Herpes Simplex Virus

Etiology

HSVs contain a double-stranded DNA genome of approximately 152 kb that encodes at least 84 proteins. The DNA is contained within an icosadeltahedral capsid, which is surrounded by an outer envelope composed of a lipid bilayer containing at least 12 viral glycoproteins. These glycoproteins are the major targets for humoral immunity, whereas other nonstructural proteins are important targets for cellular immunity. Two encoded proteins, viral DNA polymerase and thymidine kinase, are targets for antiviral drugs. HSV-1 and HSV-2 have a similar genetic composition with extensive DNA and protein homology. One important difference in the 2 viruses is their glycoprotein G genes, which have been exploited to develop a new generation of commercially available, accurate, type-specific serologic tests that can be used to discriminate whether a patient has been infected with HSV-1 or HSV-2 or both.

Epidemiology

HSV infections are ubiquitous, and there are no seasonal variations in risk for infection. The only natural host is humans, and the mode of transmission is direct contact between mucocutaneous surfaces. There are no documented incidental transmissions from inanimate objects such as toilet seats.

All infected individuals harbor latent infection and experience recurrent infections, which may be symptomatic or may go unrecognized and thus are periodically contagious. This information helps explain the widespread prevalence of HSV.

HSV-1 and HSV-2 are equally capable of causing initial infection at any anatomic site but differ in their capacity to cause recurrent infections. HSV-1 has a greater propensity to cause recurrent oral infections, whereas HSV-2 has a greater proclivity to cause recurrent genital infections. For this reason, HSV-1 infection typically results from contact with contaminated oral secretions, whereas HSV-2 infection most commonly results from anogenital contact.

HSV seroprevalence rates are highest in developing countries and among lower socioeconomic groups, although high rates of HSV-1 and HSV-2 infections are found in developed nations and among persons of the highest socioeconomic strata. Incident HSV-1 infections are more common during childhood and adolescence but are also found throughout later life. Data from the U.S. population–based National Health and Nutrition Examination Survey conducted between 1999 and 2004 showed a consistent increase of HSV-1 prevalence with age, which rose from 39% in adolescents 14-19 yr of age to 65% among those 40-49 yr of age. HSV-1 seroprevalence was not influenced by gender, but rates were highest in Mexican-Americans (80.8%), intermediate in non-Hispanic blacks (68.3%), and lowest in non-Hispanic whites (50.1%). The National Health and Nutrition Examination Survey study conducted between 2007 and 2010 found an overall HSV-2 prevalence of 15.5%, with a steady increase with age from 1.5% in the 14-19 yr old age group to 25.6% in the 40-49 yr old group. The rate was higher among females than males (20.3% and 10.6%, respectively) and varied by race and ethnic group, with an overall seroprevalence of 41.8% in non-Hispanic blacks, 11.3% in Mexican-Americans, and 11.3% in whites. Modifiable factors that predict HSV-2 seropositivity include less education, poverty, cocaine use, and a greater lifetime number of sexual partners. Studies show that only approximately 10–20% of HSV-2–seropositive subjects report a history of genital herpes, emphasizing the asymptomatic nature of most HSV infections.

A 3 yr longitudinal study of Midwestern adolescent females 12-15 yr of age found that 44% were seropositive for HSV-1 and 7% for HSV-2 at enrollment. At the end of the study, 49% were seropositive for HSV-1 and 14% for HSV-2. The attack rates, based on the number of cases per 100 person-years, were 3.2 for HSV-1 infection among all females and 4.4 for HSV-2 infection among girls who reported being sexually experienced. Findings of this study indicate that sexually active young women have a high attack rate for genital herpes and suggest that genital herpes should be considered in the differential diagnosis of any young woman who reports recurrent genitourinary complaints. In this study, participants with preexisting HSV-1 antibodies had a significantly lower attack rate for HSV-2 infection, and those who became infected were less likely to have symptomatic disease than females who were HSV seronegative when they entered the study. Prior HSV-1 infection appears to afford adolescent females some protection against becoming infected with HSV-2; in adolescent females infected with HSV-2, the preexisting HSV-1 immunity appears to protect against development of symptomatic genital herpes.

Neonatal herpes is an uncommon but potentially fatal infection of the fetus or more likely the newborn. It is not a reportable disease in most states, and therefore there are no solid epidemiologic data regarding its frequency in the general population. In King County, Washington, the estimated incidence of neonatal herpes was 2.6 cases per 100,000 live births in the late 1960s, 11.9 cases per 100,000 live births from 1978 to 1981, and 31 cases per 100,000 live births from 1982 to 1999. This increase in neonatal herpes cases parallels the increase in cases of genital herpes. The estimated rate of neonatal herpes is 1 per 3,000-5,000 live births, which is higher than reported for the reportable perinatally acquired sexually transmitted infections such as congenital syphilis and gonococcal ophthalmia neonatorum. More than 90% of the cases are the result of maternal-child transmission. The risk for transmission is greatest during a primary or nonprimary first infection (30–50%) and much lower when the exposure is during a recurrent infection (<2%). HSV viral suppression therapy in mothers does not consistently eliminate the possibility of neonatal infection. Infants born to mothers dually infected with HIV and HSV-2 are also at higher risk for acquiring HIV than infants born to HIV-positive mothers who are not HSV-2 infected. It is estimated that approximately 25% of pregnant women are HSV-2 infected and that approximately 2% of pregnant women acquire HSV-2 infection during pregnancy.

HSV is a leading cause of sporadic, fatal encephalitis in children and adults. In the United States the annual hospitalization rate for HSV encephalitis has been calculated to be 10.3 ± 2.2 cases/million in neonates, 2.4 ± 0.3 cases/million in children, and 6.4 ± 0.4 cases/million in adults.

Pathogenesis

In the immunocompetent host the pathogenesis of HSV infection involves viral replication in skin and mucous membranes followed by replication and spread in neural tissue. Viral infection typically begins at a cutaneous portal of entry such as the oral cavity, genital mucosa, ocular conjunctiva, or breaks in keratinized epithelia. Virus replicates locally, resulting in the death of the cell, and sometimes produces clinically apparent inflammatory responses that facilitate the development of characteristic herpetic vesicles and ulcers. Virus also enters nerve endings and spreads beyond the portal of entry to sensory ganglia by intraneuronal transport. Virus replicates in some sensory neurons, and the progeny virions are sent via intraneuronal transport mechanisms back to the periphery, where they are released from nerve endings and replicate further in skin or mucosal surfaces. It is virus moving through this neural arc that is primarily responsible for the development of characteristic herpetic lesions, although most HSV infections do not reach a threshold necessary to cause clinically recognizable disease. Although many sensory neurons become productively infected during the initial infection, some infected neurons do not initially support viral replication. It is in these neurons that the virus establishes a latent infection, a condition in which the viral genome persists within the neuronal nucleus in a largely metabolically inactive state. Intermittently throughout the life of the host, undefined changes can occur in latently infected neurons that trigger the virus to begin to replicate. This replication occurs despite the host's having established a variety of humoral and cellular immune responses that successfully controlled the initial infection. With reactivation of the latent neuron, progeny virions are produced and transported within nerve fibers back to cutaneous sites somewhere in the vicinity of the initial infection, where further replication occurs and causes recurrent infections. Recurrent infections may be symptomatic (with typical or atypical herpetic lesions) or asymptomatic. In either case, virus is shed at the site where cutaneous replication occurs and can be transmitted to susceptible individuals who come in contact with the site or with contaminated secretions. Latency and reactivation are the mechanisms by which the virus is successfully maintained in the human population.

Viremia, or hematogenous spread of the virus, does not appear to play an important role in HSV infections in the immunocompetent host but can occur in neonates, individuals with eczema, and severely malnourished children. It is also seen in patients with depressed or defective cell-mediated immunity, as occurs with HIV infection or some immunosuppressive therapies. Viremia can result in dissemination of the virus to visceral organs, including the liver and adrenals. Hematogenous dissemination of virus to the central nervous system appears to only occur in neonates.

The pathogenesis of HSV infection in newborns is complicated by their relative immunologic immaturity. The source of virus in neonatal infections is typically but not exclusively the mother. Transmission generally occurs during delivery, although it is well documented to occur even with cesarean delivery with intact fetal membranes. The most common portals of entry are the conjunctiva, mucosal epithelium of the nose and mouth, and breaks or abrasions in the skin that occur with scalp electrode use or forceps delivery. With prompt antiviral therapy, virus replication may be restricted to the site of inoculation (the skin, eye, or mouth). However, virus may also extend from the nose to the respiratory tract to cause pneumonia, move via intraneuronal transport to the central nervous system to cause encephalitis, or spread by hematogenous dissemination to visceral organs and the brain. Factors that may influence neonatal HSV infection include the virus type, portal of entry, inoculum of virus to which the infant is exposed, gestational age of the infant, and presence of maternally derived antibodies specific to the virus causing infection. Latent infection is established during neonatal infection, and survivors may experience recurrent cutaneous and neural infections. Persistent central nervous system infection may impact the neurodevelopment of the infant.

Clinical Manifestations

The hallmarks of common HSV infections are skin vesicles and shallow ulcers. Classic infections manifest as small, 2-4 mm vesicles that may be surrounded by an erythematous base. These may persist for a few days before evolving into shallow, minimally erythematous ulcers. The vesicular phase tends to persist longer when keratinized epithelia is involved and is generally brief and sometimes just fleeting when moist mucous membranes are the site of infection. Because HSV infections are common and their natural history is influenced by many factors, including portal of entry, immune status of the host, and whether it is an initial or recurrent infection, the typical manifestations are seldom classic. Most infections are asymptomatic or unrecognized, and nonclassic presentations, such as small skin fissures and small erythematous nonvesicular lesions, are common.

Acute Oropharyngeal Infections

Herpes gingivostomatitis most often affects children 6 mo to 5 yr of age but is seen across the age spectrum. It is an extremely painful condition with sudden onset, pain in the mouth, drooling, refusal to eat or drink, and fever of up to 40.0-40.6°C (104-105.1°F). The gums become markedly swollen, and vesicles may develop throughout the oral cavity, including the gums, lips, tongue, palate, tonsils, pharynx, and perioral skin ( Fig. 279.1 ). The vesicles may be more extensively distributed than typically seen with enteroviral herpangina. During the initial phase of the illness there may be tonsillar exudates suggestive of bacterial pharyngitis. The vesicles are generally present only a few days before progressing to form shallow indurated ulcers that may be covered with a yellow-gray membrane. Tender submandibular, submaxillary, and cervical lymphadenopathy is common. The breath may be foul as a result of overgrowth of anaerobic oral bacteria. Untreated, the illness resolves in 7-14 days, although the lymphadenopathy may persist for several weeks.

In older children, adolescents, and college students, the initial HSV oral infection may manifest as pharyngitis and tonsillitis rather than gingivostomatitis. The vesicular phase is often over by the time the patient presents to a healthcare provider, and signs and symptoms may be indistinguishable from those of streptococcal pharyngitis, consisting of fever, malaise, headache, sore throat, and white plaques on the tonsils. The course of illness is typically longer than for untreated streptococcal pharyngitis.

Cutaneous Infections

In the healthy child or adolescent, cutaneous HSV infections are generally the result of skin trauma with macro or micro abrasions and exposure to infectious secretions. This situation most often occurs in play or contact sports such as wrestling ( herpes gladiatorum ) and rugby ( scrum pox ). An initial cutaneous infection establishes a latent infection that can subsequently result in recurrent infections at or near the site of the initial infection. Pain, burning, itching, or tingling often precedes the herpetic eruption by a few hours to a few days. Like herpes labialis, lesions begin as grouped, erythematous papules that progress to vesicles, pustules, ulcers, and crusts and then heal without scarring in 6-10 days. Although herpes labialis typically results in a single lesion, a cutaneous HSV infection results in multiple discrete lesions and involves a larger surface area. Regional lymphadenopathy may occur but systemic symptoms are uncommon. Recurrences are sometimes associated with local edema and lymphangitis or local neuralgia.

Herpes whitlow is a term generally applied to HSV infection of fingers or toes, although strictly speaking it refers to HSV infection of the paronychia. Among children, this condition is most commonly seen in infants and toddlers who suck the thumb or fingers and who are experiencing either a symptomatic or a subclinical oral HSV-1 infection ( Fig. 279.2 ). An HSV-2 herpes whitlow occasionally develops in an adolescent as a result of exposure to infectious genital secretions. The onset of the infection is heralded by itching, pain, and erythema 2-7 days after exposure. The cuticle becomes erythematous and tender and may appear to contain pus, although if it is incised, little fluid is present. Incising the lesion is discouraged, as this maneuver typically prolongs recovery and increases the risk for secondary bacterial infection. Lesions and associated pain typically persist for about 10 days, followed by rapid improvement and complete recovery in 18-20 days. Regional lymphadenopathy is common, and lymphangitis and neuralgia may occur. Unlike other recurrent herpes infections, recurrent herpetic whitlows are often as painful as the primary infection but are generally shorter in duration.

Cutaneous HSV infections can be severe or life-threatening in patients with disorders of the skin such as eczema (eczema herpeticum), pemphigus, burns, and Darier disease and following laser skin resurfacing. The lesions are frequently ulcerative and nonspecific in appearance, although typical vesicles may be seen in adjacent normal skin ( Fig. 279.3 ). If untreated, these lesions can progress to disseminated infection and death. Recurrent infections are common but generally less severe than the initial infection.