ACP medicine, 3rd Edition

Infectious Disease

Herpesvirus Infections

Martin S. Hirsch MD1

1Professor of Medicine, Harvard Medical School, Director of Clinical AIDS Research and Physician, Massachusetts General Hospital

The author has received grants for clinical research from Takeda Pharmaceuticals North America, Inc., and has served as a consultant to GlaxoSmithKline, Bristol-Myers Squibb Co., and Schering-Plough Corp.

March 2007

Human and Animal Herpesviruses

The herpes group of viruses is composed of at least eight human viruses and numerous animal viruses [see 7:XXXI Viral Zoonoses]. The human herpesviruses include herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus types 6 (HHV-6), 7 (HHV-7), and 8 (HHV-8, also known as Kaposi sarcoma-associated herpesvirus [KSHV]).

All human herpesviruses are of similar size and morphology and are characterized by a core, 30 to 60 nm in diameter, that contains a double-stranded DNA genome; a nucleocapsid, 95 to 100 nm, that exhibits icosahedral symmetry; and a lipoprotein envelope with glycoprotein projections that has a diameter of 120 to 250 nm. Herpesviruses replicate primarily in cell nuclei, and a protein envelope is added as the virus passes through the nuclear membrane.

Human herpesviruses share the properties of latency and reactivation. Members of the group can cause productive lytic infections, in which infectious virus is produced and cells are killed, or nonproductive lytic infections, in which viral DNA persists but complete replication does not occur and cells survive. After acute lytic infections, herpesviruses often persist in a latent form for years; periodic reactivations are followed by recurrent lytic infections. Sites of latency vary: HSV and VZV persist in neural ganglion cells, EBV persists in B cells, and CMV probably remains latent in many cell types. The sites of latency for HHV-6 and HHV-7 have not been identified, although both herpesviruses have been detected in salivary glands.

All human herpesviruses have a worldwide distribution [see Sidebar Herpesvirus Information on the Internet]. Considerable efforts are being directed toward the development of vaccines and antiviral agents that will be active against herpesviruses.

Herpesvirus Information on the Internet

General

http://www.nesfile.com/xlp.htm

Herpes Viruses Weekly

http://www.cdc.gov/std/treatment/TOC2002TG.htm

Sexually Transmitted Disease Treatment Guidelines

http://www.cdc.gov/mmwr/preview/mmwrhtml/00021095.htm

Recommended infection-control practices for dentistry

http://www.cdc.gov/mmwr/preview/mmwrhtml/00001053.htm

Perspectives in disease prevention and health promotion: condoms for prevention of sexually transmitted diseases

HSV

http://www.cdc.gov/std/Herpes/STDFact-Herpes.htm

Patient information on genital herpes

http://www.cdc.gov/mmwr/preview/mmwrhtml/00047449.htm

Case definitions for infectious conditions under public health surveillance

VZV

http://www.cdc.gov/nip/diseases/varicella/vac-chart.htm

Varicella patient information in brief

http://www.cdc.gov/nip/diseases/varicella

Frequently asked questions about varicella and varicella vaccine

http://www.cdc.gov/od/oc/media/fact/chickenp.htm

Facts about chickenpox (varicella) from the CDC Office of Communications, Division of Media Relations

http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/00022690.htm

ACIP recommendation: varicella-zoster immune globulin for the prevention of chickenpox

http://www.cdc.gov/mmwr/preview/mmwrhtml/00042990.htm

Recommendations and Reports—June 27, 1996/Vol. 45/No. RR-1-Preview (The first statement by the Advisory Committee on Immunization Practices [ACIP] on the use of live, attenuated varicella virus vaccine)

CMV

http://www.cdc.gov/ncidod/diseases/cmv.htm

Patient information on cytomegalovirus

http://www.cdc.gov/hiv/pubs/brochure/oi_cmv.htm

Division of HIV/AIDS Prevention Brochures: You Can Prevent CMV

Herpesvirus Simiae

http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/00015936.htm

Guidelines for prevention of herpesvirus simiae (B virus) infection

Herpes Simplex Virus

HSV-1 and HSV-2 can be distinguished by a variety of properties, including clinical and epidemiologic patterns, antigenicity, DNA base composition, biologic characteristics, and sensitivity to various physical and chemical stresses.1 Advances in molecular biology technology have proved that HSV-1 and HSV-2 share certain antigens (e.g., glycoprotein B) but differ with respect to other antigens (e.g., glycoprotein G). Restriction enzyme analysis of HSV DNA and other molecular techniques are used to identify individual isolates.

Epidemiology and Etiology

Humans are the only known natural hosts for HSV, although animals can readily be infected experimentally. HSV-1 primary infection occurs mainly in childhood, whereas HSV-2 infection occurs predominantly in sexually active adolescents and young adults. The prevalence of HSV-2-specific antibodies in the United States increases from less than 6% in those younger than 19 years to more than 25% in those older than 30 years.2 In older age groups, changes in prevalence are negligible. Independent predictors of HSV-2 seropositivity include female gender, black race, increasing age, less education, more lifetime sex partners, prior occurrence of syphilis or gonorrhea, and lack of HSV-1 antibody.3 In the United States, changes in sexual mores resulted in an age-adjusted seroprevalence of HSV-2 infection in the 1990s that was 30% higher than the seroprevalence in the 1970s; HSV-2 is now detectable in one of five persons older than 12 years.2 Approximately one third of new HSV-2 infections are symptomatic.4 Prevalence of antibody to HSV-1 in different populations ranges from 44% in persons 12 to 19 years of age to above 80% in those older than 60 years.2 Between 10% and 25% of adults are dually infected with HSV-1 and HSV-2.2

Direct contact with infected secretions is the principal mode of transmission. HSV-1 is usually transmitted by an oral route and HSV-2 by a genital route. Although virus titers are higher and transmission is more likely when lesions are present, asymptomatic excretion of the virus is common. HSV-2 shedding from the genital tract can occur in seropositive persons who have no history of genital HSV infection.5 Thus, transmission occurs frequently, even in the absence of lesions. HSV-2 is transmitted more efficiently from males to females than from females to males. Autoinoculation to other skin sites also occurs, more often with HSV-2 than with HSV-1. Spread of infection through contact with oral secretions may be an occupational hazard for respiratory care and dental care providers; thus, gloves should be worn when fingers are placed in patients' mouths. Fomites, including toilet seats and towels, are not important modes of transmission. Recurrences are frequent with both HSV-1 and HSV-2 infections, usually as a result of endogenous reactivation. In the United States, lip or perioral recurrences develop in 20% to 40% of the population. Precipitating factors are sunlight, wind, local trauma, fever, menstruation, and emotional stress. Ocular herpes is present in about 5% of all patients seen at ophthalmology clinics; 25% to 50% of ocular HSV infections recur within 2 years. Of all the primary cases of genital herpes in the United States each year, 60% to 80% will recur. Although most genital recurrences represent reactivation, exogenous reinfection can also occur. Clinically significant recurrences tend to decrease over time.6

Pathogenesis

After the initial replication of the virus in epithelial cells, cytolysis and local inflammatory reactions develop, resulting in the characteristic lesion—a superficial vesicle on an inflammatory base. Multinucleated cells and Cowdry type A inclusion bodies are present. Subsequent lymphatic spread to regional nodes and viremic spread to other organs may occur, depending on the immune competence of the host. Viremia can be demonstrated in malnourished children, in certain adults with depressed T cell-mediated immunity, and, occasionally, in immunocompetent persons.

After initial infection, HSV travels along sensory nerve pathways to ganglion cells, the site of latent infection. The viral DNA persists, only to become reactivated by certain stresses. After reactivation, the virus reverses its course and spreads peripherally by sensory nerve pathways. Once HSV reaches cutaneous sites, cell-to-cell spread occurs until host immune mechanisms limit further dissemination. Various mechanisms are engaged in host responses to HSV, including T cell and natural killer cell cytotoxicity, macrophage activation, production of antibody, and production of interferon.

Clinical Syndromes

Oral-Labial Herpes

In patients younger than 5 years, primary HSV-1 infection is most often asymptomatic; when symptomatic, it presents as gingivostomatitis or pharyngitis. After an incubation period of 2 to 12 days, fever and sore throat develop. Small vesicles are observed on the oral mucosa and pharynx. Mouth pain may be severe, breath is fetid, and cervical adenopathy is present. In adolescents and young adults, posterior pharyngitis and tonsillitis may be the primary problem. The differential diagnosis includes streptococcal pharyngitis, aphthous stomatitis, Stevens-Johnson syndrome, herpangina, and infectious mononucleosis. Symptoms and signs often persist for 10 to 21 days, and autoinoculation to other sites, such as fingers and eyes, is common. Oral shedding may persist for several weeks (mean, 7 to 10 days).

Recurrent herpes labialis is a shorter and milder affliction, often heralded by local pain or tingling for a few hours. HSV-1 oral-labial lesions recur more often than HSV-2 oral-labial lesions.3 Vesicles appear most often on the vermilion border and are painful. The lesion is usually small (< 1 cm2), and the progression from vesicle to ulcer to crust is rapid (< 96 hours). Healing is complete within 8 to 10 days. Systemic complaints are uncommon in recurrent herpes labialis.

Ocular Herpes

Most ocular herpetic infections are caused by HSV-1. Primary infections may present as unilateral follicular conjunctivitis, blepharitis, or corneal epithelial opacities. Healing is usually complete within 2 to 3 weeks. Recurrences may take the form of keratitis (more than 90% of cases are unilateral), blepharitis, or keratoconjunctivitis. Branching dendritic ulcers, usually detected by fluorescein staining, are virtually diagnostic and are often associated with diminished visual acuity. Deep stromal involvement may result in scarring, corneal thinning, and abnormal vascularization, with resultant blindness or rupture of the globe.

Genital Herpes

HSV-2 is the causative agent in 70% to 95% of primary genital herpesvirus infections. After an incubation period of 2 to 7 days, fever, malaise, and inguinal adenopathy develop; these symptoms are associated with the appearance of vesicular lesions. In men, lesions are often on the glans penis or penile shaft [see Figure 1]; in women, lesions may involve the vulva, perineum, buttocks, cervix, or vagina. The differential diagnosis includes syphilis, chancroid, Beh¸et syndrome, erythema multiforme, and candidiasis. In women, lesions rapidly ulcerate and become covered with exudate, with resultant vaginal discharge. Urethral involvement sometimes results in dysuria or urinary retention. Signs and symptoms of primary genital herpes often persist for several weeks before complete healing. Previous infection with HSV-1 may reduce the severity and duration of a first episode of genital herpes caused by HSV-2.

 

Figure 1. Herpes simplex virus genital lesions in men often present as grouped vesicles on the penile shaft.

Extragenital lesions develop during the course of primary infection in 10% to 18% of patients. Aseptic meningitis is not uncommon during primary genital herpes, particularly in women, and in rare instances, herpetic sacral radiculomyelitis occurs. Urinary retention may occasionally complicate primary genital herpes, particularly in women.

Recurrent episodes of genital herpes are usually shorter and milder than primary episodes but still affect women more severely than men. Genital HSV-2 infections recur more often than genital HSV-1 infections, and on rare occasions, the two infections can be found simultaneously in lesions.7,8 Moreover, patients dually infected with HSV-1 and HSV-2 have fewer recurrences of genital herpes than those infected with HSV-2 alone.2 With either virus type, after a variable prodrome of tenderness, itching, or tingling, lesions develop on the penis, labia minora, labia majora, perineum, mons pubis, or buttocks. Healing occurs in 6 to 10 days and is usually uncomplicated; frequent asymptomatic shedding occurs, however, particularly in women.5,9 HSV-2 may also cause benign, recurrent lymphocytic meningitis that may be associated with recurrent genital lesions.10

Perianal and Anal Herpes

Perianal and anal HSV-2 infection is an important problem in men who have sex with men. Pain, itching, tenesmus, discharge, fever, chills, sacral paresthesias, headache, and difficulty in urinating may all occur. Vesicles and ulcerations may lead to an erythematous cryptitis with inguinal adenopathy. Herpes proctitis is often prolonged and severe in patients with AIDS [see Figure 2].

 

Figure 2. Perianal herpes simplex infections in patients with compromised immunity may be severe and prolonged.

Other Herpes Syndromes

Herpetic whitlow

Primary finger infections, or whitlows, usually involve one digit and are characterized by intense itching or pain followed by the formation of deep vesicles that may coalesce [see Figure 3]. Among the general public, whitlows are most often caused by HSV-2, whereas among medical and dental personnel, HSV-1 is the principal culprit. The lesions gradually resolve in 2 to 3 weeks, unless they are mistakenly incised, in which case healing may be delayed by secondary bacterial infection. Recurrent whitlows commonly appear and are sometimes associated with severe local neuralgia.

 

Figure 3. Herpetic whitlows, which occur on fingers, are often misdiagnosed as staphylococcal infections.

Neurologic complication

Encephalitis, a severe form of HSV infection, is discussed elsewhere [see 11:XVI Acute Viral Central Nervous System Diseases]. HSV-1 has also been implicated as an etiologic agent in Bell palsy11 and in rare cases of recurrent self-limited meningitis (Mollaret meningitis).12

Infection in the immunocompromised host

Disorders of T cell-mediated immunity are associated with more severe HSV infections. In clinical settings such as organ transplantation, lymphoreticular neoplasm, or AIDS, HSV infection is often slow to heal and may disseminate cutaneously or to visceral organs. Certain skin conditions, such as eczema and burns, are associated with cutaneous but not visceral dissemination. In rare instances, HSV infection during pregnancy or in the elderly is complicated by visceral dissemination, particularly to the liver. Intubation or catheterization of debilitated patients may facilitate the spread of infection; for instance, herpes esophagitis often complicates long-term use of nasogastric tubes.

Neonatal infection

Between one in 2,500 and one in 10,000 births are complicated by HSV infection, usually HSV-2. HSV neonatal infection can be localized or disseminated and results from transmission of the virus to the infant at the time of delivery, either by ascending infection after premature membrane rupture or by passage of the infant through an infected genital tract. The risk of transmission is increased in premature births, after prolonged membrane rupture, and with the use of fetal scalp monitor electrodes. About 40% to 50% of infants born to mothers with primary infections are at risk for the development of severe disease, whereas fewer than 8% of those born to women with recurrent herpes are at risk for severe disease.1,13 Maternal infection is often asymptomatic at the time of delivery, and asymptomatic shedding may occur in women with no known history of genital herpes. In women with a history of genital HSV infection, genital HSV can be detected at delivery in approximately 2% by use of tissue culture and in 14% by use of polymerase chain reaction (PCR) techniques.14

Infection becomes apparent several days to weeks after delivery. Newborns often present with vesicles or conjunctivitis, or a syndrome resembling neonatal sepsis may be evident. Neurologic signs such as seizures, cranial nerve palsies, and lethargy often predominate and are accompanied by cerebrospinal fluid pleocytosis. Disseminated infection may involve the liver, lungs, or adrenal glands. If untreated, disseminated or central nervous system infection is fatal in more than 70% of patients, whereas localized disease is generally self-limited. Treatment has greatly reduced the mortality from severe infection [see 11:XVI Acute Viral Central Nervous System Diseases].

Diagnosis

A variety of tissue culture systems support the replication of HSV, and virus isolation from specimens collected early in the course of infection is the diagnostic method of choice. The characteristic cytopathic effect of the virus is often detectable within a period of 24 to 48 hours. Typing of isolates can be accomplished most readily by immunofluorescence with monoclonal antibodies directed against type-specific antigens. Scrapings or tissue specimens can sometimes be tested directly for herpesvirus antigens by immunofluorescence or immunohistochemistry. Alternatively, scrapings may be prepared by Giemsa or Wright stain and examined for the presence of multinucleated giant cells, which indicates infection with HSV or VZV. Serologic techniques that accurately differentiate HSV-1 from HSV-2 infections are now commercially available. Such tests can be used to confirm a diagnosis of primary HSV infection, but they are seldom helpful in diagnosing recurrences. Serologic techniques can also establish a diagnosis in patients with atypical complaints, identify asymptomatic carriers, and identify persons at risk.15 PCR detection of HSV DNA in CSF has become the standard means of diagnosing HSV encephalitis. For patients with HSV encephalitis, PCR results are often positive within 24 hours of the onset of symptoms, and test results may remain positive during the first week of illness.16

Prevention

No HSV vaccine has been approved for general use, although preliminary studies of glycoprotein-D-adjuvant vaccines suggest efficacy in certain populations (i.e., women seronegative for both HSV-1 and HSV-2) but not others.17 Prophylactic measures that prevent contact with the virus may help in avoiding primary infection. For instance, the use of condoms may prevent sexual transmission when either sexual partner has a history of genital HSV infection. Application of sunscreens to susceptible skin areas before exposure to ultraviolet light can prevent reactivation of HSV. Medical and dental personnel who treat HSV-positive patients should wear gloves to prevent contact with infected areas.

The best strategy for the prevention of neonatal herpes may be close physical examination at the time of labor.18 Cesarean section is indicated to prevent perinatal infection when lesions consistent with the diagnosis of genital herpes are noted during labor. If primary genital herpes is detected during the third trimester of pregnancy, acyclovir in conventional doses should be considered for the mother during the peripartum period and for the newborn post partum [see Treatment, below]. Acyclovir in late pregnancy may also be useful in women with recurrent genital HSV infections; placebo-controlled trials have shown that 400 mg three times daily reduced lesions and HSV excretion at delivery.19,20

Treatment

Two decades of carefully controlled trials and clinical experience have made acyclovir the treatment standard for HSV infections, although the prodrug valacyclovir (which is converted to acyclovir) and famciclovir (which is converted to penciclovir) now provide alternative options [see Table 1].1 Either oral acyclovir (200 mg five times daily) or intravenous acyclovir (5 mg/kg three times daily) for 7 to 10 days is recommended for treatment of primary genital herpes or mucocutaneous herpes (HSV-1 or HSV-2). Alternatively, valacyclovir (500 to 1,000 mg twice daily) or famciclovir (250 mg three times daily) may be used. Short-term (1 to 3 days), high-dose acyclovir or valacyclovir regimens are promising therapies for both genital and orolabial recurrent HSV infections.21,22

Table 1 Drug Treatment for Primary Genital or Mucocutaneous Herpes Infection

Drug

Dose

Efficacy Rating

Cost/Mo

Comment

Acyclovir*

200 mg p.o. five times a day for
  7–10 days or 5 mg/kg I.V. t.i.d.
  for 7–10 days

First choice

Oral, $34.98

May be useful in high-dose short-term regimens

Valacyclovir*

500–1,000 mg p.o., b.i.d.

Alternative

$437.94

May be used in high-dose (1–2 g), short-term (1–2 day) regimens

Famciclovir*

250 mg p.o., t.i.d.

Alternative

$286.99

Used when its dosing of three times a day is preferred to acyclovir's five times a day

Foscarnet

40 mg/kg I.V. b.i.d. to t.i.d. for 2–3 wk

Alternative

NA

For chronic acyclovir-resistant HSV-2 infection

*Short-term, high-dose regimens show promise.
Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies.
HSV-2—herpes simplex virus type 2  NA—not available

Suppression of severe and frequently recurring genital herpes can also be accomplished by the administration of oral acyclovir (200 to 400 mg twice daily), oral famciclovir (250 mg twice daily), or oral valacyclovir (500 to 1,000 mg daily) [see Table 2]. Once-daily valacyclovir (500 mg) not only suppresses recurrences of genital herpes but also reduces genital excretion of HSV-2 and transmission to partners.23Intravenous acyclovir, in a dosage of 10 to 15 mg/kg three times daily for 14 to 21 days, is the treatment of choice for herpes encephalitis. Neonatal HSV infections are treated with intravenous acyclovir in a dosage of 20 mg/kg every 8 hours for 14 to 21 days.

Table 2 Drug Treatment for Suppression of Severe and Frequently Recurring Genital Herpes Infection

Drug

Dose

Efficacy Rating

Cost/Mo*

Comment

Acyclovir

200–400 mg p.o., b.i.d.

First choice

$27.98

 

Valacyclovir

500–1,000 mg/day p.o.

Alternative

$218.97

Has been shown to decrease viral excretion and transmission

Famciclovir

250 mg p.o., b.i.d.

Alternative

$199.98

 

*Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies.

In immunocompromised persons and, in rare instances, in immunocompetent persons, acyclovir-resistant HSV-2 may lead to chronic progressive infections.24 Intravenous foscarnet (40 mg/kg two to three times daily for 2 to 3 weeks) is useful against acyclovir-resistant HSV-2 infection. Topical preparations of foscarnet, cidofovir, and trifluridine are also under study for acyclovir-resistant HSV.25,26,27

Varicella-Zoster Virus

VZV is the causative agent of varicella (chickenpox) and herpes zoster (shingles). Because it is a strongly cell-associated member of the human herpesvirus group, it is difficult to detect or isolate in cell-free specimens. Its host range is largely limited to human cells. As with other herpesviruses, latency and reactivation are characteristic features of VZV.

Epidemiology

Varicella

Varicella is a highly communicable disease of childhood. More than 90% of patients are children younger than 9 years; most adults have antibody to the virus. Infection is spread by respiratory droplets or by direct contact with active lesions. Fomites are not an important mode of transmission. Chickenpox occurs most frequently in the winter and the spring and spreads rapidly to susceptible household members. The incubation period ranges from 11 to 20 days.

Herpes Zoster

Herpes zoster results from the reactivation of VZV infection. Varicella in one patient cannot produce herpes zoster in another; however, persons who are exposed to patients who have herpes zoster can contract varicella. There is no seasonal pattern for herpes zoster. The likelihood of reactivation is related to both age and immune status.28 The incidence of disease in patients older than 60 years is two to three times higher than that in younger persons. The incidence in immunosuppressed patients, particularly those with depressed T cell function (e.g., patients who have lymphomas, leukemias, organ transplants, or AIDS), is as much as 100 times higher than that in immunocompetent hosts.

Herpes zoster occurs more frequently in patients with neoplasms. The risk of developing herpes zoster is 13% to 15% for patients with Hodgkin disease, 7% to 9% for patients with other lymphomas, and 1% to 3% for patients with solid tumors. Approximately 15% to 30% of patients with Hodgkin disease and herpes zoster exhibit significant dissemination; however, mortality in such patients is low. Localized and disseminated herpes zoster are more common in patients with advanced malignant disease who are receiving intensive chemotherapy or irradiation. The incidence of herpes zoster is also increased after organ or bone marrow transplantation. The incidence of herpes zoster is approximately 8.6% in solid-organ transplant recipients, and it may be more common in women and in patients who are following certain immunosuppressive and prophylactic antiviral regimens.29 In patients with advanced HIV-1 infection, chronic, nonhealing VZV ulcers may persist for several months, and herpes zoster may be precipitated by the introduction of highly active antiretroviral therapy.

Clinical Syndromes

Varicella

After local replication of VZV at the site of virus entry, the virus is carried by blood leukocytes to focal skin areas and visceral organs. Replication at skin sites results in vesicle formation accompanied by degeneration of epithelial cells, accumulation of edema fluid, and infiltration of inflammatory cells; multinucleated giant cells containing intranuclear inclusions are present.

Clinical features

Subclinical infections are rare (< 4% of cases). Illness usually presents as a generalized vesicular eruption that is followed by a variable prodrome of headache, fever, and malaise. Vesicles often appear initially on the face or trunk [see Figure 4]. During the next 4 to 7 days, successive crops of lesions appear. Most childhood cases are uncomplicated and resolve in 7 to 10 days without producing scarring.

 

Figure 4. Varicella-zoster Virus Infection

The lesions characteristic of varicella-zoster virus infection often appear initially on the face and trunk and may present as maculopapules, vesicles, and scabs simultaneously.

Complications

In adolescents and adults, pneumonia may develop that is characterized by cough, tachypnea, and diffuse reticulonodular infiltrates, which may calcify with time. Pulmonary oxygen diffusion difficulties may persist for a period of weeks to months. Varicella pneumonia may be particularly severe in pregnant women and, among them, is more common in smokers and those with more than 100 skin lesions.30 Although varicella encephalopathies are uncommon, they can occur at any age and can take several forms; the presenting feature may be hyperexcitability, which can progress to coma or cerebellar ataxia. Other rare complications of varicella infection are Reye syndrome (fulminating encephalopathy and fatty liver), thrombocytopenia, arthritis, ocular involvement, carditis, gastrointestinal bleeding, nephritis, orchitis, and bacterial superinfection. A pregnant woman who contracts varicella during the first 20 weeks of pregnancy has a small (< 2%) risk of giving birth to an infant with congenital varicella syndrome, which includes limb hypoplasia, skin scarring, and ocular defects.31

Disseminated disease is more likely to develop after varicella infection in children with leukemia, lymphoma, or Hodgkin disease. Visceral dissemination occurs in 20% to 35% of children with cancer who are receiving chemotherapy; mortality in such patients is 7% to 30%. Clinical reinfection, with resultant atypical generalized varicella, can occur in the severely immunocompromised host; such reinfection tends to be mild and self-limited.

Herpes Zoster

Herpes zoster occurs in patients previously infected with varicella. After an initial episode of varicella infection, the virus persists in neurons of sensory ganglia in a relatively quiescent, extrachromosomal, cytoplasmic state.32,33 Both subclinical and clinical reactivations occur. Clinical VZV reactivation is enhanced by many factors, including increasing age, immunosuppression, and local skin injury.

Clinical features

Attacks of herpes zoster are often preceded by pain, which may persist for several days before lesions appear. The vesicular eruption is unilateral and most often appears on the thorax [see Figure 5]. Individual attacks are usually limited to one to three dermatomes, although a few isolated skin lesions at sites distant from this area are not uncommon. Vesicles surrounded by an erythematous base may continue to develop for several days; the lesions then dry and crust. Superinfections are common, and scarring can occur.

 

Figure 5. Herpes zoster is most often thoracic and dermatomal in distribution. Cutaneous dissemination, as seen in this patient, as well as visceral dissemination, may occur when immunity is severely compromised.

Complications

The most common complication of herpes zoster is postherpetic neuralgia, which may be severe, particularly in the elderly. Postherpetic neuralgia may be refractory to treatment and persist for months to years [see 11:XVI Acute Viral Central Nervous System Diseases]. Other neurologic syndromes associated with herpes zoster are segmental myelitis, Guillain-Barré syndrome, acute retinal necrosis, and Ramsay Hunt syndrome.33 Ramsay Hunt syndrome is an infection of the geniculate ganglion of the seventh cranial nerve, producing facial paralysis; vesicles on the eardrum and side of the tongue can also occur.

VZV encephalitis, another infrequent complication of herpes zoster, may present in two forms.33 Large vessel encephalitis (granulomatous arteritis) occurs predominantly in immunocompetent persons; it is characterized by acute focal deficits that occur weeks after the appearance of zoster lesions in the contralateral trigeminal pattern of distribution. Angiography demonstrates segmental narrowing, primarily in the internal carotid and middle or anterior cerebral arteries. Microscopic examination shows arterial inflammation, multinucleated giant cells, and virus particles. Small vessel encephalitis occurs almost exclusively in immunocompromised persons and is characterized by head ache, fever, mental changes, seizures, and focal deficits. Imaging studies show ischemic or hemorrhagic infarcts of gray and white matter, and CSF examination demonstrates mononuclear pleocytosis and both VZV DNA and VZV antibody.

Diagnosis

Varicella and herpes zoster can usually be diagnosed solely on clinical grounds. Varicella is sometimes confused with disseminated herpes simplex, impetigo, insect bites, or scabies; on rare occasions, HSV infection presents with zosteriform eruptions. Diagnosis of VZV infection can be confirmed by virus isolation, direct immunofluorescence of lesions, PCR detection of viral DNA, or demonstration of a fourfold rise in antibodies to viral antigens. Herpes zoster provokes a more rapid and greater rise in antibodies than varicella.

Prevention

A live attenuated VZV vaccine (Varivax) is available in the United States and appears both safe and effective for the prevention of chickenpox. It is recommended for persons older than 1 year who are in good health and have no history of clinical VZV infection. A single subcutaneous dose is recommended for children 1 to 12 years of age, whereas two doses, administered 4 to 8 weeks apart, are recommended for susceptible adolescents and adults. Varicella has declined markedly in surveillance areas secondary to vaccine use.34However, breakthrough infections in vaccinated children suggest that booster doses of vaccine may be necessary to maintain optimal immunity.35

On May 25, 2006, the FDA approved a higher-dose VZV vaccine (Zostavax) on the basis of results of a large randomized clinical study in more than 38,000 individuals.36 This study, conducted in individuals 60 years of age and older, showed that the vaccine reduced the incidence of herpes zoster by 51%, compared with placebo. In addition, in those individuals who did develop herpes zoster, postherpetic neuralgia was reduced by 39%. The vaccine is approved for the prevention of herpes zoster in individuals 60 years of age and older. Because people who had already had herpes zoster were excluded from the trials, it has not yet been determined whether such individuals might also benefit from the vaccine. The vaccine should not be given to individuals with primary or acquired immunodeficiency states (e.g., patients with AIDS, leukemia, or lymphoma or those receiving iatrogenic immunosuppression), individuals with active untreated tuberculosis, women who are or may be pregnant, or people with a history of anaphylactoid reactions to vaccine components. Additional information about the herpes zoster vaccine is available at the Centers for Disease Control and Prevention Web site:http://www.cdc.gov/nip/publications/VIS/vis-shingles.pdf.

Nosocomial transmission of VZV has been reported. Thus, hospitalized patients with varicella or herpes zoster should be isolated to prevent the spread of virus to other susceptible persons. Susceptible high-risk patients who are exposed to infected persons and have contraindications to VZV vaccine should receive prophylaxis with varicella-zoster immune globulin (VariZIG, 125 units/10 kg body weight I.M., up to 4 days after exposure) to prevent or modify clinical illness.37 Small studies suggest that high-dose acyclovir (40 to 80 mg/kg for 7 days, beginning 7 to 9 days after exposure) or VZV vaccine (one dose on the day of exposure or up to 3 days after exposure) may also be useful in postexposure prophylaxis.32

Treatment

Considerable success in the treatment of VZV infections in immunocompromised hosts has been achieved with parenteral administration of acyclovir (for adults, 10 mg/kg every 8 hours for 7 days). High-dose oral acyclovir (800 mg five times daily for 7 days), when begun early, may also shorten the course and reduce the severity of herpes zoster in otherwise healthy hosts. Oral valacyclovir (1 g three times daily) or famciclovir (500 mg three times daily) may also be used [see Table 3]. The use of corticosteroids in combination with acyclovir for the treatment of acute herpes zoster remains controversial.38,39 Steroid use may be justified in persons older than 50 years who have no relative contraindications, such as diabetes, hypertension, or glaucoma.28

Table 3 Drug Treatment for Varicella-Zoster Virus Infection

Drug

Dose

Efficacy Rating

Cost/Mo*

Comment

Acyclovir

10 mg/kg I.V. q. 8 hr for 7 days

First choice

NA

For immunocompromised patients

800 mg p.o. five times/day for 7 days

Alternative

$89.98

May shorten course and reduce severity of herpes zoster and varicella in otherwise healthy patients

Valacyclovir

1 g p.o., t.i.d.

Alternative

$542.99

May shorten course and reduce severity of herpes zoster and varicella in otherwise healthy patients

Famciclovir

500 mg p.o., t.i.d.

Alternative

$599.97

May shorten course and reduce severity of herpes zoster and varicella in otherwise healthy patients

Foscarnet

40 mg/kg I.V. q. 8 hr

Alternative

NA

For acyclovir-resistant VZV infection in immunocompromised patients

*Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies.
NA—not available

Acyclovir resistance has been described in VZV isolates from patients with HIV infection who received long-term acyclovir therapy. Foscarnet (40 mg/kg every 8 hours) is the drug of choice for acyclovir-resistant VZV infections in immunocompromised hosts [see Table 3].40Acyclovir, famciclovir, and valacyclovir are also effective in reducing the severity and shortening the course of chickenpox in patients who are immunologically competent, although children are generally not treated for uncomplicated varicella.

Postherpetic neuralgia, the most common complication of herpes zoster, is difficult to treat, particularly in elderly patients; suggested treatments include topical anesthetics, oral analgesics, tricyclic antidepressants, gabapentin, and intrathecal methylprednisolone acetate.28

Cytomegalovirus

Although cytomegalic inclusion disease of infants was recognized as a clinical entity at the turn of the 20th century, the etiologic agent, CMV, was not isolated until the mid-1950s. CMV has since become recognized as a nearly ubiquitous virus that plays an important role in many diseases, including a form of mononucleosis and disseminated disease in the immunocompromised host.

Epidemiology and Etiology

CMV has a worldwide distribution. Approximately 1% of newborns in developed countries are infected with CMV, and the incidence is much higher in developing areas. In immunocompromised patients (e.g., organ or bone marrow transplant recipients and patients with AIDS), CMV infection is a major cause of morbidity and mortality.

Transmission occurs by close contact with infected persons, most commonly by the sharing of secretions or leukocyte-containing blood products. CMV is shed in semen, cervical secretions, saliva, maternal milk, and urine. In late adolescence and adulthood, genital transmission is common. Primary infection in pregnant women may result in transplacental spread to the fetus, sometimes with devastating consequences. Naturally acquired immunity substantially reduces the likelihood of congenital infection, although infection with a different CMV strain can occur and lead to symptomatic infection of the newborn.41 Perinatal infection is also common because of spread from maternal milk or other secretions. Communal living and poor personal hygiene facilitate transmission. Spread of CMV in day care centers is common; the infected child often serves as a source of transmission to other family members. Blood transfusions and organ transplantation may also transmit CMV from an asymptomatic donor to a recipient. The proportion of CMV anti body-negative liver transplant recipients receiving organs from CMV antibody-positive donors appears to be increasing.42

Pathogenesis

Once infected, one probably carries the virus for life. Generally, such infections remain dormant, but reactivation occurs during periods of immune compromise. Reactivation is particularly common in patients with compromised T cell function (e.g., transplant recipients or patients with lymphoid neoplasms or AIDS). Reinfections with new strains of CMV can also occur in immunosuppressed patients.

In the fetus, primary infection may result in disseminated cytomegalic inclusion disease with numerous congenital abnormalities, in localized disease affecting the auditory system or the CNS, or in subclinical involvement. Perinatal infection is usually asymptomatic, although protracted interstitial pneumonitis, hepatitis, and failure to thrive may result.

Symptomatic disease is more likely to be produced by primary CMV infection than by viral reactivation. The sites of latent infection are poorly defined, although it appears likely that CMV persists in numerous cell types in many organs. If host immune responses become compromised, virus reactivation and increased replication can occur and result in various syndromes. CMV replication can further suppress immune responses, leading to profound lymphocyte hyporesponsiveness and severe opportunistic infections with protozoa (e.g.,Pneumocystis carinii and Toxoplasma gondii), fungi, or bacteria. The mechanisms by which CMV replication inhibits host responses are complex and involve virus interactions with both host lymphocytes and mono cyte-macrophages.

Clinical Syndromes

CMV Mononucleosis

Clinical features

CMV mononucleosis occurs in patients of any age but is most common in sexually active young adults. A vigorous host T cell response may contribute to the syndrome, which is characterized by fever, malaise, fatigue, and myalgia. Headache and splenomegaly are also often present. Mild liver enzyme abnormalities are common, and atypical lymphocytes are present in the peripheral blood. Heterophile antibodies are not formed in response to CMV infection; however, mild immunologic abnormalities, including the presence of rheumatoid factor and antinuclear antibodies, are common.

Complications

Occasionally, hemolytic anemia, thrombocytopenia, neurologic complications (e.g., Guillain-Barré syndrome), or other organ involvement (liver, lung) occurs and is severe.43 Acute infections generally resolve in 2 to 4 weeks, but postviral asthenia and viral excretion often persist for months.

CMV Infection in the Immunocompromised Host

CMV appears to be the most frequent and important viral pathogen in patients who have had organ transplants. Most commonly, such patients with CMV syndromes present with fever and leukopenia, which may progress to pneumonitis or, in rare instances, to disseminated disease. The period of highest risk is 1 to 4 months after transplantation and appears to relate to the degree of host immunosuppression. CMV may also increase the risk of graft loss after organ transplantation.44 CMV pneumonia occurs in nearly 20% of marrow transplant recipients; mortality in such patients, if they remain untreated, is about 90%.

CMV is recognized as an important pathogen in patients with AIDS. The virus often contributes to the immunosuppression observed in such patients and may cause disseminated disease affecting the eyes, GI tract, or CNS. At least 50% of patients with AIDS have CMV viremia, and 90% or more have evidence of CMV infection at autopsy.45 Ulcers of the esophagus, stomach, small intestine, or colon may be present and may lead to bleeding or perforation.46 It is critical to recognize CMV polyradiculopathy or encephalitis in this setting because this disorder is potentially reversible with therapy.47,48 Similarly, CMV retinitis is an important treatable cause of blindness in patients with AIDS.49 Early lesions consist of small white areas of retinal necrosis that progress in a centrifugal manner and are subsequently accompanied by hemorrhage, vessel sheathing, and retinal edema [see Figure 6]. CMV and HIV have been shown to potentiate each other's replication in vitro, and it is possible that such interactions occur in dually infected organs (e.g., the retina and brain of an AIDS patient who has CMV infection).

 

Figure 6. Cytomegalovirus retinitis may result in hemorrhage exudates and, eventually, blindness.

Two forms of CMV encephalitis are clinically and pathologically distinguishable in patients with AIDS: multifocal micronodular encephalitis, which resembles HIV encephalitis and presents with progressive dementia, and ventriculoencephalitis, which is characterized by acute cranial nerve deficits, ventriculomegaly, nystagmus, lethargy, and disorientation.48,50

Diagnosis

CMV infection cannot be reliably diagnosed on clinical grounds alone. Virus can be isolated from a variety of secretions or infected tissues, but definitive identification can take several weeks. Use of shell vial centrifugation and immunocytochemical analysis for CMV early antigens can facilitate rapid diagnosis and help monitor outcome, as can the application of immunofluorescence or PCR-based assays to plasma or peripheral blood leukocytes.51,52,53 Demonstration of viremia is a better indicator of acute infection than the detection of virus in urine or saliva. The use of PCR to detect CMV DNA in CSF is helpful in the diagnosis of CMV encephalitis and polyradiculopathy.48,50

Prevention

Several specific and nonspecific prophylactic measures to prevent CMV syndromes are under investigation. Matching of seronegative transplant or transfusion recipients with seronegative organ or blood donors may reduce the likelihood of transmission. Use of blood that has been frozen and thawed, washed with saline, or filtered through cotton wool can prevent transfusion-associated CMV infection. CMV immune globulin may be useful in certain seronegative bone marrow transplant recipients. Experimental CMV vaccines are under investigation.

Treatment

Management of CMV Mononucleosis

CMV mononucleosis is generally self-limited and requires only supportive care. Specific antiviral therapy is not indicated.

Management of CMV in the Immunocompromised Host

Intravenous ganciclovir, an analogue of deoxyguanosine, and oral valganciclovir, a prodrug for ganciclovir, are effective treatments for CMV infections (e.g., retinitis) in immunocompromised hosts [see Table 4]. Both ganciclovir administered intravenously (5 mg/kg twice daily for 21 days followed by 5 mg/kg daily maintenance) and oral valganciclovir (900 mg twice daily for 21 days followed by 900 mg daily maintenance) result in stabilization or improvement in 70% to 90% of patients with CMV retinitis.54 If the immunocompromised state persists, prolonged maintenance therapy may be required to maintain improvement of retinitis.55 Maintenance therapy can be safely discontinued in patients with AIDS whose CD4 cell counts increase substantially with antiretroviral therapy, but relapses occur if CD4 cell counts fall below 50/mm3.56

Table 4 Drug Treatment for Cytomegalovirus Infection

Drug

Dose

Efficacy Rating

Comment

Ganciclovir

5 mg/kg I.V. b.i.d. for 21 days, then 5 mg/kg I.V. q.d. for maintenance

First choice

For CMV retinitis and other advanced CMV infections in immunocompromised patients

Ganciclovir + ocular implants

1.5 g p.o., t.i.d.

For long-term therapy of CMV retinitis in patients with HIV infection

Valganciclovir

900 mg p.o., b.i.d., for 21 days, then 900 mg p.o., q.d., for maintenance

First choice

For CMV retinitis and other advanced CMV infections in immunocompromised patients

Foscarnet

90 mg/kg I.V. b.i.d. for 2–3 wk, then 90–120 mg/kg I.V. q.d.

Alternative

For CMV retinitis or GI disease; combine with ganciclovir for severe CNS infections in patients with AIDS

Cidofovir

5 mg/kg I.V. once a week for 2 wk, then 5 mg/kg I.V. every 2 wk

Alternative

For CMV retinitis

CMV—cytomegalovirus  CNS—central nervous system  GI—gastrointestinal  NA—not available

Foscarnet (90 mg/kg twice daily for 2 to 3 weeks, followed by 90 to 120 mg/kg daily) is effective in treatment of CMV retinitis and GI disease, and cidofovir (5 mg/kg weekly for 2 weeks, followed by 5 mg/kg every 2 weeks) may be useful in CMV retinitis. Ganciclovir ocular implants in combination with oral ganciclovir (1.5 g three times daily) is effective for long-term treatment of CMV retinitis in persistently immunocompromised patients with HIV infection.57 The combination of ganciclovir and foscarnet may be necessary for severe CNS infections in patients with AIDS.58 Resistance to ganciclovir and other anti-CMV drugs may complicate prolonged therapy.59,60

Prophylactic or suppressive ganciclovir may be useful in other high-risk patients, such as CMV-seropositive bone marrow or solid-organ transplant recipients. Several preventive or preemptive regimens of ganciclovir or valganciclovir are under study in both susceptible transplant recipients and patients with AIDS.61,62,63

Epstein-Barr Virus

EBV has a very limited cell tropism; its host range is generally restricted to human B cells and epithelial cells of the nasopharynx and uterine cervix. It is the cause of heterophile anti body-positive infectious mononucleosis and has been implicated in a variety of other disorders, including Burkitt lymphoma, nasopharyngeal carcinoma, oral hairy leukoplakia, and a variety of B cell and possibly T cell lymphoproliferative disorders.64,65,66

Epidemiology and Etiology

In developing countries, most of the population is exposed to EBV at an early age. In the United States, approximately 50% of the population seroconvert by 5 years of age; there is also a high rate of seroconversion in adolescence and young adulthood. Clinical infectious mononucleosis develops primarily in persons who contract primary EBV infection when they are between 10 and 20 years of age; in younger persons, primary EBV infection is usually clinically inapparent. Thus, most cases of infectious mononucleosis occur in members of higher socioeconomic groups in developed countries, where viral transmission is often delayed until the patients are older than 10 years. Approximately 12% of susceptible college-age young adults seroconvert each year; about 50% of them acquire infectious mononucleosis. As a result, EBV infection has important public health implications for young adult populations, including students and military personnel.

EBV is shed from the oropharynx in approximately 15% of the adult seropositive population at any given time, and all EBV-seropositive individuals may shed virus in their saliva at some time.67 Shedding occurs much more frequently in patients with infectious mononucleosis and in immunocompromised persons, such as renal transplant recipients and patients with AIDS. Transmission requires close contact, usually oral to oral, with a person shedding EBV. On rare occasions, virus can be transmitted by other routes, including blood transfusion. EBV infection of the uterine cervix has been documented, genital ulcerations have been observed in patients with infectious mononucleosis, and sexual activity is a highly significant risk factor for EBV seropositivity,68 suggesting the possibility of genital transmission of EBV to sexual partners and newborns.

Pathogenesis

Infection is initiated by the binding of EBV envelope proteins gp350/120 to the cell surface molecule CD21. After initial replication in nasopharyngeal cells or B cells, B cells apparently carry the virus to other parts of the body. In the nasopharynx, infectious virus is actively replicated. In contrast, in B cells, the viral genome is present, but mature infectious virus particles are not produced. In B cells in which EBV remains latent, its DNA exists as a circular episome; in cells in which infectious virus is produced, EBV DNA exists in a linear form. Infected B cells are referred to as immortalized (i.e., capable of continuous proliferation) and may produce a variety of antibodies as a consequence of polyclonal B cell activation. One of the antibodies they produce, the heterophile antibody, is a useful diagnostic marker of infection. Once infection is initiated, the host mounts a T cell response against new antigens on infected cells and a B cell antibody response against several EBV-associated antigens, including viral capsid antigen, early antigen, and Epstein-Barr nuclear antigen.64 Antibody patterns vary according to the stage of infection and the syndrome expressed (see below).

Clinical Syndromes

Age and immunocompetence greatly influence the expression of EBV infection. Young children usually have asymptomatic or trivial infections and often do not produce heterophile antibodies. In the elderly, EBV infection may present as a persistent febrile syndrome in which the patient tests negative for heterophile antibodies. The most common clinical manifestation of primary EBV infection is infectious mononucleosis.

Infectious Mononucleosis

Clinical features

Patients usually present with fever, pharyngitis, and lymphadenopathy. Hepatosplenomegaly, a palatal enanthema, periorbital edema, and jaundice are less common features. A maculopapular diffuse rash occurs in 10% of patients, particularly in patients who have been given ampicillin. Hematologic abnormalities include a peripheral blood lymphocytosis; usually more than 10% of the leukocytes in the peripheral blood consist of atypical lymphocytes. The total leukocyte count may be normal, low, or high; a relative and absolute neutropenia is observed in 60% to 90% of patients. Thrombocytopenia is also common, and hepatocellular enzymes are abnormal in about 90% of patients. Cryoproteins and antigranulocyte antibodies are frequently present but are usually of little clinical significance. Most cases of infectious mononucleosis resolve in 1 to 3 weeks, although malaise and fatigue occasionally persist for several weeks to months.

Complications

Complications of infectious mononucleosis can affect most organ systems. Tonsillar enlargement can be extreme, causing respiratory embarrassment. Splenic rupture is rare but must be considered when abdominal pain develops, particularly during the second and third weeks of illness. Patients with splenic rupture usually have left upper quadrant pain and tenderness, often accompanied by signs of peritoneal irritation and laboratory evidence of a falling hematocrit. Splenectomy may be required when a diagnosis of splenic rupture is confirmed, although splenic preservation is sometimes possible with intensive supportive care.

Neurologic complications occur in fewer than 1% of patients with infectious mononucleosis; these complications include encephalitis, aseptic meningitis, transverse myelitis, Guillain-BarrE9 syndrome, optic neuritis, and peripheral neuropathies. EBV encephalitis often presents as a cerebellitis, but it may mimic the temporal lobe presentation of herpes encephalitis [see 11:XVI Acute Viral Central Nervous System Diseases]. Despite the severity of the neurologic complications, most patients with such complications recover completely.

Autoimmune hemolytic anemia mediated by cold agglutinins directed against antigens may occur, usually during the second or third week of illness. Aplastic anemia, thrombocytopenia with bleeding, and severe granulocytopenia with superinfection are rare but potentially fatal complications. EBV has been detected in bone marrow specimens by in situ hybridization. Cardiac and pulmonary complications are rare. A rare chronic syndrome of fever, persistent hepatitis, extensive lymphadenopathy, hepatosplenomegaly, pancytopenia, uveitis, and interstitial pneumonia has been associated with persistent EBV infection.69

EBV Infection in the Immunocompromised Host

Immunocompromised hosts are susceptible to overwhelming EBV lymphoproliferative syndromes. A familial X-linked disorder, Duncan disease, has been associated with fatal infectious mononucleosis, as well as agammaglobulinemia and lymphoma. All of these disorders are apparently related to EBV infection in genetically predisposed persons. The gene involved encodes for a 128 amino acid protein that may be involved in T cell signal transduction.70 Occasionally, in transplant recipients receiving cyclosporine and in patients with AIDS, overwhelming EBV infections develop that culminate in B cell lymphoproliferative syndromes.

Oral hairy leukoplakia is a nonmalignant hyperplastic lesion of epithelial cells that occurs in immunocompromised patients, particularly those with HIV infection, and presents as raised, white, corrugated lesions on the lateral aspect of the tongue. It is associated with active EBV replication and expression of lytic viral proteins.71

EBV Infections and Cancer

The nature of the association of EBV with Burkitt lymphoma and nasopharyngeal carcinoma remains unresolved. Nearly all African patients with Burkitt lymphoma and East Asian patients with nasopharyngeal carcinoma have elevated EBV antibody titers, and EBV DNA is found in the tumors themselves. A single clonal form of EBV has been associated with nasopharyngeal carcinoma and with preinvasive lesions, although it is not clear whether or how the virus is involved in the etiology of these neoplasms. EBV has also been associated with some cases of primary CNS B cell lymphoma, T cell lymphoma, smooth muscle tumors, lymphomatoid granulomatosis, and Hodgkin disease.64,65,66

Diagnosis

In most cases of infectious mononucleosis, the diagnosis is confirmed by detection of heterophile antibodies and abnormalities in the blood, characterized by the presence of atypical lymphocytes that frequently account for more than 10% of the leukocytes in the peripheral blood. Heterophile antibodies, often detected with monospot or slide tests, are not directed against viral antigens but rather against erythrocyte antigens of a variety of species, including sheep, horses, and goats. These acute-phase reactants, present in about 90% of patients at some point during the illness, must be distinguished from naturally occurring Forssman antibodies and the antibodies present in patients with serum sickness; differentiation can be accomplished by proper absorption tests. Heterophile antibodies may be present at the onset of clinical illness or may appear later in the course of disease; they usually disappear 3 to 4 months after the onset of illness but may persist for longer periods. False positive reactions are rare.

Heterophile antibody-negative infectious mononucleosis may be caused by CMV, EBV, or other viruses. For heterophile antibody-negative cases of infectious mononucleosis and for other possibly EBV-associated syndromes, measurement of EBV-specific antibodies may be useful. Antibodies to viral capsid antigen appear early in the course of infection and are present in 85% of patients at the time of their initial physician visit. The presence of IgM antibodies to viral capsid antigen suggests acute infection, whereas IgG antibodies to viral capsid antigen indicate past infection. Antibodies to early antigen appear transiently during active infections and are also found in patients with the African variant of Burkitt lymphoma and in patients with nasopharyngeal carcinoma. Antibodies to Epstein-Barr nuclear antigen appear late in the course of illness and persist after recovery. Thus, the pattern of specific EBV antibody responses may indicate the stage of infection.

Cultures are usually not helpful in making a diagnosis. Although EBV can be isolated from the nasopharynx, culture techniques are cumbersome and time consuming. EBV DNA detection by PCR techniques may be useful for monitoring progression in certain diseases, such as encephalitis or lympho pro liferative syndromes.72,73,74

Prevention

Experimental EBV vaccines are under study, although appropriate indications for their use are unclear.64

Treatment

Management of Infectious Mononucleosis

Treatment is supportive. The administration of corticosteroids may be helpful in certain situations, such as impending airway obstruction, severe thrombocytopenia, or hemolytic anemia. Short-course regimens (1 to 2 weeks) are adequate. Specific antiviral agents such as acyclovir or ganciclovir are not recommended for most EBV-related disorders.75 Although intravenous acyclovir can reduce viral shedding in patients with infectious mononucleosis, clinical benefit appears to be minimal.

Management of Infection in the Immunocompromised Host

Infusion of donor leukocytes or EBV-specific cytotoxic T cells has also been useful in some EBV-related lymphoproliferative diseases after bone marrow transplantation.64,76 No antiviral agents have shown benefit in EBV-associated diseases.

Human Herpesvirus Type 6

In 1986, a newly recognized herpesvirus, HHV-6, was isolated from the peripheral blood leukocytes of six persons with various lymphoproliferative disorders.77 It was initially designated human B lymphotropic virus but was renamed when subsequent studies demonstrated that the virus replicated in cells of T cell origin.78 Two genetically distinct variants of HHV-6—namely, HHV-6A and HHV-6B—are recognized. Disease is most commonly associated with HHV-6B infection; however, HHV-6A may have greater neurotropism.79 An immunomodulatory protein, CD46, is a cellular receptor for HHV-6.80

HHV-6 infection typically occurs during infancy as the level of maternal antibody wanes (peak between 6 to 9 months), although intrauterine infection can also occur.81 As many as 80% of adults are seropositive for HHV-6. Infection can present as exanthema subitum (roseola infantum), a common illness characterized by fever followed by a rash or by a febrile illness without rash but often with febrile seizures.82HHV-6 has been associated with encephalitis, and it has been suggested, though not proved, that HHV-6 is a causal agent in multiple sclerosis.83 HHV-6 may be transmitted by saliva and possibly by genital secretions, blood, or transplanted organs, and HHV-6 infection may cause a mononucleosis-like syndrome.84 After primary infection, the viral genome may persist in peripheral blood mononuclear cells and in salivary glands. Reactivation accompanies immunosuppression, and 30% to 45% of bone marrow transplant recipients develop HHV-6 viremia in the first few weeks after grafting.85 In immunocompromised adults, HHV-6 may be associated with a rash resembling graft versus host disease and may cause pneumonitis, encephalitis, graft rejection, or disseminated disease, although its etiologic relationship to any of these remains unproven.85,86,87,88 There is no antiviral agent with proven clinical efficacy against HHV-6, although ganciclovir and foscarnet have been suggested as possible therapies.89

Human Herpesvirus Type 7

In 1990, another lymphotropic human herpesvirus, tentatively called HHV-7, was isolated from human T cells obtained from a healthy 26-year-old man.90 Its role in human disease has not been established, although it appears frequently in the saliva of healthy adults.91Infection generally occurs by age 5, and approximately 90% of adults are seropositive.92 The HHV-7 genome can also be detected in peripheral blood leukocytes and cervical secretions. HHV-7 may account for some cases of roseola or febrile seizures93,94 and may be associated with graft dysfunction after solid-organ transplantation.88 Although it has been suggested that both HHV-6 and HHV-7 are etiologic agents in chronic fatigue syndrome and pityriasis rosea, supportive evidence is lacking.95,96

Human Herpesvirus Type 8

Several reports in late 1994 and 1995 provided convincing evidence of unique herpesvirus-like sequences in Kaposi sarcoma (KS) and body cavity-based lymphoma tissue from patients with AIDS.97,98,99,100 Using representational difference analysis, researchers found that more than 90% of the KS tissue studied contained these sequences; appropriate control tissue tested negative, except for 15% of non-KS tissue from AIDS patients.97 The same herpesvirus-like DNA sequences were subsequently reported in KS tissue from patients who did not have AIDS98-100 and in lymph node biopsy specimens from patients with multicentric Castleman disease.101

HHV-8 has been propagated in cell cultures and closely resembles a recently identified gamma herpesvirus of rhesus monkeys. Several serologic assays have been developed.102,103,104 One, which detects antibody to a latency-associated nuclear antigen, finds seropositivity in 1% to 2% of HIV-negative blood donors; in 30% of HIV-positive hemophiliacs, transfusion recipients, and women; and in more than 80% of patients with HIV infection and KS.

The natural history and clinical spectrum of diseases caused by HHV-8 is not yet well characterized. Primary infection in immunocompetent children may be associated with fever and a maculopapular rash, and a finding of HHV-8 DNA in saliva suggests salivary transmission.105One individual developed fever, hepatosplenomegaly, angiolymphoid hyperplasia, and transient KS during seroconversion.106 Family studies suggest transmission to children via nonsexual routes and between spouses via sexual routes.107 Transmission has also been demonstrated in the intrapartum and postpartum periods, and intrauterine infection may also occur.108 Among men who have sex with men, risk factors for transmission include increased number of sex partners, amyl nitrite use, and occurrence of lymphadenopathy within the previous 6 months.109 Risk factors for transmission in North American women include HIV infection, increasing age, history of syphilis, injection drug use, and black race.110,111

Molecular and serologic evidence strongly suggests a causal role for HHV-8 in KS and associations with body cavity-based lymphomas and multicentric Castleman disease. Although it has been suggested that HHV-8 is associated with both multiple myeloma and sarcoidosis, confirmatory evidence is lacking. Studies of HHV-8 susceptibility to antiviral drugs suggest relative resistance to acyclovir and penciclovir but susceptibility to ganciclovir, foscarnet, and cidofovir.112,113 However, one pilot trial of cidofovir showed no effect on either HHV-8 viral load or on KS lesions.114 In contrast, effective antiretroviral therapy in individuals dually infected with HIV-1 and HHV-8 may reduce the HHV-8 load and may be associated with KS regression.115

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Editors: Dale, David C.; Federman, Daniel D.