HSV are extremely widespread in the human population. They exhibit a broad host range, being able to replicate in many types of cells and to infect many different animals. They grow rapidly and are highly cytolytic. The HSVs are responsible for a spectrum of diseases, ranging from gingivostomatitis to keratoconjunctivitis, encephalitis, genital disease, and infections of newborns. The HSVs establish latent infections in nerve cells and recurrences are common.
Properties of the Viruses
There are two distinct HSV, types 1 and 2 (HSV-1 and HSV-2) (Table 1). Their genomes are similar in organization and exhibit substantial sequence homology. However, they can be distinguished by sequence analysis or by restriction enzyme analysis of viral DNA. The two viruses cross react serologically, but some unique proteins exist for each type. Classically, HSV-1 is spread by contact, usually involving infected saliva and HSV-2 is transmitted sexually or from a maternal genital infection to a newborn. However, these patterns are becoming less distinct, and both viruses can cause either presentation.
Table1. Comparison of Herpes Simplex Virus Types 1 and 2
The HSV growth cycle proceeds rapidly, requiring 8–16 hours for completion. The HSV genome is large (∼150 kbp) and can encode at least 70 polypeptides; the functions of many of the proteins in replication or latency are not known. At least eight viral glycoproteins are among the viral late gene products. One (gD) is the most potent inducer of neutralizing antibodies. Glycoprotein C is a complement (C3b)-binding protein, and gE is an Fc receptor, binding to the Fc portion of immunoglobulin G (IgG). Glycoprotein G is type specific and allows for antigenic discrimination between HSV-1 (gG-1) and HSV-2 (gG-2).
Pathogenesis and Pathology
A. Pathology
Because HSV causes cytolytic infections, pathologic changes are due to necrosis of infected cells together with the inflammatory response. Lesions induced in the skin and mucous membranes by HSV-1 and HSV-2 are the same and resemble those of VZV. Changes induced by HSV are similar for primary and recurrent infections but vary in degree, reflecting the extent of viral cytopathology.
Characteristic histopathologic changes include ballooning of infected cells, production of Cowdry type A intra nuclear inclusion bodies, margination of chromatin, and formation of multinucleated giant cells. Cell fusion provides an efficient method for cell-to-cell spread of HSV, even in the presence of neutralizing antibody.
B. Primary Infection
HSV is transmitted by contact of a susceptible person with an individual excreting virus. The virus must encounter mucosal surfaces or broken skin for an infection to be initiated (unbroken skin is resistant). Viral replication occurs first at the site of infection. Virus then invades local nerve endings and is transported by retrograde axonal flow to dorsal root ganglia, where, after further replication, latency is established. Whereas oropharyngeal HSV infections result in latent infections in the trigeminal ganglia, genital HSV infections lead to latently infected sacral ganglia.
Primary HSV infections are usually mild; in fact, most are asymptomatic. Only rarely does systemic disease develop.
Occasionally, HSV can enter the central nervous system and cause meningitis or encephalitis. Widespread organ involvement can result when an immunocompromised host is not able to limit viral replication and viremia ensues.
C. Latent Infection
Virus resides in latently infected ganglia in a nonreplicating state; only a very few viral genes are expressed. Viral persistence in latently infected ganglia lasts for the lifetime of the host. No virus can be recovered between recurrences at or near the usual site of recurrent lesions. Provocative stimuli can reactivate virus from the latent state, including axonal injury, fever, physical or emotional stress, and exposure to ultraviolet light. The virus transits via axons back to the peripheral site, and replication proceeds at the skin or mucous membranes. Spontaneous reactivations occur despite HSV-specific humoral and cellular immunity in the host. However, this immunity limits local viral replication so that recurrent infections are less extensive and less severe. Many recurrences are asymptomatic, reflected only by viral shedding in secretions. When symptomatic, episodes of recurrent HSV are most often manifested as cold sores (fever blisters) near the lip. More than 80% of the human population harbor HSV-1 in a latent form, but relatively few experience recurrences. It is not known why some individuals have reactivations and others do not.
Clinical Findings
HSV-1 and HSV-2 may cause many clinical entities, and the infections may be primary or recurrent (see Table 1). Primary infections occur in persons without antibodies and in most individuals are clinically inapparent but result in antibody production and establishment of latent infections in sensory ganglia. Recurrent lesions are common.
A. Oropharyngeal Disease
Primary HSV-1 infections are usually asymptomatic. Symptomatic disease occurs most frequently in small children (1–5 years of age) and involves the buccal and gingival mucosa of the mouth (Figure 1A). The incubation period is short (∼3–5 days, with a range of 2–12 days), and clinical illness lasts 2–3 weeks. Symptoms include fever, sore throat, vesicular and ulcerative lesions, gingivostomatitis, and malaise. Gingivitis (swollen, tender gums) is the most striking and common lesion. Primary infections in adults commonly cause pharyngitis and tonsillitis. Localized lymphadenopa thy may occur.
Recurrent disease is characterized by a cluster of vesicles most commonly localized at the border of the lip (Figure 1B). Intense pain occurs at the outset but fades over 4–5 days. Lesions progress through the pustular and crusting stages, and healing without scarring usually completes in 8–10 days. The lesions may recur, repeatedly and at various intervals, in similar locations. The frequency of recurrences varies widely among individuals. Many recurrences of oral shedding are asymptomatic and of short duration (24 hours).
Fig1. A: Primary herpes simplex gingivostomatitis. (Courtesy of JD Millar. Source: Centers for Disease Control and Prevention, Public Health Image Library, ID# 2902, 2008.) B: Recurrent herpes simplex labialis. (Used with permission from Berger TG, Dept Dermatology, UCSF. Reproduced from McPhee SJ, Papadakis MA [editors]: Current Medical Diagnosis & Treatment, 48th ed. McGraw-Hill, 2009. © McGraw-Hill Education.)
B. Keratoconjunctivitis
HSV infections may occur in the eye, producing severe keratoconjunctivitis. Recurrent lesions of the eye are common and appear as dendritic keratitis or corneal ulcers or as vesicles on the eyelids. With recurrent keratitis, there may be progressive involvement of the corneal stroma, with permanent opacification and blindness. HSV infections are second only to trauma as a cause of corneal blindness in the United States.
C. Genital Herpes
Genital disease is more often caused by HSV-2, although HSV-1 can also cause clinical episodes of genital herpes. Primary genital herpes infections can be severe, with ill ness lasting about 3 weeks. Genital herpes is characterized by vesiculoulcerative lesions of the penis of the male or of the cervix, vulva, vagina, and perineum of the female. The lesions are very painful and may be associated with fever, malaise, dysuria, and inguinal lymphadenopathy. Complications include extragenital lesions (∼20% of cases) and aseptic meningitis (∼10% of cases). Viral secretion persists for about 3 weeks.
Because of the antigenic cross-reactivity between HSV-1 and HSV-2, preexisting immunity provides some protection against heterotypic infection. An initial HSV-2 infection in a person already immune to HSV-1 tends to be less severe.
Recurrences of genital herpetic infections are common and tend to be mild. A limited number of vesicles appear and heal in about 10 days. Virus is shed for only a few days. Some recurrences are asymptomatic with anogenital shedding lasting less than 24 hours. Whether a recurrence is symptomatic or asymptomatic, a person shedding virus can transmit the infection to sexual partners.
D. Skin Infections
Intact skin is resistant to HSV, so cutaneous HSV infections are uncommon in healthy persons. Localized lesions caused by HSV-1 or HSV-2 may occur in abrasions that become contaminated with the virus (traumatic herpes). These lesions are seen on the fingers of dentists and hospital personnel (herpetic whitlow) and on the bodies of wrestlers (herpes gladiatorum).
Cutaneous infections are often severe and life threatening when they occur in individuals with disorders of the skin, such as eczema or burns, that permit extensive local viral replication and spread. Eczema herpeticum is a primary infection, usually with HSV-1, in a person with chronic eczema. In rare instances, the illness may be fatal.
E. Meningitis/Encephalitis
A severe form of meningitis or encephalitis may be produced by herpesvirus. HSV-1 infections are considered the most common cause of sporadic, fatal encephalitis in the United States. The disease carries a high mortality rate, and those who survive often have residual neurologic defects. About half of patients with HSV encephalitis appear to have primary infections, and the rest appear to have recurrent infection.
F. Neonatal Herpes
HSV infection of the newborn may be acquired in utero, during birth, or after birth. The mother is the most common source of infection in all cases. Neonatal herpes is estimated to occur in about 1 in 5000 deliveries per year. The newborn infant seems to be unable to limit the replication and spread of HSV and has a propensity to develop severe disease.
The most common route of infection (∼75% of cases) is for HSV to be transmitted to a newborn during birth by con tact with herpetic lesions in the birth canal. To avoid infection, delivery by cesarean section has been used in pregnant women with genital herpes lesions. However, many fewer cases of neonatal HSV infection occur than cases of recurrent genital herpes, even when the virus is present at term.
Neonatal herpes can be acquired postnatally by exposure to either HSV-1 or HSV-2. Sources of infection include family members and hospital personnel who are shedding virus. About 75% of neonatal herpes infections are caused by HSV-2. There do not appear to be any differences between the nature and severity of neonatal herpes in premature or full-term infants, in infections caused by HSV-1 or HSV-2, or in disease when virus is acquired during delivery or postpartum.
Neonatal herpes infections are almost always symptomatic. The overall mortality rate of untreated disease is 50%. Babies with neonatal herpes exhibit three categories of dis ease: (1) lesions localized to the skin, eye, and mouth; (2) encephalitis with or without localized skin involvement; and (3) disseminated disease involving multiple organs, including the central nervous system. The worst prognosis (∼80% mortality rate) applies to infants with disseminated infection, many of whom develop encephalitis. The cause of death of babies with disseminated disease is usually viral pneumonitis or intravascular coagulopathy. Many survivors of severe infections are left with permanent neurologic impairment.
G. Infections in Immunocompromised Hosts
Immunocompromised patients are at increased risk of developing severe HSV infections. These include patients immunosuppressed by disease or therapy (especially those with deficient cellular immunity) and individuals with malnutrition. Renal, cardiac, and bone marrow transplant recipients are at particular risk for severe herpes infections. Patients with hematologic malignancies and patients with AIDS have more frequent and more severe HSV infections. Herpes lesions may spread and involve the respiratory tract, esophagus, and intestinal mucosa. Malnourished children are prone to fatal disseminated HSV infections. In most cases, the disease reflects reactivation of latent HSV infection.
Immunity
Many newborns acquire passively transferred maternal anti bodies. These antibodies are lost during the first 6 months of life, and the period of greatest susceptibility to primary herpes infection occurs between ages 6 months and 2 years. Transplacentally acquired antibodies from the mother are not totally protective against infection of newborns, but they seem to ameliorate infection if not prevent it. HSV-1 antibodies begin to appear in the population in early childhood; by adolescence, they are present in most persons. Antibodies to HSV-2 rise during the age of adolescence and sexual activity.
During primary infections, IgM antibodies appear transiently and are followed by IgG and IgA antibodies that per sist for long periods. The more severe the primary infection or the more frequent the recurrences, the greater the level of antibody response. However, the pattern of antibody response has not correlated with the frequency of disease recurrence. Cell-mediated immunity and nonspecific host factors (natural killer cells, interferon) are important in controlling both primary and recurrent HSV infections.
After recovery from a primary infection (inapparent, mild, or severe), the virus is carried in a latent state in the presence of antibodies. These antibodies do not prevent reinfection or reactivation of latent virus but may modify subsequent disease.
Laboratory Diagnosis
A. Molecular Detection
Polymerase chain reaction (PCR) assays can be used to detect virus in vesicle swabs, blood, CSF, and tissue and are sensitive and specific. PCR amplification of viral DNA from cerebrospinal fluid is the most sensitive means of detection and is recommended for diagnosis of herpes meningitis/ encephalitis.
B. Isolation and Identification of Virus
Virus culture is commonly used, particularly for diagnosis of mucocutaneous disease. Virus may be isolated from herpetic lesions and may also be found in respiratory samples, tissues and body fluids, both during primary infection and during asymptomatic periods. Therefore, the isolation of HSV is not in itself sufficient evidence to indicate that the virus is the causative agent of a disease under investigation.
Inoculation of tissue cultures is used for viral isolation. HSV is relatively easy to cultivate, with cytopathic effects typically occurring in 2–3 days. The agent is then identified by neutralization test or immunofluorescence staining with specific antiserum. Shell vial culture can be used to detect HSV replicating within cells after 24 hours of incubation using fluorescent antibodies. Typing of HSV isolates may be done using monoclonal antibody, sequence analysis, or by restriction endonuclease analysis of viral DNA.
C. Cytopathology
A rapid cytologic method is to stain scrapings obtained from the base of a vesicle (eg, with Giemsa’s stain); the presence of multinucleated giant cells indicates that herpesvirus (HSV-1, HSV-2, or varicella-zoster) is present, distinguishing lesions from those caused by coxsackieviruses and nonviral entities. A more sensitive technique is direct fluorescent antigen detection on slides containing virally infected cells.
D. Serology
Antibodies appear in 4–7 days after infection and reach a peak in 2–4 weeks. They persist with minor fluctuations for the life of the host. Detection methods available include neutralization, immunofluorescence, and enzyme-linked immunosorbent assay.
The diagnostic value of serologic assays is limited by the multiple antigens shared by HSV-1 and HSV-2. There may also be some heterotypic anamnestic responses to VZV in persons infected with HSV and vice versa. The use of HSV type-specific antibodies allows more meaningful serologic tests.
Epidemiology
HSV are worldwide in distribution. No animal reservoirs or vectors are involved with the human viruses. Transmission is by contact with infected secretions. The epidemiology of HSV-1 and HSV-2 differs.
HSV-1 primary infection typically occurs early in life and is usually asymptomatic; occasionally, it produces oropharyngeal disease (gingivostomatitis in young children, pharyngitis in young adults). Antibodies develop, but the virus is not eliminated from the body; a carrier state is established that lasts throughout life and is punctuated by transient recurrent attacks of herpes.
The highest incidence of HSV-1 infection occurs among children 6 months to 3 years of age. By adulthood, 70–90% of persons have type 1 antibodies. There is high geographic variation in seroprevalence. Middle-class individuals in developed countries acquire antibodies later in life than those in lower socioeconomic populations. Presumably, this reflects more crowded living conditions and poorer hygiene among the latter. The virus is spread by direct contact with infected saliva or through items contaminated with the saliva of a virus shedder. The source of infection for children is usually an adult with a symptomatic herpetic lesion or with asymptomatic viral shedding in saliva.
The frequency of recurrent HSV-1 infections varies widely among individuals. At any given time, 1–5% of normal adults are excreting virus, often in the absence of clinical symptoms.
HSV-2 is typically acquired as a sexually transmitted disease, so antibodies to this virus are seldom found before puberty. It is estimated that there are about 40–60 million infected individuals in the United States. Antibody prevalence studies are complicated by the cross-reactivity between HSV types 1 and 2. Surveys using type-specific glycoprotein anti gens recently determined that 17% of adults in the United States possess HSV-2 antibodies, with seroprevalence higher among women than men, higher among blacks than whites, and age related, reaching 56% in blacks ages 30–49 years.
Reactivation and asymptomatic shedding occur with both HSV-1 and HSV-2. PCR-based studies show frequent sub clinical reactivations in immunocompetent hosts that often last less than 12 hours. Both symptomatic and asymptomatic infections provide a reservoir of virus for transmission to susceptible persons. Studies have estimated that transmission of genital herpes in more than 50% of cases resulted from sexual contact in the absence of lesions or symptoms.
Maternal genital HSV infections pose risks to both the mother and the fetus. Rarely, pregnant women may develop disseminated disease after primary infection, with a high mortality rate. Primary infection before 20 weeks of gestation is associated with spontaneous abortion. The fetus may acquire infection as a result of viral shedding from recur rent lesions in the mother’s birth canal at the time of delivery. Estimates of the frequency of cervical shedding of virus among pregnant women vary widely.
Genital HSV infections increase acquisition of human immunodeficiency virus (HIV) type 1 infections due to the ulcerative lesions in the mucosal surface.
Treatment, Prevention, and Control
Several antiviral drugs have proved effective against HSV infections, including acyclovir, valacyclovir, and vidarabine. All are inhibitors of viral DNA synthesis. Acyclovir, a nucleoside analog, is monophosphorylated by the HSV thymidine kinase and is then converted to the triphosphate form by cellular kinases. The acyclovir triphosphate is efficiently incorporated into viral DNA by the HSV polymerase, where it then prevents chain elongation. The drugs may suppress clinical manifestations, shorten time to healing, and reduce recurrences of genital herpes. However, HSV remains latent in sensory ganglia. Drug-resistant virus strains may emerge.
Newborns and persons with eczema should be protected from exposure to persons with active herpetic lesions.
Patients with genital herpes should be counseled that asymptomatic shedding is frequent and that the risk of trans mission can be reduced by antiviral therapy and condom usage.
Experimental vaccines of various types are being developed. One approach is to use purified glycoprotein antigens found in the viral envelope, expressed in a recombinant system. Such vaccines might be helpful for the prevention of primary infections. A promising recombinant HSV-2 glycoprotein vaccine failed to prevent herpesvirus infections in a large clinical trial in 2010.
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