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The genomes of herpes simplex 1 and 2 (HSV-1 and HSV-2, respectively) are both approximately 150 kbp of DNA. Although they are distinct epidemiologic and antigenic viruses, their genomes contain approximately 50% homology, making them the most closely related HHVs. Nearly all of the genes of HSV-1 have colinear homologs in HSV-2. HSV-1 and HSV-2 share many glycoprotein and structural antigens, but differences in glycoprotein B, among other glycoproteins, enable them to be distinguished antigenically. The viruses can also be distinguished by PCR assays as well.
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HSV-1 and HSV-2 are closely related
HSV-1 and HSV-2 can be distinguished epidemiologically, antigenically, and by DNA homology
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HERPES SIMPLEX DISEASE
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HSV-1 is more often associated with disease “above the waist” or facial herpes, whereas HSV-2 is most often associated with genital infections or “below the waist” infections. However, an increasing number of genital infections are caused by HSV-1. HSV-1 is most often spread by direct contact of mucosal tissue, especially the lip area. Both HSV-1 and HSV-2 are prevalent worldwide. There are no known animal vectors for HSV-1 or HSV-2. Seroepidemiologic studies indicate that the prevalence of HSV antibody varies by age and socioeconomic status of the population studied. In most developing countries, up to 90% of the population has HSV-1 antibody by the age of 30 years. In the United States, HSV-1 antibody is found in 18% to 35% of children by the age of 5 years with the percentages varying according to the population studied. In the United States, the seroprevalence rises to approximately 60% to 70% by the age of 30 years for middle-class populations; among lower socioeconomic groups, however, the percentage is higher. Detection of HSV-2 antibody before puberty is less common. Direct sexual transmission is the major mode of spread. Approximately 15% to 30% of sexually active adults in Western industrialized countries have HSV-2 antibody and seropositive rates are positively correlated with the number of sexual partners. The virus can be isolated from the cervix and urethra of approximately 5% to 12% of adults attending sexually transmitted disease clinics; many of these patients are asymptomatic or have small, unnoticed lesions on penile or vulvar skin. Asymptomatic shedding accounts for transmission from a partner who has no active genital lesions and often no history of genital herpes. Genital herpes is not a reportable disease in the United States, but it is estimated that more than 1 million new cases occur per year.
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✺ HSV-1 is highly prevalent in the population
✺ HSV-2 is more associated with sexual activity
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There are no known animal vectors for HSV-1 or HSV-2
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Both HSV-1 and HSV-2 initially infect and replicate in the mucoepithelial cells and initiate lytic or productive infection at the site of contact. Pathologic changes during acute infections consist of development of multinucleated giant cells (Figure 14–3), ballooning degeneration of epithelial cells, focal necrosis, eosinophilic intranuclear inclusion bodies, and an inflammatory response characterized by an initial polymorphonuclear neutrophil (PMN) infiltrate and a subsequent mononuclear cell infiltrate. The virus spreads to local sensory neurons and travels in retrograde fashion to the sensory ganglia that innervate the site of infection. In the case of facial herpes, the virus infects neurons in the trigeminal ganglia and in the case of genital herpes, the dorsal root or sacral ganglia. Latency is established in the ganglionic neurons. A round of replication may occur in the ganglia, but is not necessary for the establishment of latency.
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Lytic replication at the site of infection produces inflammation and giant cells
Virus can infect and spread to neurons and establishes latency in sensory ganglia
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In humans, latent infection by HSV-1 has been demonstrated in trigeminal, superior cervical, and vagal nerve ganglia, and occasionally in the S2-S3 dorsal sensory nerve root ganglia. Latent HSV-2 infection has been demonstrated in the sacral (S2-S3) region. Latent infection of neurons by HSV does not result in the death of the cell. Multiple viral genomes exist in a circular extrachromosomal form in the nucleus, and transcription of only a small portion of the viral genome occurs, limited to a single viral transcript, the latency-associated transcript (LAT). The LAT encodes a number of miRNAs that serve as regulatory RNAs that can alter host cell gene expression without expressing foreign proteins. Because latency is established in nondividing neurons, HSV does not encode direct functions to maintain the viral episome. Latent infection does not require synthesis of early or late viral polypeptides and, therefore, antiviral drugs directed at the thymidine kinase enzymes or viral DNA polymerase do not eradicate the virus in its latent state.
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✺ HSV genomes exist as episomes during latency
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There are no drugs to treat latent infections by herpesviruses
There is no synthesis of early or late viral polypeptides during latent infection
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A subset of patients exhibit overt clinical disease from reactivation of the virus. This can occur over the entire life of the host. However, people without obvious clinical disease can also reactivate and spread the virus through subclinical shedding. The mechanisms by which latent infection is reactivated are unknown. Precipitating factors that are known to initiate reactivation of HSV and subsequent clinical disease include exposure to ultraviolet light, sunlight, fever, excitement, emotional stress, and trauma (eg, oral intubation). However, it is clear that reactivation and viral shedding between overt disease episodes is common, and may account for some of the spread of the virus. Upon reactivation, the virus initiates lytic replication and virus particles travel down the neuronal axons, most often to a site near the site of initial infection. The epithelium is subsequently infected and leads to localized spread and ulceration in a subset of reactivations.
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✺ Reactivation can be induced by sun exposure, fever, trauma, or stress
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Only a subset of infected patients exhibit overt clinical disease
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Host factors have a major effect on clinical manifestations of HSV infection. Many episodes of HSV infection are either asymptomatic or mildly symptomatic. Initial symptomatic clinical episodes of the disease are often more severe than recurrent episodes, likely due to the presence of anti-HSV antibodies and immune lymphocytes in persons with recurrent infections. Prior infection with HSV-1 may provide some level of protection against or shorten the duration of symptoms and lesions from subsequent infection with HSV-2 as a result of some degree of cross-protection, though dual infections certainly occur.
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Both cellular and humoral immune responses are important in immunity to HSV. Neutralizing antibodies directed against HSV envelope glycoproteins appear to be important in preventing exogenous reinfection. Antibody-dependent cellular cytotoxicity (ADCC) may be important in limiting early spread of HSV. By the second week after infection, cytotoxic T lymphocytes can be detected, which have the ability to destroy HSV-infected cells before completion of the replication cycle. Conversely, in immunosuppressed patients, especially those with depressed cell-mediated immunity, reactivation of HSV may be associated with prolonged viral excretion and persistence of lesions as well as more disseminated lesions. During latency, the HSV-1 and HSV-2 do not express viral proteins and are thus effectively hidden from the immune system. However, the immune system plays a role in keeping latency in check as immunosuppression leads to more common reactivation. It is possible that the virus may initiate reactivation more often than previously thought and that the adaptive immune system shuts down those cells once they reactivate.
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✺ ADCC may limit early spread of HSV; cytotoxic T lymphocytes destroy HSV-infected cells
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Reactivation is controlled by the adaptive immune system
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HSVs express a number of genes that have evolved to inhibit innate and adaptive immunity. There are a number of genes capable of inhibiting interferon pathways at different stages. HSV-1 also encodes an IE protein that blocks peptide loading onto MHC-I and prevents the complex from reaching the cell surface. Additionally, HSV inhibits apoptosis during both latent and lytic phases.
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HSV encodes inhibitors of innate and adaptive immunity
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Herpes Simplex Type 1
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Infection with HSV-1 is more often, associated with facial disease though it causes an increasing number of genital infections. It consists characteristically of grouped or single vesicular lesions that become pustular and coalesce to form single or multiple ulcers. On dry surfaces, these ulcers scab before healing; on mucosal surfaces, they reepithelialize directly. HSV can be isolated from almost all ulcerative lesions, but the titer of virus decreases as the lesions evolve. Infections generally involve ectoderm (skin, mouth, conjunctiva, and the nervous system).
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✺ Vesicular lesions become pustular and then ulcerate
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Primary infection with HSV-1 is most often asymptomatic. When symptomatic, typically in children, it appears most frequently as gingivostomatitis, with fever and ulcerative lesions involving the buccal mucosa, tongue, gums, and pharynx. The lesions are painful, and the acute illness usually lasts 5 to 12 days. During this initial infection, HSV spreads to the sensory neurons and becomes latent within neurons of the trigeminal ganglia, the ganglia that innervated the oral and nasal area.
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Primary infections are often asymptomatic
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Lesions usually recur on a specific area of the lip and the immediate adjacent skin; these lesions are referred to as mucocutaneous and are commonly called “cold sores” or “fever blisters” (Figure 14–4). Lesions are typically unilateral. Their recurrence may be signaled by premonitory tingling or burning in the area. Systemic complaints are unusual, and the episode generally lasts approximately 7 days. It should be noted that HSV may be reactivated and excreted into the saliva with no apparent mucosal lesions present. HSV has been isolated from saliva in 5% to 8% of children and 1% to 2% of adults who were asymptomatic at the time.
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✺ Recurrent cold sores are usually unilateral
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Virus in saliva with asymptomatic reactivation
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In rare instances, HSV infects the finger or nail area. This infection, termed herpetic whitlow, usually results from the inoculation of infected secretions through a small cut in the skin or from needle sticks. Painful vesicular lesions of the finger develop and pustulate; they are often mistaken for bacterial infection and mistreated accordingly.
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Herpetic whitlow mimics bacterial paronychia
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HSV infection of the eye is one of the most common causes of corneal damage and blindness in the developed world. Infections usually involve the conjunctiva and cornea, and characteristic dendritic ulcerations are produced. With recurrence of disease, there may be deeper involvement with corneal scarring. Occasionally, there may be extension into deeper structures of the eye, especially when topical steroids are used.
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✺ Herpetic corneal and conjunctival infection can cause blindness
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In rare cases, encephalitis may result from HSV-1 infection. Most cases occur in adults with high levels of anti-HSV-1 antibody, suggesting reactivation of latent virus in the trigeminal nerve root ganglion and extension of productive (lytic) infection into the temporoparietal area of the brain. Primary HSV infection with neurotropic spread of the virus from peripheral sites up the olfactory bulb into the brain may also result in parenchymal brain infection. Classically, HSV encephalitis affects one temporal lobe, leading to focal neurologic signs and cerebral edema. If untreated, mortality rate is approximately 70%. Clinically, the disease can resemble brain abscess, tumor, or intracerebral hemorrhage. Rapid diagnosis by polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) has replaced brain biopsy as the diagnostic test. Intravenous acyclovir reduces the morbidity and mortality of the disease, especially if treatment is initiated early. There are small number of familiar genetic mutations leading to increased herpes encephalitis. These mutations appear to be in genes involved in specific innate immune responses.
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✺ HSV encephalitis typically localized to temporal lobe and has high mortality without treatment
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Rapid PCR diagnosis of CSF allows antiviral therapy
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Herpes Simplex Type 2
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Genital herpes is a significant sexually transmitted disease. Both HSV-1 and HSV-2 can cause genital disease, and the symptoms and signs of acute infection are similar for both viruses. Seventy percent of the first episodes of genital HSV infection in the United States are caused by HSV-2, and genital HSV-2 disease is also more likely to recur than genital HSV-1 infection. Ninety percent of the HSV-2 antibody-positive patients have never had a clinically evident genital HSV episode. In many instances, the first clinical episode is years after primary infection.
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✺ HSV-2 associated with genital infections
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HSV-2 infected patients often do not exhibit overt disease
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Primary Genital Herpes Infection
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For individuals who develop clinically evident primary genital HSV disease, the mean incubation period from sexual contact to onset of lesions is 5 days. Lesions begin as small erythematous papules, which soon form vesicles and then pustules (Figure 14–5). Within 3 to 5 days, the vesiculopustular lesions break to form painful coalesced ulcers that subsequently dry; some form crusts and heal without scarring. With primary disease, the genital lesions are usually multiple (mean number 20), bilateral, and extensive. The urethra and cervix are also infected frequently, with discrete or coalesced ulcers on the exocervix. Bilateral enlarged tender inguinal lymph nodes are usually present and may persist for weeks to months. About one-third of patients show systemic symptoms such as fever, malaise, and myalgia, and approximately 1% develop aseptic meningitis with neck rigidity and severe headache. First episodes of disease last an average of 12 days.
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✺ Multiple painful vesiculopustular lesions
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Systemic symptoms and adenopathy can occur
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Recurrent Genital Herpes Infection
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In contrast to primary infection, recurrent genital herpes is a disease of shorter duration, usually localized in the genital region and without systemic symptoms. A common symptom is prodromal paresthesias in the perineum, genitalia, or buttocks that occur 12 to 24 hours before the appearance of lesions. Recurrent genital herpes usually presents with grouped vesicular lesions in the external genital region. Local symptoms such as pain and itching are mild, lasting 4 to 5 days, and lesions usually last 2 to 5 days.
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Prodromal paresthesias and shorter duration
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At least 80% of patients with primary, symptomatic, genital HSV-2 infection develop recurrent episodes of genital herpes within 12 months. In patients whose lesions recur, the median number of recurrences is four or five per year. They are not evenly spaced, and some patients experience a succession of monthly attacks followed by a period of quiescence. Over time, the number of recurrences decreases by a median of one-half to one recurrence per year. Recurrences result from reactivation of virus from dorsal root ganglia. Recurrent infections due to reinfection with a different strain of HSV-2 are extremely rare. Recurrent viral shedding from the genital tract often occurs without clinically evident disease.
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Recurrent episodes common; may involve shedding without lesions
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Neonatal herpes usually results from transmission of virus during delivery through infected genital secretions from the mother. In utero infection, though possible, is uncommon. In most cases, severe neonatal herpes is associated with primary infection of a seronegative woman near the time of delivery. This results in an intense viral exposure of a seronegative infant as it passes through the birth canal. The incidence of symptomatic neonatal herpes simplex infection varies greatly among populations, but it is estimated at between 1 per 6000 and 1 per 20 000 live births in the United States. Because a normal immune response is absent in the neonate born to a mother with recent primary infection, neonatal HSV infection is an extremely severe disease with an overall mortality rate of approximately 60%, and neurologic sequelae are high in those who survive. Manifestations vary. Some infants show disseminated vesicular lesions with widespread internal organ involvement and necrosis of the liver and adrenal glands; others have involvement of the central nervous system only, with listlessness and seizures.
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Primary infection of mother late during pregnancy is the most common cause
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✺ Usually transmitted during birth and leads to high mortality if disseminated
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Herpes simplex viruses (HSVs) can be cultured in cell lines inoculated with infected secretions or lesions. The cytopathic effects of HSV can usually be demonstrated 24 to 48 hours after inoculation of the culture. Isolates of HSV-1 and HSV-2 can be differentiated by staining virus-infected cells with type-specific monoclonal antibodies. A direct smear prepared from the base of a suspected lesion and stained by either Giemsa or Papanicolaou method may show intranuclear inclusions or multinucleated giant cells typical of herpes (Tzanck test), but this is less sensitive than viral culture and not specific. Similar changes can be seen in cells infected with VZV. Enzyme immunoassays and immunofluorescence are rapid and relatively sensitive assays for direct detection of herpes antigen in lesions. Although early versions of these noncultural tests lacked sensitivity, more recent procedures have correlations with culture that approach 90%. Serology should not be used to diagnose active HSV infections, such as those affecting the genital or central nervous systems; frequently there is no change in antibody titer when reactivation occurs. Serology can be useful in detecting those with asymptomatic HSV-2 infection. PCR of CSF and blood is the best test to diagnose HSV encephalitis.
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✺ Virus can be isolated from lesions and grown in cell culture
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HSV-1 and HSV-2 distinguished by type-specific monoclonal antibodies
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✺ PCR of CSF used for diagnosis of herpes encephalitis
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Several antiviral drugs that inhibit HSV have been developed. The most commonly used is the nucleoside analog acyclovir, which is converted by a viral enzyme (thymidine kinase) to a monophosphate form and then by cellular enzymes to the triphosphate form. The triphosphate form is then incorporated by the viral polymerase into the ongoing replicating viral genome leading to chain termination due to the lack of a hydroxyl group to build upon. Acyclovir significantly decreases the duration of primary infection and has a lesser but definite effect on recurrent mucocutaneous HSV infections. If taken daily, it has been shown to suppress recurrences of genital and oral–labial HSV. In its intravenous form, it is effective in reducing mortality of HSV encephalitis and neonatal herpes. Acyclovir-resistant HSV has been recovered from immunocompromised patients with persistent lesions, especially those with acquired immunodeficiency syndrome (AIDS). Foscarnet is active against acyclovir-resistant HSV.
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Intravenous acyclovir effective in HSV encephalitis and neonatal disease
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The US Food and Drug Administration has approved both valacyclovir and famciclovir for the treatment of recurrent genital HSV. Valacyclovir is an oral prodrug of acyclovir with better bioavailability than acyclovir (54% compared with 15-20%). It is rapidly converted to acyclovir and, in every characteristic except absorption, it is identical with the parent compound. Valacyclovir is not more effective than acyclovir, but can be given in lower doses and less frequently (500 mg twice daily). Famciclovir is the prodrug of another guanosine nucleoside analog, penciclovir. The bioavailability of famciclovir is also high (77%). After conversion, penciclovir must be phosphorylated, similarly to acyclovir. Penciclovir has a longer tissue half-life than acyclovir and can be given as 125 mg twice daily for treatment of recurrent genital HSV. Valacyclovir and famciclovir are now also approved for chronic suppression of recurrent genital HSV. Valacyclovir taken daily was shown to decrease spread between discordant partners in a long-term study.
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✺ Acyclovir or prodrugs can decrease duration of acute and recurrent disease
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Daily valacylovir can decrease spread of HSV-2 between partners
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Avoiding contact with individuals with lesions reduces the risk of spread; however, virus may be shed asymptomatically and transmitted from the saliva, urethra, and cervix by individuals with no evident lesions. Safe sexual practices should reduce transmission. Acyclovir has been shown to reduce asymptomatic shedding and transmission of genital herpes, especially from males to females. Because of the high morbidity and mortality rates of neonatal infection, special attention must be paid to preventing transmission during delivery. Where active HSV lesions are present on maternal tissues, Cesarean section delivery may be used to minimize contact of the infant with infected maternal genital secretions, but Cesarean delivery may not be effective if rupture of the membranes precedes delivery by more than several hours. Avoiding the birth canal is particularly important if the mother has a primary HSV infection late during pregnancy. There is no current HSV vaccine available though a number have been under study for years.
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Cesarean section may be performed to avoid neonatal infection