1476 PART 5 Infectious Diseases

through postnatal contact with immediate family members who have

symptomatic or asymptomatic oral–labial HSV-1 infection or through

nosocomial transmission within the hospital. All neonates with presumed herpes should be treated with IV acyclovir and then placed on

maintenance oral antiviral therapy for the first 6–12 months of life.

Antiviral chemotherapy with high-dose IV acyclovir (60 mg/kg per

day) has reduced the mortality rate from neonatal herpes to ~15%.

However, rates of morbidity, especially among infants with HSV-2

infection involving the CNS, are still very high.

HSV in Pregnancy In the United States, 21% of all pregnant

women and 51% of non-Hispanic black pregnant women are seropositive for HSV-2. However, the risk of mother-to-child transmission of

HSV in the perinatal period is highest when the infection is acquired

near the time of labor—that is, in previously HSV-seronegative women.

The clinical manifestations of recurrent genital herpes—including

the frequency of subclinical versus clinical infection, the duration of

lesions, pain, and constitutional symptoms—are similar in pregnant

and nonpregnant women. Recurrences increase in frequency over

the course of pregnancy. However, when women are seropositive for

HSV-2 at the outset of pregnancy, no effect on neonatal outcomes

(including birth weight and gestational age) is seen. First-episode

infections in pregnancy have more severe consequences for mother

and infant. Maternal visceral dissemination during the third trimester

occasionally occurs, as does premature birth or intrauterine growth

retardation. The acquisition of primary disease in pregnancy, whether

related to HSV-1 or HSV-2, carries the risk of transplacental transmission of virus to the neonate and can result in spontaneous abortion,

although this outcome is relatively uncommon. For newly acquired

genital HSV infection during pregnancy, most authorities recommend

treatment with acyclovir (400 mg three times daily) or valacyclovir

(500–1000 mg twice daily) for 7–10 days. However, the impact of this

intervention on transmission is unknown. The high HSV-2 prevalence

rate in pregnancy and the low incidence of neonatal disease (1 case

per 6000–20,000 live births) indicate that only a few infants are at risk

of acquiring HSV. Therefore, cesarean section is not warranted for all

women with recurrent genital disease. Because intrapartum transmission of infection accounts for the majority of cases, abdominal delivery

need be considered only for women who are shedding HSV at delivery.

Several studies have shown no correlation between recurrence of viral

shedding before delivery and viral shedding at term. Hence, weekly

virologic monitoring and amniocentesis are not recommended.

The frequency of transmission from mother to infant is markedly

higher among women who acquire HSV near term (30–50%) than

among those in whom HSV-2 infection is reactivated at delivery (<1%).

Although maternal antibody to HSV-2 is protective, antibody to HSV-1

offers little or no protection against neonatal HSV-2 infection. Primary

genital infection with HSV-1 leads to a particularly high risk of transmission during pregnancy and accounts for an increasing proportion

of neonatal HSV cases. Moreover, during reactivation, HSV-1 appears

more transmissible to the neonate than HSV-2. Only 2% of women

who are seropositive for HSV-2 have HSV-2 isolated from cervical

secretions at delivery, and only 1% of infants exposed in this manner

develop infection, presumably because of the protective effects of

maternally transferred antibodies and perhaps lower viral titers during

reactivation. Despite the low frequency of transmission of HSV in this

setting, 30–50% of infants with neonatal HSV are born to mothers with

established genital herpes.

Isolation of HSV by cervicovaginal swab at the time of delivery is the

greatest risk factor for intrapartum HSV transmission (relative risk = 346);

however, culture-negative, PCR-positive cases of intrapartum transmission are well described. New acquisition of HSV (odds ratio [OR] =

49), isolation of HSV-1 versus HSV-2 (OR = 35), cervical versus vulvar

HSV detection (OR = 15), use of fetal scalp electrodes (OR = 3.5), and

young maternal age confer further risk of transmission, whereas cesarean delivery is protective (OR = 0.14). Physical examination poorly

predicts the absence of shedding, and PCR far exceeds culture in terms

of sensitivity and speed. Therefore, PCR detection at the onset of labor

should be used to aid clinical decision-making for women with HSV-2

antibody. Because cesarean section appears to be an effective means of

reducing maternal–fetal transmission, patients with recurrent genital

herpes should be encouraged to come to the hospital early at the time

of delivery for careful examination of the external genitalia and cervix

as well as collection of a swab sample for viral isolation. Women who

have no evidence of lesions can have a vaginal delivery. The presence

of active lesions on the cervix or external genitalia is an indication for

cesarean delivery.

If first-episode exposure has occurred (e.g., if HSV serologies show

that the mother is seronegative or if the mother is HSV-1-seropositive

and the isolate at delivery is found to be HSV-2), many authorities

would initiate antiviral therapy for the infant with IV acyclovir. At a

minimum, samples for viral cultures and PCR should be obtained from

the throat, nasopharynx, eyes, and rectum of these infants immediately

and at 5- to 10-day intervals. Lethargy, skin lesions, or fever should be

evaluated promptly. All infants from whom HSV is isolated 24 h after

delivery should be treated with IV acyclovir at recommended doses.

■ DIAGNOSIS

Both clinical and laboratory criteria are useful for diagnosing HSV

infections. A clinical diagnosis can be made accurately when characteristic multiple vesicular lesions on an erythematous base are present.

However, herpetic ulcerations may resemble skin ulcerations of other

etiologies. Mucosal HSV infections may also present as urethritis or

pharyngitis without cutaneous lesions. Thus, laboratory studies to

confirm the diagnosis and to guide therapy are recommended. While

staining of scrapings from the base of the lesions with Wright’s, Giemsa’s

(Tzanck preparation), or Papanicolaou’s stain to detect giant cells or

intranuclear inclusions of Herpesvirus infection is a well-described

procedure, few clinicians are skilled in this technique, the sensitivity of

staining is low (<30% for mucosal swabs), and these cytologic methods

do not differentiate between HSV and VZV infections.

HSV infection is best confirmed in the laboratory by detection of

virus, viral antigen, or viral DNA in scrapings from lesions. HSV DNA

detection by PCR is the most sensitive laboratory technique for detecting mucosal or visceral HSV infections and is the recommended test

for laboratory confirmation of a diagnosis. HSV causes a discernible

cytopathic effect in a variety of cell culture systems, and this effect can

be identified within 48–96 h after inoculation. Spin-amplified culture

with subsequent staining for HSV antigen has shortened the time

needed to identify HSV to <24 h. Culture is indicated when antiviral

sensitivity testing is required. The sensitivity of all detection methods

depends on the stage of the lesions (with higher sensitivity for vesicular than for ulcerative lesions), on whether the patient has a first or

a recurrent episode of the disease (with higher sensitivity in first than

in recurrent episodes), and on whether the sample is from an immunosuppressed or an immunocompetent patient (with more antigen

or DNA in immunosuppressed patients). Laboratory confirmation

permits subtyping of the virus; information on subtype may be useful

epidemiologically and may help to predict the frequency of reactivation

after first-episode oral–labial or genital HSV infection.

Both type-specific and type-common antibodies to HSV develop

during the first several weeks after infection and persist indefinitely.

Serologic assays with whole-virus antigen preparations, such as complement fixation, neutralization, indirect immunofluorescence, passive

hemagglutination, radioimmunoassay, and enzyme-linked immunosorbent assay, are useful for differentiating uninfected (seronegative)

persons from those with past HSV-1 or HSV-2 infection, but they

do not reliably distinguish between the two viral subtypes. Serologic

assays that identify antibodies to the type-specific glycoprotein G of the

two viral subtypes (G1 and G2) are available commercially and can distinguish reliably between the human antibody responses to HSV-1 and

HSV-2. Point-of-care assays that provide results from capillary blood

or serum during a clinic visit are available. A western blot assay that can

detect several HSV type-specific proteins can also be used. The presence of type-specific HSV-2 antibody implies past HSV-2 infection—i.e.,

latent infection and likely subclinical reactivation.

Acute- and convalescent-phase serum samples can be useful in

demonstrating seroconversion during primary HSV-1 or HSV-2 infection.

1477CHAPTER 192 Herpes Simplex Virus Infections

However, few available tests report titers, and increases in index values

do not reflect first episodes in all patients. Serologic assays based on

type-specific proteins should be used to identify asymptomatic carriers

of HSV-1 or HSV-2. No reliable IgM method for defining acute HSV

infection is available.

Several studies have shown that persons with previously unrecognized HSV-2 infection can be taught to identify symptomatic reactivations. Individuals seropositive for HSV-2 should be told about the high

frequency of subclinical reactivation on mucosal surfaces that are not

visible to the eye (e.g., cervix, urethra, perianal skin) or in microscopic

ulcerations that may not be clinically symptomatic. Transmission of

infection during such episodes is well established. HSV-2-seropositive

persons should be educated about the high likelihood of subclinical

shedding and the role that condoms (male or female) may play in

reducing transmission. Antiviral therapy with valacyclovir (500 mg

once daily) has been shown to reduce the transmission of HSV-2

between sexual partners.

TREATMENT

Herpes Simplex Virus Infections

Many aspects of mucocutaneous and visceral HSV infections are

amenable to antiviral chemotherapy. For mucocutaneous infections, acyclovir and its congeners famciclovir and valacyclovir have

been the mainstays of therapy. Several antiviral agents are available

for topical use in HSV eye infections: idoxuridine, trifluorothymidine, topical vidarabine, and cidofovir. For HSV encephalitis and

neonatal herpes, IV acyclovir is the treatment of choice.

All licensed antiviral agents for use against HSV inhibit the viral

DNA polymerase. One class of drugs, typified by the drug acyclovir, is made up of substrates for the HSV enzyme TK. Acyclovir,

ganciclovir, famciclovir, and valacyclovir are all selectively phosphorylated to the monophosphate form in virus-infected cells. Cellular enzymes convert the monophosphate form of the drug to the

triphosphate, which is then incorporated into the viral DNA chain.

Acyclovir is the agent most frequently used for the treatment of

HSV infections and is available in IV, oral, and topical formulations.

Valacyclovir, the valyl ester of acyclovir, offers greater bioavailability

than acyclovir and thus can be administered less frequently. Famciclovir, the oral formulation of penciclovir, is clinically effective in

the treatment of a variety of HSV-1 and HSV-2 infections. Ganciclovir is active against both HSV-1 and HSV-2; however, it is more

toxic than acyclovir, valacyclovir, and famciclovir and generally is

not recommended for the treatment of HSV infections. Anecdotal

case reports suggest that ganciclovir may also be less effective

than acyclovir for the treatment of HSV infections. All three recommended compounds—acyclovir, valacyclovir, and famciclovir—

have proved effective in shortening the duration of symptoms and

lesions of mucocutaneous HSV infections in both immunocompromised and immunocompetent patients (Table 192-1).

IV and oral formulations prevent reactivation of HSV in seropositive immunocompromised patients during induction chemotherapy or in the period immediately after bone marrow or solid

organ transplantation. Chronic daily suppressive therapy reduces

the frequency of reactivation disease among patients with frequent

genital or oral–labial herpes. Only valacyclovir has been subjected

to clinical trials that demonstrated reduced transmission of HSV-2

infection between sexual partners. IV acyclovir (30 mg/kg per day,

given as a 10-mg/kg infusion over 1 h at 8-h intervals) is effective in

reducing rates of death and morbidity from HSV encephalitis. Early

initiation of therapy is a critical factor in outcome. The major side

effect associated with IV acyclovir is transient renal insufficiency,

usually due to crystallization of the compound in the renal parenchyma. This adverse reaction can be avoided if the medication is

given slowly over 1 h and the patient is well hydrated. Because CSF

levels of acyclovir average only 30–50% of plasma levels, the dosage

of acyclovir used for treatment of CNS infection (30 mg/kg per

day) is double that used for treatment of mucocutaneous or visceral

disease (15 mg/kg per day). Even higher doses of IV acyclovir are

used for neonatal HSV infection (60 mg/kg per day in three divided

doses). Antiviral drugs neither eradicate latent infection nor affect

the risk, frequency, or severity of subclinical or clinical recurrence

after the drug is discontinued.

Increasingly, shorter courses of therapy are being used for recurrent mucocutaneous infection with HSV-1 or HSV-2 in immunocompetent patients. One-day courses of famciclovir and valacyclovir

are clinically effective, more convenient, and generally less costly

than longer courses of therapy (Table 192-1). These short-course

regimens should be reserved for immunocompetent hosts.

SUPPRESSION OF MUCOCUTANEOUS HERPES

Recognition of the high frequency of subclinical reactivation provides a well-accepted rationale for the use of daily antiviral therapy

to suppress reactivations of HSV, especially in persons with frequent

clinical reactivations (e.g., those with recently acquired genital

HSV infection). Immunosuppressed persons, including those with

HIV infection, may also benefit from daily antiviral therapy. Daily

acyclovir and valacyclovir reduce the frequency of HSV reactivations among HIV-positive persons. Regimens used include acyclovir (400–800 mg twice daily), famciclovir (500 mg twice daily), and

valacyclovir (500 mg twice daily); valacyclovir at a dose of 4 g/d

was associated with thrombotic thrombocytopenic purpura in one

study of HIV-infected persons. Daily acyclovir therapy is associated

with a modest reduction in the titer of HIV RNA in plasma (0.5-log10

reduction) and in the genital mucosa (0.33-log10 reduction).

REDUCED HSV TRANSMISSION TO SEXUAL PARTNERS

Once-daily valacyclovir (500 mg) has been shown to reduce transmission of HSV-2 between sexual partners. Transmission rates are

higher from males to females and among persons with frequent

HSV-2 reactivation. Serologic screening can be used to identify

at-risk couples. Daily valacyclovir appears to be more effective at

reducing subclinical shedding than daily famciclovir.

ACYCLOVIR RESISTANCE

Clinically relevant acyclovir-resistant strains of HSV do occur. Most

of these strains have an altered substrate specificity for phosphorylating acyclovir. Thus, cross-resistance to famciclovir and valacyclovir is usually found. Occasionally, an isolate with altered TK

specificity arises and is sensitive to famciclovir but not to acyclovir.

In some patients infected with TK-deficient virus, higher doses of

acyclovir are associated with clearing of lesions. In others, clinical

disease progresses despite high-dose therapy. The majority of clinically significant acyclovir resistance has been seen in immunocompromised patients. HSV-2 isolates appear to be more resistant

than HSV-1 strains. The frequency of acyclovir resistance is not

well characterized or monitored; the lack of appreciable change in

the past 40 years probably reflects the reduced transmission of TKdeficient mutants. Isolation of HSV from lesions persisting despite

adequate dosages and blood levels of acyclovir should raise the

suspicion of acyclovir resistance. Clinical management of acyclovir

resistance is challenging. Therapy with the antiviral drug foscarnet

(40–80 mg/kg IV every 8 h until clinical resolution) is the only clinically demonstrated approach (Chap. 191). Because of its toxicity

and cost, this drug is usually reserved for patients with extensive

mucocutaneous infections. Cidofovir is a nucleotide analogue and

exists as a phosphonate or monophosphate form. Most TKdeficient strains of HSV are sensitive to cidofovir. Cidofovir ointment

speeds healing of acyclovir-resistant lesions. No well-controlled

trials of systemic cidofovir have been reported. Occasional cases

may respond to topical imiquimod. True TK-negative variants of

HSV appear to have a reduced capacity to spread because of altered

neurovirulence—a feature important in the relatively infrequent

presence of such strains in immunocompetent populations, even

with increasing use of antiviral drugs. A new class of drugs that

inhibit HSV-specific helicase/primase activity (pritelivir) is under

clinical investigation and may offer a better toxicity profile for the

treatment of acyclovir-resistant strains of HSV.

1478 PART 5 Infectious Diseases

TABLE 192-1 Antiviral Chemotherapy for Herpes Simplex Virus (HSV) Infection

I. Mucocutaneous HSV infections

A. Infections in immunosuppressed patients

1. Acute symptomatic first or recurrent episodes: IV acyclovir (5 mg/kg q8h) or oral acyclovir (400 mg qid), famciclovir (500 mg bid or tid), or valacyclovir

(500 mg bid) is effective. Treatment duration may vary from 7 to 14 days. IV therapy may be given for 2–7 days until clinical improvement and followed

by oral therapy.

2. Suppression of reactivation disease (genital or oral–labial): IV acyclovir (5 mg/kg q8h) or oral valacyclovir (500 mg bid) or acyclovir (400–800 mg 3–5 times

per day) prevents recurrences during the 30-day period immediately after transplantation. Longer-term HSV suppression is often used for persons with

continued immunosuppression. In bone marrow and renal transplant recipients, oral valacyclovir (2 g/d) is also effective in reducing cytomegalovirus

infection. Oral valacyclovir at a dose of 4 g/d has been associated with thrombotic thrombocytopenic purpura after extended use in HIV-positive persons. In

HIV-infected persons, oral acyclovir (400–800 mg bid), valacyclovir (500 mg bid), or famciclovir (500 mg bid) is effective in reducing clinical and subclinical

reactivations of HSV-1 and HSV-2.

B. Infections in immunocompetent patients

1. Genital herpes

a. First episodes: Oral acyclovir (200 mg 5 times per day or 400 mg tid), valacyclovir (1 g bid), or famciclovir (250 mg tid) for 7–14 days is effective. IV

acyclovir (5 mg/kg q8h for 5 days) is given for severe disease or neurologic complications such as aseptic meningitis.

b. Symptomatic recurrent genital herpes: Short-course (1- to 3-day) regimens are preferred because of low cost, likelihood of adherence, and convenience.

Oral acyclovir (800 mg tid for 2 days), valacyclovir (500 mg bid for 3 days), valacyclovir (1 g orally once a day for 3 days), or famciclovir (750 or 1000 mg

bid for 1 day, a 1500-mg single dose, or 500 mg stat followed by 250 mg q12h for 2 days) effectively shortens lesion duration. Other options include oral

acyclovir (200 mg 5 times per day), valacyclovir (500 mg bid), and famciclovir (125 mg bid for 5 days).

c. Suppression of recurrent genital herpes: Oral acyclovir (400–800 mg bid) or valacyclovir (500 mg daily) is given. Patients with >9 episodes per year should

take oral valacyclovir (1 g daily or 500 mg bid) or famciclovir (250 mg bid or 500 mg bid).

2. Oral–labial HSV infections

a. First episode: Oral acyclovir is given (200 mg 5 times per day or 400 mg tid); an oral acyclovir suspension can be used (600 mg/m2

 qid). Oral famciclovir

(250 mg bid) or valacyclovir (1 g bid) has been used clinically. The duration of therapy is 5–10 days.

b. Recurrent episodes: If initiated at the onset of the prodrome, single-dose or 1-day therapy effectively reduces pain and speeds healing. Regimens include

oral famciclovir (a 1500-mg single dose or 750 mg bid for 1 day) or valacyclovir (a 2-g single dose or 2 g bid for 1 day). Self-initiated therapy with 6-timesdaily topical penciclovir cream effectively speeds healing of oral–labial HSV infection. Topical acyclovir cream has also been shown to speed healing.

c. Suppression of reactivation of oral–labial HSV: If started before exposure and continued for the duration of exposure (usually 5–10 days), oral acyclovir

(400 mg bid) prevents reactivation of recurrent oral–labial HSV infection associated with severe sun exposure.

3. Surgical prophylaxis of oral or genital HSV infection: Several surgical procedures, such as laser skin resurfacing, trigeminal nerve-root decompression, and

lumbar disk surgery, have been associated with HSV reactivation. IV acyclovir (3–5 mg/kg q8h) or oral acyclovir (800 mg bid), valacyclovir (500 mg bid), or

famciclovir (250 mg bid) effectively reduces reactivation. Therapy should be initiated 48 h before surgery and continued for 3–7 days.

4. Herpetic whitlow: Oral acyclovir (200 mg) is given 5 times daily (alternative: 400 mg tid) for 7–10 days.

5. HSV proctitis: Oral acyclovir (400 mg 5 times per day) is useful in shortening the course of infection. In immunosuppressed patients or in patients with severe

infection, IV acyclovir (5 mg/kg q8h) may be useful.

6. Herpetic eye infections: In acute keratitis, topical trifluorothymidine, vidarabine, idoxuridine, acyclovir, penciclovir, and interferon are all beneficial.

Debridement may be required. Topical steroids may worsen disease.

II. Central nervous system HSV infections

A. HSV encephalitis: IV acyclovir (10 mg/kg q8h; 30 mg/kg per day) is given for 10 days or until HSV DNA is no longer detected in cerebrospinal fluid.

B. HSV aseptic meningitis: No studies of systemic antiviral chemotherapy exist. If therapy is to be given, IV acyclovir (15–30 mg/kg per day) should be used.

C. Autonomic radiculopathy: No studies are available. Most authorities recommend a trial of IV acyclovir.

III. Neonatal HSV infections: IV acyclovir (60 mg/kg per day, divided into 3 doses) is given. The recommended duration of IV treatment is 21 days. Monitoring for

relapse should be undertaken. Continued suppression with oral acyclovir suspension should be given for 3–4 months.

IV. Visceral HSV infections

A. HSV esophagitis: IV acyclovir (15 mg/kg per day) is given. In some patients with milder forms of immunosuppression, oral therapy with valacyclovir or

famciclovir is effective.

B. HSV pneumonitis: No controlled studies exist. IV acyclovir (15 mg/kg per day) should be considered.

V. Disseminated HSV infections: No controlled studies exist. IV acyclovir (5 mg/kg q8h) should be tried. Adjustments for renal insufficiency may be needed. No

definite evidence indicates that therapy will decrease the risk of death.

VI. Erythema multiforme associated with HSV: Anecdotal observations suggest that oral acyclovir (400 mg bid or tid) or valacyclovir (500 mg bid) will suppress

erythema multiforme.

VII. Infections due to acyclovir-resistant HSV: IV foscarnet (40 mg/kg IV q8h) should be given until lesions heal. The optimal duration of therapy and the usefulness

of its continuation to suppress lesions are unclear. Some patients may benefit from cutaneous application of trifluorothymidine or 1% cidofovir gel, both of which

must be compounded at a pharmacy. These preparations should be applied once daily for 5–7 days. Topical imiquimod can be considered. The helicase primase

inhibitor pritelivir is being studied for treatment of acyclovir-resistant HSV infection. IV cidofovir (5 mg/kg weekly) may be considered.

VIII. Acyclovir and pregnancy: No adverse effects to the fetus or newborn have been attributable to acyclovir. Acyclovir can be used in all stages of pregnancy and

among women who are breastfeeding (the drug can be found in breast milk). Suppressive acyclovir treatment in late pregnancy (acyclovir 400 mg orally tid or

valacyclovir 500 mg orally bid from ~34 weeks until delivery) reduces the frequency of cesarean delivery among women with recurrent genital herpes. Such

treatment may not protect against transmission to neonates.

ACYCLOVIR EFFICACY IN THE DEVELOPING WORLD

Initial studies of acyclovir-like drugs were performed solely in the

developed world. While acyclovir, valacyclovir, and famciclovir are

effective in the developing world, their clinical and virologic benefits, especially in reducing the frequency of genital lesions among

patients in Africa, seem reduced from those in European and U.S.

populations. The mechanism of this phenomenon is uncertain.

Acyclovir therapy does not reduce the rate of HIV acquisition;

however, HIV load among MSM in the U.S. decreased by 1.3 log10

in contrast to 0.9 log10 among Peruvian MSM and 0.5 log10 among

African women. Curiously, the anti-HIV drug tenofovir reduces

HSV-2 acquisition among women in Africa, although it has no

demonstrable clinical benefit or antiviral effects among persons

with established HSV-2 infection in studies in the United States.

The reasons for these disparate results are unclear.

1479CHAPTER 193 Varicella-Zoster Virus Infections

■ PREVENTION

Efforts to control HSV disease on a population basis through suppressive antiviral therapy and/or educational programs have been limited.

Barrier forms of contraception (especially condoms) decrease the likelihood of transmission of HSV infection, particularly during periods of

asymptomatic viral excretion. When lesions are present, HSV infection

may be transmitted by skin-to-skin contact despite the use of a condom.

Nevertheless, the available data suggest that consistent condom use is

an effective means of reducing the risk of genital HSV-2 transmission.

Chronic daily antiviral therapy with valacyclovir can also be partially

effective in reducing acquisition of HSV-2, especially among susceptible women. There are no comparative efficacy studies of valacyclovir

versus condom use. Most authorities suggest both approaches. The

need for a vaccine to prevent acquisition of HSV infection is great,

especially in light of the role HSV-2 plays in enhancing the acquisition

and transmission of HIV-1.

A substantial portion of neonatal HSV cases could be prevented by

reducing the acquisition of HSV by women in the third trimester of

pregnancy. Neonatal HSV infection can result from either the acquisition of maternal infection near term or the reactivation of infection

at delivery in the already-infected mother. Women without known

genital herpes should be counseled to abstain from vaginal intercourse

during the third trimester with partners known to have or suspected of

having genital herpes. Some authorities have recommended that antiviral therapy with acyclovir or valacyclovir be given to HSV-2-infected

women in late pregnancy as a means of reducing reactivation of HSV-2

at term. Data are not available to support the efficacy of this approach,

and the high treatment-to-prevention ratio makes this a difficult if not

dubious public health strategy, even though it can reduce the frequency

of HSV-associated cesarean delivery.

■ FURTHER READING

Centers for Disease Control and Prevention: 2015 Sexually

transmitted diseases treatment guidelines. Available at https://www

.cdc.gov/std/tg2015/herpes.htm.

James C et al: Herpes simplex virus: Global infection prevalence and

incidence estimates, 2016. Bull World Health Organ 98:315, 2020.

Looker KJ et al: Global and regional estimates of the contribution of

herpes simplex virus type 2 infection to HIV incidence: A population

attributable fraction analysis using published epidemiological data.

Lancet Infect Dis 20:240, 2020.

Mahant S et al: Neonatal herpes simplex virus infection among

Medicaid-enrolled children: 2009–2015. Pediatrics 143:e20183233,

2019.

Yousuf W et al: Herpes simplex virus type 1 in Europe: Systematic

review, meta-analyses and meta-regressions. BMJ Global Health

5:e002388, 2020.

■ DEFINITION

Varicella-zoster virus (VZV) causes two distinct clinical syndromes:

varicella (chickenpox) and herpes zoster (shingles). Chickenpox, a

ubiquitous and extremely contagious infection, is usually a benign

illness of childhood characterized by an exanthematous vesicular rash.

With reactivation of latent VZV (which is most common after the sixth

decade of life), herpes zoster presents as a dermatomal vesicular rash

and is usually associated with severe pain.

193 Varicella-Zoster Virus

Infections

Richard J. Whitley

■ ETIOLOGY

Early in the twentieth century, similarities in the histopathologic features of skin lesions resulting from varicella and herpes zoster were

described. Viral isolates from patients with each of these diseases

produced similar pathology in tissue culture—specifically, the appearance of eosinophilic intranuclear inclusions and multinucleated giant

cells. These results suggested that the viruses were biologically similar.

Restriction endonuclease analyses of viral DNA from a patient with

chickenpox who subsequently developed herpes zoster verified the

molecular identity of the two viruses responsible for these different

clinical presentations.

VZV is a member of the family Herpesviridae, sharing with other

members such structural characteristics as a lipid envelope surrounding a nucleocapsid with icosahedral symmetry, a total diameter of

~180–200 nm, and centrally located double-stranded DNA that is

~125,000 bp in length.

■ PATHOGENESIS AND PATHOLOGY

Primary Infection Transmission occurs readily by the respiratory

route; the subsequent localized replication of the virus at an undefined

site (presumably the nasopharynx) leads to seeding of the lymphatic/

reticuloendothelial system and ultimately to the development of viremia. Viremia in patients with chickenpox is reflected in the diffuse

and scattered nature of the skin lesions and can be confirmed by the

recovery of VZV from the blood (rarely) or routinely by the detection

of viral DNA in either blood or lesions by polymerase chain reaction

(PCR). Vesicles involve the corium and dermis, with degenerative

changes characterized by ballooning, the presence of multinucleated

giant cells, and eosinophilic intranuclear inclusions. Infection may

involve localized blood vessels of the skin, resulting in necrosis and epidermal hemorrhage. With the evolution of disease, the vesicular fluid

becomes cloudy because of the recruitment of polymorphonuclear leukocytes and the presence of degenerated cells and fibrin. Ultimately, the

vesicles either rupture and release their fluid (which includes infectious

virus) or are gradually reabsorbed.

Recurrent Infection The mechanism of reactivation of VZV

that results in herpes zoster is unknown. The virus infects dorsal root

ganglia during chickenpox, where it remains latent until reactivated.

Histopathologic examination of representative dorsal root ganglia

during active herpes zoster demonstrates hemorrhage, edema, and

lymphocytic infiltration. Latent virus has been detected in sensory

(dorsal, cranial, and enteric) ganglia.

Active replication of VZV in other organs, such as the lung or the

brain, can occur during either chickenpox or herpes zoster but is

uncommon in the immunocompetent host. Pulmonary involvement

is characterized by interstitial pneumonitis, multinucleated giant

cell formation, intranuclear inclusions, and pulmonary hemorrhage.

Central nervous system (CNS) infection leads to histopathologic evidence of perivascular cuffing similar to that encountered in measles

and other viral encephalitides. Focal hemorrhagic necrosis of the brain,

characteristic of herpes simplex virus (HSV) encephalitis, develops

infrequently in VZV infection.

■ EPIDEMIOLOGY AND CLINICAL

MANIFESTATIONS

Chickenpox Humans are the only known reservoir for VZV.

Chickenpox is highly contagious, with an attack rate of at least 90%

among susceptible (seronegative) individuals. Persons of both sexes

and all races are infected equally. The virus is endemic in the population at large; however, it becomes epidemic among susceptible individuals during seasonal peaks—namely, late winter and early spring in the

temperate zone. Much of our knowledge of the disease’s natural history

and incidence predates the licensure of the chickenpox vaccine in 1995.

Historically, children 5–9 years old were most commonly affected,

accounting for 50% of all cases. Most other cases involved children

1–4 and 10–14 years old. Approximately 10% of the population of

the United States over the age of 15 was susceptible to infection. VZV

vaccination during the second year of life has dramatically changed the