Herpes Virus Infections

Clinical Features

Based on seropositivity studies, greater than 50% of adults in the United States have been infected with HSV-1, whereas 20% or more have been infected with HSV-2. Primary infection with HSV most commonly occurs in early childhood. As many as one out of five cases will present with acute HSV gingivomastitis (herpes labialis), characterized by the sudden appearance of a multitude of ulcers on the cheeks and gums. Primary infection is often preceded by a prodrome of fever, malaise, anorexia, and lymphadenopathy. The virus will then undergo latency and may subsequently recur when triggered by factors such as stress, illness, and hormonal changes. Genital herpes is a less common manifestation of HSV infection and may involve the genital mucosa, cervix, and surrounding skin. Like gingivomastitis, primary herpes genitalis is typically more severe than recurrent infections. Herpes simplex infections involving the oral mucosa are most frequently associated with HSV-1, although a smaller proportion of these infections may be caused by HSV-2. In contrast, most genital herpes simplex infections were traditionally thought to be caused by HSV-2, but an increasing number of these infections have been found to be caused by HSV-1, particularly in young adults.

Superficial lesions may rarely occur in other anatomic sites such as the eyes and nonmucosal surfaces such as herpetic whitlow (typically fingers) or superinfection of traumatized skin (e.g., burn injury). Herpetic whitlows are most commonly seen in health care workers following contact with infected oral secretions.

In adults, HSV-1 central nervous system (CNS) infection is most commonly manifested as encephalitis, whereas HSV-2 tends to cause meningitis. In contrast, nearly 50% of infants who acquire HSV-2 during the birth process develop encephalitis. Herpes encephalitis frequently presents clinically in adults as altered mood, memory, and behavior. The course of HSV-1 encephalitis may be subacute, developing over a 4- to 6-week period. Concurrent infection with the human immunodeficiency virus (HIV) may result in a more acute presentation.

Neonatal herpes simplex infection is a rare condition that results from vertical transmission of HSV. The risk of transmission to the infant is highest during primary maternal infections. Neonatal herpes simplex virus is most often caused by HSV-2 (70%) and typically occurs when the neonate contacts infected genital secretions in the birth canal. Rarely, transmission may result from in utero or postnatal exposure. Three clinical categories of neonatal herpes simplex infection may be observed: ocular/mucocutaneous, encephalitis, and disseminated infection. These categories do demonstrate some overlap with extension of ocular/mucocutaneous or disseminated infection to the CNS. The ocular/mucocutaneous form involves the eyes, skin, and mucous membranes and may be localized without involvement of other organ systems. Neonatal HSV encephalitis most commonly involves the cerebral cortex, although occasionally the brainstem may be affected. It is not necessarily accompanied by fever or systemic symptoms and may not become clinically evident for several months after birth. When CNS disease is present, the cerebrospinal fluid indices usually show elevated protein and a mononuclear pleocytosis. The untreated mortality rate for neonatal HSV encephalitis is 15%. Disseminated HSV infection is the most serious category and is fatal in 60% to 85% of neonates if left untreated. Symptoms are generally observed during the first week of life and may include respiratory distress, seizures, irritability, jaundice, disseminated intravascular coagulation, and hemorrhagic pneumonitis. These may be accompanied by a vesicular rash.

Pathologic Features

Microscopic Findings

Early cutaneous or mucosal lesions demonstrate intraepidermal or intramucosal acantholysis with edema and accumulation of proteinaceous fluid. This later develops into vesicles or “blisters” containing fluid with an overlying thin layer of epidermis ( Figure 2-1A ). The base of the vesicles may demonstrate marked ballooning degeneration in which the keratinocytes are enlarged and often contain viral inclusions ( Figure 2-1B ). Two types of viral inclusions may be observed: Cowdry type A inclusions and “ground-glass” nuclear inclusions. Cowdry Type A inclusions are characterized by a condensed eosinophilic central structure surrounded by a cleared area, which may impart a targetoid appearance, whereas “ground-glass” inclusions are indistinct eosinophilic inclusions that obscure the entire nucleus. Infected cells may demonstrate the classic 3 Ms of HSV infection, with m ultinucleation, nuclear m olding, and m argination of the nuclear chromatin ( Figure 2-2 ). Acute inflammatory cells are frequently seen within the upper dermis as well as within the vesicle fluid. Inflammation and ulceration may be extensive and obscure the correct diagnosis when classic inclusions are not readily visible.

Herpes Simplex Virus Types 1 And 2—Pathologic Features

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  Closely grouped fluid-filled vesicles exist on an erythematous base.

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  Two types of intranuclear inclusions are involved: Cowdry type A and “ground glass.”

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  Infected cells may demonstrate the “3 Ms” of HSV cytopathic changes: m ultinucleation, nuclear m olding, m argination of chromatin.

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  Ulceration or acute inflammation may obscure the diagnosis.

Differential Diagnosis

The differential diagnosis of mucocutaneous herpes simplex virus may include varicella zoster virus, as this also produces vesicular skin eruptions with similar appearing cytopathic changes. In addition, other infectious and noninfectious blistering diseases such as bullous impetigo, bullous pemphigoid, and pemphigus vulgaris may be considered, depending on the clinical presentation.

Ancillary Studies

Immunohistochemistry or in situ hybridization (ISH) performed on tissue sections may aid in the diagnosis of HSV when the characteristic viral inclusions are not observed on hematoxylin and eosin (H&E) staining or when it is necessary to distinguish from varicella zoster virus.

Resistance to acyclovir is uncommon, and if suspected it is detected by viral culture with subsequent susceptibility testing at specialized laboratories.

Prognosis and Therapy

Primary infections with HSV are generally not treated with antiviral medications, although recurrent reactivations of mucocutaneous or genital HSV may be treated using suppressive therapy with acyclovir.

Early diagnosis and treatment is critical in CNS and disseminated infections, as these are frequently fatal if left untreated. Treatment with antiviral agents including acyclovir, valacyclovir, or famciclovir may significantly alter the course of infections with HSV. Severe or disseminated HSV infections may require intravenous therapy.

Clinical Features

Varicella zoster virus is distributed worldwide. Most primary infections occur in early childhood, although nonimmune adults may also become infected. Transmission may occur through inhalation of infectious respiratory secretions or direct contact with lesions on the skin or mucous membranes. The peak season for primary infection with VZV occurs in the winter and spring.

Primary VZV infection presents as an exanthematous syndrome referred to as chickenpox. Following an incubation period of approximately 14 days, patients develop a prodrome consisting of fever, chills, headache, and anorexia. After 2 to 3 days, a rash composed of crops of closely grouped maculopapular lesions appears on the trunk. The rash spreads to the extremities and head, and the lesions begin to develop into fluid-filled vesicles on an erythematous base (so-called “dewdrop on a rose petal”). These are frequently associated with intense pruritus. The lesions generally become crusted over within 8 to 12 hours; however, new crops of vesicles continually appear within a 2- to 5-day period, so lesions at multiple stages of development may be present together. Disseminated infection, with or without neurologic involvement, is unusual in immunocompetent patients. Following primary infection, the virus establishes latency within the dorsal root or trigeminal ganglia.

Serious complications of primary infection are uncommon and are more likely to occur in patients with impaired cell-mediated immunity. These may include varicella pneumonia, disseminated infection, hepatitis, and central nervous system involvement.

Reactivation of VZV is characterized by a painful vesicular skin eruption in a dermatomal distribution, referred to as shingles or herpes zoster. Triggers may include stress, localized trauma, or a decrease in immune function. Frequently, patients will experience a prodrome of pain, itching, numbness, or burning in the specific dermatome. Fever or other systemic symptoms may also be present. The most common dermatomes involved are the thoracic, cranial, lumbar, cervical, and sacral. Herpes zoster is generally a self-limited process, although some patients, particularly adults over age 60, experience persistent pain for months or even years in the area where the shingles occurred, a syndrome known as postherpetic neuralgia. Ocular involvement may occur when the ophthalmic branch of the trigeminal nerve is involved (known as herpes zoster ophthalmicus) and can result in conjunctival ulcers, iritis, keratitis, and chorioretinitis. Similarly, Ramsay-Hunt syndrome is a peripheral facial nerve palsy that occurs as a complication of herpes zoster. The features typically include unilateral facial weakness associated with vesicles in the ipsilateral ear, hard palate, or tongue. Other symptoms may include tinnitus, hearing loss, nausea, vomiting, vertigo, or nystagmus.

Congenital VZV may be associated with congenital abnormalities, particularly if maternal infection occurs prior to 20 weeks’ gestation. Congenital varicella syndrome is associated with a high mortality rate (up to 30%) and is characterized by low birth weight and congenital skin lesions in a dermatomal distribution. Other features that may be present include microcephaly, neurologic signs, eye defects, limb deformities, and neonatal seizures.

Pathologic Features

Microscopic Findings

The cytologic and histopathologic features of mucocutaneous VZV infections may be difficult to distinguish from those of herpes simplex virus. Biopsy of an intact vesicle may demonstrate intraepidermal acantholysis and splitting at the suprabasal level ( Figure 2-3A ). Involvement of hair follicles and other adnexal structures is not uncommon. Viral inclusions similar to those seen in HSV are frequently present, with Cowdry type A or “ground-glass” inclusions, multinucleated cells, margination of chromatin, and nuclear molding ( Figure 2-3B ).

In contrast to HSV, VZV frequently demonstrates a leukocytoclastic vasculitis, characterized by fibrinoid degeneration of small vessels in the dermis with acute inflammation, accumulation of neutrophilic nuclear debris, and extravasation of red blood cells.

Varicella Zoster Virus (VZV)—Pathologic Features

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  Primary VZV lesions appear as crops of closely grouped fluid-filled vesicles on an erythematous base (so-called “dewdrops on a rose petal”).

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  Viral inclusions are similar to those seen in HSV, with Cowdry A or “ground-glass” type inclusions, multinucleated cells, marginated chromatin, and nuclear molding.

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  May see leukocytoclastic vasculitis with fibrinoid degeneration of small vessels in the dermis, acute inflammation, and accumulation of nuclear debris (not seen in HSV infections).

Ancillary Studies

Immunohistochemical and in situ hybridization studies can identify VZV in histologic tissue sections, and this is especially helpful in distinguishing VZV from HSV (see Figure 2-4 ). It is also useful in cases where viral inclusions are not classic or are obscured by inflammation and ulceration.

Differential Diagnosis

Because both VZV and HSV present with blistering lesions, HSV may be considered in the differential where the diagnosis is unclear. Smallpox or monkeypox should also be considered, although the likelihood of disease with these agents is extremely low. Other noninfectious blistering disorders should also be considered.

Prognosis and Therapy

Treatment of primary VZV infections in immunocompetent patients is aimed primarily at reduction of symptoms (i.e., antipyretics for fever, antihistamines for itching). Antivirals are generally not recommended for this group. Patients at risk for severe complications (including immunocompromised patients) may be treated with acyclovir. Alternative agents include valacyclovir and famciclovir. For herpes zoster, antivirals started early have been shown to decrease pain and duration of symptoms. Childhood vaccination for VZV has been shown to successfully prevent VZV infection. Since the introduction of the vaccine, the number of deaths and hospitalizations due to VZV infection has significantly decreased. Vaccination is now available to prevent zoster and is recommended for individuals 60 and older.