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Herpes Simplex Viruses

Herpes Simplex Viruses

Lawrence Corey

DEFINITION

Herpes simplex viruses (HSV-1, HSV-2; Herpesvirus hominis) produce a variety of infections involving mucocutaneous surfaces, the central nervous system (CNS), and—on occasion—visceral organs. Prompt recognition and treatment reduce the morbidity and mortality of HSV infections.

ETIOLOGIC AGENT

The genome of HSV is a linear, double-stranded DNA molecule (molecular weight, ~100 × 10⁶ units) that encodes >90 transcription units with 84 identified proteins. The genomic structures of the two HSV subtypes are similar, and the overall sequence homology between HSV-1 and HSV-2 is ~50%. The homologous sequences are distributed over the entire genome map, and most of the polypeptides specified by one viral type are antigenically related to polypeptides of the other viral type. Many type-specific regions unique to HSV-1 and HSV-2 proteins do exist, however, and a number of them appear to be important in host immunity. These type-specific regions have been used to develop serologic assays that distinguish between the two viral subtypes. Either restriction endonuclease analysis of viral DNA or DNA sequencing can be used to distinguish between the two subtypes and among strains of each subtype. The variability of nucleotide sequences from clinical strains of HSV-1 and HSV-2 is such that HSV isolates obtained from two individuals can be differentiated by restriction enzyme patterns or genomic sequences unless the isolates are from epidemiologically related sources, such as sexual partners, mother-infant pairs, or persons involved in a common-source outbreak.

The viral genome is packaged in a regular icosahedral protein shell (capsid) composed of 162 capsomers. The outer covering of the virus is a lipid-containing membrane (envelope) derived from modified cell membrane and acquired as the DNA-containing capsid buds through the inner nuclear membrane of the host cell. Between the capsid and lipid bilayer of the envelope is the tegument. Viral replication has both nuclear and cytoplasmic phases. Attachment and fusion between the viral envelope and the cell membrane involve several ubiquitous heparin-like surface receptors. Replication is highly regulated. After fusion and entry, the nucleocapsid enters the cytoplasm and several viral proteins are released from the virion. Some of these viral proteins shut off host protein synthesis (by increasing cellular RNA degradation), while others “turn on” the transcription of early genes of HSV replication. These early gene products, designated α genes, are required for synthesis of the subsequent polypeptide group, the β polypeptides, many of which are regulatory proteins and enzymes required for DNA replication. Most current antiviral drugs interfere with β proteins, such as the viral DNA polymerase enzyme. The third (γ) class of HSV genes requires viral DNA replication for expression and constitutes most of the structural proteins specified by the virus.

After replication of the viral genome and synthesis of structural proteins, nucleocapsids are assembled in the nucleus of the cell. Envelopment

occurs as the nucleocapsids bud through the inner nuclear membrane into the perinuclear space. In some cells, viral replication in the nucleus forms two types of inclusion bodies: type A basophilic Feulgen-positive bodies that contain viral DNA and an eosinophilic inclusion body that is devoid of viral nucleic acid or protein and represents a “scar” of viral infection. Virions are then transported via the endoplasmic reticulum and the Golgi apparatus to the cell surface.

HSV infection of some neuronal cells does not result in cell death. Instead, viral genomes are maintained by the cell in a repressed state compatible with survival and normal activities of the cell, a condition called latency. Latency is associated with transcription of only a limited number of virus-encoded proteins. Subsequently, the viral genome may become activated; its activation results in the normal pattern of regulated viral gene expression, replication, and release of HSV. The release of virus from the neuron and its subsequent entry into epithelial cells result in viral replication and reappearance of virus on mucosal surfaces. This process is termed reactivation. Whereas infectious virus is rarely recovered from sensory or autonomic nervous system ganglia dissected from cadavers, maintenance and growth of the neural cells in tissue culture result in production of infectious virions (explantation) and in subsequent permissive infection of susceptible cells (cocultivation). The mechanisms by which latency is established, maintained, or recovered are incompletely understood. Two RNA “latency-associated” transcripts that overlap the immediate early (α) gene products, called ICP-O, are found in abundance in the nuclei of latently infected neurons. Deletion mutants of this region that can become latent have been made. However, the efficiency of their later reactivation is reduced; thus, the antisense transcripts may play a role in maintaining rather than in establishing latency. Data from animal models suggest that HSV-specific T cell immunity may influence the process of reactivation in neuronal cells. At present, strategies to interrupt latency or to maintain molecular latency in neurons are not available. In experimental animals, ultraviolet light, systemic and local immunosuppression, and trauma to the skin or ganglia are associated with reactivation.

PATHOGENESIS

Exposure to HSV at mucosal surfaces or abraded skin sites permits entry of the virus and initiation of its replication in cells of the epidermis and dermis. HSV infections are usually acquired subclinically. Both clinical acquisition and subclinical acquisition are associated with sufficient viral replication to permit infection of either sensory or autonomic nerve endings. On entry into the neuronal cell, the virus—or, more likely, the nucleocapsid—is transported intraaxonally to the nerve cell bodies in ganglia. In humans, the interval from inoculation of virus in peripheral tissue to spread to the ganglia is unknown. During the initial phase of infection, viral replication occurs in ganglia and contiguous neural tissue. Virus then spreads to other mucosal skin surfaces through centrifugal migration of infectious virions via peripheral sensory nerves. This mode of spread helps explain the large surface area involved, the high frequency of new lesions distant from the initial crop of vesicles that is characteristic in patients with primary genital or oral-labial HSV infection, and the recovery of virus from neural tissue distant from neurons innervating the inoculation site. Contiguous spread of locally inoculated virus also may take place and allow further mucosal extension of disease.

Analysis of the DNA from sequentially isolated strains of HSV or from isolates from multiple infected ganglia in any one individual has revealed similar, if not identical, restriction endonuclease or DNA sequence patterns in most persons. Occasionally (most frequently in immunocompromised persons), multiple strains of the same viral subtype are detected in one individual. As exposure to mucosal shedding is relatively common during a person's lifetime, these data suggest that exogenous infection with different strains of the same subtype is possible, albeit very uncommon.

IMMUNITY

Host responses to infection with HSV influence the acquisition of disease, the severity of infection, resistance to the development of latency, the maintenance of latency, and the frequency of recurrences. Both antibody-mediated and cell-mediated reactions are clinically important. Immunocompromised patients with defects in cell-mediated immunity experience more severe and more extensive HSV infections than those with deficits in humoral immunity, such as agammaglobulinemia. Experimental ablation of lymphocytes indicates that T cells play a major role in preventing lethal disseminated disease, although antibodies help reduce virus titers in neural tissue. Some of the clinical manifestations of HSV disease appear to be related to the host immune response (e.g., stromal opacities associated with recurrent herpetic keratitis). The surface viral glycoproteins have been shown to be antigens recognized by antibodies mediating neutralization and immune-mediated cytolysis (antibody-dependent cell-mediated cytotoxicity). Monoclonal antibodies specific for each of the known viral glycoproteins have, in experimental infections, conferred protection against subsequent neurologic disease or ganglionic latency. However, the use of subunit glycoprotein vaccines in humans has been, up to the present, only partially successful in reducing acquisition of infection. Multiple cell populations, including natural killer cells, macrophages, and a variety of T lymphocytes, play a role in host defenses against HSV infections, as do lymphokines generated by T lymphocytes. In animals, passive transfer of primed lymphocytes confers protection from subsequent challenge. Maximum protection usually requires the activation of multiple T cell subpopulations, including cytotoxic T cells and T cells responsible for delayed hypersensitivity. The latter cells may confer protection by the antigen-stimulated release of lymphokines (e.g., interferons), which may have a direct antiviral effect and may activate and enhance a variety of specific and nonspecific effector cells. Increasing evidence suggests that HSV-specific CD8+ T cell responses are critical for clearance of virus from lesions. In addition, immunosuppressed patients with frequent and prolonged HSV lesions have fewer functional CD8+ T cells directed at HSV. The HSV virion contains a variety of genes that are directed at the inhibition of host responses. These include gene no. 12 (US-12), which can bind to the cellular transporter-activating protein TAP-1 and reduce the ability of this protein to bind HSV peptides to HLA class I, thereby reducing recognition of viral proteins by cytotoxic T cells of the host. This effect can be overcome by the addition of interferon γ, but this reversal requires 24 to 48 h; thus, the virus has time to replicate and invade other host cells. Prior HSV-1 infection appears not to reduce the frequency of acquisition of HSV-2, as measured by seroconversion. However, persons with prior HSV-1 infection who acquire HSV-2 appear to have a higher frequency of subclinical acquisition. These data suggest that type-specific immune responses are central to the control of HSV infection.

EPIDEMIOLOGY

Seroepidemiologic studies have documented HSV infections worldwide. Serologic assays with whole-virus antigen preparations, such as complement fixation, neutralization, indirect immunofluorescence, passive hemagglutination, radioimmunoassay, and enzyme-linked immunosorbent assay, are useful for differentiating uninfected (seronegative) persons from those with past HSV-1 or HSV-2 infection, but they do not reliably distinguish between the two viral subtypes. Serologic assays that identify antibodies to type-specific surface proteins (epitopes) of the two viral subtypes have been developed and can distinguish reliably between the human antibody responses to HSV-1 and HSV-2. The most commonly used assays are those that measure antibodies to glycoprotein G of HSV-1 (gG1) and HSV-2 (gG2). A western blot assay that can detect several HSV type-specific proteins can also be used.

Infection with HSV-1 is acquired more frequently and earlier than infection with HSV-2. More than 90% of adults have antibodies to HSV-1 by the fifth decade of life. In populations of low socioeconomic status, most persons acquire HSV-1 infection before the third decade of life.

Antibodies to HSV-2 are not detected routinely until puberty. Antibody prevalence rates correlate with past sexual activity and vary greatly among different population groups. Serosurveys indicate that ~20% of the U.S. population has antibodies to HSV-2. In most routine obstetric and family planning clinics, 25% of women have HSV-2 antibodies, although only 10% report a history of genital lesions. As many as 50% of heterosexual adults attending sexually transmitted disease clinics have antibodies to HSV-2. A wide variety of serologic surveys have indicated a similar or even higher seroprevalence of HSV-2 in most parts of Europe, Central and South America, and Africa. Antibody prevalence rates average ~5% higher among women than among men. Several studies suggest that much of this “asymptomatic” infection is largely unrecognized: when “asymptomatic” seropositive persons are shown pictures of genital lesions, more than 60% subsequently identify episodes of symptomatic reactivation. Most important, these asymptomatic seropositive persons with reactivation shed virus on mucosal surfaces as frequently as those with symptomatic disease. The large reservoir of unidentified carriers of HSV-2 and the frequent asymptomatic reactivation of virus from the genital tract have fostered the continued spread of genital herpes throughout the world. HSV-2 infection is an independent risk factor for the acquisition and transmission of infection with HIV type 1. Among co-infected persons, HIV-1 virions can be shed from herpetic lesions of the genital region. This shedding may facilitate the spread of HIV through sexual contact.

HSV infections occur throughout the year. Transmission can result from contact with persons with active ulcerative lesions or with persons without clinical manifestations of infection who are shedding HSV or on whose mucosal surfaces the virus is replicating. Studies using the polymerase chain reaction (PCR) have shown that HSV reactivation on mucosal surfaces is much more frequent than previously recognized. Among immunocompetent adults, HSV-2 can be isolated by culture from the genital tract on 2 to 10% of days, and HSV DNA can be detected on 20 to 30% of days by PCR. Corresponding figures for HSV-1 in oral secretions are similar. Shedding rates are highest during the initial years after acquisition, and viral shedding may occur on as many as 30 to 50% of days during this period. Immunosuppressed patients shed HSV on mucosal sites at even higher frequency (20 to 70% of days). Daily antiviral chemotherapy can markedly reduce shedding rates, as measured by PCR. These data indicate that potential exposure to HSV from sexual or other close contact (kissing, sharing of glasses or silverware) is common, and these high rates of mucosal reactivation are consistent with the continuing spread and high seroprevalence of HSV infections worldwide.

CLINICAL SPECTRUM

HSV has been isolated from nearly all visceral and mucocutaneous sites. The clinical manifestations and course of HSV infection depend on the anatomical site involved, the age and immune status of the host, and the antigenic type of the virus. Primary HSV infections (i.e., first infections with either HSV-1 or HSV-2 in which the host lacks HSV antibodies in acute-phase serum) are frequently accompanied by systemic signs and symptoms. Primary infections involve both mucosal and extramucosal sites; compared with recurrent episodes of disease, they are characterized by a longer duration of symptoms and virus isolation from lesions as well as a higher rate of complications. The incubation period ranges from 1 to 26 days (median, 6 to 8 days). Both viral subtypes can cause genital and oral-facial infections, and the infections caused by the two subtypes are clinically indistinguishable. However, the frequency of reactivation of infection is influenced by anatomical site and virus type. Genital HSV-2 infection is twice as likely to reactivate and recurs 8 to 10 times more frequently than genital HSV-1 infection. Conversely, oral-labial HSV-1 infection recurs more frequently than oral-labial HSV-2 infection. Asymptomatic shedding rates follow the same pattern.

Oral-Facial Infections

Gingivostomatitis and pharyngitis are the most frequent clinical manifestations of first-episode HSV-1 infection, while recurrent herpes labialis is the most frequent clinical manifestation of reactivation HSV infection. HSV pharyngitis and gingivostomatitis usually result from primary infection and are most commonly seen in children and young adults. Clinical symptoms and signs, which include fever, malaise, myalgias, inability to eat, irritability, and cervical adenopathy, may last from 3 to 14 days. Lesions may involve the hard and soft palate, gingiva, tongue, lip, and facial area. HSV-1 or HSV-2 infection of the pharynx usually results in exudative or ulcerative lesions of the posterior pharynx and/or tonsillar pillars. Lesions of the tongue, buccal mucosa, or gingiva may occur later in the course in one-third of cases. Fever lasting from 2 to 7 days and cervical adenopathy are common. It can be difficult to differentiate HSV pharyngitis clinically from bacterial pharyngitis, Mycoplasma pneumoniae infections, and pharyngeal ulcerations of noninfectious etiologies (e.g., Stevens-Johnson syndrome). No substantial evidence suggests that reactivation oral-labial HSV infection is associated with symptomatic recurrent pharyngitis.

Reactivation of HSV from the trigeminal ganglia may be associated with asymptomatic virus excretion in the saliva, development of intraoral mucosal ulcerations, or herpetic ulcerations on the vermilion border of the lip or external facial skin. About 50 to 70% of seropositive patients undergoing trigeminal nerve root decompression and 10 to 15% of those undergoing dental extraction develop oral-labial HSV infection a median of 3 days after these procedures.

In immunosuppressed patients, infection may extend into mucosal and deep cutaneous layers. Friability, necrosis, bleeding, severe pain, and inability to eat or drink may result. The lesions of HSV mucositis are clinically similar to mucosal lesions caused by cytotoxic drug therapy, trauma, or fungal or bacterial infections. Persistent ulcerative HSV infections are among the most common infections in patients with AIDS. HSV and Candida infections often occur concurrently. Systemic antiviral therapy speeds the rate of healing and relieves the pain of mucosal HSV infections in immunosuppressed patients. The frequency of HSV reactivation during the early phases of transplantation or induction chemotherapy is high (50 to 90%), and prophylactic systemic antiviral agents such as intravenous acyclovir or penciclovir are used to reduce reactivation rates. Patients with atopic eczema may also develop severe oral-facial HSV infections (eczema herpeticum), which may rapidly involve extensive areas of skin and occasionally disseminate to visceral organs. Extensive eczema herpeticum has resolved promptly with the administration of intravenous acyclovir. Erythema multiforme may also be associated with HSV infections; some evidence suggests that HSV infection is the precipitating event in ~75% of cases of cutaneous erythema multiforme. HSV antigen has been demonstrated both in circulatory immune complexes and in skin lesion biopsy samples from these cases. Patients with severe HSV-associated erythema multiforme are candidates for chronic suppressive oral antiviral therapy.

HSV-1 and varicella-zoster virus (VZV) have been implicated in the etiology of Bell's palsy (flaccid paralysis of the mandibular portion of the facial nerve). Although uniform recommendations for treatment of this entity are not available, recent evidence suggests that antiviral chemotherapy, usually with a short course of glucocorticoids, may improve outcome.

Genital Infections

First-episode primary genital herpes is characterized by fever, headache, malaise, and myalgias. Pain, itching, dysuria, vaginal and urethral discharge, and tender inguinal lymphadenopathy are the predominant local symptoms. Widely spaced bilateral lesions of the external genitalia are characteristic. Lesions may be present in varying stages, including vesicles, pustules, or painful erythematous ulcers. The cervix and urethra are involved in >80% of women with first-episode infections. First episodes of genital herpes in patients who have had prior HSV-1 infection are associated with less frequent systemic symptoms and faster healing than primary genital herpes. The clinical courses of acute first-episode genital herpes among patients with HSV-1 and HSV-2 infections are similar. However, the recurrence rates of genital disease differ with the viral subtype: the 12-month recurrence rates among patients with first-episode HSV-2 and HSV-1 infections are ~90% and ~55%, respectively (median number of recurrences, 4 and <1, respectively). Recurrence rates for genital HSV-2 infections vary greatly among individuals and over time within the same individual. HSV has been isolated from the urethra and urine of men and women without external genital lesions. A clear mucoid discharge and dysuria are characteristics of symptomatic HSV urethritis. HSV has been isolated from the urethra of 5% of women with the dysuria-frequency syndrome. Occasionally, HSV genital tract disease is manifested by endometritis and salpingitis in women and by prostatitis in men. About 15% of cases of HSV-2 acquisition are associated with these nonlesional clinical syndromes, such as aseptic meningitis, cervicitis, or urethritis. →A more complete discussion of the differential diagnosis of genital herpes is presented in.

Both HSV-1 and HSV-2 can cause symptomatic or asymptomatic rectal and perianal infections. HSV proctitis is usually associated with rectal intercourse. However, subclinical perianal shedding of HSV is detected both in heterosexual men and in women who report no rectal intercourse. This phenomenon is due to the establishment of latency in the sacral dermatome from prior genital tract infection, with subsequent reactivation in epithelial cells in the perianal region. Such reactivations are often subclinical. Symptoms of HSV proctitis include anorectal pain, anorectal discharge, tenesmus, and constipation. Sigmoidoscopy reveals ulcerative lesions of the distal 10 cm of the rectal mucosa. Rectal biopsies show mucosal ulceration, necrosis, polymorphonuclear and lymphocytic infiltration of the lamina propria, and (in occasional cases) multinucleated intranuclear inclusion–bearing cells. Perianal herpetic lesions are also found in immunosuppressed patients receiving cytotoxic therapy. Extensive perianal herpetic lesions and/or HSV proctitis is common among patients with HIV infection.

Herpetic Whitlow

Herpetic whitlow—HSV infection of the finger—may occur as a complication of primary oral or genital herpes by inoculation of virus through a break in the epidermal surface or by direct introduction of virus into the hand through occupational or some other type of exposure. Clinical signs and symptoms include the abrupt onset of edema, erythema, and localized tenderness of the infected finger. Vesicular or pustular lesions of the fingertip that are indistinguishable from lesions of pyogenic bacterial infection are seen. Fever, lymphadenitis, and epitrochlear and axillary lymphadenopathy are common. The infection may recur. Prompt diagnosis (to avoid unnecessary and potentially exacerbating surgical therapy and/or transmission) is essential. Antiviral chemotherapy (to speed the healing of the process) is usually recommended (see below).

Herpes Gladiatorum

HSV may infect almost any area of skin. Mucocutaneous HSV infections of the thorax, ears, face, and hands have been described among wrestlers. Transmission of these infections is facilitated by trauma to the skin sustained during wrestling. Several recent outbreaks of this infection have illustrated the importance of prompt diagnosis and therapy, which are required to contain the spread of this infection.

Eye Infections

HSV infection of the eye is the most frequent cause of corneal blindness in the United States. HSV keratitis presents with an acute onset of pain, blurring of vision, chemosis, conjunctivitis, and characteristic dendritic lesions of the cornea. Use of topical glucocorticoids may exacerbate symptoms and lead to involvement of deep structures of the eye. Debridement, topical antiviral treatment, and/or interferon therapy hastens healing. However, recurrences are common, and the deeper structures of the eye may sustain immunopathologic injury. Stromal keratitis due to HSV appears to be related to T cell–dependent destruction of deep corneal tissue. An HSV-1 epitope that is autoreactive with T cell–targeting corneal antigens has been postulated to be a factor in this infection. Chorioretinitis, usually a manifestation of disseminated HSV infection, may occur in neonates or in patients with HIV infection. HSV and VZV can cause acute necrotizing retinitis as an uncommon but severe manifestation.

Central and Peripheral Nervous System Infections

HSV accounts for 10 to 20% of all cases of sporadic viral encephalitis in the United States. The estimated incidence is ~2.3 cases per 1 million persons per year. Cases are distributed throughout the year, and the age distribution appears to be biphasic, with peaks at 5 to 30 and >50 years of age. Subtype 1 virus causes >95% of cases of HSV encephalitis.

The pathogenesis of HSV encephalitis varies. In children and young adults, primary HSV infection may result in encephalitis; presumably, exogenously acquired virus enters the CNS by neurotropic spread from the periphery via the olfactory bulb. However, most adults with HSV encephalitis have clinical or serologic evidence of mucocutaneous HSV-1 infection before the onset of the CNS symptoms. In ~25% of the cases examined, the HSV-1 strains from the oropharynx and brain tissue of the same patient differ; thus some cases may result from reinfection with another strain of HSV-1 that reaches the CNS. Two theories have been proposed to explain the development of actively replicating HSV in localized areas of the CNS in persons whose ganglionic and CNS isolates are similar. Reactivation of latent HSV-1 infection in trigeminal or autonomic nerve roots may be associated with extension of virus into the CNS via nerves innervating the middle cranial fossa. HSV DNA has been demonstrated by DNA hybridization in brain tissue obtained at autopsy—even from healthy adults. Thus, reactivation of long-standing latent CNS infection may be another mechanism for the development of HSV encephalitis.

The clinical hallmark of HSV encephalitis has been the acute onset of fever and focal neurologic symptoms and signs, especially in the temporal lobe. Clinical differentiation of HSV encephalitis from other viral encephalitides, focal infections, or noninfectious processes is difficult. The most sensitive noninvasive method for early diagnosis of HSV encephalitis is the demonstration of HSV DNA in cerebrospinal fluid (CSF) by PCR. Although titers of CSF and serum antibodies to HSV increase in most cases of HSV encephalitis, they rarely do so earlier than 10 days into the illness and therefore, while useful retrospectively, are generally not helpful in establishing an early clinical diagnosis. Demonstration of HSV antigen, HSV DNA, or HSV replication in brain tissue obtained by biopsy is highly sensitive and has a low complication rate; examination of such tissue also provides the best opportunity to identify alternative, potentially treatable causes of encephalitis. Antiviral chemotherapy reduces the rate of death from HSV encephalitis. Intravenous acyclovir is more effective than vidarabine. Even with therapy, however, neurologic sequelae are frequent, especially in persons >50 years of age. Most authorities recommend the administration of intravenous acyclovir to patients with presumed HSV encephalitis until the diagnosis is confirmed or an alternative diagnosis is made. Among proven cases of HSV encephalitis, intravenous therapy is usually recommended until HSV DNA levels in CSF are substantially reduced or at nearly undetectable levels.

HSV DNA has been detected in CSF from 3 to 15% of persons presenting to the hospital with aseptic meningitis. HSV meningitis, which is usually seen in association with primary genital HSV infection, is an acute, self-limited disease manifested by headache, fever, and mild photophobia and lasting from 2 to 7 days. Lymphocytic pleocytosis in the CSF is characteristic. Neurologic sequelae of HSV meningitis are rare. HSV is the most commonly identified cause of recurrent lymphocytic meningitis (Mollaret's meningitis). Demonstration of HSV antibodies in CSF or persistence of HSV DNA in CSF can establish the diagnosis. For persons with frequent recurrences of HSV meningitis, antiviral therapy has been successful in reducing the frequency of such episodes.

Autonomic nervous system dysfunction, especially of the sacral region, has been reported in association with both HSV and VZV infections. Numbness, tingling of the buttocks or perineal areas, urinary retention, constipation, CSF pleocytosis, and (in males) impotence may occur. Symptoms appear to resolve slowly over days to weeks. Occasionally, hypesthesia and/or weakness of the lower extremities may persist for many months. Rarely, transverse myelitis manifested by a rapidly progressive symmetric paralysis of the lower extremities or a Guillain-Barré syndrome may follow HSV infection. Similarly, peripheral nervous system involvement (Bell's palsy) or cranial polyneuritis may also be related to reactivation of HSV-1 infection. Transitory hypesthesia of the area of skin innervated by the trigeminal nerve and vestibular system dysfunction as measured by electronystagmography are the predominant signs of disease. Studies to determine whether antiviral chemotherapy may abort these signs or reduce their frequency and severity are unavailable.

Visceral Infections

HSV infection of visceral organs usually results from viremia, and multiple-organ involvement is common. Occasionally, however, the clinical manifestations of HSV infection involve only the esophagus, lung, or liver. HSV esophagitis may result from direct extension of oral-pharyngeal HSV infection into the esophagus or may occur de novo by reactivation and spread of HSV to the esophageal mucosa via the vagus nerve. The predominant symptoms of HSV esophagitis are odynophagia, dysphagia, substernal pain, and weight loss. There are multiple oval ulcerations on an erythematous base with or without a patchy white pseudomembrane. The distal esophagus is most commonly involved. With extensive disease, diffuse friability may spread to the entire esophagus. Neither endoscopic nor barium examination can reliably differentiate HSV esophagitis from Candida esophagitis or from esophageal ulcerations due to thermal injury, radiation, or corrosives. Endoscopically obtained secretions for cytologic examination and culture provide the most useful material for diagnosis. Systemic antiviral chemotherapy usually reduces symptoms and heals esophageal ulcerations.

HSV pneumonitis is uncommon except in severely immunosuppressed patients and may result from extension of herpetic tracheobronchitis into lung parenchyma. Focal necrotizing pneumonitis usually ensues. Hematogenous dissemination of virus from sites of oral or genital mucocutaneous disease may also occur and produce bilateral interstitial pneumonitis. Bacterial, fungal, and parasitic pathogens are commonly present in HSV pneumonitis. The mortality rate from untreated HSV pneumonia in immunosuppressed patients is high (>80%). HSV has also been isolated from the lower respiratory tract of persons with adult respiratory distress syndrome. However, the relationship between the isolation of HSV and the pathogenesis of this syndrome is unclear.

HSV is an uncommon cause of hepatitis in immunocompetent patients. HSV infection of the liver is associated with fever, abrupt elevations of bilirubin and serum aminotransferase levels, and leukopenia (<4000 white blood cells per microliter). Disseminated intravascular coagulation may also develop.

Other reported complications of HSV infection include monarticular arthritis, adrenal necrosis, idiopathic thrombocytopenia, and glomerulonephritis. Disseminated HSV infection in immunocompetent patients is rare. In immunocompromised, burned, or malnourished patients, HSV occasionally disseminates to other visceral organs, such as the adrenal glands, pancreas, small and large intestines, and bone marrow. Rarely, primary HSV infection in pregnancy disseminates and may be associated with the death of both mother and fetus. This uncommon event is usually related to the acquisition of primary infection in the third trimester.

Neonatal HSV Infection

Of all HSV-infected populations, neonates (infants younger than 6 weeks) have the highest frequency of visceral and/or CNS infection. Without therapy, the overall rate of death from neonatal herpes is 65%; <10% of neonates with CNS infection develop normally. Although skin lesions are the most commonly recognized features of disease, many infants do not develop lesions until well into the course of disease. Neonatal infection is usually acquired perinatally from contact with infected genital secretions at the time of delivery. Congenitally infected infants have been reported. In most series, 30% of neonatal HSV infections are due to HSV-1 and 70% to HSV-2. The risk of developing neonatal HSV infection is 10 times higher for an infant born to a mother who has recently acquired HSV than for other infants. Neonatal HSV-1 infections may also be acquired through postnatal contact with immediate family members who have symptomatic or asymptomatic oral-labial HSV-1 infection or through nosocomial transmission within the hospital. All neonates with presumed neonatal herpes should be treated with intravenous acyclovir (see below). Antiviral chemotherapy has reduced the rate of death from neonatal herpes to 25%. However, the rate of morbidity, especially among infants with HSV-2 infection involving the CNS, is still very high.

DIAGNOSIS

Both clinical and laboratory criteria are useful for establishing the diagnosis of HSV infections. A clinical diagnosis can be made accurately when characteristic multiple vesicular lesions on an erythematous base are present. However, it is increasingly being recognized that herpetic ulcerations may clinically resemble skin ulcerations of other etiologies. Mucosal HSV infections may also present as urethritis or pharyngitis without cutaneous lesions. Thus, laboratory studies to confirm the diagnosis and to guide therapy are recommended. While staining of scrapings from the base of the lesions with Wright's, Giemsa's (Tzanck preparation), or Papanicolaou's stain to detect giant cells or intranuclear inclusions of Herpesvirus infection is a well-described procedure, few clinicians are skilled in these techniques. Moreover, these cytologic methods do not differentiate between HSV and VZV infections.

HSV infection is best confirmed in the laboratory by isolation of the virus in tissue culture or by demonstration of HSV antigens or DNA in scrapings from lesions. HSV causes a discernible cytopathic effect in a variety of cell culture systems, and this effect can be identified within 48 to 96 h after inoculation. Spin-amplified culture with subsequent staining for HSV antigen has shortened the time needed to identify HSV to <24 h. Increasingly, PCR is being used for the detection of HSV DNA, and several studies have shown this assay to be more sensitive than culture for detection of HSV in CSF and at mucosal sites. The sensitivity of viral isolation and of antigen or DNA detection depends on the stage of the lesions (with higher sensitivity in vesicular than in ulcerative lesions), on whether the patient has a first or a recurrent episode of the disease (with higher sensitivity in first than in recurrent episodes), and on whether the sample is from an immunosuppressed or an immunocompetent patient (with more antigen in immunosuppressed patients). Laboratory confirmation permits subtyping of the virus; information on subtype may be useful epidemiologically and may help to predict the frequency of reactivation after first-episode oral-labial or genital HSV infection.

Acute- and convalescent-phase serum can be useful in demonstrating seroconversion during primary HSV-1 or HSV-2 infection. However, only 5% of patients with recurrent mucocutaneous HSV infections have a fourfold or greater rise in titer of antibody to HSV in the interval between the collection of the first and second samples. Serologic assays, especially type-specific assays, should be used to identify asymptomatic carriers of HSV-1 or HSV-2 infection.

Several studies have shown that persons seropositive for HSV-2 to whom the clinical manifestations of HSV have been explained are able to identify symptomatic reactivations. Individuals seropositive for HSV-2 should be told about the high frequency of subclinical reactivation in mucosal surfaces not visible to the eye (e.g., cervix, urethra, perianal skin) or in microscopic ulcerations that may not be clinically symptomatic. Transmission of infection during such episodes is well established. HSV-2-seropositive persons should be educated about the high likelihood of subclinical shedding and the role condoms (male or female) may play in reducing transmission. Antiviral therapy with the drug valacyclovir (500 mg once daily) has been shown to reduce the transmission of HSV-2 between sexual partners.

TREATMENT

Many aspects of mucocutaneous and visceral HSV infections are amenable to antiviral chemotherapy. For mucocutaneous infections, acyclovir and its congeners famciclovir and valacyclovir have been the mainstay of therapy. Several antiviral agents are available for topical use in HSV eye infections: idoxuridine, trifluorothymidine, topical vidarabine, and cidofovir. For HSV encephalitis and neonatal herpes, intravenous acyclovir is the treatment of choice.

All licensed antiviral agents for use against HSV inhibit the viral DNA polymerase. One class of drugs, typified by the drug acyclovir, is made up of substrates for the HSV enzyme thymidine kinase. Acyclovir, ganciclovir, famciclovir, and valacyclovir are all selectively phosphorylated to the monophosphate form in virus-infected cells. Cellular enzymes convert the monophosphate form of the drug to the triphosphate, which is then incorporated into the viral DNA chain.

Acyclovir is the most frequently used agent for the treatment of HSV infections and is available in intravenous, oral, and topical formulations. Valacyclovir is the valyl ester of acyclovir and offers greater bioavailability than acyclovir. Famciclovir, the oral formulation of penciclovir, is clinically effective in the treatment of a variety of HSV-1 and HSV-2 infections. Ganciclovir is active against both HSV-1 and HSV-2; however, it is more toxic than acyclovir, valacyclovir, and famciclovir and generally is not recommended for the treatment of HSV infections.

All three recommended compounds—acyclovir, valacyclovir, and famciclovir—have proven effective in shortening the duration of symptoms and lesions of mucocutaneous HSV infections in both immunocompromised and immunocompetent patients. Intravenous and oral formulations prevent reactivation of HSV in seropositive immunocompromised patients during induction chemotherapy or in the period immediately after bone marrow or solid organ transplantation. Chronic daily suppressive therapy reduces the frequency of reactivation disease among patients with frequent genital or oral-labial herpes. Only valacyclovir has been shown to reduce transmission of HSV-2 infection between sexual partners.

Intravenous acyclovir (30 mg/kg per day, given as a 10-mg/kg infusion over 1 h at 8-h intervals) is effective in reducing rates of death and morbidity from HSV encephalitis. Early initiation of therapy is a critical factor in outcome. The major side effect associated with intravenous acyclovir is transient renal insufficiency, usually due to crystallization of the compound in the renal parenchyma. This adverse reaction can be avoided if the medication is given slowly over 1 h and the patient is well hydrated. Because CSF levels of acyclovir average only 30 to 50% of plasma levels, the dosage of acyclovir used for treatment of CNS infection (30 mg/kg per day) is double that used for treatment of mucocutaneous or visceral disease (15 mg/kg per day). Even higher doses of intravenous acyclovir are used for neonatal HSV infection (60 mg/kg per day in 3 divided doses).

Among immunocompetent patients, recent studies have shown the effectiveness of short-course oral therapy to reduce the signs and symptoms of oral and genital HSV infection. These regimens include valacyclovir (1 or 3 days) for oral-labial HSV and acyclovir (2 days) or valacyclovir (3 days) for recurrent-episode genital herpes (Table 1).

Suppression of Mucocutaneous Herpes

Recognition of the high frequency of subclinical reactivation has provided an ever-greater rationale for the use of daily antiviral therapy to suppress reactivations of HSV, especially in persons with frequent clinical reactivations (e.g., those with recently acquired genital HSV infection). Immunosuppressed persons, including those with HIV infection, may also benefit from daily antiviral therapy. Of the various regimens used, famciclovir (500 mg twice daily) and valacyclovir (1 g twice daily) are two of the most common; valacyclovir at a dose of 4 g daily was associated with thrombotic thrombocytopenic purpura in one study of HIV-infected persons.

Reduction in Transmission of HSV to Sexual Partners

Once-daily valacyclovir (500 mg) has been shown to reduce transmission of HSV-2 between sexual partners. Transmission rates are higher from males to females and among persons with frequent HSV-2 reactivation. Serologic screening can be used to identify at-risk couples.

Acyclovir Resistance

Acyclovir-resistant strains of HSV have been identified. Most of these strains have an altered substrate specificity for phosphorylating acyclovir. Thus, cross-resistance to famciclovir and valacyclovir is usually found. Occasionally, an isolate with altered thymidine kinase (TK) specificity arises and is sensitive to famciclovir but not to acyclovir. In some patients infected with TK-deficient virus, higher doses of acyclovir are associated with clearing of lesions. In others, clinical disease progresses despite high-dose therapy. Almost all clinically significant acyclovir resistance has been seen in immunocompromised patients, and HSV-2 isolates are more often resistant than HSV-1 strains. A study by the Centers for Disease Control and Prevention indicated that ~5% of HSV-2 isolates from HIV-positive persons exhibit some degree of in vitro resistance to acyclovir. Among immunocompetent patients attending sexually transmitted disease clinics,

<0.5% of HSV-2 isolates show reduced in vitro sensitivity to acyclovir. The lack of appreciable change in the frequency of detection of such isolates in the past 20 years probably reflects the reduced transmission of TK-deficient mutants. Isolation of HSV from lesions persisting despite adequate dosages and blood levels of acyclovir should raise the suspicion of acyclovir resistance. Therapy with the antiviral drug foscarnet is useful. Because of its toxicity and cost, this drug is usually reserved for patients with extensive mucocutaneous infections. Cidofovir is a nucleotide analogue and exists as a phosphonate or monophosphate form. Most TK-deficient strains of HSV are sensitive to cidofovir. Cidofovir ointment speeds healing of acyclovir-resistant lesions. No well-controlled trials of systemic cidofovir have been reported. True TK-negative variants of HSV appear to have a reduced capacity to spread because of altered neurovirulence—a feature important in the relatively infrequent presence of such strains in immunocompetent populations, even with increasing use of antiviral drugs.

PREVENTION

The success of efforts to control HSV disease on a population basis through suppressive antiviral chemotherapy and/or educational programs will be limited.

Barrier forms of contraception (especially condoms) decrease the likelihood of transmission of HSV infection, particularly during periods of asymptomatic viral excretion. When lesions are present, HSV infection may be transmitted by skin-to-skin contact despite the use of a condom. Nevertheless, the available data suggest that consistent condom use is an effective means of reducing the risk of genital HSV-2 transmission. Recent studies have shown that chronic daily antiviral therapy with valacyclovir can also be partially effective in reducing acquisition of HSV-2, especially among susceptible women. There are no comparative efficacy studies of valacyclovir versus condom use. Most authorities suggest both approaches. Several candidate HSV vaccines are under investigation.

Prevention of neonatal HSV requires the prevention of acquisition of HSV by women in the third trimester of pregnancy. Identification

of women or couples susceptible to acquisition of HSV in pregnancy through serologic screening is receiving increasing attention, and such screening is being used with increasing frequency.

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