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Harrison’s Manual of Medicine



Herpes Simplex Viruses
Varicella-Zoster Virus
Human Herpesvirus types 6, 7, and 8
The genome of herpes simplex virus (HSV) is a linear, double-stranded DNA molecule that encodes for >75 gene products. Overall DNA sequence homology between HSV-1 and HSV-2 is ~50%. HSV infection of some neuronal cells does not result in cell death; instead, viral genomes are maintained by the cell in a repressed state known as latency. The process of activation of the viral genome that leads to viral replication and causes recurrent lesions is known as reactivation.
PATHOGENESIS   Exposure of mucosal surfaces or abraded skin to HSV permits entry of the virus and initiation of its replication in epidermal and dermal cells. Sensory or autonomic nerve endings may become infected whether or not clinically apparent lesions develop. Initially, virus replicates in ganglia and contiguous neural tissue; spread occurs via peripheral sensory nerves. While the mechanism of reactivation is not known, stimuli such as UV light, immunosuppression, and trauma to skin or ganglia are associated with reactivation.
EPIDEMIOLOGY   Infection with HSV-1 is acquired more frequently and at an earlier age than infection with HSV-2. By the fifth decade of life, >90% of adults have antibodies to HSV-1. Antibodies to HSV-2 are not routinely detected until puberty; their prevalence varies with the population studied. In obstetric and family planning clinic populations, 25% of women have antibody to HSV-2, although only 10% give a history of genital lesions. In heterosexual adults attending STD clinics, the prevalence of antibody to HSV-2 is up to 50%. The incubation period for HSV infection ranges from 1 to 26 d (median, 6–8 d). HSV can be transmitted by contact with active lesions or with an asymptomatic person excreting the virus; the efficiency of transmission is greater from active lesions.
CLINICAL MANIFESTATIONS   Oral-Facial Infections   Gingivostomatitis and pharyngitis are the most common clinical manifestations of first- episode HSV-1 infection and are most prevalent among children and young adults. Clinical symptoms and signs include fever, malaise, myalgias, inability to eat, irritability, and cervical adenopathy that may last 3–14 d. Lesions may involve the hard and soft palates, gingiva, tongue, lips, and facial area. Reactivation may lead to asymptomatic excretion in the saliva, intraoral mucosal ulcerations, or herpetic ulcerations of the vermilion border of the lip or external facial skin. In immunosuppressed pts, including those with AIDS, severe mucositis due to HSV can develop. Pts with eczema may develop severe oral-facial lesions (eczema herpeticum) with occasional visceral dissemination. HSV-1 has recently been implicated as a cause of Bell’s palsy. Some evidence suggests that HSV infection is the precipitating event in ~75% of cases of erythema multiforme.
Rectal and Perianal Infections   HSV-1 and HSV-2 can cause symptomatic or asymptomatic rectal and perianal infections. Symptoms of HSV proctitis include anorectal pain, discharge, tenesmus, and constipation, with ulcerative lesions of the distal 10 cm of rectal mucosa. HSV proctitis is usually associated with rectal intercourse; however, subclinical perianal shedding can occur in persons who report no rectal intercourse.
Genital Infections See Chap. 83.
Herpetic Whitlow   Clinical symptoms of herpetic whitlow (HSV infection of the finger) include an abrupt onset of edema, erythema, and localized tenderness of the infected finger after direct inoculation. Vesicular or pustular lesions, fever, and lymphadenitis make this infection clinically indistinguishable from a pyogenic infection. Surgical debridement may exacerbate the condition.
Herpes Gladiatorum   Mucocutaneous HSV infections of the thorax, ears, face, and hands have been described among wrestlers.
Herpetic Eye Infections   HSV infection is the most common cause of corneal blindness in the U.S. Herpetic keratitis presents as an acute onset of pain, blurring of vision, chemosis, conjunctivitis, and characteristic dendritic lesions of the cornea. Chorioretinitis occurs in neonates or HIV-infected pts, usually as a manifestation of disseminated infection. Acute necrotizing retinitis is a rare but serious manifestation of HSV and varicella-zoster virus (VZV) infection.
Central and Peripheral Nervous System Infections   HSV is the most common cause of acute sporadic viral encephalitis in the U.S., accounting for 10– 20% of cases. HSV-1 causes >95% of cases, with peaks at 5–30 years and >50 years of age. Clinical manifestations include an acute onset of fever and focal neurologic (especially temporal lobe) symptoms. The diagnosis can be made by brain biopsy; the most sensitive early noninvasive method is demonstration of HSV DNA in the CSF by PCR. Treatment with IV acyclovir is started for a presumptive diagnosis. HSV meningitis, usually seen in association with primary genital HSV infection, is a self-limited disease, with headache, fever, and mild photophobia but no neurologic sequelae. Autonomic nervous system dysfunction, especially of the sacral region, is associated with both HSV and VZV infections. Symptoms include numbness, tingling of the buttock or perineal areas, urinary retention, constipation, CSF pleocytosis, and (in males) impotence; these symptoms resolve slowly over days or weeks. In rare instances, HSV infection is associated with transverse myelitis, manifested by rapidly progressive symmetric lower-extremity paralysis or Guillain-Barré syndrome. Peripheral nervous system involvement includes Bell’s palsy or cranial polyneuritis related to reactivation of HSV-1 infection.
Visceral Infections   Visceral HSV infection commonly involves multiple organs and results from viremia. HSV esophagitis presents as odynophagia, dysphagia, substernal pain, weight loss, and multiple oval ulcerations on an erythematous base with or without a patchy white pseudomembrane. The distal esophagus is most frequently involved. The diagnosis can be made only by endoscopic biopsy with cytology and culture. HSV pneumonitis mainly affects severely immunocompromised pts. Focal necrotizing pneumonitis results from the extension of herpetic tracheobronchitis. Hematogenous dissemination from mucocutaneous disease causes bilateral interstitial pneumonitis. The mortality rate from untreated HSV pneumonia in immunosuppressed pts is high (>80%). HSV is an uncommon cause of hepatitis. The presentation includes fever, abrupt elevations of serum levels of bilirubin and aminotransferases, and leukopenia. DIC may be present. Other rare disseminated manifestations include monarticular arthritis, adrenal necrosis, idiopathic thrombocytopenia, and glomerulonephritis. In immunocompromised pts, rare sites of organ involvement can include the adrenal glands, pancreas, small and large intestines, and bone marrow.
Neonatal Infections   Infants <6 weeks of age have the highest frequency of visceral and/or CNS infection due to HSV. Without treatment, the overall rate of death from neonatal herpes is 65%. Neonatal cases almost always result from contact with infected genital secretions at delivery; 70% of cases are caused by HSV-2.
DIAGNOSIS   A clinical diagnosis can be made by scraping the base of lesions and demonstrating multinucleated giant cells with Wright’s stain or Giemsa’s stain (Tzanck preparation) or characteristic giant cells or intranuclear inclusions by cytology (Papanicolaou’s stain). Cultures become positive in 48–96 h. Methods such as immunofluorescence assay, ELISA, and some DNA hybridization techniques are almost as sensitive as viral isolation from genital or orolabial lesions; however, they are only 50% as sensitive as viral culture for cervical lesions or salivary secretions. PCR is more sensitive than culture for CNS infections and late-stage ulcerative lesions. Seroconversion can be used to document primary infections, but only 5% of pts with reactivation of HSV infection have a fourfold or greater rise in antibody titer.

See Table 102-1.

Table 102-1 Antiviral Chemotherapy for HSV Infection

VZV is a herpesvirus that causes two distinct clinical entities: varicella (chickenpox) and herpes zoster (shingles).
PATHOGENESIS   Primary infection occurs via the respiratory route and is followed by viremia. Reactivation results in herpes zoster by mechanisms that are unknown. It is presumed that VZV infects the dorsal root ganglia during chickenpox and remains latent at that site until reactivated.
EPIDEMIOLOGY   Attack rates for chickenpox are at least 90% among susceptible pts. Cases occur throughout the year, but the disease is epidemic during the late winter and early spring in temperate climates. Children 5–9 years of age account for 50% of cases. The incubation period ranges between 10 and 21 d but is usually 14–17 d. Pts are infectious 48 h before vesicles erupt, during vesicle formation (usually 4–5 d), and until all vesicles are crusted. The incidence of herpes zoster is highest in the sixth through eighth decades of life, but the disease can occur at any age. Most pts with herpes zoster have no exposure to other persons infected with VZV.
CLINICAL MANIFESTATIONS   Chickenpox   Low-grade fever and malaise may precede the exanthem by 24–48 h. Fever and lassitude generally last 3–5 d in immunocompetent hosts. The rash consists of maculopapules, vesicles, and scabs in various stages of evolution. Crops of lesions develop over 2–4 d. Lesions may be found on the pharyngeal or vaginal mucosa. Younger pts tend to have fewer lesions overall than older individuals. Lesions of immunocompromised pts, especially those with leukemia, may be more numerous, may be hemorrhagic, and may take longer to resolve; these pts may be at greater risk of visceral complications. The most common complication of varicella is bacterial superinfection of the skin, usually caused by Streptococcus pyogenes or Staphylococcus aureus. In children, CNS involvement is the most common extracutaneous manifestation. A syndrome of cerebellar ataxia and meningeal irritation generally develops ~21 d after the onset of rash, is usually self-limited, and does not require hospitalization. Other CNS manifestations include aseptic meningitis, encephalitis, transverse myelitis, Guillain-Barré syndrome, and Reye’s syndrome. Varicella pneumonia is the most common serious complication of chickenpox, occurring more frequently among adults (in up to 20% of cases) than among children. Usually developing 3–5 d into the illness, varicella pneumonia is associated with tachypnea, cough, dyspnea, and fever. CXR findings include nodular infiltrates and interstitial pneumonitis. Other complications include myocarditis, corneal lesions, nephritis, arthritis, bleeding diatheses, acute glomerulonephritis, and hepatitis. Hepatic involvement distinct from Reye’s syndrome is common, is usually characterized by elevation of serum aminotransferase levels, and is generally asymptomatic. Perinatal varicella is most severe when maternal disease develops within 5 d before or 48 h after delivery. Congenital varicella is extremely uncommon.
Herpes Zoster   Herpes zoster is characterized by a unilateral vesicular eruption within a dermatome accompanied by severe local pain. Pain heralds infection and may precede the development of lesions by 48–72 h. Erythematous maculopapules evolve rapidly into vesicles. The most debilitating consequences of herpes zoster are acute neuritis and postherpetic neuralgia, both of which are more common among adults than among children and the latter of which is increasingly common with advancing age. At least 50% of pts >50 years old with zoster report pain months after resolution of cutaneous disease. Zoster ophthalmicus is an infection involving the ophthalmic division of the trigeminal nerve. Ramsay Hunt syndrome occurs with involvement of the sensory branch of the facial nerve and is characterized by lesions on the ear canal, ipsilateral facial palsy, and loss of taste in the anterior two-thirds of the tongue. CNS involvement includes asymptomatic CSF pleocytosis; symptomatic meningoencephalitis with headache, fever, photophobia, meningitis, and vomiting; and, in rare instances, granulomatous angiitis with contralateral hemiplegia. Transverse myelitis with or without paralysis may also develop. In immunocompromised pts, especially those with Hodgkin’s or non-Hodgkin’s lymphoma, the clinical syndrome is more severe and the risk of disseminated skin lesions—or even visceral dissemination—is greater. Cutaneous dissemination occurs in ~40% of these pts. Visceral dissemination, including pneumonitis, meningoencephalitis, and hepatitis, occurs in 5–10% of pts with cutaneous dissemination. Even disseminated infection is rarely fatal.
DIAGNOSIS   The diagnosis of both chickenpox and herpes zoster can be made clinically on the basis of the epidemiology, appearance, and distribution of lesions. The Tzanck preparation has a sensitivity of only ~60% and does not distinguish VZV from HSV infection. Serologic tests include fluorescent antibody to membrane antigen (FAMA) and ELISA. Confirmation is possible with viral isolation in tissue culture. VZV takes longer to isolate than HSV. PCR is available in a limited number of diagnostic laboratories.

For chickenpox of £24 h duration in adolescents or adults, acyclovir (800 mg PO 5 times daily for 5–7 d) is recommended. When initiated early, therapy with acyclovir at a dose of 20 mg/kg q6h also may be of benefit to children <12 years old. Aspirin should not be administered to children because of its association with Reye’s syndrome. Palliative measures are directed at the control of itching and drying lesions. For herpes zoster, acyclovir (800 mg PO 5 times daily for 7–10 d) speeds the healing of skin lesions and decreases acute pain but does not alter the incidence of postherpetic neuralgia. Famciclovir (500 mg tid for 7 d) is at least as effective as acyclovir and may accelerate resolution of postherpetic neuralgia. Valacyclovir (1 g tid for 5–7 d) is superior to acyclovir in accelerating healing and resolution of zoster-associated pain. Pts with zoster ophthalmicus should see an ophthalmologist in addition to receiving acyclovir. Postherpetic neuralgia is extremely difficult to treat; analgesics, amitriptyline hydrochloride, and fluphenazine hydrochloride are used. For immunocompromised pts with either chickenpox or herpes zoster, IV acyclovir is recommended at a dose of 10–12.5 mg/kg q8h for 7 d; oral therapy should not be used. Indications for the administration of varicella-zoster immune globulin (VZIG) are summarized in Table 102-2. A live attenuated vaccine is now available for the prevention of VZV infection and is recommended for routine immunization of children and for vaccination of susceptible adults.

Table 102-2 Recommendations for VZIG Administration

HHV-6 is a T-lymphotropic virus that causes exanthem subitum (roseola), a common childhood illness characterized by fever and subsequent rash. HHV-6 has also been associated with febrile seizures (without rash) during infancy and, in older age groups, with mononucleosis syndromes and focal encephalitis. It causes pneumonitis and disseminated disease in immunocompromised hosts. HHV-7 is frequently acquired during childhood and is present in saliva but has not been definitively linked with any known disease. HHV-8 has been assigned a putative etiologic role in Kaposi’s sarcoma and body-cavity lymphoma in AIDS pts.

For a more detailed discussion, see Corey L: Herpes Simplex Viruses, Chap. 182, p. 1100; Whitley RJ: Varicella-Zoster Virus Infections, Chap. 183, p. 1106; and Hirsch MS: Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8, Chap. 185, p. 1111, in HPIM-15.



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