1480 PART 5 Infectious Diseases

epidemiology of infection, causing a significant decrease in the annualized incidence of chickenpox, as noted below.

The incubation period of chickenpox ranges from 10 to 21 days but

is usually 14–17 days. Secondary attack rates in susceptible siblings

within a household are 70–90%. Patients are infectious ~48 h before

the onset of the vesicular rash, during the period of vesicle formation

(which generally lasts 4–5 days), and until all vesicles are crusted.

Clinically, chickenpox presents as a rash, low-grade fever, and

malaise, although a few patients develop a prodrome 1–2 days before

onset of the exanthem. In the immunocompetent patient, chickenpox

is usually a benign illness associated with lassitude and with body

temperatures of 37.8°–39.4°C (100°–103°F) of 3–5 days’ duration. The

skin lesions—the hallmark of the infection—include maculopapules,

vesicles, and scabs in various stages of evolution (Fig. 193-1; see also

Fig. A1-30). These lesions, which evolve from maculopapules to vesicles over hours to days, appear on the trunk and face and rapidly spread

to involve other areas of the body. Most are small and have an erythematous base with a diameter of 5–10 mm. Successive crops appear over

a 2- to 4-day period. Lesions can also be found on the mucosa of the

pharynx and/or the vagina. Their severity varies from one person to

another. Some individuals have very few lesions, while others have as

many as 2000. Younger children tend to have fewer vesicles than older

individuals. Within families, secondary and tertiary cases are associated with a larger number of vesicles than the first family case. Immunocompromised patients—both children and adults, particularly those

with leukemia—have lesions (often with a hemorrhagic base) that are

more numerous and take longer to heal than those of immunocompetent patients. Immunocompromised individuals are also at greater risk

for visceral complications, which occur in 30–50% of cases and are fatal

15% of the time in the absence of antiviral therapy.

The most common infectious complication of varicella is secondary

bacterial superinfection of the skin, which is usually caused by Streptococcus pyogenes or Staphylococcus aureus, including strains that are

methicillin-resistant. Skin infection results from excoriation of lesions

after scratching. Gram’s staining of skin lesions may help clarify the

etiology of unusually erythematous and pustulated lesions.

The most common extracutaneous site of involvement in children

is the CNS. The syndrome of acute cerebellar ataxia and meningeal

inflammation generally appears ~21 days after onset of the rash and

rarely develops in the pre-eruptive phase. The cerebrospinal fluid (CSF)

contains lymphocytes and elevated levels of protein. CNS involvement

is a benign complication of VZV infection in immunocompetent children and generally does not require hospitalization. Aseptic meningitis, encephalitis, transverse myelitis, and Guillain-Barré syndrome can

FIGURE 193-1 Varicella lesions at various stages of evolution: vesicles on an

erythematous base, umbilical vesicles, and crusts.

also occur. Encephalitis is reported in 0.1–0.2% of children with chickenpox. Reye’s syndrome can occur in children concomitantly treated

with aspirin, and therefore, aspirin is no longer utilized. Other than

supportive care, no specific therapy (e.g., acyclovir administration) has

proved efficacious for patients with CNS involvement.

Varicella pneumonia, the most serious complication following

chickenpox, develops more often in adults (up to 20% of cases) than in

children and is particularly severe in pregnant women. Pneumonia due

to VZV usually has its onset 3–5 days into the illness and is associated

with tachypnea, cough, dyspnea, and fever. Cyanosis, pleuritic chest

pain, and hemoptysis are frequently noted. Roentgenographic evidence

of disease consists of nodular infiltrates and interstitial pneumonitis.

Resolution of pneumonitis parallels improvement of the skin rash;

however, patients may have persistent fever and compromised pulmonary function for weeks.

Other complications of chickenpox include myocarditis, corneal

lesions, nephritis, arthritis, bleeding diatheses, acute glomerulonephritis, and hepatitis. Hepatic involvement, distinct from Reye’s syndrome

and usually asymptomatic, is common in chickenpox and is generally

characterized by elevated levels of liver enzymes, particularly aspartate

and alanine aminotransferases.

Perinatal varicella is associated with mortality rates as high as 30%

when maternal disease develops within 5 days before delivery or within

48 h thereafter. Illness in this setting is unusually severe because the

newborn does not receive protective transplacental antibodies and has

an immature immune system. Congenital varicella, with clinical manifestations of limb hypoplasia, cicatricial skin lesions, and microcephaly

at birth, is extremely uncommon.

Herpes Zoster Herpes zoster (shingles) is a sporadic disease that

results from reactivation of latent VZV from dorsal root ganglia. Most

patients with shingles have no history of recent exposure to other

individuals with VZV infection. Herpes zoster occurs at all ages, but

its incidence is highest (5–10 cases per 1000 persons) among individuals in the sixth decade of life and beyond. Data suggest that at least

1.2 million cases occur annually in the United States. Recurrent herpes

zoster is exceedingly rare except in immunocompromised hosts, especially those with AIDS.

Herpes zoster is characterized by a unilateral vesicular dermatomal

eruption, often associated with severe pain. The dermatomes from T3

to L3 are most frequently involved. If the ophthalmic branch of the

trigeminal nerve is involved, zoster ophthalmicus results. The factors

responsible for the reactivation of VZV are not known. In children,

reactivation is usually benign; in adults, it can be debilitating because

of pain. The onset of disease is heralded by pain within the dermatome,

which may precede lesions by 48–72 h; an erythematous maculopapular rash evolves rapidly into vesicular lesions (Fig. 193-2). In the

normal host, these lesions may remain few in number and continue to

form for only 3–5 days. The total duration of disease is generally 7–10

days; however, it may take as long as 2–4 weeks for the skin to return

to normal. Patients with herpes zoster can transmit infection to seronegative individuals, resulting in chickenpox. In a few patients, characteristic localization of pain to a dermatome with serologic evidence of

herpes zoster has been reported in the absence of skin lesions, an entity

known as zoster sine herpetica. When branches of the trigeminal nerve

are involved, lesions may appear on the face, in the mouth, in the eye,

or on the tongue. Zoster ophthalmicus is usually a debilitating condition

that can result in blindness in the absence of antiviral therapy. In Ramsay Hunt syndrome, pain and vesicles appear in the external auditory

canal, and patients lose their sense of taste in the anterior two-thirds

of the tongue while developing ipsilateral facial palsy. The geniculate

ganglion of the sensory branch of the facial nerve is involved.

In both normal and immunocompromised hosts, the most debilitating complication of herpes zoster is pain associated with acute neuritis

and postherpetic neuralgia. Postherpetic neuralgia is uncommon in

young individuals; however, at least 50% of patients over age 50 report

some degree of pain in the involved dermatome for months after the

resolution of cutaneous disease. Changes in sensation in the dermatome, resulting in either hypo- or hyperesthesia, are common.

1481CHAPTER 193 Varicella-Zoster Virus Infections

FIGURE 193-2 Close-up of lesions of disseminated zoster. Note lesions at different

stages of evolution, including pustules and crusting. (Photo courtesy of Lindsey

Baden; with permission.)

CNS involvement may follow localized herpes zoster. Many patients

without signs of meningeal irritation have CSF pleocytosis and moderately elevated levels of CSF protein. Symptomatic meningoencephalitis is characterized by headache, fever, photophobia, meningitis, and

vomiting. A rare manifestation of CNS involvement is granulomatous

angiitis with contralateral hemiplegia, which can be diagnosed by cerebral arteriography. Other neurologic manifestations include transverse

myelitis with or without motor paralysis.

Like chickenpox, herpes zoster is more severe in immunocompromised than immunocompetent individuals. Lesions continue to form

for >1 week, and scabbing is not complete in most cases until 3 weeks

into the illness. Patients with Hodgkin’s disease and non-Hodgkin’s

lymphoma are at greatest risk for progressive herpes zoster. Cutaneous dissemination (Fig. 193-3) develops in ~40% of these patients.

Among patients with cutaneous dissemination, the risk of pneumonitis, meningoencephalitis, hepatitis, and other serious complications is

increased by 5–10%. However, even in immunocompromised patients,

disseminated zoster is rarely fatal.

FIGURE 193-3 Herpes zoster in an HIV-infected patient is seen as hemorrhagic

vesicles and pustules on an erythematous base grouped in a dermatomal

distribution.

Recipients of hematopoietic stem cell transplants are at particularly

high risk of VZV infection. Of all cases of post-transplantation VZV

infection, 30% occur within 1 year (50% of these within 9 months);

45% of the patients involved have cutaneous or visceral dissemination.

The mortality rate in this situation is 10%. Postherpetic neuralgia,

scarring, and bacterial superinfection are especially common in VZV

infections occurring within 9 months of transplantation. Among

infected patients, concomitant graft-versus-host disease increases the

chance of dissemination and/or death.

■ DIFFERENTIAL DIAGNOSIS

The diagnosis of chickenpox is not difficult. The characteristic rash and

a history of recent exposure should lead to a prompt diagnosis. Other

viral infections that can mimic chickenpox include disseminated HSV

infection in patients with atopic dermatitis and the disseminated vesiculopapular lesions sometimes associated with coxsackievirus infection,

echovirus infection, or atypical measles. However, these rashes are

more commonly morbilliform with a hemorrhagic component rather

than vesicular or vesiculopustular. Rickettsialpox (Chap. 187) is sometimes confused with chickenpox; however, rickettsialpox can be distinguished easily by detection of the “herald spot” at the site of the mite

bite and the development of a more pronounced headache. Serologic

testing is also useful in differentiating rickettsialpox from varicella and

can confirm susceptibility in adults unsure of their chickenpox history.

Monkeypox should be considered in travelers returning from endemic

areas (Chap. 196). Concern about smallpox has increased because

of the threat of bioterrorism (Chap. S3). The lesions of smallpox are

larger than those of chickenpox and are all at the same stage of evolution at any given time.

Unilateral vesicular lesions in a dermatomal pattern should lead

rapidly to the diagnosis of herpes zoster, although the occurrence of

shingles without a rash has been reported. Both HSV and coxsackievirus infections can cause dermatomal vesicular lesions. Supportive

diagnostic virology and fluorescent staining of skin scrapings with

monoclonal antibodies are helpful in ensuring the proper diagnosis. In

the prodromal stage of herpes zoster, the diagnosis can be exceedingly

difficult and may be made only after lesions have appeared or by retrospective serologic assessment.

■ LABORATORY FINDINGS

Unequivocal confirmation of the diagnosis is possible only through the

isolation of VZV in susceptible tissue-culture cell lines, the demonstration of either seroconversion or a fourfold or greater rise in antibody

titer between acute-phase and convalescent-phase serum specimens, or

the detection of VZV DNA by PCR. Specimens for detection of VZV

DNA by PCR include lesions, blood, and saliva. A rapid impression can

be obtained by a Tzanck smear, with scraping of the base of the lesions

in an attempt to demonstrate multinucleated giant cells; however,

the sensitivity of this method is low (~60%). PCR technology for the

detection of viral DNA in vesicular fluid is available in many diagnostic

laboratories and has become the diagnostic method of choice. Direct

immunofluorescent staining of cells from the lesion base or detection

of viral antigens by other assays (such as the immunoperoxidase assay)

is also useful. The most frequently employed serologic tools for assessing host response are the immunofluorescent detection of antibodies to

VZV membrane antigens, the fluorescent antibody to membrane antigen (FAMA) test, immune adherence hemagglutination, and enzymelinked immunosorbent assay (ELISA). The FAMA test and the ELISA

appear to be most sensitive.

TREATMENT

Varicella-Zoster Virus Infections

Medical management of chickenpox in the immunologically normal host is directed toward the prevention of avoidable complications. Obviously, good hygiene includes daily bathing and

soaks. Secondary bacterial infection of the skin can be avoided by

meticulous skin care, particularly with close cropping of fingernails.

1482 PART 5 Infectious Diseases

Pruritus can be decreased with topical dressings or the administration of antipruritic drugs. Tepid water baths and wet compresses are

better than drying lotions for the relief of itching. Administration of

aspirin to children with chickenpox should be avoided because of

the association of aspirin derivatives with the development of Reye’s

syndrome. Acyclovir (800 mg by mouth five times daily), valacyclovir (1 g three times daily), or famciclovir (250 mg three times

daily) for 5–7 days is recommended for adolescents and adults with

chickenpox of ≤24 h duration. (Valacyclovir is licensed for use in

children and adolescents. Famciclovir is recommended but not

licensed for varicella.) Likewise, acyclovir therapy may be of benefit

to children <12 years of age if initiated early in the disease (<24 h)

at a dose of 20 mg/kg every 6 h. The advantages (i.e., pharmacokinetics) of the second-generation agents valacyclovir and famciclovir

are described in Chap. 191.

Aluminum acetate soaks for the management of herpes zoster

can be both soothing and cleansing. Patients with herpes zoster

benefit from oral antiviral therapy, as evidenced by accelerated

healing of lesions and resolution of zoster-associated pain with

acyclovir, valacyclovir, or famciclovir. Acyclovir is administered

at a dosage of 800 mg five times daily for 7–10 days. However,

valacyclovir and famciclovir have superior pharmacokinetics and

pharmacodynamics and should be used preferentially. Famciclovir,

the prodrug of penciclovir, is at least as effective as acyclovir and

perhaps more so; the dose is 500 mg by mouth three times daily

for 7 days. Valacyclovir, the prodrug of acyclovir, accelerates healing and resolution of zoster-associated pain more promptly than

acyclovir. The dose is 1 g by mouth three times daily for 5–7 days.

Compared with acyclovir, both famciclovir and valacyclovir offer

the advantage of less frequent administration. All three of these

drugs are now available as generic products.

In severely immunocompromised hosts (e.g., transplant recipients, patients with lymphoproliferative malignancies), both chickenpox and herpes zoster (including disseminated disease) should be

treated, at least at the outset, with IV acyclovir, which reduces the

occurrence of visceral complications but has no effect on healing

of skin lesions or pain. The dose is 10 mg/kg every 8 h for 7 days.

For low-risk immunocompromised hosts, oral therapy with valacyclovir or famciclovir appears beneficial. If medically feasible, it

is desirable to decrease immunosuppressive treatment concomitant

with the administration of IV acyclovir.

Patients with varicella pneumonia typically require ventilatory

support. Persons with zoster ophthalmicus should be referred

immediately to an ophthalmologist. Therapy for this condition consists of the administration of analgesics for severe pain and the use

of atropine. Acyclovir, valacyclovir, and famciclovir all accelerate

healing. Decisions regarding the use of corticosteroids should be

made by the ophthalmologist.

The management of acute neuritis and/or postherpetic neuralgia can be particularly difficult. In addition to the judicious use

of analgesics ranging from nonnarcotics to narcotic derivatives,

drugs such as gabapentin, pregabalin, amitriptyline hydrochloride,

lidocaine (patches), and fluphenazine hydrochloride are reportedly beneficial for pain relief. In one study, glucocorticoid therapy

administered early in the course of localized herpes zoster significantly accelerated such quality-of-life improvements as a return to

usual activity and termination of analgesic medications. The dose of

prednisone administered orally was 60 mg/d on days 1–7, 30 mg/d

on days 8–14, and 15 mg/d on days 15–21. This regimen is appropriate only for relatively healthy elderly persons with moderate or

severe pain at presentation. Patients with osteoporosis, diabetes

mellitus, glycosuria, or hypertension may not be appropriate candidates. Glucocorticoids should not be used without concomitant

antiviral therapy.

■ PREVENTION

Three methods are used for the prevention of VZV infections. First, a

live attenuated varicella vaccine (Oka) is recommended for all children

>1 year of age (up to 12 years of age) who have not had chickenpox

and for adults known to be seronegative for VZV. Two doses are recommended for all children: the first at 12–15 months of age and the

second at ~4–6 years of age. VZV-seronegative persons >13 years of

age should receive two doses of vaccine at least 1 month apart. The

vaccine is both safe and efficacious. Breakthrough cases are mild and

may result in spread of the vaccine virus to susceptible contacts. The

universal vaccination of children has resulted in a decreased incidence

of chickenpox in sentinel communities. Furthermore, inactivation

of the vaccine virus significantly decreases the occurrence of herpes

zoster after hemotopoietic stem cell transplantation.

In individuals >50 years of age, only one shingles vaccine is currently available in the United States, namely Shingrix. It is a subunit

vaccine (HZ/su) that consists of VZV glycoprotein E and the AS01B

adjuvant. A randomized, placebo-controlled study administered two

doses of vaccine or placebo 1 month apart to 15,411 participants

aged 50 years or older. Overall vaccine efficacy for the prevention of

herpes zoster virus was 97.2% (95% confidence interval, 93.7-99.0%;

p <.001). Injection-site and systemic reactions were more frequent

in vaccine recipients, but the proportions of participants who had

serious adverse events were similar in the vaccine and placebo groups.

The Advisory Committee on Immunization Practices has therefore

recommended that persons in this age group be offered this vaccine in order to reduce the frequency of shingles and the severity of

postherpetic neuralgia. Of note, vaccine immunity wanes over time,

and reassessment of current recommendations or the use of a promising inactivated vaccine in development will be required.

A second approach is to administer varicella-zoster immune globulin

(VZIG) to individuals who are susceptible, are at high risk for developing

complications of varicella, and have had a significant exposure. This product should be given within 96 h (preferably within 72 h) of the exposure

but may be administered up to 10 days with similar efficacy. Indications

for administration of VZIG appear in Table 193-1, which has been

adapted from the American Academy of Pediatrics Redbook.

Lastly, antiviral therapy can be given as prophylaxis to individuals

at high risk who are ineligible for vaccination or who are beyond the

96-h window after direct contact. While the initial studies have used

acyclovir, similar benefit can be anticipated with either valacyclovir or

TABLE 193-1 Recommendations for VZIG Administration

Exposure Criteria

1. Significant exposure to a person with chickenpox or zoster

a. Household: residence in the same household

b. Playmate: face-to-face indoor play

c. Hospital

Varicella: same 2- to 4-bed room or adjacent beds in a large ward, face-toface contact with an infectious staff member or patient, visit by a person

deemed contagious

Zoster: intimate contact (e.g., touching or hugging) with a person deemed

contagious

d. Newborn infant: onset of varicella in the mother ≤5 days before delivery or

≤48 h after delivery; VZIG not indicated if the mother has zoster

2. Patient should receive VZIG as soon as possible but not >96 h after exposure.

Candidates (Provided They Have Significant Exposure) Include

1. Immunocompromised susceptible children without a history of varicella or

varicella immunization

2. Susceptible pregnant women

3. Newborn infants whose mother had onset of chickenpox within 5 days before

or within 48 h after delivery

4. Hospitalized premature infant (≥28 weeks of gestation) whose mother lacks

a reliable history of chickenpox or serologic evidence of protection against

varicella

5. Hospitalized premature infant (<28 weeks of gestation or ≤1000-g birth

weight), regardless of maternal history of varicella or VZV serologic status

Abbreviation: VZIG, varicella-zoster immune globulin.

Note: Table is adapted from the American Academy of Pediatrics Red Book.

1483CHAPTER 194 Epstein-Barr Virus Infections, Including Infectious Mononucleosis

famciclovir. Therapy is instituted 7 days after intense exposure. At this

time, the host is midway into the incubation period. This approach

significantly decreases disease severity, if not totally preventing disease.

■ FURTHER READING

Arvin A: Aging, immunity, and the varicella-zoster virus. N Engl J

Med 352:2266, 2005.

Cohen JI: A new vaccine to prevent herpes zoster. N Engl J Med

372:2149, 2015.

Gershon AA et al: Varicella zoster virus infection. Nat Rev Dis

Primers 1:15016, 2015.

Gnann JW, Whitley RJ: Herpes zoster. N Engl J Med 347:340, 2002.

Hata A et al: Use of an inactivated varicella vaccine in recipients of

hematopoietic-cell transplants. N Engl J Med 347:26, 2002.

Kimberlin DW, Whitley RJ. Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med 356:1338, 2007.

Lai H et al: Efficacy of an adjuvanted herpes zoster subunit vaccine in

older adults. N Engl J Med 372:2087, 2015.

Levin MJ et al: Varicella zoster immune globulin (VARIZIG) administration up to 10 days after varicellas exposure in pregnant women,

immunocompromised participants, and infants: Varicellas outcomes

and safety results from a large, open-label, expanded access program.

PLoS One 14:e0217749, 2019.

Morrison VA et al: Long-term persistence of zoster vaccine efficacy.

Clin Infect Dis 60:900, 2015.

Nguyen HQ et al: Decline in mortality due to varicella after implementation of varicella vaccination in the United States. N Engl J Med

352:450, 2005.

Oxman MN et al: A vaccine to prevent herpes zoster and postherpetic

neuralgia in older adults. N Engl J Med 352:2271, 2005.

Seward JF et al: Varicella disease after introduction of varicella vaccine

in the United States, 1995-2000. JAMA 287:606, 2002.

Seward JF et al: Contagiousness of varicella in vaccinated cases: A

household contact study. JAMA 292:704, 2004.

Shaw J, Gershon AA: Varicella virus vaccination in the United States.

Viral Immunol 31:96, 2018.

Willis ED et al: Herpes zoster vaccine live: A 10 year review of

post-marketing safety experience. Vaccine 35:7231, 2017.

Wutzler P et al: Varicella vaccination−the global experience. Expert

Rev Vaccines 16:833, 2017.

■ DEFINITION

Epstein-Barr virus (EBV) is the cause of heterophile-positive infectious mononucleosis (IM), which is characterized by fever, sore throat,

lymphadenopathy, and atypical lymphocytosis. EBV is also associated

with several tumors, including nasopharyngeal and gastric carcinoma,

Burkitt’s lymphoma, Hodgkin’s lymphoma, T-cell lymphoma, and (in

patients with immunodeficiencies) B-cell lymphoma and smooth muscle tumors. The virus is a member of the family Herpesviridae. The two

types of EBV that are widely prevalent in nature are not distinguishable

by conventional serologic tests.

■ EPIDEMIOLOGY

EBV infections occur worldwide. These infections are most common

in early childhood, with a second peak during late adolescence. By

194 Epstein-Barr Virus

Infections, Including

Infectious Mononucleosis

Jeffrey I. Cohen

adulthood, >90% of individuals have been infected and have antibodies

to the virus. IM is usually a disease of young adults. In lower socioeconomic groups and in areas of the world with deficient standards

of hygiene (e.g., developing regions), EBV tends to infect children at

an early age, and IM is uncommon. In areas with higher standards of

hygiene, infection with EBV is often delayed until adulthood, and IM

is more prevalent.

EBV is spread by contact with oral secretions. The virus is frequently

transmitted from asymptomatic adults to infants and among young

adults by transfer of saliva during kissing. Transmission by less intimate contact is rare. EBV has been transmitted by blood transfusion

and by bone marrow transplantation. More than 90% of asymptomatic

seropositive individuals shed the virus in oropharyngeal secretions.

Shedding is increased in immunocompromised patients and those

with IM.

■ PATHOGENESIS

EBV is transmitted by salivary secretions. The virus infects the epithelium of the oropharynx and the salivary glands and is shed from these

cells. While B cells may become infected after contact with epithelial

cells, studies suggest that lymphocytes in the tonsillar crypts can be

infected directly. The virus then spreads through the bloodstream. The

proliferation and expansion of EBV-infected B cells along with reactive

T cells during IM result in enlargement of lymphoid tissue. Polyclonal

activation of B cells leads to the production of antibodies to host-cell

and viral proteins. During the acute phase of IM, up to 1 in every 100

B cells in the peripheral blood is infected by EBV; after recovery, 1–50

in every 1 million B cells is infected. During IM, there is an inverted

CD4+/CD8+ T-cell ratio. The percentage of CD4+ T cells decreases,

while there are large clonal expansions of CD8+ T cells; up to 40% of

CD8+ T cells are directed against EBV antigens during acute infection.

Memory B cells, not epithelial cells, are the reservoir for EBV in the

body. When patients are treated with acyclovir, shedding of EBV from

the oropharynx stops but the virus persists in B cells.

The EBV receptor (CD21) on the surface of B cells is also the receptor for the C3d component of complement. Another EBV receptor

(CD35) on B cells binds to CD21. Human leukocyte antigen class II

serves as a co-receptor for EBV entry into B cells. EBV infection of

epithelial cells occurs by virus binding to ephrin A2 and results in viral

replication and production of virions. When B cells are infected by

EBV in vitro, they become transformed and can proliferate indefinitely.

During latent infection of B cells, the EBV nuclear antigens (EBNAs),

latent membrane proteins (LMPs), multiple microRNAs, and small

EBV RNAs (EBERs) are expressed in vitro. EBV-transformed B cells

secrete immunoglobulin; only a small fraction of these cells produce

virus.

Cellular immunity is more important than humoral immunity in controlling EBV infection. In the initial phase of infection, suppressor T cells,

natural killer (NK) cells, and nonspecific cytotoxic T cells are important

in controlling the proliferation of EBV-infected B cells. Levels of markers

of T-cell activation and serum interferon γ are elevated. Later in infection, human leukocyte antigen–restricted cytotoxic T cells that recognize

EBNAs and LMPs and destroy EBV-infected cells are generated.

If T-cell immunity is compromised, EBV-infected B cells may begin

to proliferate. When EBV is associated with lymphoma in immunocompetent persons, virus-induced proliferation is but one step in a multistep process of neoplastic transformation. In many EBV-containing

tumors, LMP-1 mimics members of the tumor necrosis factor receptor

family (e.g., CD40), transmitting growth-proliferating signals.

■ CLINICAL MANIFESTATIONS

Signs and Symptoms Most EBV infections in infants and young

children either are asymptomatic or present as mild pharyngitis with or

without tonsillitis. In contrast, ~75% of infections in adolescents present as IM. IM in the elderly often presents with nonspecific symptoms,

including prolonged fever, fatigue, myalgia, and malaise. In contrast,

pharyngitis, lymphadenopathy, splenomegaly, and atypical lymphocytes are relatively rare in elderly patients.

1484 PART 5 Infectious Diseases

levels of CD8+ T cells and EBV DNA in the blood. Most patients have

symptoms for 2–4 weeks, but nearly 10% have fatigue that persists for

≥6 months.

Laboratory Findings The white blood cell count is usually elevated and peaks at 10,000–20,000/μL during the second or third week

of illness. Lymphocytosis is usually demonstrable, with >10% atypical lymphocytes. The latter cells are enlarged lymphocytes that have

abundant cytoplasm, vacuoles, and indentations of the cell membrane

(Fig. 194-2). CD8+ T cells predominate among the atypical lymphocytes.

Low-grade neutropenia and thrombocytopenia are common during the

first month of illness. Liver function is abnormal in >90% of cases. Serum

levels of aminotransferases and alkaline phosphatase are usually mildly

elevated. The serum concentration of bilirubin is elevated in ~40% of cases.

Complications Most cases of IM are self-limited. Deaths are

very rare and are most often due to central nervous system (CNS)

complications, splenic rupture, upper-airway obstruction, or bacterial

superinfection.

When CNS complications develop, they usually do so during the

first 2 weeks of EBV infection; in some patients, especially children,

they are the only clinical manifestations of acute infection. Heterophile

antibodies and atypical lymphocytes may be absent. Meningitis and

encephalitis are the most common neurologic abnormalities, and

patients may present with headache, meningismus, or cerebellar ataxia.

Acute hemiplegia and psychosis also have been described. The cerebrospinal fluid contains mainly lymphocytes, with occasional atypical

lymphocytes. Most cases resolve without neurologic sequelae. Acute

EBV infection has also been associated with cranial nerve palsies (especially those involving cranial nerve VII), Guillain-Barré syndrome,

acute transverse myelitis, and peripheral neuritis.

Autoimmune hemolytic anemia occurs in ~2% of cases during the

first 2 weeks. In most cases, the anemia is Coombs-positive, with cold

agglutinins directed against the red blood cell antigen. Most patients

with hemolysis have mild anemia that lasts for 1–2 months, but

some patients have severe disease with hemoglobinuria and jaundice.

Nonspecific antibody responses may also include rheumatoid factor,

antinuclear antibodies, anti–smooth muscle antibodies, antiplatelet

antibodies, and cryoglobulins. IM has been associated with red-cell

aplasia, severe granulocytopenia, thrombocytopenia, pancytopenia,

and hemophagocytic lymphohistiocytosis. The spleen ruptures in

<0.5% of cases. Splenic rupture is more common among male than

female patients and may manifest as abdominal pain, referred shoulder

pain, or hemodynamic compromise.

Hypertrophy of lymphoid tissue in the tonsils or adenoids can result

in upper-airway obstruction, as can inflammation and edema of the

epiglottis, pharynx, or uvula. About 10% of patients with IM develop

streptococcal pharyngitis after their initial sore throat resolves.

TABLE 194-1 Signs and Symptoms of Infectious Mononucleosis

MANIFESTATION

MEDIAN PERCENTAGE OF

PATIENTS (RANGE)

Symptoms

Sore throat 75 (50–87)

Malaise 47 (42–76)

Headache 38 (22–67)

Abdominal pain, nausea, or vomiting 17 (5–25)

Chills 10 (9–11)

Signs

Lymphadenopathy 95 (83–100)

Fever 93 (60–100)

Pharyngitis or tonsillitis 82 (68–90)

Splenomegaly 51 (43–64)

Hepatomegaly 11 (6–15)

Rash 10 (0–25)

Periorbital edema 13 (2–34)

Palatal enanthem 7 (3–13)

Jaundice 5 (2–10)

FIGURE 194-1 Rash in a patient with infectious mononucleosis due to Epstein-Barr

virus. (Courtesy of Maria Turner, MD; with permission.)

FIGURE 194-2 Atypical lymphocytes from a patient with infectious mononucleosis

due to Epstein-Barr virus.

The incubation period for IM in young adults is ~4–6 weeks. A prodrome of fatigue, malaise, and myalgia may last for 1–2 weeks before

the onset of fever, sore throat, and lymphadenopathy. Fever is usually

low-grade and is most common in the first 2 weeks of the illness; however, it may persist for >1 month. Common signs and symptoms are

listed along with their frequencies in Table 194-1. Lymphadenopathy

and pharyngitis are most prominent during the first 2 weeks of the

illness, while splenomegaly is more prominent during the second and

third weeks. Lymphadenopathy most often affects the posterior cervical nodes but may be generalized. Enlarged lymph nodes are frequently

tender and symmetric but are not fixed in place. Pharyngitis, often

the most prominent sign, can be accompanied by enlargement of the

tonsils with an exudate resembling that of streptococcal pharyngitis.

A morbilliform or papular rash, usually on the arms or trunk, develops in ~5% of cases (Fig. 194-1). Earlier studies reported that many

patients treated with penicillin derivatives develop a macular rash;

penicillin-associated rashes are not predictive of future adverse reactions to penicillins. More recent studies suggest that EBV-associated

rashes may occur with similar frequency in those exposed to penicillin

derivatives and those not taking these drugs. Erythema nodosum

(Fig. A1-39) and erythema multiforme (Fig. A1-24) also have been

described (Chap. 58). The severity of the disease correlates with the