts [58,59]. Genital manifestations Human papillomavirus has been identified as the etiologic agent for condyloma acuminata (genital warts, Fig. 4). Genital warts usually are found on the penis and around the anus in men. In women, frequent areas of infection include the vulva, vaginal introitus, perineal area, perianal area, and cervix. Human papillomavirus also is associated with premalignant and malignant genital lesions. Types 6, 11, 16, and 18 are most prevalent in HPV-related lesions of the genital area [3,60]. Anogenital HPV lesions may regress spontaneously or may progress to carcinoma. Oncogenic progression most often is associated with high-risk types 16 and 18 [61,62]. Malignancies strongly associated with HPV include squamous cell carcinomas of the anal canal, vulva, and penis [63 68]. Papillomaviruses are also responsible for cervical intraepithelial neoplasias and their progression to cervical cancer. Immunocompromised patients Immunocompromised patients represent a distinct population with respect to HPV infections. This

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ever, showing promise for its use in combination therapy with other medications [78].

Epidemiology Epidemiologic data suggest that cutaneous warts are common in children but tend to vary in age distribution according to type [79,80]. Transmission occurs by means of physical contact with contaminated objects (ie, the wart itself or toys). Most cutaneous warts are self-limiting and spontaneously regress within 2 years of onset [81]. Condyloma acuminata are transmitted sexually, and HPV infection is one of the most common viral sexually transmitted diseases in the world, with one prevalence estimate of 1% in the sexually active population in the U.S. [31]. Estimated prevalence rates of HPV DNA or HPV antigens in young women in the United States are as high as 10.6% to 11.4% [82]. Anogenital HPV types 6 and 11 rarely progress to invasive disease and are considered low risk (although DNA of these types is found rarely in malignancies). High-risk HPV types 16 and 18 are found in approximately 40% to 60% and 10% to 20% of all cervical carcinomas, respectively, and also are found most frequently in other anogenital cancers. Additional types associated with malignancy include 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, and 56 [83]. Cervical cancer is the seventh most common cancer overall and third most common in women worldwide [84]. Epidemiologic projections for cervical cancer in the United States estimated 12,800 new cases and 4600 deaths in 2000 [85]. Recent studies show that HPV DNA is detectable by polymerase chain reaction in more than 99.7% of cervical cancers, making HPV infection the most important risk factor in the development of this disease [86].

Fig. 3. Epidermodysplasia verruciformis.

observation is true not only because these patients are less able to effectively mount immune responses to HPV infection but also because they frequently are infected with HPV types not seen in immunocompetent people (Table 1). Human papillomavirus also tends to cause more severe disease in those with depressed immune systems and more frequently leads to oncogenic transformation. The incidence of infection with high-risk HPV and the development of carcinoma are increased markedly in HIV-positive patients [69 72]. Several HPV types have been found in biopsy specimens of renal transplant and HIV-positive patients that are not typically found in immunocompetent patients [73 76]. Treatment for HPV infection also presents a greater challenge, because therapies traditionally effective in the immunocompetent are often less efficacious in immunocompromised individuals [77,90]. For example, imiquimod (an otherwise effective medication in healthy individuals) was not significantly better than placebo in achieving complete responses in patients with HIV [78]. Imiquimod use did result in a significant reduction in the surface area of warts, how-

Fig. 4. Genital warts (condyloma acuminata).

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Even with infection by high-risk types, however, these lesions most often spontaneously regress with no long-term adverse effects [87,88]. Additional risk factors are required for oncogenic transformation. Possible co-factors in the development of cervical carcinoma include the number of male sexual partners, age at first sexual intercourse, reproductive characteristics of the patient (ie, parity, number of abortions, age at menarche and menopause, and so forth), smoking, long-term use of oral contraceptives, and host genetic predisposition [89,91 95].

Treatment To date, no single therapy has proven uniformly successful and practicable in treating HPV infections. Recurrence rates for most therapies are relatively high, and treatment requirements or side effects limit some otherwise effective regimens. Treatment may be categorized into cytodestructive methods (surgical excision, cryotherapy, laser therapy, bichloroacetic acid/trichloroacetic acid, and podophyllotoxin), antimetabolic therapy (5-fluorouracil [FU]), antiviral therapy (cidofovir and IFNs), and immunomodulation (imiquimod). Combination therapies also have been studied. Cytodestruction remains the most widely used treatment for nongenital warts, while clinical trials of other modalities focus largely on anogenital warts (and cervical condylomas in particular). Recent research has focused on therapeutic vaccines, especially for high-risk types 16 and 18. Surgical excision remains one of the primary modalities for the treatment of cutaneous warts. Recurrence rates are high, however, perhaps because clinically unaffected tissue surrounding warts often still harbors HPV [96 100]. Side effects include scar formation, bleeding from the excision site, and possible infection. Excision also may be performed by electrodessication, reducing some of the side effects associated with surgical excision, such as bleeding. For cervical condylomas and dysplasia, loop electrosurgical excision procedures are performed frequently. Loop electrosurgical excision procedures have an advantage when compared with other ablative techniques, such as cryotherapy and laser ablation, in that tissue specimens are available for histopathologic diagnosis. Recurrence rates are high with loop electrosurgical excision procedures, however, especially when the margins of excision are histologically positive for dysplasia. One recent article reported an overall recurrence of 31.9%, with 47% recurrence in those with positive margins [101].

Cryotherapy is another common cytodestructive technique. This procedure usually uses liquid nitrogen to freeze the lesion and some of the surrounding tissue, resulting in necrosis. Compared with surgical excision, it has the advantage of being bloodless, but it also can be painful. Cryotherapy seems to be less effective in treating warts than either surgical excision or laser therapy [102]. One recent study found that 24 of 25 patients treated for plantar warts still harbored HPV DNA on repeat biopsy after cryotherapy [103]. Patients often need multiple doctor visits to adequately control warts with this method. Carbon dioxide laser ablation demonstrates similar efficacy to surgical excision in the treatment of genital warts [102,104]. This type of therapy is useful for difficult anatomic locations where other cytodestructive methods are not feasible. Recurrence rates are significant, however, ranging from 3% to 77% in genital warts, according to a comprehensive review by Beutner et al [105]. Human papillomavirus DNA also has been found in the smoke plumes of carbon dioxide lasers during laser ablation, leading to the potential for respiratory infection of the laser operator [106]. On the other hand, yttrium aluminum garnet laser therapy (hyperthermia treatment) has not been found to have HPV DNA in its smoke plume, and one recent study showed that HPV DNA was undetectable in posthyperthermia biopsy samples of plantar warts [103,107]. Laser therapy is expensive and requires specialized training on the part of the operator, making it impractical for widespread use in HPV infections. Chemical cytodestructive methods also are used frequently in the treatment of warts. Bichloroacetic acid (BCA) and trichloroacetic acid (TCA) cause destruction of warts by chemical coagulation of cellular proteins. These treatments also can cause necrosis of tissue adjacent to warts and require application by a physician or nurse. Patients often need multiple applications to obtain a complete response [108]. Few clinical trials have been published about the efficacy of TCA or BCA, and in these studies, recurrence rates are high (36% 50% for genital warts) [109,110]. Side effects of BCA or TCA include skin ulceration, pain, and burning [105]. Trichloroacetic acid also has been studied as an adjunct to other available modalities, although without a clear advantage compared with monotherapy. Podophyllin and podophyllotoxin are also cytodestructive chemicals. Podophyllin comes in a solution, with concentrations from 10% to 25%. Podophyllin is not a standardized compound, however, leading to variable efficacy in treatment [111]. Two chemical mutagens (quercetin and kaempherol)

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are found in the solution [112]. Clearance rates range from 30% to 60%, with recurrence rates of 30% to 70% [30]. Podophyllotoxin has been isolated and identified as the most potent active ingredient in podophyllin. This therapy shows improved clearance and recurrence rates as compared with podophyllin [113]. It also has the advantage of allowing for selfapplication (the only other Food and Drug Administration approved therapy for self-application is imiquimod). A recent single-blind study of podophyllotoxin solution and cream showed complete response rates of 63% overall [114]. Complete clearance and early recurrence rates with podophyllotoxin gel were 45% and 31%, respectively, in one study of patients with multiple condylomas [115]. Side effects of podophyllin and podophyllotoxin are similar, with burning, inflammation, erosions, pain, and bleeding being most notable. At least two deaths have been reported from reactions to topical podophyllin, however [111]. The antimetabolite 5-FU acts to disrupt cell division by inhibiting DNA synthesis and RNA function. This medication may be applied topically or injected directly into warts. Results of trials with topical therapy seem mixed. One randomized, double-blind, placebo-controlled trial of topical 5-FU for cervical and vaginal HPV infections demonstrated cytologic regression in 28% of treated patients versus 69% of those taking placebo [116]. On the other hand, a case series of seven women with genital warts treated with 5% 5-FU cream demonstrated complete absence of detectable HPV DNA in six of seven women after 6 weeks [117]. A double-blind, placebo-controlled study of 60 women with intravaginal HPV infection found an 83% complete clearance rate, with three patients having recurrences within 16 months [118]. One study estimated a 1-year recurrence rate of 29% (6 of 21 subjects) for flat condylomas treated with 5-FU cream alone [119]. Side effects of topical 5-FU include local inflammation. Intralesional treatment of warts with 5-FU also has been studied. A recent phase III trial evaluated intralesional 5-FU injections, 5-FU/epinephrine injections, and placebo. Of condylomas treated with 5-FU/epinephrine, 77% cleared completely, whereas 60% of condylomas treated with 5-FU gel cleared (both significantly better than placebo). Also, of cleared lesions treated with 5-FU/ epinephrine, 35% recurred within 3 months, whereas 41% of cleared lesions recurred in the 5-FU only group [147]. Side effects of topical application are limited to local inflammation and irritation [121,122]. Side effects of intralesional 5-FU treatment include pain, erythema, skin discoloration, ulcerations, and erosions [120]. 5-FU is a known mutagen and tera-

togen, and its use should be avoided in pregnant and lactating women. Cidofovir, an antiviral nucleotide analogue initially approved for treatment of cytomegalovirus infections, also has shown promise in treating HPV. There are several case studies describing the successful treatment of warts refractory to other treatment modalities with topically administered cidofovir. The patients described in these studies remained wart-free for follow-up periods ranging from 9 weeks in 18 months [123 125]. Data from only a few clinical trials using cidofovir have been presented, however, and all trials involved immunocompromised patients. An open-label study evaluated topical cidofovir in HIV-positive patients with either molluscum contagiosum or HPV infections and showed complete responses in 13 of 14 individuals, with recurrences in 4 of 13 patients [126]. Another phase I/II study evaluated 67 HIV-positive patients treated with varying doses of topical cidofovir for condyloma acuminata. Overall, the complete clearance rate was 18%, and partial response was observed in 48%. Recurrences were found in zero of nine patients after 3 months and one of six evaluable patients after 6 months [127]. More recently, a placebo-controlled randomized trial of 1% topical cidofovir in HIVpositive patients was conducted. The study found a greater than 50% reduction in total wart area in 58% of cidofovir-treated patients compared with none in the placebo controls [128]. Side effects of topical cidofovir include erythema, local irritation, ulcerations, and post-treatment hyperpigmentation. Cidofovir also has been studied for the treatment of cervical intraepithelial neoplasias grade III with encouraging results, but it has not proven to be of value in the treatment of epidermodysplasia verruciformis [129,130]. Interferons are naturally occurring antiproliferative and antiviral compounds. Three IFNs have been identified: IFN-a, IFN-b, and IFN-g. Interferon-a and IFN-b share the same cellular receptor, whereas IFN-g has a separate receptor. All have been studied as therapies for HPV infection. Their therapeutic actions in HPV infection seem to be secondary to induction of antiviral protein synthesis and stimulation of cell-mediated immunity [131,132]. Interferons may be administered topically, systemically, or intralesionally. Clinical trials with topical IFN (mainly on mucosal surfaces) have resulted in complete response rates ranging from 42% to 90% [133 137]. Side effects of topical therapy were mild [135]. Systemic therapy may be given intramuscularly or subcutaneously. Given systemically, IFN may be more efficacious than placebo (although at least one

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study found this not to be true), but no better than other modalities, with response rates from 7% to 79% [138 141]. One study reported appearance of new warts in 37% of patients at 12 weeks after the start of systemic therapy [138]. Intralesional IFN injections seem to have the greatest efficacy in the treatment of HPV. Studies of this method revealed complete wart clearances between 35% and 80% (with recurrence rates of 7% 24%) [142 146,148]. Interferons-a, -b, and -g also have been compared. One recent study of subcutaneous injections of IFN-a and IFN-g found no significant differences in response rates. The same study also did not demonstrate any advantage to using a combination of the two [149]. Interferon therapy for warts is extremely expensive, and systemic side effects frequently occur (including headaches and a flu-like syndrome of fever, myalgias, and malaise). A cost-effectiveness analysis by Alam and Stiller [150] estimates that intralesional IFN would cost 10 to 23 times as much as surgical excision of genital warts. Imiquimod is another immune response modifier that has been studied extensively for the treatment of warts. Imiquimod is applied topically overnight 3 times a week and seems to act by locally increasing cytokine production, thereby stimulating cell-mediated immunity. One study measured IFN-a, -b, and -g and tumor necrosis factor-a mRNA during treatment with imiquimod and found significantly increased levels of all four during the course of treatment [151]. Interleukin-2 mRNA also was increased in this study. Imiquimod has been investigated most often as a therapeutic regimen for external anogenital warts. Numerous studies demonstrate the efficacy and tolerability of imiquimod. Complete response rates ranged from 24% to 79% with 5% cream and 14% to 21% with 1% cream [151 156]. Even those patients who did not have complete response after treatment demonstrated significant reduction of total wart area [151 155]. Response rates tended to be higher for women, perhaps secondary to increased keratinization in penile warts compared with vulvar warts. Recurrence rates after treatment in three of these studies were 19% at 10 weeks, 19% at 12 weeks, and 13% at 12 weeks [152 154]. Imiquimod also seems to have a beneficial effect on high-grade intraepithelial neoplasias of the female genital tract. One pilot study showed a complete response in 67% of patients (six of nine) with high-grade lesions. Sixty-seven percent (four of six) of complete responders remained disease-free, with mean followup of 18 months [157]. Much less information is available on the efficacy of imiquimod in nongenital HPV lesions. Case studies demonstrating the effec-

tiveness of imiquimod in lip papillomatosis, verrucae planae of the hands, facial warts, actinic keratosis, and stucco keratosis have been published, however [47,158 162]. One open-label study of imiquimod for common warts demonstrated a complete response rate of 30% [163]. Fourteen of fifteen patients treated with imiquimod for Bowens disease had complete clearance of their lesions (assessed histologically) after treatment with 5% imiquimod daily for periods of up to 16 weeks in a phase II trial [164]. Side effects of imiquimod are minimal, with local irritation cited most frequently. Other side effects include itching, erythema, ulceration, erosions, and edema. These effects are largely dose-dependent, however. The optimal dosing regimen seems to be 3 times weekly for imiquimod 5% cream [155,165]. Imiquimod is approved by the Food and Drug Administration for self-administration, making it an attractive therapeutic modality and reducing office visits. Therapeutic vaccines for high-risk HPV types have been developed recently and currently are undergoing clinical trials. Effective immune response to HPV infection is believed to depend largely on cellmediated factors (as evidenced by increased incidence of HPV-associated tumors in those with compromised cell-mediated immunity) [71,166]. Most therapeutic vaccines focus on HPV E6 and E7 proteins because these proteins are almost ubiquitously expressed in cervical cancer [167]. Published studies indicate that therapeutic vaccination with a wide variety of papillomavirus vaccines aimed at high-risk types effectively induces regression of papillomavirus tumors in animals [168]. A recently published article showed that a fusion protein consisting of Mycobacterium rin heat shock protein and bovis bacilli Calmette-Gue HPV type 16 E7 induces tumor regression in mice [169]. Results of phase III trials of therapeutic vaccines have not been published yet, but various therapeutic human vaccines are now under study. Results of phase I and IIa human trials using an L2E7 fusion protein in men have been published [170,171]. The phase I trial showed that this vaccine has relatively mild side effects. Those men receiving the vaccine showed increased T-cell proliferative responses, with increased IFN-g and interleukin-5 production. Antigen-specific antibody responses also were noted in this study. The phase IIa trial (for men with genital HPV lesions) revealed that 2 of 19 patients (11%) who received only vaccine had complete responses, and 5 of 27 (19%) overall had a complete response (8 of 27 patients in this study received concomitant podophyllotoxin therapy) [170]. Preliminary therapeutic vaccine studies also have been performed in patients with genital cancer. One study examined the

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effect of vaccination with an HPV E7 lipopeptide in 12 women with vaginal or cervical cancer. Although there were no clinical responses, five of seven evaluable patients were able to mount a specific immune response to E7 after two vaccinations [172]. Three clinical studies evaluated the response of patients with cervical cancer or cervical intraepithelial neoplasia grade III to a vaccine composed of vaccinia virus expressing modified HPV 16 and 18 E6 protein sequences [173]. This vaccine elicited both cellmediated and humoral immune responses in some of these patients. Clinical efficacy was difficult to determine, however, because all of these studies used the vaccine as an adjuvant to currently accepted therapies. In the absence of convincing data about their efficacy, therapeutic vaccines still require further clinical study before general use in those with highrisk HPV infections. Combinations involving most of these therapies also have been tested. It seems intuitively reasonable to suppose that there may be benefit to using therapies with different mechanisms of action when treating HPV infection. Cytodestructive therapies (laser or cryotherapy) along with immunomodulation or antimetabolic therapies have been attempted, as have other dual-modality treatments. Trials using combination therapy have not shown unequivocal superiority to monotherapy, however. More trials are needed before these treatments become widely recommended. Other treatments for HPV-induced lesions have been used with varying degrees of success, but they are now largely avoided because of unacceptable side-effect profiles and the superior performance of more recent methods. These methods include salicylic acid, glutaraldehyde, formaldehyde, monochloroacetic acid, cantharidin, retinoids, bleomycin, dinitrochlorobenzene, squaric acid dibutylester, rin diphencyprone, and topical bacillus Calmette-Gue [30,174].

Prevention Because HPV plays a large role in the oncogenic transformation of a variety of lesions (especially cervical intraepithelial neoplasia), there is great interest in primary and secondary prevention of the sequelae of these infections. Primary prevention refers to avoiding infection by high-risk HPV types, whereas secondary prevention aims to avoid the potential sequelae of HPV infection. Primary prevention efforts range from education about HPV infections to vaccine development. Numerous vaccine candidates have been identified for prevention of

high-risk HPV infections, and clinical trials are under way. To date, however, secondary prevention measures have had the greatest effect in terms of reducing mortality from HPV-related cancers. Wide use of the Papanicolaou (Pap) smear as a screening mechanism has led to a sharp decrease in the incidence of cervical cancer in the United States and other industrialized countries. Additional efforts to reduce mortality associated with HPV infection by means of secondary prevention involve providing wider availability of cervicovaginal testing and possibly using HPV typing to improve risk assessment. The importance of education in the prevention of sexually transmitted diseases (STDs) has been emphasized in the wake of the HIV epidemic. Physician involvement with preventive education and teaching of sexual safety skills may reduce the incidence of HIV and other STDs. More research in this field is needed, however. Little has been published regarding the effects of education on reduction of STD incidence, but education is a low-cost, no-risk intervention. Evidence suggests that the groups at highest risk for STDs are not adequately informed of the potential consequences of STDs or prevention strategies. In the case of HPV, one recent study of adolescents and young adult women found a considerable lack of knowledge regarding HPV and the potential consequences of infection [175]. All physicians should promote safe-sex practices and encourage their patients to ask questions and express concerns. The most promising avenue for future primary prevention strategies in HPV infections involves vaccination against high-risk HPV types. Although no phase III trial results have been published to date, preliminary data suggest that several vaccine candidates may effectively prevent high-risk HPV infections. Virus-like particles (VLPs) are noninfectious particles containing epitopes that are conformationally equivalent to those found in HPV proteins. They lack the ability to cause infections. Virus-like particles consisting of L1, L2, E6, or E7 protein epitopes from high-risk HPV types are capable of producing immunogenic responses in vitro, in animals and in humans [169,176,177]. Immune responses elicited from these vaccines involve either humoral or cellular pathways. The type of response seems to depend on whether it is induced with structural L1/L2 VLPs (inducing largely neutralizing antibody responses), or nonstructural E6/E7 protein epitopes (inducing largely cell-mediated immune responses) [169,176,178,179]. Chimeric particles consisting of E6 or E7 epitopes combined with L1 or L2 epitopes also have been tested in vitro and in animal models. These particles show great promise in preventing and treating HPV infec-

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tions [180,181]. The advantage of using chimeric particles in vaccinations is related to the ability to stimulate both humoral and cell-mediated immune responses. Currently, primary prevention strategies are focusing on vaccines inducing neutralizing antibody-mediated responses. Phase I and phase II clinical trials using L1 VLPs have demonstrated the safety and immunogenicity of these protein particles [168,176]. At least one phase III trial evaluating an HPV type 16 L1 VLP is under way. Although further study of vaccine candidates is necessary (for example, regarding the specificity of vaccines for particular HPV genotypes), vaccination against high-risk types presents an exciting avenue in primary prevention of HPV-related cancers. The single greatest success in prevention of morbidity and mortality from HPV infection is the Pap smear. In the years since the introduction of Pap smear tests, the incidence of and mortality caused by invasive cervical cancer have declined considerably in industrialized countries. Recently, the rate of decline has leveled off, however [85]. This leveling off can be attributed in part to the lack of universal use of Pap smears (possibly secondary to a lack of access to preventive health care) [85,182]. Lack of access to routine Pap testing has stimulated the search for effective evaluation of self-collected cervicovaginal samples. One study recently describing the efficacy of HPV testing of self-obtained vaginal samples versus physician-dependent testing revealed that this method might be as sensitive (but not as specific) in detecting intraepithelial lesions as Pap testing [182]. The value of Pap smear testing also may be enhanced by the addition of screening for high-risk HPV types or specific typing of HPV viruses. In a recent study, Schiffman et al [183] showed that testing for high-risk HPV types correlated extremely well with the presence of high-grade squamous intraepithelial lesions and cancer. Typing of HPV has largely been restricted to clinical trials because of the high cost and labor-intensive nature of HPV typing. New methods are being tested that may decrease the cost and time involved with this procedure, however [184]. Ultimately, HPV typing in conjunction with Pap smear testing may enhance the ability of clinicians to assess risk in patients with HPV infections.

led to a wide variety of possible new treatment modalities to combat HPV-related disease. Most HPV infections (whether high risk or low risk) resolve without any medical intervention. Persistent or progressive disease, however, remains difficult to treat. Although currently available therapies have proved efficacious and tolerable in the treatment of nongenital and genital warts, no single therapy is uniformly effective in eradicating persistent HPV infection. Cytodestructive methods, such as cryotherapy, remain the primary treatment modality for nongenital warts. Immune response modifiers, such as imiquimod, currently show the greatest promise in treating HPVinduced anogenital lesions, both with respect to complete response and in preventing recurrence. Human papillomavirus infection is one of the most common sexually transmitted diseases in the world, and cervical cancer still causes significant morbidity and mortality. Pap smear tests have greatly reduced the incidence and mortality of cervical cancer in developed countries. Additional research will focus on primary and secondary prevention strategies. Vaccines against high-risk HPV types are promising modalities currently under investigation to prevent HPV infections and possibly to treat them.

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Treatment of external genital warts in men using 5% imiquimod cream applied three times a week, once daily, twice daily, or three times a day. Sex Transm Dis 2001;28:226. Wagman FA, Estape RE, Angioli R, Penalver MA. Self-administered topical 5% imiquimod cream for external anogenital warts in adolescent girls. Obstet Gynecol 2001;97:S14. Diaz-Arrastia C, Salas-Robazetti S, Dinh T, Arany I, Tyring S, Hannigan E. Clinical and molecular responses in high-grade intraepithelial neoplasia treated with topical imiquimod 5%. Clin Cancer Res, in press. Cutler K, Kagen MH, Don PC, McAleer P, Weinberg JM. Treatment of facial verrucae with topical imiquimod cream in a patient with human immunodeficiency virus. Acta Derm Venereol 2000;80:134. Oster-Schmidt C. Imiquimod: a new possibility for treatment-resistant verrucae planae. Arch Dermatol 2001;137:666. Rinne D, Linhart C, Schofer H. Lip papillomatosis in immunodeficiency: therapy with imiquimod. Br J Dermatol 2000;142:196. Schwab RA, Elston DM. Topical imiquimod for recalcitrant facial flat warts. Cutis 2000;65:160. Stockfleth E, Meyer T, Benninghoff B, Christophers E. Successful treatment of actinic keratosis with imiquimod cream 5%: a report of six cases. Br J Dermatol 2001;144:1050. Hengge UR, Esser S, Schultewolter T, Behrendt C, Meyer T, Stockfleth E, et al. Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum. Br J Dermatol 2000; 143:1026. Mackenzie-Wood A, Kossard S, de Launey J, Wilkinson B, Owens ML. Imiquimod 5% cream in the treatment of Bowens disease. J Am Acad Dermatol 2001;44:462. Gollnick H, Barasso R, Jappe U, Ward K, Eul A, Carey-Yard M, et al. Safety and efficacy of imiquimod 5% cream in the treatment of penile genital warts in uncircumcised men when applied three times weekly or once per day. Int J STD AIDS 2001;12:22. Petry KU, Scheffel D, Bode U, Gabrysiak T, Kochel H, Kupsch E, et al. Cellular immunodeficiency enhances the progression of human papillomavirus-associated cervical lesions. Int J Cancer 1994;57:836. Da Silva DM, Eiben GL, Fausch SC, Wakabayashi MT, Rudolf MP, Velders MP, et al. Cervical cancer vaccines: emerging concepts and developments. J Cell Physiol 2001;186:169. Bosch FX, Rohan T, Schneider A, Frazer I, Pfister H, Castellsague X, et al. Papillomavirus research update: highlights of the Barcelona HPV 2000 International Papillomavirus Conference. J Clin Pathol 2001;54:163. Chu NR, Wu HB, Wu T, Boux LJ, Siegel MI, Mizzen LA. Immunotherapy of a human papillomavirus (HPV) type 16 E7-expressing tumour by administration of fusion protein comprising Mycobacterium bovis bacille Calmette-Guerin (BCG) hsp65 and HPV16 E7. Clin Exp Immunol 2000;121:216. Lacey CJ, Thompson HS, Monteiro EF, ONeill T, Davies ML, Holding FP, et al. Phase IIa safety and immunogenicity of a therapeutic vaccine, TA-GW, in persons with genital warts. J Infect Dis 1999;179:612. Thompson HS, Davies ML, Holding FP, Fallon RE, Mann AE, ONeill T, et al. Phase I safety and antigenicity of TA-GW: a recombinant HPV6 L2E7 vaccine for the treatment of genital warts. Vaccine 1999;17:40. Steller MA, Gurski KJ, Murakami M, Daniel RW, Shah KV, Celis E, et al. Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7. Clin Cancer Res 1998;4:2103. Adams M, Borysiewicz L, Fiander A, Man S, Jasani B, Navabi H, et al. Clinical studies of human papilloma vaccines in pre-invasive and invasive cancer. Vaccine 2001;19:2549. Bohle A, Doehn C, Kausch I, Jocham D. Treatment of recurrent penile condylomata acuminata with external application and intraurethral instillation of bacillus Calmette-Guerin. J Urol 1998;160:394. Hoover DR, Carfioli B, Moench EA. Attitudes of adolescent/young adult women toward human papillomavirus vaccination and clinical trials. Health Care Women Int 2000;21:375. Harro CD, Pang YY, Roden RB, Hildesheim A, Wang Z, Reynolds MJ, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001;93:284. Schiller J, Lowy D. Papillomavirus-like particle vaccines. J Natl Cancer Inst Monogr 2001;50. He Z, Wlazlo AP, Kowalczyk DW, Cheng J, Xiang ZQ, Giles-Davis W, et al. Viral recombinant vaccines to the E6 and E7 antigens of HPV-16. Virology 2000;270:146.

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Parvovirus B19: a review

Rajani Katta, MD
Department of Dermatology, Baylor College of Medicine, 6560 Fannin, Suite 802, Houston, TX 77030, USA

Background Parvovirus B19 is a human pathogen that may result in a spectrum of clinical findings. Clinical features range from subclinical infection to dermatologic, rheumatologic, and hematologic findings, to potentially fatal effects. New evidence even suggests a role in the pathogenesis of collagen-vascular diseases. Parvovirus B19 is the only parvovirus clearly linked with human disease. The virus belongs to the family Parvoviridae and the genus Erythrovirus and is a nonenveloped, single-stranded DNA virus [1]. It is resistant to heat and detergent because of its small genome and lack of a membrane [2]. The virus itself was originally discovered in 1974, and the name B19 refers to the blood bank code by which the original positive serum sample was labeled [3]. The virus is highly tropic for erythroid progenitor cells and thus is classified as an erythrovirus. In fact, complete replication of the virus has been found only in these cells [2]. The cellular receptor for B19 is a globoside, also known as blood group P antigen. Clinically, this classification means that those persons lacking this antigen on their erythroid cells are not susceptible to infection with B19 [2]. The virus is composed of three proteins in association with a DNA molecule. These proteins include one nonstructural protein, NS1, and two structural proteins, VP1 and VP2. Although not fully defined, studies have made some progress in identifying antigenic regions on these proteins [4,5]. Epidemiology

demonstrated to rise from approximately 40% in children and adolescents, to 60% in adults, to 75% in adults older than 40 [6]. The prevalence varies among countries, and interestingly, it seems to be more common in temperate versus tropical countries. Although the prevalence in England and Wales is similar to that of Australia, countries such as Singapore and South Africa demonstrate a lower prevalence of immunity in adults [6]. Transmission Transmission of the virus occurs through the respiratory route in most cases. The virus is shed in nasal and oral secretions during periods of viremia, so patients may transmit the virus before development of rash [7]. Much less likely is transmission by way of blood products or bone marrow. Evidence supports transmission through transfusion with blood products, primarily pooled blood products [8,9]. Because parvovirus B19 lacks a lipid envelope, it is not inactivated during treatment with solvents and detergents [9]. Although neutralizing antibodies present in pooled plasma may prevent transmission, the infectivity of donor blood is not fully understood [2,8]. A workshop convened by the National Heart, Lung, and Blood Institute recommended additional research in this area but concluded that there was insufficient evidence to recommend universal testing [2]. Transmission by way of bone marrow (during bone marrow transplant) also has been demonstrated [10]. Clinical features

Infection with parvovirus is ubiquitous and occurs worldwide. The prevalence of immunity to parvovirus, indicative of prior infection, has been shown to rise with age. In Australia, this prevalence was

The main clinical features of infection with B19 include dermatologic manifestations, rheumatologic findings, and hematologic effects. It should be noted

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specifically that asymptomatic infection with parvovirus B19 is considered common. In one outbreak, 26% of adults were reported to be asymptomatic [11]. Less commonly, infection may result in neurologic and hepatic disease [3]. Much of what is known concerning the clinical features of B19 infection comes from epidemiologic studies and case reports; however, Anderson et al [12] studied patients with experimental infection. After intranasal administration of virus to healthy adults, some patients were asymptomatic, whereas others experienced fever, chills, headache, and myalgias on day 6. These symptoms correlated with a peak in viremia. On approximately day 10, IgM anti-B19 antibody appeared, followed by IgG anti-B19 a few days later. The appearance of IgG correlated with appearance of the classic dermatologic findings of slapped-cheek appearance of the face and reticular erythema on the extremities. Although these healthy volunteers did not develop anemia, they did exhibit reticulocytopenia. In outbreaks of natural infection, the incubation period has been reported to vary between 6 to 18 days, although incubation as long as 28 days has been reported [7]. The IgG antibody has been demonstrated to persist for many years, probably lifelong, and confers long-lasting immunity.

Dermatologic manifestations The first description of parvovirus infection was made by a dermatologist two centuries ago with a report of clinical features recognized today as erythema infectiosum [3]. It has since been shown that B19 infection may result in a spectrum of dermatologic diseases. Infection may result in two specific B19related dermatologic diseases, erythema infectiosum and papular purpuric gloves-and-socks syndrome. Infection also may result in nonspecific findings, such as reticular erythema, maculopapular eruptions, and purpuric eruptions. Other dermatologic entities, such as erythema multiforme and Gianotti-Crosti syndrome, which may occur because of a number of causes, also have been linked to B19 infection. The most well-known dermatologic manifestation of parvovirus B19 is erythema infectiosum. This well-recognized exanthem also is called fifth disease, and it often is described with the term slapped cheek. Less widely recognized and described only a decade ago, papular purpuric gloves-and-socks syndrome also is associated with parvovirus B19. Nonspecific dermatologic findings are linked less frequently to parvovirus, which is understandable, because such nonspecific findings typically are not

investigated; however, Seishima et al [13] undertook a study of the clinical features of adults with IgM antibodies positive to B19. In their study of 22 adults, they found that the cutaneous manifestations fell into three groups. In the first, reticular erythema occurred, similar to that seen in erythema infectiosum. The second group exhibited maculopapular eruptions similar to rubella. The third group exhibited petechiae and purpura, although none of the cases were limited to the hands and feet. Most of these patients were febrile and complained of multiple arthralgias and general fatigue. In approximately one fourth to one third of cases, lymph node swelling, lower extremity edema, and swelling of the fingers were seen. In their series of 16 patients, Cathebras et al [14] also noted dermatologic findings of vascular purpura and edema. Magro et al [15] described patients with cutaneous findings associated either with serologic evidence of B19 infection or documentation of B19 genome in lesional skin. In their series of 14 patients, 3 patients presented with typical erythema infectiosum. Other presentations included eruptions resembling cutaneous lupus, dermatomyositis, and Sweets syndrome, in addition to two cases of palpable purpura. Scattered case reports also describe nonspecific findings. One case described generalized livedo reticularis [16]. Others have described desquamation [17] and vesiculopustular skin eruptions [18]. Pruritus in the absence of rash has been described [19]. Numerous case reports have described other types of specific dermatologic disorders in association with parvovirus infection. Erythema multiforme has occurred in association with acute infection [20], as has erythema nodosum [21]. Angioedema has been described with B19 infection, both in adults [22] and in a neonate after intrauterine infection [23]. Gianotti-Crosti syndrome, also known as papular acrodermatitis of childhood, has been noted after B19 infection [24]. The purpuric manifestations of B19 infection merit special mention. Several types of purpuric manifestations have been described [25], including nonspecific vascular petechiae and purpura [26]. Thrombotic thrombocytopenic purpura [27] and idiopathic thrombocytopenic purpura [28] have been described in case reports. Other specific syndromes manifesting purpura have been described, including the aforementioned papular purpuric gloves-andsocks syndrome, leukocytoclastic vasculitis, and Henoch-Schonlein purpura. Erythema infectiosum The distinct clinical features of erythema infectiosum were recognized well before the discovery of the

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virus. Confirmation of viral infection is not necessary, because the diagnosis usually is made easily on the basis of the characteristic and unique clinical features. Infected persons experience a nonspecific prodrome followed by an exanthem that typically proceeds through three stages. The distinctive dermatologic signs of infection include a slappedcheek appearance and reticulated erythema of the trunk and extremities. The other primary clinical findings are rheumatologic. The clinical features of erythema infectiosum vary depending on the age of the patient. In children, the classic rash typically is present, whereas in adults, the rash is more subtle. Adults experience a higher incidence of associated arthralgia and arthritis and typically experience more severe constitutional symptoms, however. The distinctive slapped-cheek appearance of an infected child represents the first stage of the exanthem (Fig. 1). In this stage, erythema of the cheeks is associated with relative circumoral pallor [1]. In the second stage, an erythematous maculopapular rash is noted 1 to 4 days later on the trunk and extremities. During this stage, another distinctive clinical feature of the rash may be seen. Central clearing of the rash results in the characteristic reticular pattern (Fig. 2) [29]. In the last stage, which may last from 1 to 3 weeks, the exanthem persists and may vary related to factors such as sunlight and heat. Healthy individuals, by the time they present with a rash, are no longer infectious. The prognosis in

these individuals is excellent; although the rash may recur or persist for months, no long-term sequelae are expected. It is important, however, to determine any possible exposures to members of at-risk populations, as discussed in a following section. Papular purpuric gloves-and-socks syndrome Papular purpuric gloves-and-socks syndrome is a distinctive rash that was described only in the past decade [30]. The typical features include acral purpuric erythema, occasionally associated with fever and oral lesions. The rash typically occurs in young adults, but it has been reported in children. A seasonal incidence is noted, with most cases occurring in the spring and summer [31]. Clinically, the rash consists of symmetric erythema and edema of the hands and feet, with gradual progression to petechiae and purpura. One of the clinical hallmarks of the rash is the sharp demarcation on the wrists and ankles, leading to the name gloves-and-socks syndrome. The rash typically is painful. It has been reported that other areas of the body have been involved, albeit less frequently, including the cheeks, thighs, elbows, knees, and buttocks [31]. Mucosal involvement is a common finding. Oral erosions, petechiae, and edema may involve the lips, buccal mucosa, and palate. In immunocompetent patients, some cases may be associated with systemic symptoms, typically fever and arthralgias; however, the patients usually appear

Fig. 1. Erythema of the cheeks in a child, resulting in the slapped-cheek appearance of erythema infectiosum.

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Fig. 2. Reticulated erythema of the trunk and extremities typical of erythema infectiosum, in a child seated in a bathtub. (Courtesy of Denise Metry, MD.)

nontoxic. On laboratory examination, lymphopenia often is seen, whereas findings such as elevated liver enzymes and transient anemia are much less frequent. The overall prognosis for this exanthem is excellent. Resolution occurs within 1 to 2 weeks, and no permanent sequelae are expected. In immunosuppressed patients, however, papular purpuric gloves-andsocks syndrome may lead to more serious complications. The eruption may cause prolonged cutaneous lesions and pruritus and has been shown to cause persistent anemia [32]. The link to parvovirus B19 is widely accepted. Other viruses have been implicated based on serologic evidence, including cytomegalovirus, Coxsackievirus, measles virus, and human herpesviruses 6 and 7 [33]. At present, the evidence linking the syndrome to parvovirus B19 is more convincing, however. Serologic studies of patients with papular purpuric gloves-and-socks syndrome have demonstrated the widespread prevalence of IgM antibodies to parvovirus B19 [34]. In addition, tissue studies have supported the role of parvovirus B19, with demonstration of viral antigens in dermal vessel walls and keratinocytes by immunohistochemistry, and demonstration of specific viral DNA in skin biopsy samples by polymerase chain reaction [35]. Unlike patients with erythema infectiosum, patients are considered infectious when the rash is present [31]. Counseling of these patients against ongoing exposures to at-risk populations, as discussed later, is mandatory.

Histopathology Skin biopsy is not typically needed or performed in most patients suspected of parvovirus infection; however, in cases in which a biopsy is performed, certain histopathologic features may be more suggestive of the diagnosis. Magro et al [15] examined a series of patients presenting with skin eruptions accompanied by clinical signs or serology suggestive of B19 infection. In 11 of 14 patients, B19 genome was present in the skin biopsy specimen. Most cases revealed interstitial histiocytic and lymphocytic infiltrates along with collagen fragmentation. Some cases also revealed findings of interface dermatitis, lymphocytic vasculitis, or leukocytoclastic vasculitis. The additional findings correlated in some cases with unusual clinical features, resembling connective tissue disease or cutaneous vasculitis. Takahashi et al [36] obtained a biopsy sample from a truncal rash in a patient with features typical of erythema infectiosum. Light microscopy showed dilated and irregularshaped dermal vessels, with swelling of endothelial cells. Mild to moderate perivascular infiltrates of mononuclear cells were noted.

Diagnosis In most cases, the diagnosis rests on the characteristic clinical features; however, serology may be useful in atypical cases. Enzyme immunoassay may

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be used to test for parvovirus IgG and IgM. The test has been shown to have a high sensitivity (97% 100%) and a relatively high specificity (79% 99%) [37]. Detection of IgG antibody is not likely to be helpful diagnostically, because seroprevalence in most countries, particularly in adults, is relatively high. Detection of IgM may be more useful clinically, because it may be present for as long as 2 to 3 months after acute infection [7]. In the patient who presents with an atypical skin eruption, punch biopsy is used mainly to exclude other processes. Although suggestive features may be found, features diagnostic of parvovirus infection have not been identified. Culture of the virus is not performed in most settings, because the virus is not culturable using routine diagnostic methods. Erythroid progenitor cell culture is needed for successful culture [1]. Multiple investigators have used the technique of polymerase chain reaction to amplify and identify B19 DNA in tissue samples, such as synovium or skin [15,35,38]. Electron microscopy may demonstrate viral particles in involved tissues [36]. Both of these techniques are primarily of use in research settings.

rus antigens. In the case of collagen-vascular diseases such as systemic lupus erythematosus, it has been suggested that B19 infection serves as one of many possible triggers resulting in a disordered immune response and the resulting clinical complex [1].

At-risk populations In certain populations, infection with parvovirus B19 may lead to devastating complications. These populations include patients with hematologic disease, immunosuppressed patients, and pregnant women. Because B19 exhibits tropism for erythroid progenitor cells, any individual who has a shortened red blood cell survival time is at risk for an aplastic crisis. Because patients are no longer able to compensate for shortened red blood cell survival with increased red blood cell production, their anemia worsens. In fact, in patients with chronic hemolytic anemia, parvovirus B19 is the most common cause of transient aplastic crisis. Patients with sickle cell anemia, thalassemia, autoimmune hemolytic anemia, and other conditions involving red blood cell destruction are susceptible. These diseases may even be initially diagnosed because of the aplastic crisis. These patients rarely exhibit a rash; they present with fever, constitutional symptoms, and worsening anemia [3]. The crisis is indeed transient; most patients recover in a week, although fatalities do occur. Patients who are immunocompromised represent another population prone to complications from B19 infection. In this population, chronic anemia may be seen. In patients who are immunocompromised because of HIV infections [40], transplantation, [41], or congenital immunodeficiencies [42], chronic B19 infection may occur. This infection results in persistent lysis of red blood cell precursors, which results in prolonged anemia. Prolonged cutaneous signs and symptoms also have been reported [32]. The other main population at risk of serious complications caused by B19 infection is pregnant women. In this case, devastating effects on the fetus may result. This population is reviewed in greater detail. Pregnancy The diagnosis of parvovirus B19 in any individual, child or adult, necessitates inquiries as to all possible exposures to pregnant women. Although the risk of fetal infection and subsequent adverse outcomes is not high, when infection occurs it can be devastating. In the patient who presents with parvovirus infection, this aspect of counseling is crucial.

Pathogenesis In the case of erythema infectiosum, many authors hypothesize that the clinical findings result from the humoral response exhibited by patients. Although patients often experience bone marrow suppression during the initial viremic phase, the typical dermatologic and rheumatologic symptoms appear only with the development of specific B19 antibodies, suggesting that deposition of immune complexes in skin, joints, and other organs results in the typical pattern of clinical findings [2]. In support of this hypothesis, patients with arthritis caused by B19 infection demonstrate low serum complement levels and circulating immune complexes [39]. Others have hypothesized that the typical cutaneous findings result from an inflammatory reaction to parvovirus antigens in the skin. Takahashi et al [36] examined involved skin by immunohistochemistry and electron microscopy. Positive reactions with parvovirus monoclonal antibody were seen in endothelial cells, whereas examination by electron microscopy revealed virus particles in the cytoplasm of endothelial cells. In the perivascular region, deposits of C3 were seen, along with a mild to moderate infiltrate of mononuclear cells. The authors hypothesized that the clinical finding of skin rash was attributable to the inflammatory reaction directed against these parvovi-

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Unfortunately, by the time a patient presents with the rash of erythema infectiosum, the damage has been done already. Because the virus is transmitted before the rash appears, any exposures in the household, at the workplace, or at school or daycare centers must be reviewed carefully. Although an infected patient may have been exposed to a pregnant woman, many factors affect the likelihood of transmission to that woman. These factors range from duration and type of exposure to immune status of the woman. In one study conducted in Denmark, several factors were related to increased risk of acute B19 infection during pregnancy, including having children at home, a history of serious medical disease, and having a stressful job [43]. Overall, even if a pregnant woman is infected by the virus, most fetuses are not infected, and even if infected, they usually do not experience adverse outcomes. In infected pregnant women, parvovirus B19 is believed to affect the fetus approximately 30% of the time; however, only 9% of infected fetuses experience poor outcomes [44]. Possible adverse fetal outcomes range from hydrops fetalis to congenital anemia to death. Hydrops fetalis, also known as nonimmune fetal hydrops, is the most common complication. The fetus is quite dependent on increased erythropoiesis because of decreased erythrocyte survival and an increased red cell mass. When erythropoeisis is decreased during fetal B19 infection, an aplastic crisis results, which leads to the clinical findings of nonimmune fetal hydrops with high-output cardiac failure and edema. This complication may result in diverse outcomes: complete recovery with no permanent sequelae, congenital anemia, cardiac or hepatic dysfunction, or fetal death [7]. Prolonged congenital anemia also may result [45]. Fetal death also may result from fetal infection, with miscarriage more likely in the first half of pregnancy. In one study, women infected during weeks 9 to 20 of pregnancy had a 10% incidence of fetal loss. If infection occurred later than week 20, fetal loss was rare [46]. Another study estimated the overall risk of fetal death as 6.5% in infected mothers [47]. If a pregnant woman has been exposed to an infected individual, serologic testing for IgG and IgM should be performed. Infected women are monitored closely by their obstetricians with examinations and serial ultrasounds. Even in fetuses displaying evidence of infection, spontaneous resolution is common. The monitoring and treatment of hydrops fetalis has improved with advances in fetal medicine, including the use of ultrasound and intrauterine transfusions [48].

Systemic diseases A number of systemic illnesses have been noted to occur in association with B19 virus infections. It is unclear if the virus occurs coincidentally, acts as an exciting agent, or is causal [3]. The list is impressive and includes systemic vasculitic disorders and rheumatologic disorders. A brief review follows.

Vascular effects A number of case reports and case series have described vascular effects in association with B19 infection. The clinical manifestations have ranged from vasospasm to leukocytoclastic vasculitis to specific vasculitic syndromes. These vascular effects are not unexpected. In an infected patient, viral particles were found to concentrate in endothelial cells [36], and in the human fetus infected by B19, placental villi demonstrate histologic features of vasculitis [49]. Clinically, multiple case reports have described leukocytoclastic vasculitis [50,51] during B19 infection. Multiple cases of Henoch-Schonlein purpura have occurred in conjunction with acute infection in children and adults [25,52 54]. A link also has been suggested in children with Kawasaki disease [52]. Apart from inflammation of vessel walls, B19 infection may lead to other vascular effects. In one case, bilateral digital arterial occlusive disease was reported, in the absence of vasculitis [55]. Raynauds phenomenon induced by B19 also has been reported [56]. B19 infection also has been linked to specific vasculitic disorders, including giant cell arteritis, polyarteritis nodosa, and Wegeners granulomatosis. An association between parvovirus infection and giant cell arteritis initially was suggested on the basis of epidemiologic studies. In Denmark, surveillance serologic data compared with histopathologic data revealed that peaks of positive temporal artery biopsies occurred after major parvovirus epidemics [57]. Investigators in the United States also have noted this association, and in addition found significantly higher levels of B19 DNA in temporal artery biopsy tissues of affected patients [58]. The evidence supporting a link between B19 infection and polyarteritis nodosa or Wegeners granulomatosis is weaker. Although case reports have described an association, no significant prevalence of B19 infection was found when screening larger series of patients with polyarteritis nodosa and Wegeners granulomatosis [7].

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Rheumatologic findings Parvovirus may lead to either acute or chronic rheumatologic symptoms. The clinical pattern of these symptoms has been noted by many clinicians to bear several striking similarities to specific rheumatologic diseases. Investigators have taken these observations further and have attempted to determine whether parvovirus is involved in the pathogenesis of certain rheumatologic diseases, such as systemic lupus erythematosus and rheumatoid arthritis. Conflicting evidence has made it difficult to draw any definite conclusions on the subject, however. Joint symptoms are a major clinical feature of parvovirus infection, and nonspecific arthritis and arthralgias often are seen. Joint symptoms occur only in approximately 8% of infected children, whereas that number rises to approximately 60% of infected adults [59]. The joint symptoms may either coincide with or follow the skin eruption. Many infected adults experience arthritis alone. The joints typically involved in children are the large joints, particularly the knees. In adults, the pattern is that of acute-onset symmetric polyarthritis, typically of the small joints of the hands or the knees, with women affected more frequently than men [59]. The incidence of chronic joint symptoms has been difficult to determine. In one study of patients followed up for a mean of almost 5 years, 80% of patients had arthritis acutely, whereas 17% noted chronic joint pain [60]. Another study, however, found that although 61% of patients had arthritis acutely, none had chronic arthritis after 5 years [61]. Even in the absence of obvious acute infection, parvovirus has been suggested as a cause of chronic undifferentiated arthritis, owing to the findings of viral DNA in synovial tissue [38]. Such findings are difficult to interpret, however. In another study of patients with rheumatoid arthritis, B19 DNA was found in the synovial tissue of 28% of patients; however, it also was seen in half of adults without rheumatoid arthritis [62]. Parvovirus infection has been linked to several chronic rheumatologic disorders. Several investigators have studied a possible link to systemic lupus erythematosus. A number of investigators also have examined the role that parvovirus may play in the pathogenesis of rheumatoid arthritis and juvenile idiopathic arthritis (Stills disease). A smaller body of evidence has proposed a role for B19 in the pathogenesis of scleroderma and dermatomyositis. Several investigators have focused on a link between B19 infection and systemic lupus erythematosus. The clinical features of these diseases exhibit several similarities, with the presence of fever, rash,

joint symptoms, and hematologic abnormalities. Acute B19 infection may not only mimic systemic lupus erythematosus but also exacerbate it [63]. One study of seroprevalence, however, found no difference between patients with systemic lupus erythematosus and control patients [64]. It has been suggested that parvovirus may serve as only one of many possible triggers in induction of systemic lupus erythematosus [1]. Parvovirus has been hypothesized to play a role in the pathogenesis of rheumatoid arthritis for multiple reasons, including the fact that chronic arthritis after B19 infection may be clinically indistinguishable from rheumatoid arthritis. Supportive studies also have investigated rheumatoid factor production, IgM B19 antibodies, and the presence of B19 DNA in involved tissues [1]; however, these studies have provided conflicting evidence. Similar issues have been raised in the pathogenesis of Stills disease; although the clinical presentation of acute B19 infection is similar to Stills disease, studies have provided conflicting data. In both cases, it is again believed that parvovirus B19 may serve as only one of many possible triggers [1]. A link with systemic sclerosis also has been suggested. A comparison of affected patients with control patients showed a marked increase in the presence of B19 DNA in bone marrow biopsy specimens as detected by polymerase chain reaction. Serum antibodies to parvovirus B19 were detected more frequently in affected patients [65]. Such findings do not confirm causality, however, and further evidence is needed to draw any such conclusions. The same difficulty arises when examining the evidence linking parvovirus to dermatomyositis. Skin biopsy samples of two patients with dermatomyositis were examined because of atypical clinical features and atypical histology. Investigation of the skin biopsy specimens by polymerase chain reaction revealed the B19 genome, suggesting that persistent B19 infection may be of importance in pathogenesis [66]. In another patient with dermatomyositis, molecular evidence revealed parvovirus B19 DNA in two muscle biopsy samples. The authors suggested that an aberrant host immune response triggered by the parvovirus led to muscle destruction [67].

Treatment Treatment of patients with either dermatologic or rheumatologic symptoms is primarily symptomatic. In the immunocompetent, healthy individual, patients do well, and the acute symptoms typically resolve

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without complications. Some persons may develop chronic arthritis, however, and should be referred for appropriate care. Treatment of certain groups of patients raises more challenges. In pregnant women, immunosuppressed persons, or those with any type of chronic hemolytic anemia, care must be coordinated with a specialist (ie, infectious disease, obstetrics, hematology). In these patients, devastating systemic effects may occur, and early monitoring for complications is crucial. One advance in treatment is the use of high-dose intravenous immunoglobulin in immunocompromised patients at high risk of complications [68]. Intravenous immunoglobulin has been used to treat B19-induced anemia in patients with immunodeficiency [42], transplant recipients [41], and in patients with AIDS [40]. Intravenous immunoglobulin from a variety of sources has been demonstrated by immunoblot to have high titers of antibody against VP1 and VP2. These antibodies lead to clearance of the virus from blood and bone marrow and thus permit recovery of erythropoiesis [2]. One aspect of treatment should never be overlooked. Even in the healthy patient, an important aspect of care is identifying any prior or ongoing exposure to susceptible populations. These populations, as mentioned previously, include pregnant women, immunosuppressed persons, or those with any type of chronic hemolytic anemia. If a member of these groups has been exposed, notification of the patient and subsequent observation by his or her treating physician are necessary. A frequent question that arises is the issue of contagion. In infected adults or children, recommendations vary depending on the type of dermatologic manifestations seen. In the case of erythema infectiosum, patients with the rash are no longer considered contagious, and if feeling well, may attend school. Patients with papular and purpuric gloves-andsocks syndrome are considered contagious, however, and should take appropriate steps to avoid infecting others.

erythema multiforme and erythema nodosum, also have been described. A role in the pathogenesis of various collagen vascular disorders has been suggested and is under investigation. The diagnosis of infection rests on the typical clinical findings. Whenever parvovirus B19 infection is diagnosed, the physician must ensure that neither the patient nor his or her contacts is a member of certain vulnerable populations. In these populations, infection with parvovirus B19 may result in devastating complications. The vulnerable populations include those with hematologic disease, immunosuppressed patients, and pregnant women. Treatment of infection in the healthy immunocompetent individual is asymptomatic, and the acute infections typically resolve without complications. References
[1] Kerr JR. Pathogenesis of human parvovirus B19 in rheumatic disease. Ann Rheum Dis 2000;59:672 83. [2] Brown KE, Young NS, Barbosa LH. Parvovirus B19: implications for transfusion medicine. Summary of a workshop. Transfusion 2001;41:130 5. [3] Cherry JD. Parvovirus infections in children and adults. Adv Pediatr 1999;46:245 69. [4] Tolfvenstam T, Lundqvist A, Levi M, Wahren B, Broliden K. Mapping of B-cell epitopes on human parvovirus B19 non-structural and structural proteins. Vaccine 2000;19:758 63. [5] Tolfvenstam T, Oxenius A, Price DA, et al. Direct ex vivo measurement of CD8+ T-lymphocyte responses to human parvovirus B19. J Virol 2001;75:540 3. [6] Kelly HA, Siebert D, Hammond R, et al. The agespecific prevalence of human parvovirus immunity in Victoria, Australia compared with other parts of the world. Epidemiol Infect 2000;124:449 57. [7] Naides SJ. Infection with parvovirus B19. Curr Inf Dis Reports 1999;1:273 8. [8] Koenigbauer UF, Eastlund T, Day JW. Clinical illness due to parvovirus B19 infection after infusion of solvent/ detergent-treated pooled plasma. Transfusion 2000; 40:1203 6. [9] Teitel JM. Viral safety of haemophilia treatment products. Ann Med 2000;32:485 92. [10] Heegaard ED, Petersen Laub B. Parvovirus B19 transmitted by bone marrow. Br J Haematol 2000; 111:659 61. [11] Woolf AD, et al. Clinical manifestations of human parvovirus B19 in adults. Arch Intern Med 1989;149: 1153 6. [12] Anderson MJ, Higgins PG, Davis LR, et al. Experimental parvoviral infection in humans. J Infect Dis 1985;152:257 65. [13] Seishima M, Kanoh H, Izumi T. The spectrum of cutaneous eruptions in 22 patients with isolated serological evidence of infection by parvovirus B19. Arch Dermatol 1999;135:1556 7.

Summary Infection with parvovirus B19 may result in a wide range of dermatologic manifestations. The specific skin findings include erythema infectiosum and papular purpuric gloves-and-socks syndrome. The nonspecific findings include reticular erythema, maculopapular eruptions, and petechiae and purpura, as well as other less frequently described findings. Associations with other dermatologic diseases, such as

R. Katta / Dermatol Clin 20 (2002) 333342 [14] Cathebras P, Robert F, Guglielminotti C, et al. Primary parvovirus B19 infection in immunocompetent adults: clinical and biological manifestations. Retrospective study of 16 patients. Rev Med Interne 2000;21:324 9. [15] Magro CM, Dawood MR, Crowson AN. The cutaneous manifestations of human parvovirus B19 infection. Hum Pathol 2000;31:488 97. [16] Dereure O, Montes B, Guilhou JJ. Acute generalised livedo reticularis with myasthenia-like syndrome revealing parvovirus B19 primary infection. Arch Dermatol 1995;131:744 5. [17] Yetgin S, Cetin M, Yenicesu I, et al. Acute parvovirus B19 infection mimicking juvenile myelomonocytic leukemia. Eur J Haematol 2000;65:276 8. [18] Naides SJ, Piette W, Veach LA, Argenyi Z. Human parvovirus B19-induced vesiculopustular skin eruption. Am J Med 1988;84:968 72. [19] Lyon CC. Severe acral pruritus associated with parvovirus B19 infection. Br J Dermatol 1998;139:152 4. [20] Lobkowicz F, Ring J, Schwarz TF, et al. Erythema multiforme in a patient with acute human parvovirus B19 infection. J Am Acad Dermatol 1989;20:849 50. [21] Imbert B, Brion JP, Janbon B, et al. Erythema nouveau associe a une infection par le parvovirus B19. Presse Med 1989;18:1753 4. [22] Fawaz-Estrup F. Human parvovirus infection: rheumatic manifestations, angioedema, C1 esterase inhibitor deficiency, ANA positivity, and possible onset of systemic lupus erythematosus. J Rheumatol 1996;23: 1180 5. [23] Miyagawa S, Takahashi Y, Nagai A, et al. Angio-oedema in a neonate with IgG antibodies to parvovirus B19 following intrauterine parvovirus B19 infection. Br J Dermatol 2000;143:428 30. [24] Carrascosa JM, Just M, Ribera M, et al. Papular acrodermatitis of childhood related to poxvirus and parvovirus B19 infection. Cutis 1998;61:265 7. [25] Veraldi S, Rizzitelli G. Henoch-Schonlein purpura and human parvovirus B19. Dermatology 1994;189:213 4. [26] Mortimer PP, Cohen BJ, Rossiter MA. Human parvovirus and purpura. Lancet 1985;2(8457):730 1. [27] Kok RH, Wolfhagen MJ, Klosters G. A syndrome resembling thrombotic thrombocytopenic purpura associated with human parvovirus B19 infection. Clin Infect Dis 2001;32:311 2. [28] Lefrere JJ, Courouce AM, Kaplan C. Parvovirus and idiopathic thrombocytopenic purpura. Lancet 1989;1 (8632):279. [29] Feder HM, Anderson I. Fifth disease: a brief review of infections in childhood, in adulthood, and in pregnancy. Arch Intern Med 1989;149:2176 8. [30] Harms M, Feldmann R, Saurat JH. Papular-purpuric gloves and socks syndrome. J Am Acad Dermatol 1990;23:850 4. [31] Nelson JS, Stone MS. Update on selected viral exanthems. Curr Opin Pediatr 2000;12:359 64. [32] Ghigliotti G, Mazzarello G, Nigro A, et al. Papular-purpuric gloves and socks syndrome in HIV-positive patients. J Am Acad Dermatol 2000;43(5 Pt 2):916 17.

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[33] Ongradi J, Becker K, Horvath A, et al. Simultaneous infection by human herpesvirus 7 and human parvovirus B19 in papular-purpuric gloves-and-socks syndrome. Arch Dermatol 2000;136:672. [34] Trattner A, David M. Purpuric gloves and socks syndrome: histologic, immunofluorescence and polymerase chain reaction study. J Am Acad Dermatol 1994; 30:267 8. [35] Aractingi S, Bakhos D, Flageul B, et al. Immunohistochemical and virological study of skin in the papularpurpuric gloves and socks syndrome. Br J Dermatol 1996;135:599 602. [36] Takahashi M, Ito M, Sakamoto F, et al. Human parvovirus B19 infection: immunohistochemical and electron microscopic studies of skin lesions. J Cutan Pathol 1995;22:168 72. [37] Sloots T, Devine PL. Evaluation of four commercial enzyme immunoassays for detection of immunoglobulin M antibodies to human parvovirus B19. Eur J Clin Microbiol Infect Dis 1996;15:758 61. [38] Stahl HD, Seidl B, Hubner B, et al. High incidence of parvovirus B19 DNA in synovial tissue of patients with undifferentiated mono- and oligoarthritis. Clin Rheumatol 2000;19:281 6. [39] White DG, Woolf AD, Mortimer PP, et al. Human parvovirus arthropathy. Lancet 1985;1:419 21. [40] Frickhofen N, Abkowitz JL, Safford M, et al. Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type I (HIV-1): a treatable cause of anemia in AIDS. Ann Intern Med 1990; 113:926 33. [41] Geetha D, Zachary JB, Baldado HM, Kronz JD, Kraus ES. Pure red cell aplasia caused by parvovirus B19 infection in solid organ transplant recipients: a case report and review of literature. Clin Transplant 2000; 14:586 91. [42] Kurtzman GJ, Ozawa K, Cohen B, et al. Chronic bone marrow failure due to persistent B19 parvovirus infection. N Engl J Med 1987;317:287 94. [43] Jensen IP, Thorsen P, Jeune B, Moller BR, Vestergaard BF. An epidemic of parvovirus B19 in a population of 3,596 pregnant women: a study of sociodemographic and medical risk factors. BJOG 2000;107:637 43. [44] Public Health Laboratory Service Working Party on Fifth Disease. Prospective study of human parvovirus (B19) infection in pregnancy. BMJ 1990;200:1166 70. [45] Heegaard ED, Hasle H, Skibsted L, et al. Congenital anemia caused by parvovirus B19 infection. Pediatr Infect Dis J 2000;19:1216 8. [46] Miller E, Fairley CK, Cohen BJ, et al. Immediate and long term outcome of human parvovirus B19 infection in pregnancy. Br J Obstet Gynaecol 1998;105: 174 8. [47] Levy R. Infection by parvovirus B19 during pregnancy: a review. Obstet Gynecol Surv 1997;52:254 9. [48] Sahakian V, Weiner CP, Naides SJ, et al. Intrauterine transfusion treatment of nonimmune hydrops fetalis secondary to human parvovirus B19 infection. Am J Obstet Gynecol 1991;164:1090 1.

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R. Katta / Dermatol Clin 20 (2002) 333342 [59] Moore TL. Parvovirus-associated arthritis. Curr Opin Rheumatol 2000;12:289 94. [60] Kerr JR, Coyle PV, Deleys RJ, et al. Follow-up study of clinical and immunological findings in patients presenting with acute parvovirus B19 infection. J Med Virol 1996;48:68 75. [61] Speyer I, Breedveld FC, Dijkmans BAC. Human parvovirus B19 infection is not followed by inflammatory joint disease during long-term follow-up. Clin Exp Rheumatol 1998;16:576 8. [62] Soderlund M, von Essen R, Haapasaari J, et al. Persistence of parvovirus B19 DNA in synovial membranes of young patients with and without chronic arthropathy. Lancet 1997;349:1063 5. [63] Trapani S, Ermini M, Falcini F. Human parvovirus B19 infection: its relationship with systemic lupus erythematosus. Semin Arthritis Rheum 1999;28:319 25. [64] Bengtsson A, Widell A, Elmstahl S, Sturfelt G. No serological indications that systemic lupus erythematosus is linked with exposure to human parvovirus B19. Ann Rheum Dis 2000;59:64 6. [65] Ferri C, Zakrzewska K, Longombardo G, et al. Parvovirus B19 infection of bone marrow in systemic sclerosis patients. Clin Exp Rheumatol 1999;17:718 20. [66] Crowson AN, Magro CM, Dawood MR. A causal role for parvovirus B19 infection in adult dermatomyositis and other autoimmune syndromes. J Cutan Pathol 2000;27:505 15. [67] Chevrel G, Calvet A, Belin V, et al. Dermatomyositis associated with the presence of parvovirus B19 DNA in muscle. Rheumatology (Oxford) 2000;39: 1037 9. [68] Keller MA, Stiehm ER. Passive immunity in prevention and treatment of infectious diseases. Clin Micriobiol Rev 2000;13:602 14.

[49] Morey AL, Keeling JW, Porter JH, et al. Clinical and histopathological features of parvovirus B19 infection in the human fetus. Br J Obstet Gynaecol 1992;99: 566 74. [50] Chakravarty K, Merry P. Systemic vasculitis and atypical infections: report of two cases. Postgrad Med J 1999;75:544 6. [51] Martinelli C, Azzi A, Buffini G, et al. Cutaneous vasculitis due to human parvovirus B19 in an HIVinfected patient: report of a case. AIDS 1997;11: 1891 3. [52] Diaz F, Collazos J. Glomerulonephritis and HenochSchoenlein purpura associated with acute parvovirus B19 infection. Clin Nephrol 2000;53:237 8. [53] Hakim A. Concurrent Henoch-Schonlein purpura and papular-purpuric gloves-and-socks syndrome. Scand J Rheumatol 2000;29:131 2. [54] Lefrere JJ, Courouce AM, Soulier JP, et al. HenochSchonlein purpura and human parvovirus infection. Pediatrics 1986;78:183 4. [55] Dingli D, Pfizenmaier DH, Arromdee E, et al. Severe digital arterial occlusive disease and acute parvovirus B19 infection. Lancet 2000;356:312 14. [56] Harel L, Straussberg R, Rudich H, et al. Raynauds phenomenon as a manifestation of parvovirus B19 infection: case reports and review of parvovirus B19 rheumatic and vasculitic syndromes. Clin Infect Dis 2000;30:500 3. [57] Elling H, Olsson AT, Elling P. Human parvovirus and giant cell arteritis: a selective arteritic impact? Clin Exp Rheumatol 2000;18(4 Suppl 20):S12 4. [58] Gabriel SE, Espy M, Erdman DD, et al. The role of parvovirus B19 in the pathogenesis of giant cell arteritis: a preliminary evaluation. Arthritis Rheum 1999; 42:1255 8.

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A review of the dermatologic manifestations of poxvirus infections

Ashley G. Perna, MD a, Stephen K. Tyring, MD, PhD b,c,*
Baylor College of Medicine, One Baylor Plaza, Student Box 559, Houston, TX 77030, USA b Departments of Dermatology, Internal Medicine, and Microbiology/Immunology, The University of Texas Medical Branch Galveston, Route 1070, Galveston, TX, USA c University of Texas Medical Branch Center for Clinical Studies, 2060 Space Park Drive, Suite 200, Houston, TX 77058, USA
a

The poxvirus family consists of DNA viruses that can infect animals or human beings. They are brick-shaped or oval-shaped and are generally large enough to be seen with light microscopy. The skin is the portal of entry for most poxviruses, but some enter by way of the respiratory tract (i.e., variola). The skin is commonly the site of local infection, as it is for the molluscum contagiosum virus or milkers nodules; however, other poxviruses, such as variola and vaccinia, can cause systemic disease. Poxvirus infections are generally acute and selflimited [1]. There are four genera of poxviruses that are of concern to human beings. The molluscum contagiosum virus, which is classified within the Molluscipoxvirus genus, is the most common clinically encountered poxvirus. The genus Orthopoxvirus contains several species that infect humans, most notably the variola, or smallpox, virus. Vaccinia, cowpox, and monkeypox are other species within the Orthopoxvirus genus. Orf and pseudocowpox are poxviruses classified within the Parapoxvirus genus. The Yatapoxvirus genus contains the tanapox virus, which infects humans and monkeys [2]. There are numerous other poxvirus species that infect only animals and are not included in this article.

Genus Molluscipoxvirus Molluscum contagiosum virus Molluscum contagiosum virus (MCV) infection is seen in children and adults. The infection is acquired most commonly by skin-to-skin contact but also can be acquired by contact with fomites. In adults, the infection usually is transmitted during sexual activity. Incubation periods range from 1 week to several months. The illness is characterized by typical skin lesions at the site of contact with the virus, but no systemic manifestations are seen [2]. The typical lesions of MCV infection are umbilicated papules covered by a pearly surface. These lesions are generally 3 to 5 mm wide but can range from 1 mm to 1 cm wide. Patients present with just a few lesions to hundreds of lesions, but the average number of lesions is 10 to 20. The groin, axillae, antecubital fossa, and popliteal fossa are common sites of the lesions, and involvement of the groin, lower abdomen, and upper thighs is particularly common when the disease is transmitted sexually [2]. The lesions are characterized by a virus-rich core that can be removed carefully with a sterile hypodermic needle, resulting in resolution of the lesion [3]. These papular lesions generally resolve spontaneously, but it takes several months for this to happen, and the risk of spread of the infection to other body parts is high. The infection, therefore, usually is treated with cryotherapy, curettage, cautery, podophylotoxin, cantharidin, cidofovir, or imiquimod [2,3]. Unfortunately, multiple

* Corresponding author. University of Texas Medical Branch Center for Clinical Studies, 2060 Space Park Drive, Suite 200, Houston, TX 77058, USA. E-mail address: styring@utmb.edu (S.K. Tyring).

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 0 6 - 7

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treatments are often necessary because lesions that cannot be detected during the first treatment appear later. Occasionally, an eczematous reaction around a molluscum papule occurs, termed molluscum dermatitis. This reaction usually resolves on its own [2]. Unlike other poxviruses, which generally cause necrotic, vesicular pox lesions, MCV causes a benign tumor. It is believed that the lesions are caused by hypertrophy and hyperplasia of keratinocytes. Pathologically, lobules of cellular and viral debris are seen within the epidermis. Molluscum bodies can be identified as intracellular eosinophilic globules and are diagnostic when seen histologically. The virus cannot be isolated in cell culture, but it can be identified by polymerase chain reaction. Although the virus can be easily identified by electron microscopy and immunohistochemistry and the diagnosis can be made histologically, the diagnosis generally is made based on the physical examination alone [2]. Although most people with MCV infection are not HIV positive, this virus has become important in the HIV-positive population [3]. Because MCV infection generally resolves, the presence of severe infection that does not respond to treatment should suggest to the treating physician the possibility of HIV infection or other immunodeficient state. The best treatment of MCV infection in HIV-positive patients includes initial treatment of HIV with antiretroviral medications. Patients with AIDS are more likely to have MCV lesions on the face, eyelids, and neck that tend to be difficult to treat [2,3].

Genus Orthopoxvirus Variola (smallpox)

respiratory tract is the portal of entry. The illness begins after a 12 -to 13-day incubation period with systemic manifestations of fever and malaise. Two to four days later, skin lesions begin to erupt on the palms and soles, centrifugally, and on extensor surfaces. The lesions evolve all together, at one time, from macules to papules to vesicles to pustules to crusting lesions. The lesions are firm on palpation. As the lesions resolve, potentially severe scarring occurs. The most severe form of the infection, called variola major, is generally fatal because of heart failure. Other forms cause few fatalities, but no identifiable differences in the virus have been found to account for the different forms of the disease [2]. Pathologically, ballooning degeneration and inclusion bodies are seen within keratinocytes. Polymorphonucleocytes invade the dermis, and the epithelium develops a crust and then regenerates. Diagnosis of smallpox is confirmed through silver impregnation or fluorescent antibody staining of smear samples taken from the lesions. Electron microscopy, tissue culture, or a fourfold increase in antibody titer all can be used to diagnose the disease. Varicella can be confused with smallpox, as can syphilis and monkeypox infection. If smallpox is suspected, immediate isolation must occur as well as evaluation of all close contacts [2]. No specific treatment is available for variola infection. The patient must receive supportive care and treatment for any secondary bacterial infections that may arise. Vaccinations are not currently offered to the general population, but they should be considered for laboratory workers who handle variola. Because the smallpox vaccine also protects against monkeypox virus infection, persons who study monkeypox virus should receive the vaccination [2]. Vaccinia

The variola virus, a member of the genus Orthopoxvirus, causes the disease smallpox, which caused disastrous epidemics throughout the world for thousands of years. In 1980, however, the World Health Organization declared that smallpox had been eradicated after a 13-year worldwide vaccination campaign. There has not been a documented case of smallpox in the world since 1978, and vaccinations are generally no longer administered. There are only two laboratories in the world that still have the variola virus, one in Moscow and one in Atlanta. There are concerns regarding unauthorized storage of the variola virus in other laboratories, however. A great deal of controversy surrounds the continued existence of stores of variola virus [2]. The route of transmission of variola is through intimate contact. Unlike most other poxviruses, the

Currently, it is believed that this member of the Orthopoxvirus genus has no natural reservoir, although it has been isolated in the past from cows and horses. It is considered to be a laboratory virus that infects laboratory workers only. Vaccinia is used in vaccinations for smallpox. If the vaccination is successful, a large Jennerian vesicle forms, followed by a pustule on an erythematous base. Fever, malaise, and lymphadenopathy generally occur 10 days after vaccination. The vaccination site is eventually marked by a typical pitted scar. Because the vaccinia vaccine is not attenuated, it is possible for the vaccinated individual to develop complications. Among these complications, the one that is of highest concern is eczema vaccinatum, which is seen in eczematous patients or eczematous contacts of

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patients. This syndrome is associated with a 5% mortality rate. Other worrisome complications include postvaccinal encephalitis in the elderly and infant encephalopathy, both of which are rare [2]. Interestingly, the vaccinia virus is most useful today as a potential immunogenic vector for gene insertion. Because it has a large genome and a wide range of host animals, including humans, there is great potential for this virus to be used as a vector. Furthermore, the virus replicates in the cytoplasm, so interference with human nuclear DNA transcription is not encountered [2]. Cowpox The cowpox virus is not common in cows, but rather in small rodents and domestic cats. The infections seem to be isolated to Europe and the former Soviet Union. Human infection occurs most commonly from infected cats. It manifests as painful papules predominantly on the hands and face, which evolve into vesicles, then umbilicated pustules, then eventually ulcers. The infections often resemble Parapoxvirus infections, such as orf or milkers nodules, or herpesvirus infections. Flu-like symptoms and lymphadenopathy may occur. The illness is self-limited and resolves in 4 to 12 weeks, with scarring. Fatal infections are rare, except in immunosuppressed patients [2]. Monkeypox

weeping nodules, then dry nodules with black dots, then papillomatous lesions, then dry crust. The lesions generally stay in each of these stages for 6 days. Generally, there is little scarring and there are few systemic manifestations. Diagnosis often is based on history and physical examination, but cell culture, complement fixation, fluorescent antibody, and identification of the virus by electron microscopy can be used. No treatment is available for orf infection, but it is a self-limited illness. Infection does confer lasting immunity but not cross-immunity for other poxvirus infections [2]. Pseudocowpox Pseudocowpox also is referred to as paravaccinia or milkers nodules because it infects the teats of cattle and is transmitted to humans who milk infected cow teats. The infection in humans looks exactly like the orf infection described in the preceding paragraph. Milkers nodules in humans are self-limited and require no treatment. The virus can infect the mouth of a cow and cause bovine papular stomatitis, which then can be transmitted to humans through contact with the infected cows mouth. Most scientists consider pseudocowpox and bovine papular stomatitis to be caused by different species, however [2].

Genus Yatapoxvirus Tanapox Monkeypox virus infections occur in central and western Africa in rodents and monkeys and occasionally are diagnosed in humans. The illness is similar to smallpox infection, but it is less serious. Patients who have received the smallpox vaccine also are protected against monkeypox [2]. Tanapox virus affects humans and monkeys in central Africa, particularly Kenya and Zaire. Most likely, the transmission route is through mosquitos that have fed on infected monkeys. The illness generally is characterized by fewer than 10 lesions, usually on exposed body parts. The lesions are typically 1- to 2-cm indurated papules surrounded by edematous skin. These papules tend to ulcerate and become necrotic, eventually healing with a scar after several weeks. Pruritus, fever, and lymphadenopathy are common. There is no effective treatment or vaccination, but the illness is generally benign and self-limited [2].

Genus Parapoxvirus Orf Orf infections also are referred to as ecthyma contagiosum, infectious pustular dermatitis, contagious pustular dermatosis, and scabby mouth. This infection is important in sheep and goats but relatively minor in humans. Humans become infected by contact with infected lesions on animals or by fomites, such as barn doors, fences, and so forth. Humans generally are not infected by person-to-person transmission. The infection manifests as a few papules, generally on the hands, that progress to target lesions, then acute

Summary Physicians need to be familiar with the presentation of poxvirus infections. The poxvirus infections that are common, such as MCV, are rarely serious; however, physicians need to understand them because they can be bothersome to patients and

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require reassurance and, if available, treatment. The more rare poxvirus infections, such as variola, need to be recognized because they are generally serious. It is important to consider that these infections can suggest underlying systemic disease, as in the case of severe, recalcitrant MCV infection, which may be indicative of HIV infection or another immunocompromised state.

References
[1] Buller RM, Palumbo GJ. Poxvirus pathogenesis [abstract]. Microbiol Rev 1991;55:80 122. [2] Diven DG. An overview of poxviruses. J Am Acad Dermatol 2001;44:1 14. [3] Waugh MA. Sexually transmitted diseases: molluscum contagiosum. Dermatol Clin 1998;16:839 41.

Dermatol Clin 20 (2002) 347 355

Current therapy

Management of pyoderma gangrenosum

Frank C. Powell*, Marina OKane
Regional Centre of Dermatology, Mater Hospital, Eccles Street, Dublin 7, Ireland

Pyoderma gangrenosum (PG) can be defined as an inflammatory, reactive, non-infective, non-neoplastic skin disease. It is one of the cutaneous disorders that may range from being relatively mild, chronic and localized to the skin, to multisystem involvement and life threatening severity, and may herald or occur in association with serious systemic disease. It usually requires a careful measured approach to management, and in many cases potentially toxic treatments are used to control the disease. Because of its rarity, large referral centers often only see two or three cases per year, and most dermatologists in clinical practice will be presented with a patient with PG only once or twice in their professional lifetime. This review will formulate a practical systematic approach to the management of a suspected case of PG for the clinical dermatologist. It will focus on: 1. 2. 3. 4. 5. 6. 7. Establishing the diagnosis; Search for systemic disease; Stabilisation of the patient; Wound care; Topical and intralesional agents; Systemic treatments; Other approaches.

cutaneous disorders, establishing the diagnosis in PG requires: 1. 2. 3. Recognition of the clinical features Performing a skin biopsy to reveal histologic findings consistent with PG Investigations to rule out other similar cutaneous eruptions.

The four main clinical types of PG are: Ulcerative, Pustular, Bullous and Vegetative.

Ulcerative PG This destructive cutaneous lesion is well recognized by most dermatologists. Starting usually as a pustule, sometimes at the site of minor trauma, most often on the lower limb, the ulcer rapidly evolves with progressive pustular enlargement and necrosis (Fig. 1). There is associated pain (often severe and out of proportion to the size of the lesion). The established ulcer in the acute inflammatory stage is surrounded by an areolar zone of erythema with a slough-filled base and an angry, at times undermined border (Fig. 2). Ulcerative PG is often associated with systemic disease, such as arthritis, inflammatory bowel disease (IBD) or monoclonal gammopathy [1].

Establishing the diagnosis The diagnosis of PG may be difficult because of its protean morphologic manifestations. It is important to be aware of the clinical circumstances in which this disorder is likely to present. As with many other

Pustular PG It has long been recognized that a pustule may be the initiating lesion of ulcerative PG as detailed in the description above. Less well accepted is the fact that not all PG pustules progress to ulceration and in some patients multiple painful eruptive inflammatory cutaneous pustules develop without subsequent ulceration.

Bruce H. Thiers, MD, Consulting Editor * Corresponding author. E-mail address: fpow@indigo.ie (F.C. Powell).

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 2 9 - 8

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PG develop painful, rapidly enlarging Bullous lesions which become superficially erosive and then ulcerative. Lesions commonly evolve with waves of intense inflammatory activity alternating with short quiescent periods. Since its first description this type of PG has been closely associated with hematologic disease [4], and patients with Bullous PG and hematologic disease seem to have a poor prognostic outlook [5]. Vegetative PG In 1988 Wilson-Jones and Winkleman defined a subgroup of PG patients with chronic, indolent, slowly progressive, usually localized cutaneous disease, the majority of whom were otherwise in good health [6]. They referred to this form of PG as Superficial Granulomatous Pyoderma: a localized vegetative form of Pyoderma Gangrenosum. Vegetative PG typically occurs as a solitary lesion, usually on the trunk. Histologically histeocytes are prominent within the neutrophilic infiltrate, there is granuloma formation and the presence of giant cells. Sinus tracts may be present. These lesions often respond readily to simple modes of therapy and there is not usually associated systemic disease. Patients with this variant of PG can be offered a good prognosis. Thus the diagnosis of PG is established based on a knowledge of the clinical spectrum of findings which can occur in these patients. Since there are no diagnostic histopathologic changes which occur in this

Fig. 1. Early PG lesion showing progressive enlargement of pustule with central crusting and erosion as active ulceration evolves. Note further active pustule at periphery of lesion, which subsequently merged with expansion of the PG ulcer.

This distinctive eruption has been reported almost exclusively in the setting of acute inflammatory bowel disease (IBD), both ulcerative colitis and Crohns disease. Some authors have referred to this as the vesiculopustular eruption of inflammatory bowel disease, but the clinical and histologic similarity to the preulcerative pustular lesion of PG as described above and the common association of inflammatory bowel disease lead others to classify it as a form of PG [2]. Bullous PG Bullous PG was recognized as a distinctive variant of this disease in 1972 [3]. Patients with this type of

Fig. 2. Established expanding ulcerative PG lesion with necrotic base and erythematous inflammatory border which was partially undermined. Such aggressive destructive skin ulcerations are acutely painful and the patient is often distressed.

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disease, and since pathergy (the initiation of a new lesion at the site of trauma in the skin) is a feature of PG, it has been argued that biopsying for histological assessment is not essential. However, the wide range of overlapping clinical conditions which can mimic PG, including those of infective and neoplastic cause, mandate that a biopsy be taken in all but the most extenuating circumstances. Tissue should be taken from the active edge of a border, together with a portion of the ulcer floor and surrounding tissue. A wedge biopsy with its apex within the lesion and its base in the surrounding skin is often most satisfactory. Tissue is examined histologically to rule out other pathologic causes, and it is good practice to send tissue for microbiologic culture, including fungal, microbacterial, atypical microbacterial and bacterial. The diagnosis of PG is thus established with as much certainty as possible by consideration of the clinical features, review of the histopathologic findings and with the benefit of negative tissue culture results and other investigations listed in Table 1, undertaken as appropriate in the individual patient. As in all dermatologic conditions a detailed history is important to avoid overlooking causes of ulceration such as infection, trauma, artifact, and drug induced (iodides, bromides). A thorough general physical examination is important to search for any underlying or associated disease. Recording the clinical details of the PG lesions is important in regard to the features of morphology, size, outline and location. A clinical photograph is often helpful for a later comparison when estimating progress. A graduated flexible plastic transparency overlaid on the lesion, with tracing of the outline of the PG on the transparency is very helpful as a nursing guide to progress of healing. Blood and other investigations are carried out as indicated by the history and examination. There are reports of patients with PG who have developed possibly related neutrophilic abscess in pulmonary, hepatic and splenic tissue, and the clinician must remain vigilant to this possibility.

Table 1 Work-up of patient with PG Detailed history incl. drugs/trauma/insect bites/exposure to injections/detailed systems review General examination PG lesions location type size outline depth clinical photograph/transparency tracing Blood tests FBC, ESR Renal/liver/bone profiles Serum protein electrophoresis Serum iron/vitamin B12/folate levels Serum thyroxine Cryoglobulins/cold agglutinins Autoantibody screen Antiphospholipid antibody Alpha-1-antitrypsin level Antineutrophilic cytoplasmic antibody (pANCA; cANCA) Serum bromide/iodine (if indicated) Blood cultures Other tests Chest x-ray. Other x-rays as indicated. MSU Skin Biopsies Histology with stains for organisms Culture (bacterial, atypical microbacterial, fungal, viral) Ulcer Cultures Bacterial/microbaterial etc. Viral Fungal Special investigations C.T. Scan (if deep or multiorgan neutrophilic abscesses suspected) Other investigations (endoscopy, bone marrow aspirate etc.) dictated by type of PG and likelihood of associated systemic disease Consider re-biopsy if unexpected deterioration during course

Search for systemic disease Categorising PG according to its predominant morphologic features is helpful as a guide to the possibility of underlying systemic disease. Thus, it has been shown in many series that the majority of patients (over 70%) with ulcerative PG will have an associated disease. Arthritis, inflammatory bowel disease, monoclonal gammopathy and internal malignancy are the most common associations [7]. As already outlined, eruptive pustular PG occurs

almost exclusively in the setting of acute inflammatory bowel disease, both ulcerative colitis and Crohns, while bullous PG has a strong association with underlying hematologic dysgrasias. Vegetative PG, on the other hand, tends not to be associated with systemic disease. Thus appropriate investigations are pursued in each group of patients, ranging from joint x-rays, through endoscopy to bone marrow aspiration. It is recognized that there can be clinical overlap of the morphologic lesions of PG, and that in some cases evolution can occur from one form to another. However, these are relatively uncommon situations, and in the majority of patients

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the morphology of the PG will give some indication as to the need to pursue investigations for underlying disease, as well as the direction in which these investigations should be pursued (Table 1). It is also important to be vigilant during the course of managing this disorder, as complications and side effects of therapy are frequent, and the possibility of superinfection of the denuded area of skin produced by ulceration should not be overlooked. Repeat biopsy and culture of tissue may be necessary if an unexpected deterioration occurs during otherwise adequate treatment.

are less likely to become despondent if changes in therapy are required to achieve healing.

Wound care The principle guiding wound care in a patient with PG should be the avoidance of undue trauma or irritation of the wound surface, and the prevention of secondary infection. Local relief of pain using bland cleansing agents or topical steroids and the creation of a suitable milieu or environment to promote tissue growth with wound healing is important. In the initial evaluation of an ulcerative PG lesion it is important to document location, size, outline and depth as indicated earlier. Clinical photographs are helpful in the overall assessment of the success of treatment, but weekly detailed tracing of the outline of ulcers on calibrated transparencies is of paramount importance in the clinical monitoring of individual lesions by both doctors and nurses involved in the care of these patients. Swabs for bacterial and fungal culture are taken on presentation, and repeated at intervals during treatment, especially if there is clinical deterioration, as secondary infection is always a possibility. Ulcers should be gently cleansed with tepid saline lavage. Sometimes diluted potassium permangate solution (1:2,000) is helpful if the wound is exhibiting marked exudation with surface bacterial colonisation. With both of these solutions slight warming of the fluid will reduce the irritation and discomfort when they are applied to the skin. In the moderate to deep ulceration, silver sulphadiazine cream applied daily on the floor of the ulcer has a soothing effect on the degree of discomfort and seems to promote granulation. It is important to confine this cream to the cavity of the ulcer or erosion, as excessive contact with surrounding skin will encourage maceration and tissue breakdown. The type of dressing used to cover the ulcer varies, but gauze impregnated with vaseline or antibacterial agents should be avoided, as these tend to dry out rapidly, adhere to the ulcer base, and cause a type of debridement with considerable pain and trauma with each dressing change. Much more suitable are the non adherent telfacoated dressings which sit on top of the cream in the ulcer cavity. These are easily changed and reduce the likelihood of trauma. Very superficial erosions such as those resulting from breakdown of bullous PG are often very painful and sensitive. Hydrocolloid dressings, cut to overlap such erosions with a one-centimetre margin for adhesion to normal skin create a moist fluid occlusive wound environment which the patient often finds comforting and eases pain substantially. Such dressings often need

Stabilization of the patient Patients who present to dermatologists with PG are often experiencing extremely painful and progressive destruction of their skin tissue. In many cases they have previously received inappropriate treatment which has proved to be of no benefit. They are usually frightened, insecure, and may have lost confidence in their medical care. Some may be experiencing adverse effects of previous therapies. Having established the diagnosis with as much certainty as possible, and while instigating the search for systemic disease, the initial management of a patient with PG begins with an overall evaluation of their individual circumstances. Age, degree of mobility and social support networks, as well as number, size and type of PG lesions, severity and persistence of pain and the likely presence of associated disease are all important considerations in the decision whether to hospitalize or not. It is my preference (FCP) to admit patients to hospital with significant PG lesions in the initial stages in order to institute supervised bed rest, get expert advice on pain relief, rule out infective causes of lesions, and ensure adequate nutrition and correction of anemia and other comorbidities while therapy is being initiated. Hospitalization also allows evaluation of the patients response to and tolerance of treatment. A suitable wound care regimen can be established, and the patients ability to continue with local wound care as an out-patient can be assessed. Education of the patient as to the nature of PG, its chronicity and potential for precipitation or exacerbation with minor trauma, as well as the available modes of therapy and their relative potential for side effects is important. Treatment is much more likely to be successful in the well informed, confident pain-free individual who has realistic expectations of the speed of healing of lesions (weeks to months, rather than days to weeks). If patients have an understanding of the overall strategy being adopted for their care they

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to be changed on a daily basis in the acute inflammatory phase as there is often quite a marked exudate, but when the eruption has become more settled the exudate diminishes and the hydrocolloid will require changing every 48 to 96 hours (Fig. 3). Chemical desloughing agents should be avoided in PG, as should the use of caustics (e.g. silver nitrate) to hypergranulating tissue. These agents may promote inflammation by tissue destruction and the pathergic phenomenon. Application of a potent topical ointment such as Clobetesol diproproniate can have a flattening effect on granulation tissue as well as reducing their vascularity and easing pain. Protection of the area of PG with a multilayered wound pad is important. If on a limb a shin guard as used by football players, held in place with a tubigrip dressing is important as it minimizes the likelihood of trauma to the area. The use of a lubricating ointment to the normal surrounding skin, and the avoidance of adhesive plasters to hold dressings in place on to surrounding skin all contribute to the comfort of the patient and reduce the likelihood of skin irritation. Relief of pain and good wound care provide the basis to successful nursing treatment of PG lesions [8].

Corticosteroids (topically/intralesional) Disodium chromoglycate (topical) Nicotine (topical) Cyclosporin (intralesional) Tacrolimus (topical/intralesional) Macrophage colony stimulating factor (intralesional) Human platelet-derived growth factor Skin grafts Cultured allografts/autografts X-ray therapy Local agents can be used in isolation in slowly progressive Vegetative PG lesions, or in combination with systemic therapy for more aggressive disease. Hyperbaric oxygen [9] and Benzyl peroxide [10] have both been reported to be useful in individual case reports of patients with PG. Presumably they act by increasing oxygenation of wound tissue. Topical corticosteroids are useful to reduce the irritation in the skin surrounding a PG lesion, and as previously mentioned potent fluorinated topical steroids have been used to reduce the hypergranulation sometimes seen in the base of a healing ulcer in PG. Intralesional triamcinolone diacetate injections (40mg/ml) twice weekly into the borders of PG lesions at 2 to 3 inch intervals have been effectively used in some patients [11]. This form of treatment is most effective on small isolated chronic lesions. Intralesion steroid injections can also be helpful as an adjunct to systemic treatment when one section of a border of a PG lesion is slow to heal. Disodium chromoglycate has been used topically in the treatment of PG, and presumably

Topical and intralesional agents Therapies used locally in the skin for lesions of PG are listed below: Hyperbaric oxygen Benzyl peroxide

Fig. 3. Hydrocolloid dressing being removed from almost completely healed PG lesion. Such dressings are often soothing, and are suitable for superficial PG when exudation is not excessive. In addition they offer a measure of protection against trauma to the area.

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works through its effect on the stabilization of mast cells and the modulation of the inflammatory process [12]. It seems to be most effective when used under occlusion; e.g., applied to the ulcer and covered by a hydrocolloid dressing for 12 h. The application of topical nicotine patches has likewise been reported to be effective in individual patients. It is of interest in this regard that there are reports of an inverse relationship between cigarette smoking and inflammatory bowel disease and oral apthons ulcers. It is possible that in the clinical circumstances of cutaneous and mucosal ulceration, nicotine may exert some type of antiflammatory effect. As yet there is insufficient evidence to recommend this form of treatment on a routine basis. Both cyclosporin and tacrolimus have been shown to be effective when used intralesionally in PG. The number of reported patients to date have been few, but these approaches hold forth promise. Tacrolimus has the advantage in that it can also be used topically, as it is absorbed through the skin [13]. Granulocytemacrophage Colony Stimulating Factor (MCSF) has also been reported to be of use in a patient with PG [14], but until there is collaboratory evidence to prove a beneficial effect, caution should be exercised in the use of this agent. There have been cases of PG in which the initiation of lesions was linked to the use of this agent. Skin grafting is usually avoided in patients with PG because of the danger of inducing pathergy in the donor site. A successful outcome of skin grafting may ensue if systemic steroid cover is given to the patient during the procedure and until both the graft and donor sites have healed. Skin Substitute Cell Culture Grafts offer the possibility of providing a temporary ulcer cover in patients in whom the inflammatory element of the disease is controlled, but where re-epithelialization is slow to progress. Future advances in this area show great promise in the management of PG. X-ray therapy of the active border of lesions has also been reported to be successful in PG, but its use remains to be validated and cannot be recommended at this stage.

patients with vegetative PG respond to local wound care, or require some of the milder systemic treatments listed below: Corticosteroids Minocycline Dapsone Cyclosporin Tacrolimus Clofazamine Cyclophosphamide Melphalan Chlorambucil Azathioprine Methotrexate Interferon-a Potassium iodide Thalidomide Infliximab Mycophenolate mofetil Colchicine The diversity of systemic therapy in this list is an indication of the difficulty of managing this condition, the necessity to individualize therapy to the patient and the state of aggression of the disease, and also the incomplete understanding of the pathogenesis of PG. Review articles which deal in detail with some of the agents listed here are indexed [15 17]. Systemic steroid therapy (1 2 mg/kg/day given in divided doses) is probably the treatment of choice in most patients. If given in sufficient dosage the patient will experience rapid relief of pain within 24 h. This is usually accompanied by clinical improvement in the inflammatory component of PG, with fading of the areolar zone of erythema in ulcerative PG and the cessation of the progressive waves of erosion in bullous PG. The bright inflammatory border loses its hectic hue and undermining ceases as re-epithelialization commences (Fig. 4). If these changes are achieved, it is important to maintain the steroid dosage until the initiation of granulation is observed, and epithelialization of the border becomes apparent. The use of low steroid dosage leads often to disappointing results. Incomplete control of the disease ensues, and subsequently increasing the dose of steroid therapy lacks the beneficial impact that the initial initiation of treatment with a substantial dosage steroid therapy provides. The patient treated with insufficient oral steroids is often thus placed in the dilemma of partially controlled disease with progressive steroid side effects. As soon as control of the disease is achieved with systemic steroid therapy and healing becomes apparent, the next step in manage-

Systemic treatments The majority of patients with PG will require systemic treatment to control their disease. This is particularly so in patients with either ulcerative or bullous PG. Patients with the explosive pustular variant of PG often show poor response to systemic treatment and require active intervention in the closely related acute inflammatory bowel disease to achieve control of their cutaneous lesions. Many

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Probably the least toxic of these agents is Minocycline, given in a dose of 100 mg twice daily, and can be effective in many patients. Interestingly, the patient whose PG lesions heal while on Minocycline therapy often demonstrate deposition of pigmentation in the healed ulcer border (Fig. 5). When the use of systemic steroids is contraindicated, or if they have been unsuccessful, the introduction of cyclosporin is probably indicated. The experience with this agent in the management of PG has been fairly extensive, with the majority of patients showing clinical benefit without serious adverse side effects. A review of the use of this agent in immunoregulatory disorders is detailed in reference [22]. Tacrolimus may surplant cyclosporin as the alternative treatment of choice for PG if future experience validates its present promise. This macrolide lactone inhibits interleukin-2 gene expression in T cells with interference with epidermal cytokine networks. It can thus have a profound effect on the inflammatory infiltrate in this disease. Its safety profile appears to be better than that of cyclosporin, in which the risk of renal disease or hypertension is a significant consideration [23]. The tumor necrosis factor inhibitor thalidomide [24], and Infliximab, a tumor necrosis factor-a-monoclonal antibody may also be effective in PG. Possibly their effectiveness may provide a clue to the components of the pathogenic inflammatory cascade which occurs in this disease, and may indicate the direction for future research for a specific systemic agent to treat PG.

Other approaches Although it is important to have a logical and sequential approach to the management of a patient with PG, the unpredictable nature of this disease and its variation in aggressiveness in individual patients mean that a flexible approach must be adopted. Often more than one therapeutic agent will be required, and improvisation may be necessary if standard approaches fail to bring about satisfactory results. Thus treatments as diverse as plasma exchange, intestinal decontamination and Chinese herbal therapy [25] have been used in patients with PG with reported success. These should be regarded as alternatives to consider only in the event of conventional treatments proving unsuccessful. The occurrence of PG in certain clinical situations also requires innovation. Peristomal PG is an increasingly reported problem. It is most likely to occur in female patients, especially those with Crohns disease of the colon and peri-anal Crohns disease [26]. Intra-

Fig. 4. (a) Large active lesion of ulcerative PG on hip of patient at time of diagnosis. Note biopsy site through border at superior margin. (b) Same lesion after three weeks of oral steroid therapy (60 mg/d) and Dapsone (100 mg/d). Note reepithelialisation of border. The patient was completely painfree at this stage. (c) Complete healing of this PG lesion after 4 months of oral steroid/Dapsone therapy.

ment is the addition of a steroid sparing agent to allow for reduction of steroid dosage and lessen the morbidity associated with these agents. Dapsone, Clofazamine [18], Azathioprine, Methotrexate [19], and Minocycline [20,21] have all been used with varying success either as solitary agents or in this role of steroid-sparing drugs. Some of these agents have also been used as primary or monotherapy of PG.

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Fig. 5. Hyperpigmentation outlining the border of a healed lesion of PG in a patient treated with Minocycline as an adjunct to steroid therapy. The pigmentation is thought to be due to deposition of the drug at the site of inflammation.

lesional steroid injections seem to be particularly helpful for this kind of problem [27] which is often exacerbated by surgical stomal revision. Post-operative and post-caesarean section PG is reported in the surgical literature [28,29]. Cooperation with the surgeon is also important to avoid precipitating new lesions at the site of trauma [30]. When elective surgery is necessary on a patient with a history of PG, the use of subcuticular sutures and systemic steroid cover during surgery may prevent the precipitation or recurrence of PG lesions [31]. By whichever modality control of PG is achieved, maintenance of therapy should be continued until there is complete healing. Premature reduction of dosage or discontinuation of therapy is likely to lead to relapse, particularly in patients with ulcerative or bullous PG. If a lesion is unresponsive or deteriorates during treatment, consideration should be given to rebiopsy and re-culture, because secondary infection of existing PG lesions has been reported. Reinvestigation for the onset of underlying systemic disease should also be considered, as PG may precede the development of such a problem. Once healing is achieved, the clinician is faced with a further decision: whether to maintain suppressive treatment or not. The answer to this is unclear, but in our experience approximately one third of patients with ulcerative PG will require ongoing maintenance treatment. This can often be carried out with doses of one third to one quarter of the initiated dosage of treatment. The patient should be educated to avoid possible precipitating or exacerbating factors of PG (trauma, drugs, surgery, etc.).

Since this is a disease with significant mortality and morbidity, long-term follow-up of these patients is indicated [32].

References
[1] Powell FC, Schroeter AL, Su WPD, Perry HO. Pyoderma gangrenosum: A review of 86 patients. Quarterly J Med, New Series 55 1985;217:173 186. [2] Powell FC, Su WPD, Perry HO. Pyoderma gangrenosum: Classification and management. J Am Acad Dermatol 1996;34:395 409. [3] Perry HO, Winkelmann RK. Bullous pyoderma gangrenosum and leukaemia. Arch Dermatol 1972;106: 901 5. [4] Ho KK-L, Otridge BW, Vandenberg E, Powell FC. Pyoderma gangrenosum, polycythemia rubra vera, and the development of leukemia. J Am Acad Dermatol 1992;27:804 8. [5] Collins S, Carolan D, OLoughlin S, Powell FC. Prognostic indicators in pyoderma gangrenosum. A study of 31 patients. Submitted for publication. [6] Wilson-Jones E, Winkelmann RK. Superficial granulomatous pyoderma: a localized vegetative form of pyoderma gangrenosum. J Am Acad Dermatol 1988; 18:511 21. [7] Duguid CM, Powell FC. Pyoderma gangrenosum. Clin Dermatol 1993;11:129 33. [8] Dunwoody CJ, McCann SA, Zumbo M. Pyoderma gangrenosum: A case study for pain management in dermatology nursing. Dermatology Nursing 2000;12,5: 313 326. [9] Wasserteil V, Bruce S, Sessoms SL, Guntupalli KK.

F.C. Powell, M. OKane / Dermatol Clin 20 (2002) 347355 Pyoderma gangrenosum treated with hyperbaric oxygen therapy. Int J Dermatol 1992;31:594 6. Nguyen LQ, Weiner J. Treatment of pyoderma gangrenosum with benzoyl peroxide. Cutis 1977;19: 842 4. Gardener LW, Acker DW, Arbor A. Triamcinolone and pyoderma gangrenosum. Letters to the editor. Arch Derm 1972;106:599 600. Cave DR, Burakoff R. Pyoderma gangrenosum associated with ulcerative colitis: Treatment with disodium cromoglycate. Am J Gastroenterol 1987;82: 802 4. Richter-Hintz D, Schuppe HC, Homey B, Lehman P, et al. Topical tacrolimus (FK506) is effective in the treatment of pyoderma gangrenosum. J Am Acad Dermatol 2000;42:304 5. Shpiro D, Gilat D, Fisher-Feld L, Shemer A, Gold I, Tran H. Pyoderma gangrenosum successfully treated with perilesional gramlocyte-macrophage colony stimulating factor. Br J Dermatol 1998;138:368 9. Chow RKP, Ho VC. Treatment of pyoderma gangrenosum. J Am Acad Dermatol 1996;34:1047 60. Powell RJ, Holbrook MR, Stevens A. Pyoderma gangrenosum and its treatment. Lancet 1997;350: 1720 1. Callen JP. Pyoderma gangrenosum. Lancet 1998;351: 581 5. Lovett GW, Field JP, King LE. Treatment of pyoderma gangrenosum with clofazimine. J Tenn Med Assoc 1981;74:567 8. Teitel AD. Treatment of pyoderma gangrenosum with methotrexate. Cutis 1996;57:326 8. Berth-Jones J, Tan SV, Grahan-Brown RAC, Pembroke AC. The successful use of minocycline in pyoderma gangrenosum a report of seven cases and a review of the literature. J Dermatol Treat 1989;1:23 5. Lynch WS, Bergfeld WF. Pyoderma gangrenosum re-

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[24]

[13]

[25]

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[14]

[27] [28]

[15] [16]

[17] [18]

[29]

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[21]

sponsive to minocycline hydrochloride. Cutis 1978;21: 535 8. Faulds D, Goa KL, Benfield P. Cyclosporin: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993;45(6):953 1040. Ruzicka T, Assman T, Homey B. Tacrolimus: The drug for the turn of the millenium. Arch Dermatol 1999;135: 574 80. Federman GL, Federman DG. Recalitrant pyoderma gangrenosum treated with thalidomide. Mayo Clin Proc 2000;75:842 4. Li LE. Treatment of pyoderma gangrenosum with oral tripterygium wilford ii multiglycoside. J Dermatol 2000;27:478 81. Cairns BA, Herbst CA, Sator BR, Briggaman RA, Koruda MJ. Peristomal pyoderma gangrenosum and inflammatory bowel disease. Arch Surg 1994;129: 769 72. Keltz M, Lebwohl M, Bishop S. Peristomal pyoderma gangrenosum. J Am Acad Dermatol 1992;27:360 4. Rothenburger M, Tjan TD, Schmid C, Schmidt C, Schwarz T, et al. Pyoderma gangrenosum after aortic valve replacement. Ann Thorac Surg 2001;71(1): 349 51. Ronnau AC, Schmiedeberg SV, Bielfeld P, Ruzicka T, Schuppe H-C. Pyoderma gangrenosum after cesarean delivery. Am J Obstet Gynecol 2000;183(2):502 4. Esnault P, Dompmartin A, et al. Recurring post-operative pyoderma gangrenosum. Int J Dermatol 1995; 34:647 50. Long CC, Jessop J, Young M, Holt PJ. Minimising the risk of post-operative pyoderma gangrenosum. Br J Dermatol 1992;127:45 8. Von Den Driesch P. Pyoderma gangrenosum: A report of 44 cases with follow-up. Br J Dermatol 1997;137: 1000 5.

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Current therapy

New therapeutic options for chronic wounds

ta L mova , MD* Marke
Wound and Ulcer Clinic, University of California San Francisco, San Francisco, CA, USA

Chronic wounds have become a major medical problem in our society as well as the Western world, which is due at least in part to the increasing average age of the population [1,2]. It is estimated that in the US alone there are more than 1.5 million patients with decubitus ulcers, over 1 million patients with venous insufficiency-related ulcerations, and 0.6 million patients with ulcers due to diabetes in addition to other various causes. This in turn leads to a tremendous number of work days lost as well as having a major impact on the cost of medial care associated with these conditions. Significant progress has been done in research related to the area of wound healing. Initial research was done in the 1950s, when acute wound healing and its phases (inflammatory, proliferation and remodeling) were described. More recently, research has shown that chronic wounds are biochemically distinctly different from acute wounds. These differences can be measured by a variety of markers including levels of growth factors that are or are not expressed in the chronic wound as compared to the acute wound, different expressions of matrix metalloproteases, and deposition of various matrix proteins. In an effort to help heal chronic wounds, a number of synthetic occlusive dressings have been developed over the last several decades. All of these dressings are based upon the concept of moist wound healing, which has shown that a moist, crust free wound will heal and epithialize better than an air exposed wound. A variety of studies have shown

that this principle can be demonstrated, not only in animal models but in clinical practice on human wounds. It is currently estimated that there are more than 3,000 such synthetic dressings on the market and they can broadly be divided into several categories: thin films, hydrogels, hydrocolloids, alginates and hydrofibers, foams and composite dressings [3]. These dressings differ in their chemical composition and physical properties which, it turn, make them more suitable for a particular type of wound. Despite the availability of these materials, there are still wounds that do not heal regardless of how hard we try to optimize the wound healing environment and the underlying pathophysiology. With our increased understanding of the wound healing cascade, as well as the variety of growth factors that play a role in the many complex steps, efforts have been dedicated to improving and stimulating wound healing with biologically active materials. These efforts can be broadly divided into three categories: (1) development of individual growth factors or a mixture of growth factors that could be used as a pharmacological agent, (2) animal derived skin type coverings and (3) artificially produced living human skin tissue.

Growth factors As researchers have described individual growth factors that can be isolated from epidermal or dermal tissue, studies have looked at their use and applicability in wound healing. Though many have been investigated, research has focused on only a few of these growth factors and at this time only a small number have been shown to be clinically useful in healing chronic wounds.

Bruce H. Thiers, MD, Consulting Editor. ta L mova , MD, * Address for correspondence: Marke 1340 W. Herndon Avenue, Suite 101, Fresno, CA 93711, USA. mova ). E-mail address: mlimova@earthlink.net (M. L

0733-8635/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 1 ) 0 0 0 3 0 - 4

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mova / Dermatol Clin 20 (2002) 357363 M. L Table 1 Cultured cell products involved in wound healing Cytokines TGF-a Amphiregulin Interleukins (-1,-3,-6,-8) TNF-a Granulocyte-macrophage CSF Platelet-derived growth factor Basic fibroblast growth factor TGF-b Nerve growth factor Extracellular matrix molecules Collagens, type IV and VII Laminin Kalinin Fibronectin Thrombospondin Glycosaminoglycans Plasminogen activator

Fig. 1. Oasis2 small intestinal submuccosa is a thin transparent sheet.

The first such material to be used in clinical practice was Procuren1 (Curative Health Services,

Hauppauge, NY) which is a preparation of predominately platelet derived growth factor with a mixture of several other factors that is prepared from the patients own platelets. This material has been used mainly in diabetic foot ulcers along with standard aggressive wound care which included debridement,

Fig. 2. Clinical example: 86 year old white man with history of venous insufficiency ulcer for 3 y despite treatment with various dressings and compression therapy. A: shows the ulcer prior to treatment with cultured epithelial autografts (CEA). B: after three weeks the wound had closed > 50% and another CEA was applied. C: shows the wound completely epithelialized and healed 6 weeks after initiating treatment.

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Another growth factor that is currently available on the market is granulocyte-macrophage colony stimulating factor (GM-CSF) which is available under the trade name of Leukine1 (Immunex Corp., Seattle, WA) and has been approved for the treatment of hematologic disorders. Since macrophages and inflammation play an important role in the first phase of wound healing, this material has been tried in some chronic wounds as an injectible material around the area of the ulcers as well as topically applied in an aqueous solution [6,7]. Though it is not currently approved for use in chronic wounds, the preliminary reports indicate promising results. Another material that is currently in the developmental stage is keratinocyte derived growth factor (repifermin) which has been shown to significantly increase healing and epithelialization over the wound bed [8,9]. The initial trial in venous ulcers has shown very promising results and currently this material is in clinical trial that is to involve over 60 centers and several hundred patients.

Animal derived materials

Fig. 2 (continued ).

offloading and treatment of infection. In some select instances, Procuren has been used in other wounds with varying success. The first recombinant human growth factor to be used in clinical practice was pure platelet derived growth factor, the BB sub unit. This is currently on the market under the name Regranex1 (Ortho-McNeil Pharmaceutical, Raritan, NJ) and it is an aqueous gel base. Several studies have evaluated the efficacy of human derived platelet derived growth factor in diabetic foot ulcers [4]. Though the individual study results vary, in general, Regranex has been shown to substantially increase wound healing in diabetic foot ulcers when compared to standard care alone. However, the treatment needs to be carried out with aggressive standard wound care, including debridement of necrotic or hyperkeratotic tissue and offloading of the area of the ulceration. It appears that Regranex can be useful in a variety of other types of wounds such as pressure ulcers and currently trials for venous insufficiency ulcers are underway [5]. There have also have been select instances of case reports utilizing Regranex in other chronic and acute wounds such as pyoderma gangrenosum, ulcers of vasculitis, as well as acute surgical defects.

Traditional xenograft is produced from porcine skin and has been used for several decades. Pigskin is anatomically close to human skin, so this was one of the earliest dressing materials used to improve healing of a number of different wounds. This material is still available on the market today, though its role in wound healing is becoming more obsolete as better skin replacement materials are developed. In 1999, the FDA approved the use of small intestinal sub-mucosa derived from porcine intestine for the use in partial and full thickness wounds. This material called Oasis2 (Cook Wound/Ostomy/Continence, Spencer, IN) is manufactured through a number of steps which separate off the other layers of the small intestine leaving a rather thin, acellular membrane. It consists predominantly of collagen and a number of lipids, glycosaminoglycans and growth factors including epidermal growth factor, platelet derived growth factor, transforming growth factor b and others. Oasis comes in strips of various lengths that are approximately seven centimeters wide and is available in its natural state, fenestrated or meshed (Fig. 1). The main advantage of this material is that it can be easily packaged and can be stored on the shelf without special requirements. Though large multi-center trial studies have not been done, in a variety of case studies and small series of patients, this material has been shown to improve wound healing by increasing granulation as well as

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improving epithelialization of a number of different types of wounds. At our center, Oasis has been used on acute surgical wounds, chronic ulcerations of various etiologies including venous, arterial, pyoderma gangrenosum, scleroderma, radiation sites and others. As a material, it is extremely easy to handle and all the clinician needs to do is to apply it into a clean debrided wound base that is relatively free of necrotic, fibinous or infected tissue and secure it with a traditional dressing of choice. The material itself is absorbed into the wound base and over time stimulates wound healing. Generally, several applications over a few weeks are used in the wound healing process.

Bioengineered human skin Attempts to culture human epidermal tissues began in the 1950s, but met with limited success until 1975 when Rhienwald and Green [10] described a new method of culturing human keratinocytes which allowed rapid expansion of the original sample several thousand fold. From 2 to 3 square centimeters of skin one could grow between 1 and 2 square meters of human epidermis. This technique was shown to be lifesaving in 1981 when this was used to treat 97% and 98% body surface area burns in two pediatric patients, a condition which, without this technique, would have been fatal [11]. Since that time clinicians have used cultured keratinocyte sheets not only on extensive burns but also on a variety of other conditions including chronic ulcers of various etiologies, on ulcers of epidermalysis bullosa, for reconstruction of post urethral surgery and lining of the mastoid cavity in ENT surgery [12,13]. Cultured keratinocyte sheets in the instance of large body surface area burns not only stimulate wound healing but also provide permanent epidermal coverage in wounds where no other source of intrinsic keratinocytes exist (full thickness burns below the level of epidermal appendages). In smaller wounds such as leg ulcers, these cultured keratinocyte sheets work by releasing a variety of growth factors and stimulating the granulation of the wound bed and proliferation of keratinocytes in the wound periphery; the edge effect (Table 1). In smaller wounds, even with the patients own keratinocyte sheets, the actual graft take would be seen in only 20% 30% of the time, otherwise the remaining wounds heal as a result of epithelialization from the periphery (Fig. 2). Though this material can have quite impressive results clinically, it does pose several problems. The actual keratinocyte sheets are only a few cell layers thick and therefore quite fragile. They need to be

mounted onto petrolatum gauze backing to which they are attached with surgical clips in order to facilitate the clinicians handling of the product (Fig. 3). Also, the grafts need to be used within several hours once they are prepared in order to maintain maximum viability of the cells. Several centers have been experimenting with different cryopreservation techniques so the grafts may be grown and harvested at the optimum time and preserved for future use. This also helps solve the issue of transportation to the various clinics since there are only a few laboratories around the country that can produce such keratinocyte grafts and in their fresh state they have to be hand-delivered to the clinician. The cryopreserved grafts are sealed in individual pouches and can be shipped frozen to the clinicians or medical centers. Another issue with the production of cultured keratinocyte sheets is the time it takes to grow the sheets. When the skin sample is harvested from the donor it takes approximately 3 weeks to go through all the steps of the tissue culture before the final confluent sheets are ready to be mounted onto the gauze backing. Researchers have looked at the possibility of using allogeneically-derived tissue form cells of an

Fig. 3. Cultured epithelial autografts: the keratinocyte sheet is a thin membrane attached to the petrolatum gauze with surgical clips.

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unrelated donor. Because cultured keratinocyte sheets lack the major HLA histocompatibility complex markers and are generally free of Langerhans cells, melanocytes, and other immunologically recognized cells, they do not exhibit rejection and could potentially stay in the wound permanently. The first experiments examining cultured keratinocyte allografts were conducted in the 1980s and showed that these grafts stimulate wound healing by release of a variety of growth factors. Even though the recipient wound bed shows no sign of rejection, these grafts are not permanently retained, as shown by DNA analysis. Research has also focused on the development of a dermal replacement, because although keratinocyte sheets can provide permanent coverage, it may take

years for the site to develop an actual underlying dermis or dermis like tissue [14]. Human cadaver skin can be specially processed to provide an acellular, three dimensional dermal tissue which is available commercially as AlloDerm1 (LifeCell Corp., Branchburg, NJ). A similar material, Integra1 Dermal Regeneration Template (Integra LifeSciences Holdings Corp., Plainsboro, NJ), is a non-living dermal skin substitute made from bovine collagen and glycosaminoglycans covered with a synthetic silicone membrane [15]. A living dermal replacement that is currently on the market for acute surgical wounds as well as diabetic foot ulcers is Dermagraft1 (Advanced Tissue Sciences, La Jolla, CA). It consists of cultured fibro-

Fig. 4. Dermagraft1: it is a transparent membrane that is cut to size for a particular wound.

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Fig. 5. Apligraf1: this is the closest replacement for human skin commercially available. It is grown and shipped in the same culture dish.

blasts on a polygalactin mesh. It is relatively easy to handle and is simply laid down into the clean wound bed (Fig. 4). The fibroblasts in the material produce a number of growth factors that help stimulate wound healing and tissue regeneration and the polygalactic mesh is naturally hydrolyzed over time. A similar type product, though not available clinically and currently in the earliest stages of development is Vitrix2 (Organogenesis, Inc., Canton, MA) which is a collagen matrix seeded with human cultured fibroblasts. The most technologically advanced cultured skin substitute that is currently on the market is Apligraf1 (Organogenesis, Canton, MA). This material consists of cultured human fibroblasts on a collagen mesh and covered on one side with cultured human keratinocytes. The resulting material histologically resembles normal skin although without appendegial structures and the undulations of the rete ridges which are characteristic of intact skin. It is delivered in a modi-

fied petri dish and can easily be peeled off the carrier medium (Fig. 5). It is relatively easy to handle and resilient. Apligraf also has the additional advantage that is can be easily shipped in a refrigerated container to the clinician and has a shelf life of several days. Apligraf is currently approved for the treatment of chronic ulcers due to venous insufficiency that have not responded to standard care. In the clinical trials, Apligraf was shown to be significantly better at healing venous insufficiency ulcers along with the use of occlusive dressings and compression therapy [16,17]. Apligraf1 has also been used in a variety of other clinical settings such as acute surgical defect following Mohs micrographic surgery, on ulcerations due to inflammatory conditions such as pyoderma gangrenosum, on split thickness skin donor sites, pressure ulcers and a number of other skin defects [18]. A similar material is being developed called Composite Cultured Skin (CCS) (Ortec International, New

Table 2 Bioengineered skin replacements Composition Cultured keratinocytes autografts Treated cadaver skin allograft Bovine collagen/GAG/Silastic Neonatal fibroblasts/polyglactin mesh allograft Neonatal fibroblasts/keratinocytes collagen allografts Structure Epidermal Dermal Dermal Dermal Composite Living Yes No No Yes Yes Trade name Epicel AlloDerm Integra Dermagraft Apligraf, CCS

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York, NY) is currently being used in a large multicenter trial for venous insufficiency ulcerations. This material is also relatively easy to handle, it is shipped frozen in a sealed pouch and after a brief thawing and rinsing procedure can be placed onto the wound and secured with a non-adherent dressing of choice. Bioengineered skin dressings are summarized in Table 2.

[7]

[8]

[9]

Conclusion With increased research and understanding of acute and chronic wounds, new pharmacological agents and bioengineered tissue have been developed to stimulate, modify and improve wound healing of difficult wounds. Over time, as our understanding and knowledge improves, these materials will be used with increasing frequency to improve wound healing in instances where all other therapies have failed and allow the patients to resume their normal daily activities as quickly as possible.
[10]

[11]

[12]

[13]

References
[14] [1] Margolis DJ, Cohen JH. Management of chronic venous ulcers: A literature-guided approach. Clin Dermatol 1994;12:19 26. [2] Waldorf H, Fewkes J. Wound healing. Adv Dermatol 1995;10:77 96. mova M, Grekin RC. Synthetic membranes and cul[3] L tured keratinocyte grafts. JAAD 1990;23:713 19. [4] Wieman TJ, Smiell JM, Su Y. Efficacy and safety of topical gel formulation of recombinant human plateletderived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. Diabetes Care 1998;21:822 7. [5] Kallianen LK, Hirshberg J, Marchant B, Rees RS. Role of platelet-derived growth factor as an adjunct to surgery in the management of pressure ulcers. Plast Reconstr Surg 2000;106:1243 8. [6] Da Costa RM, Ribeiro Jesus FM, Aniceto C, Mendes M. Randomized, double-blind, placebo-controlled, dose-ranging study of granulocyte-macrophage colony

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stimulating factor in patients with chronic venous leg ulcers. Wound Repair Regen 1999;7:17 25. Groves RW, Schmidt-Lucke JA. Recombinant human GM-CSF in the treatment of poorly healing wounds. Adv Skin Wound Care 2000;13:107 12. Jiminez PA, Teliska M, Liu B, et al. Keratinocyte growth factor-2: A wound healing agent with epidermal and dermal activity. Wound Healing Society Seventh Annual Meeting, June 1977. Repifermin RM. (rhuKGF-2) as a human wound healing agent. First World Wound Healing Congress, Melborne, Australia, September 13, 2000. Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 1975;6: 331 43. Gallico GG III, OConnor NE, Compton CC, et al. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 1984;311:448 51. Leigh IM, Purkis PE, Navsaria HA, Phillips TJ. Treatment of chronic venous ulcers with sheets of cultured allogenic keratinocytes. Br J Dermatol 1987;117: 591 7. mova M, Mauro T. Treatment of leg ulcers with L cultured epithelial autografts: Treatment protocol and five year experience. Wounds 1995;7:170 80. Compton CC, Gill JM, Bradford DA, et al. Skin regenerated from cultured epithelial autografts on full-thickness burn wounds from 6 days to 5 years after grafting: A light, electron microscopic and immunohistochemical study. Lab Invest 1989;60:600 12. Hansbrough JF, Boyce ST, Cooper ML, Foreman TJ. Burn wound closure with cultured autologous keratinocytes and fibroblasts attached to a collagen-glycosaminoglycan substrate. JAMA 1989;262:2125 30. Dolynchuk K, Hull P, Guenther L, et al. The role of Apligraf in the treatment of venous leg ulcers. Ostomy/ Wound Management. 1999;45:34 43. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol 1998;134:293 300. Falabella AF, Schachner LA, Valencia IC, Eaglstein WH. The use of tissue-engineered skin (Apligraf ) to treat a newborn with epidermolysis bullosa. Arch Dermatol 1999;135:1219 22.