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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 associated with HSV infections.


ETIOLOGIC AGENT

The genome of HSV is a linear, double-strand 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. The overall genomic sequence homology between HSV-1 and HSV-2 is ~50%, whereas the proteome homology is >80%. 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. Moreover, epidemiologically related sources, such as sexual partners, mother-infant pairs, or persons involved in a common-source outbreak, can be inferred from such patterns.


The viral genome is packaged in a regular icosahedral protein shell (capsid) composed of 162 capsomeres (see Fig. 78-1). The outer covering of the virus is a lipidcontaining membrane (envelope) acquired as the DNAcontaining 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 of 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), whereas others “turn on” the transcription of early genes of HSV replication.These early gene products, designated á genes, are required for synthesis of the subsequent polypeptide group, the â polypeptides, many of which are regulatory proteins and enzymes required for DNA replication. Most current antiviral drugs interfere with â proteins, such as the viral DNA polymerase enzyme.


The third (ã) 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 eosinophilic inclusion bodies that are devoid of viral nucleic acid or protein and represent a “scar” of viral infection. Enveloped 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, viral replication, and viral release.


The release of HSV from the neuron and its subsequent entry into epithelial cells result in viral replication in these cells, destruction of the cells, and the subsequent 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 (as “explants”) in tissue culture result in production of infectious virions and in subsequent permissive infection of susceptible cells (cocultivation). The mechanisms by which latency is established, maintained, or broken are incompletely understood. Two RNA “latency-associated” transcripts that overlap the immediate early (á) 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 these latencyassociated transcripts may play a role in maintaining rather than in establishing latency. Recent studies suggest that HSV-specific micro-RNAs in these and other regions of the viral genome may play an important role in virus maintenance in and release from neurons. CD8+ T cells have been found in ganglia of experimental animals and humans and appear to influence the process of reactivation, possibly by inducing antiviral factors such as interferon (IFN) ã.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. Whether clinical or subclinical, HSV acquisition is 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 intra-axonally to the nerve cell bodies in ganglia. In humans, the transit 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 mucocutaneous 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 ability to recover 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.


Recent studies have demonstrated HSV viremia—another mechanism for extension of infection throughout the body—in ~30–40% of persons with primary HSV-2 infection. Latent infection with both viral subtypes in both sensory and autonomic ganglia has been demonstrated. Analysis of the DNA from sequential isolates 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.


IMMUNITY

Host responses influence the acquisition of HSV 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 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 targets of antibodies that mediate 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. In humans, however, subunit glycoprotein vaccines have been 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. Maximal 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., IFNs), which in turn have a direct antiviral effect and both 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 human leukocyte antigen (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 IFN-ã, but this reversal requires 24–48 h; thus the virus has time to replicate and invade other host cells.To date, the immunodominant T-cell responses appear to be typespecific.


Entry of infectious HSV-1 and HSV-2 inhibits several signaling pathways of both CD4+ and CD8+ T cells, leading to their functional impairment in killing and influencing the spectrum of their cytokine secretion. 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 typespecific 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.There is some evidence that the prevalence of HSV-2 has decreased slightly over the past 5 years in the United States. Serosurveys indicate that 15–20% 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% of those who are seropositive for HSV-2 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 Central America, South America, and Africa. There is an epidemiologic synergy between HSV-2 and HIV-1. HSV-2 infection is associated with a two- to fourfold increase in HIV-1 acquisition. In addition, HSV-2 is reactivated and transmitted more frequently in persons co-infected with HIV-1 and HSV-2 than in persons not infected with HIV-1.


Thus most areas of the world with a high HIV-1 prevalence also have a high HSV-2 prevalence. In Africa, HSV-2 seroprevalence has ranged from 40 to 70% in obstetric and other sexually experienced populations. Antibody prevalence rates average ~5–10% higher among women than among men. Several studies suggest that many cases of “asymptomatic” genital HSV-2 infection are, in fact, simply unrecognized: when “asymptomatic” seropositive persons are shown pictures of genital lesions, >60% subsequently identify episodes of symptomatic reactivation. Most important, these asymptomatic seropositive persons with reactivation shed virus on mucosal surfaces almost as frequently as those with symptomatic disease. The large  reservoir of unidentified carriers of HSV-2 and the frequent asymptomatic reactivation of the 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-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 who have active ulcerative lesions or with persons who have no clinical manifestations of infection but who are shedding HSV from mucocutaneous surfaces. Studies using the polymerase chain reaction (PCR) have shown that HSV reactivation on genital skin and mucosal surfaces is much more common than previously recognized. Among immunocompetent adults, HSV-2 can be cultured from the genital tract on 2–10% of days tested, and HSV DNA can be detected on 20–30% of days by PCR. Corresponding figures for HSV-1 in oral secretions are similar. Rates of shedding are highest during the initial years after acquisition, with viral shedding occurring on as many as 30–50% of days during this period. Immunosuppressed patients shed HSV from mucosal sites at an even higher frequency (20–80% of days). Reactivation rates vary widely among individuals. Among HIV-positive patients, a low CD4+ T-cell count and a heavy viral load are associated with increased rates of HSV reactivation. (Daily antiviral chemotherapy for HSV-2 can markedly reduce shedding rates, as measured by PCR.) These high rates of mucocutaneous reactivation suggest that exposure to HSV from sexual or other close contact (kissing, sharing of glasses or silverware) is common and help explain 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 anatomic 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. Compared with recurrent episodes, primary infections, which involve both mucosal and extramucosal sites, are characterized by a longer duration of symptoms and virus isolation from lesions. The incubation period ranges from 1 to 26 days (median, 6–8 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 anatomic site and virus type. Genital HSV-2 infection is twice as likely to reactivate and recurs 8–10 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 common clinical manifestations of first-episode HSV-1 infection, whereas recurrent herpes labialis is the most common clinical manifestation of reactivation HSV-1 infection.


HSV pharyngitis and gingivostomatitis usually result from primary infection and are most commonly seen among children and young adults. Clinical symptoms and signs, which include fever, malaise, myalgias, inability to eat, irritability, and cervical adenopathy, may last 3–14 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 2–7 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 of 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 50–70% of seropositive patients undergoing trigeminal nerve-root decompression and 10–15% of those undergoing dental extraction develop oral-labial HSV infection a median of 3 days after these procedures. Clinical differentiation of intraoral mucosal ulcerations due to HSV from aphthous, traumatic, or drug-induced ulcerations is difficult. In immunosuppressed patients, HSV 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 (50–90%), and prophylactic systemic antiviral agents such as IV acyclovir, penciclovir, or the oral congeners of these drugs 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 IV 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 in conjunction with a short course of glucocorticoids may result in improved outcomes. 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 (Fig. 80-1). 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 systemic symptoms in a few patients and with faster healing than primary genital herpes.The clinical courses of acute first-episode genital herpes are similar for HSV-1 and HSV-2 infection. 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 dysuriafrequency 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 nonlesional clinical syndromes, such as aseptic meningitis, cervicitis, or urethritis.A more complete discussion of the differential diagnosis of genital herpes is presented in Chap. 28.


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 in women and men 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 abrupt-onset 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 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 have illustrated the importance of prompt diagnosis and therapy to contain the spread of this infection. Eye Infections HSV infection of the eye is the most common cause of corneal blindness in the United States. HSV keratitis presents as an acute onset of pain, blurred 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 IFN 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 10–20% 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 5–30 and >50 years of age. HSV-1 causes >95% of cases. 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 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. Recent studies have identified genetic polymorphisms in two separate genes among children with HSV encephalitis.


Peripheral-blood mononuclear cells from these children appear to secrete reduced levels of IFN in response to HSV; if confirmed, this observation suggests that sporadic HSV encephalitis may be related to a variety of host genetic determinants. The clinical hallmark of HSV encephalitis has been the acute onset of fever and focal neurologic symptoms and signs, especially in the temporal lobe (Fig. 80-2). Clinical differentiation of HSV encephalitis from other viral encephalitides, focal infections, or noninfectious processes is difficult. Elevated cerebrospinal fluid (CSF) protein levels, leukocytosis (predominantly lymphocytes), and red blood cell counts due to hemorrhagic necrosis are common.Although brain biopsy has been the gold standard for defining HSV encephalitis, the high sensitivity and specificity of HSV DNA detection by PCR in CSF has largely replaced biopsy for defining HSV CNS infection. Although titers of antibody to HSV in CSF and serum increase in most cases of HSV encephalitis, they rarely do so earlier than 10 days into the illness and therefore, although 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 with acyclovir reduces the rate of death from HSV encephalitis. Even with therapy, however, neurologic sequelae are common, especially in persons >50 years of age. Most authorities recommend the administration of IV acyclovir to patients with presumed HSV encephalitis until the diagnosis is confirmed or an alternative diagnosis is made. Among proven cases of HSV encephalitis, IV therapy is usually recommended until HSV DNA levels in CSF are substantially reduced or nearly undetectable. HSV DNA has been detected in CSF from 3–15% 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 2–7 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 reduced the occurrence 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 or weeks. Occasionally, hypoesthesia and/or weakness of the lower extremities persists for many months. Rarely, transverse myelitis, manifested by a rapidly progressive symmetric paralysis of the lower extremities or Guillain- Barré syndrome, follows HSV infection. Similarly, peripheral nervous system involvement (Bell’s palsy) or cranial polyneuritis may be related to reactivation of HSV-1 infection. Transitory hypoesthesia of the area of skin innervated by the trigeminal nerve and vestibular system dysfunction as measured by electronystagmography are the predominant signs of disease. Whether antiviral chemotherapy can abort these signs or reduce their frequency and severity is not yet known. 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. Multiple oval ulcerations appear 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 or DNA detection by PCR 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, producing 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 and prolonged intubation.The role of lower respiratory tract HSV infection in overall rates of morbidity and mortality associated with these conditions 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/ìL). 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. Disseminated HSV infection is best detected by the presence of HSV DNA in plasma or blood.


Neonatal HSV Infections 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 at all or do so only well into the course of disease. Neonatal infection is usually acquired perinatally from contact with infected genital secretions at 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 IV acyclovir. Antiviral chemotherapy with high-dose IV acyclovir (60 mg/kg per day) has reduced the mortality rate from neonatal herpes to ~15%. However, morbidity, especially among infants with HSV-2 infection involving the CNS, is still very high.


DIAGNOSIS

Both clinical and laboratory criteria are useful for diagnosing HSV infections. A clinical diagnosis can be made accurately when characteristic multiple vesicular lesions on an erythematous base are present. However, herpetic ulcerations may 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. Although 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, the sensitivity of staining is low (<30% for mucosal swabs), and these cytologic methods do not differentiate between HSV and VZV infections. HSV infection is best confirmed in the laboratory by detection of virus, viral antigen, or viral DNA in scrapings from lesions. HSV DNA detection by PCR, when available, is the most sensitive laboratory technique.


HSV causes a discernible cytopathic effect in a variety of cell culture systems, and this effect can be identified within 48–96 h after inoculation. Spin-amplified culture with subsequent staining for HSV antigen has shortened the time needed to identify HSV to <24 h. The sensitivity of all detection methods 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 or DNA 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 orallabial or genital HSV infection. Acute- and convalescent-phase serum can be useful in demonstrating seroconversion during primary HSV-1 or HSV-2 infection. However, few available tests report titers, and increases in index values do not reflect first episodes in all patients.


Serologic assays based on type-specific proteins should be used to identify asymptomatic carriers of HSV-1 or HSV-2 infection. No reliable IgM method for defining acute HSV infection is available. Several studies have shown that persons with previously unrecognized HSV-2 infection can be taught to identify symptomatic reactivations. Individuals seropositive for HSV-2 should be told about the high frequency of subclinical reactivation in mucosal surfaces that are 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 valacyclovir (500 mg once daily) has been shown to reduce the transmission of HSV-2 between sexual partners.


HERPES SIMPLEX VIRUS INFECTIONS

any 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 mainstays 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, IV 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 (TK). Acyclovir, ganciclovir, famciclovir, and valacyclovir are all selectively phosphorylated to the monophosphate form in virusinfected 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 agent most frequently used for the treatment of HSV infections and is available in IV, oral, and topical formulations. Valacyclovir, the valyl ester of acyclovir, offers greater bioavailability than acyclovir and thus can be administered less frequently.


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. Anecdotal case reports suggest that ganciclovir may also be less effective than acyclovir for treatment of HSV infections. All three recommended compounds—acyclovir, valacyclovir, and famciclovir—have proved effective in shortening the duration of symptoms and lesions of mucocutaneous HSV infections in both immunocompromised and immunocompetent patients (Table 80-1). IV 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 subjected to clinical trials that demonstrated reduced transmission of HSV-2 infection between sexual partners. IV 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 IV 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 30–50% of plasma levels, the dosage of acyclovir used for treatment of CNS infection (30 mg/kg per day) is double that used for treatment ofmucocutaneous or visceral disease (15 mg/kg per day). Even higher doses of IV acyclovir are used for neonatal HSV infection (60 mg/kg per day in three divided doses). Among immunocompetent patients, recent studies have shown the effectiveness of short-course, high-dose oral therapy to reduce the signs and symptoms of oral and genital HSV infection. These regimens include valacyclovir (for 1–3 days) for oral-labial HSV and acyclovir (2 days), valacyclovir (3 days), or famciclovir (1 or 2 days) for recurrent-episode genital herpes (Table 80-1). These short-course regimens are less expensive and more convenient but should be reserved for immunocompetent hosts.


SUPPRESSION OF MUCOCUTANEOUS HERPES

Recognition of the high frequency of subclinical reactivation provides a well-accepted 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. Recent studies have shown the efficacy of daily acyclovir and valacyclovir in reducing the frequency of HSV reactivations among HIV-positive persons. Regimens used include acyclovir (400 mg three times daily), famciclovir (500 mg twice daily), and valacyclovir (1 g twice daily); valacyclovir at a dose of 4 g daily was associated with thrombotic thrombocytopenic purpura in one study of HIV-infected persons. In addition, daily treatment of HSV-2 reduces the titer of HIV RNA in plasma (0.5-log reduction) and in genital mucosa (0.33-log reduction).


REDUCED HSV TRANSMISSION 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. Daily valacyclovir appears more effective at reducing subclinical shedding than daily famciclovir. 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 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. Of HSV-2 isolates from immunocompetent patients attending sexually transmitted disease clinics, <0.5% 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 in acyclovir-resistant cases (Chap. 79). 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. 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.The need for a vaccine to prevent acquisition of HSV infection is great, especially in light of the role HSV-2 plays in enhancing the acquisition and transmission of HIV-1. A substantial portion of neonatal HSV cases could be prevented by reducing the acquisition of HSV by women in the third trimester of pregnancy. Identification of women susceptible to HSV acquisition in pregnancy through serologic screening, with a focus on counseling against unprotected oral or genital sex, is receiving increasing attention. Neonatal HSV infection can result from either the acquisition of maternal infection near term or the reactivation of infection at delivery in the already-infected mother. Thus strategies for reducing neonatal HSV are complex. Some authorities have recommended that antiviral therapy with acyclovir or valacyclovir be given to HSV-2–infected women in late pregnancy as a means of reducing reactivation of HSV-2 at term. Data are not available to support the efficacy of this approach. Moreover, the high treatment-to-prevention ratio makes this a dubious public health approach, even though it can reduce the frequency of HSV-associated cesarean delivery.