1485CHAPTER 194 Epstein-Barr Virus Infections, Including Infectious Mononucleosis

Other rare complications associated with acute EBV infection

include hepatitis (which can be fulminant), myocarditis or pericarditis,

pneumonia with pleural effusion, interstitial nephritis, genital ulcerations, and vasculitis.

EBV-Associated Diseases Other Than IM EBV-associated

lymphoproliferative disease has been described in patients with congenital or acquired immunodeficiency, including those with severe

combined immunodeficiency, patients with AIDS, and recipients of

bone marrow or organ transplants who are receiving immunosuppressive drugs (especially cyclosporine). Proliferating EBV-infected B cells

infiltrate lymph nodes and multiple organs, and patients present with

fever and lymphadenopathy or gastrointestinal symptoms. Pathologic

studies show B-cell hyperplasia or poly- or monoclonal lymphoma.

X-linked lymphoproliferative disease is a recessive disorder of

young boys who have a normal response to childhood infections

but develop fatal lymphoproliferative disorders after infection

with EBV. The protein associated with most cases of this syndrome

(SAP, encoded by SH2D1A) binds to a protein that mediates interactions of B and T cells. Most patients with this syndrome die of acute

IM. Others develop hypogammaglobulinemia, malignant B-cell lymphomas, aplastic anemia, or agranulocytosis. Disease resembling

X-linked lymphoproliferative disease, but with more prominent hemophagocytosis, has also been associated with mutations in BIRC4. Mutations in ITK, MAGT1, CORO1A, CD70, or CD27 are associated with

inability to control EBV and lymphoma. Mutations in other genes, such

as GATA2, PIK3CD, CTPS1, RSGRP1, TNFRSF9, and several genes

associated with severe combined immunodeficiency, also can predispose to severe or fatal EBV disease as well as other infections. Moreover, IM has proved fatal to some patients with no obvious preexisting

immune abnormality.

Oral hairy leukoplakia (Fig. 194-3) is an early manifestation of

infection with HIV in adults (Chap. 202). Most patients present with

raised, white corrugated lesions on the tongue (and occasionally on

the buccal mucosa) that contain EBV DNA. Children infected with

HIV can develop lymphoid interstitial pneumonitis; EBV DNA is often

found in lung tissue from these patients.

Patients with chronic fatigue syndrome may have titers of antibody

to EBV that are elevated but are not significantly different from those

in healthy EBV-seropositive adults. These patients do not have elevated

levels of EBV DNA in the blood. While some patients have malaise and

fatigue that persist for weeks or months after IM, persistent EBV infection is not a cause of chronic fatigue syndrome. Chronic active EBV

infection is very rare and is distinct from chronic fatigue syndrome.

The affected patients have an illness lasting >6 months, with elevated

levels of EBV DNA in the blood (in T cells, NK cells, or B cells); high

titers of antibody to EBV; and evidence of organ involvement, including hepatosplenomegaly, lymphadenopathy, and hepatitis, pneumonitis, uveitis, or neurologic disease. Some have somatic mutations in

DD3X and other tumor driver genes.

EBV is associated with several malignancies. About 15% of cases of

Burkitt’s lymphoma in the United States and ~90% of those in Africa

are associated with EBV (Chap. 108). African patients with Burkitt’s

lymphoma have high levels of antibody to EBV, and their tumor tissue

usually contains viral DNA. Malaria in African patients may impair

cellular immunity to EBV and induce polyclonal B-cell activation with

an expansion of EBV-infected B cells. In addition, malaria may target

B cells and result in expansion of germinal centers, with consequently

increased activity of activation-induced cytidine deaminase, which

can mutate DNA. These changes may enhance the proliferation of B

cells with elevated EBV DNA in the bloodstream, thereby increasing

the likelihood of a c-myc translocation—the hallmark of Burkitt’s lymphoma. EBV-containing Burkitt’s lymphoma also occurs in patients

with AIDS.

Anaplastic nasopharyngeal carcinoma is common in southern

China and is uniformly associated with EBV; the affected tissues contain viral DNA and antigens. Patients with nasopharyngeal carcinoma

often have elevated titers of antibody to EBV (Chap. 77). Measurement

of EBV DNA in plasma is useful for early detection of nasopharyngeal carcinoma. High levels of EBV plasma DNA before treatment or

detectable levels of EBV DNA after radiation therapy correlate with

lower rates of overall survival and relapse-free survival among patients

with nasopharyngeal carcinoma.

Worldwide, the most common EBV-associated malignancy is gastric

carcinoma. About 9% of these tumors are EBV-positive including >90%

of gastric lymphoepithelioma-like carcinomas (Chap. 80).

EBV has been associated with Hodgkin’s lymphoma, especially the

mixed-cellularity type (Chap. 109). Patients with Hodgkin’s lymphoma

often have elevated titers of antibody to EBV. In about half of cases in

the United States, viral DNA and antigens are found in Reed-Sternberg

cells. The risk of EBV-positive Hodgkin’s lymphoma is significantly

increased in young adults for several years after EBV-seropositive IM.

About 50% of non-Hodgkin’s lymphomas in patients with AIDS are

EBV-positive.

EBV is present in B cells of lesions from patients with lymphomatoid

granulomatosis. In some cases, EBV DNA has been detected in tumors

from immunocompetent patients with angiocentric nasal NK/T-cell

lymphoma, aggressive NK leukemia/lymphoma, T-cell lymphoma, and

CNS lymphoma. Studies have demonstrated viral DNA in leiomyosarcomas from AIDS patients and in smooth-muscle tumors from organ

transplant recipients. Virtually all CNS lymphomas in AIDS patients

are associated with EBV. Studies have found that a history of IM and

higher levels of antibodies to EBNA before the onset of disease is more

common in persons with multiple sclerosis than in the general population; additional research on a possible causal relationship is needed.

■ DIAGNOSIS

Serologic Testing (Fig. 194-4) The heterophile test is used for

the diagnosis of IM in children and adults. In the test for this antibody,

human serum is absorbed with guinea pig kidney, and the heterophile

titer is defined as the greatest serum dilution that agglutinates sheep,

horse, or cow erythrocytes. The heterophile antibody does not interact

with EBV proteins. A titer of ≥40 is diagnostic of acute EBV infection in a patient who has symptoms compatible with IM and atypical

lymphocytes. Tests for heterophile antibodies are positive in 40% of

patients with IM during the first week of illness and in 80–90% during

the third week. Therefore, repeated testing may be necessary, especially if the initial test is performed early. Tests usually remain positive

for 3 months after the onset of illness, but heterophile antibodies can

persist for up to 1 year. These antibodies usually are not detectable in

children <5 years of age, in the elderly, or in patients presenting with

symptoms not typical of IM. The commercially available monospot test

for heterophile antibodies is somewhat more sensitive than the classic

heterophile test. The monospot test is ~75% sensitive and ~90% specific compared with EBV-specific serologies (see below). False-positive

monospot results are more common among persons with connective

tissue disease, lymphoma, viral hepatitis, and malaria.

EBV-specific antibody testing is used for patients with suspected

acute EBV infection who lack heterophile antibodies and for patients

with atypical infections. Titers of IgM and IgG antibodies to viral

capsid antigen (VCA) are elevated in the serum of >90% of patients

FIGURE 194-3 Oral hairy leukoplakia often presents as white plaques on the lateral

surface of the tongue and is associated with Epstein-Barr virus infection.

1486 PART 5 Infectious Diseases

Time of symptoms

Anti-VCA IgM Anti-VCA IgG

Anti-EBNA

Heterophile

1 week0

0

40

80

160

Antibody titer

320

640

1280

1 month 2 months 3 months

FIGURE 194-4 Pattern of Epstein-Barr virus (EBV) serology during acute infection. EBNA, Epstein-Barr nuclear antigen; VCA, viral capsid antigen. (Reproduced with

permission from JI Cohen, in NS Young et al [eds]: Clinical Hematology. Philadelphia, Mosby, 2006.)

TABLE 194-2 Differential Diagnosis of Infectious Mononucleosis

SIGN OR SYMPTOM

ETIOLOGY FEVER ADENOPATHY SORE THROAT ATYPICAL LYMPHOCYTES DIFFERENCES FROM EBV MONONUCLEOSIS

EBV infection + + + + —

CMV infection + ± ± + Older age at presentation, longer duration of fever

HIV infection + + + ± Diffuse rash, oral/genital ulcers, aseptic meningitis

Toxoplasmosis + + ± ± Less splenomegaly; exposure to cats or raw meat

HHV-6 infection + + + + Older age at presentation

Streptococcal pharyngitis + + + – No splenomegaly, less fatigue

Viral hepatitis + ± – ± Higher aminotransferase levels

Rubella + + ± ± Maculopapular rash, no splenomegaly

Lymphoma + + + + Fixed, nontender lymph nodes

Drugsa + + – ± Occurs at any age

a

Most commonly phenytoin, carbamazepine, sulfonamides, or minocycline.

Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus.

at the onset of disease. IgM antibody to VCA is most useful for the

diagnosis of acute IM because it is present at elevated titers only during

the first 2–3 months of the disease; in contrast, IgG antibody to VCA

usually is not useful for diagnosis of IM but often is used to assess past

exposure to EBV because it persists for life. Seroconversion to EBNA

positivity also is useful for the diagnosis of acute infection with EBV.

Antibodies to EBNA become detectable relatively late (3–6 weeks after

the onset of symptoms) in nearly all cases of acute EBV infection and

persist for the lifetime of the patient. These antibodies may be lacking

in immunodeficient patients and in those with chronic active EBV

disease.

Titers of other antibodies also may be elevated in IM; however, these

elevations are less useful for diagnosis. Antibodies to early antigens

are detectable 3–4 weeks after the onset of symptoms in patients with

IM. About 70% of individuals with IM have antibodies to early antigen

diffuse (EA-D) during the illness; the presence of EA-D antibodies is

especially likely in patients with relatively severe disease. These antibodies usually persist for only 3–6 months. Levels of EA-D antibodies

are elevated in patients with nasopharyngeal carcinoma or chronic

active EBV infection. Antibodies to early antigen restricted (EA-R) are

often found at elevated titers in patients with African Burkitt’s lymphoma or chronic active EBV infection; however, they are not useful

for diagnosis. IgA antibodies to EBV antigens have proved useful for

the identification of patients with nasopharyngeal carcinoma and of

persons at high risk for the disease.

Other Studies Detection of EBV DNA, RNA, or proteins has been

valuable in demonstrating the association of the virus with various

malignancies. The polymerase chain reaction has been used to detect

EBV DNA in the cerebrospinal fluid of some AIDS patients with CNS

lymphomas and to monitor the amount of EBV DNA in the blood of

patients with lymphoproliferative disease. Detection of high levels of

EBV DNA in blood for a few days to several weeks after the onset of IM

may be useful if serologic studies yield equivocal results. Culture of

EBV from throat washings or blood is not helpful in the diagnosis of

acute infection, since EBV persists in the oropharynx and in B cells for

the lifetime of the infected individual.

Differential Diagnosis Whereas ~90% of cases of IM are due to

EBV, 5–10% of cases are due to cytomegalovirus (CMV) (Chap. 195).

CMV is the most common cause of heterophile-negative mononucleosis; less common causes of IM and differences from IM due to EBV are

shown in Table 194-2.

TREATMENT

EBV-Associated Disease

Therapy for IM consists of supportive measures, with rest and

analgesia. Excessive physical activity during the first month should

be avoided to reduce the possibility of splenic rupture, which often

necessitates splenectomy. Glucocorticoid therapy is not indicated

for uncomplicated IM and in fact may predispose to bacterial superinfection. Prednisone (40–60 mg/d for 2–3 days, with subsequent

tapering of the dose over 1–2 weeks) has been used for the prevention of airway obstruction in patients with severe tonsillar hypertrophy, for autoimmune hemolytic anemia, for hemophagocytic

lymphohistiocytosis, and for severe thrombocytopenia. Glucocorticoids have also been administered to rare patients with severe malaise and fever and to patients with severe CNS or cardiac disease.

Acyclovir has had no significant clinical impact on IM in

controlled trials. In one study, the combination of acyclovir and

prednisolone had no significant effect on the duration of symptoms

of IM.

Acyclovir, at a dosage of 400–800 mg five times daily, has

been effective for the treatment of oral hairy leukoplakia (despite

1487CHAPTER 195 Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8

common relapses). Post-transplantation EBV lymphoproliferative

disease (Chap. 143) generally does not respond to antiviral therapy. When possible, therapy should be directed toward reduction

of immunosuppression. Antibody to CD20 (rituximab) has been

effective in some cases. Infusions of donor lymphocytes are often

effective for stem cell transplant recipients, although graft-versushost disease can occur. Infusions of HLA-matched EBV-specific

cytotoxic T cells have been used to prevent EBV lymphoproliferative disease in high-risk settings as well as to treat the disease.

Interferon α administration, cytotoxic chemotherapy, and radiation

therapy (especially for CNS lesions) also have been used. Infusion

of autologous EBV-specific cytotoxic T lymphocytes has shown

promise in small studies of patients with nasopharyngeal carcinoma

and Hodgkin’s lymphoma. Treatment of several cases of X-linked

lymphoproliferative disease with antibody to CD20 resulted in a

successful outcome of what otherwise would probably have been

fatal acute EBV infection.

■ PREVENTION

The isolation of patients with IM is unnecessary. A vaccine directed

against the major EBV glycoprotein reduced the frequency of IM but

did not affect the rate of asymptomatic infection in a phase 2 trial.

Additional vaccines are under development.

■ FURTHER READING

Chan KCA et al: Analysis of plasma Epstein-Barr virus DNA to screen

for nasopharyngeal cancer. N Engl J Med 377:513, 2017.

Chen YP et al: Nasopharyngeal carcinoma. Lancet 394:64, 2019.

Cohen JI et al: Epstein-Barr virus NK and T cell lymphoproliferative

disease: Report of a 2018 international meeting. Leuk Lymphoma

61:808, 2020.

Dierickx D, Habermann TM: Post-transplantation lymphoproliferative disorders in adults. N Engl J Med 378:549, 2018.

Mclaughlin LP et al: Adoptive T cell therapy for Epstein-Barr virus

complications in patients with primary immunodeficiency disorders.

Front Immunol 9:556, 2018.

Murray PG, Young LS: An etiological role for the Epstein-Barr virus

in the pathogenesis of classical Hodgkin lymphoma. Blood 134:591,

2019.

Tangye SG, Latour S: Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection.

Blood 135:644, 2020.

CYTOMEGALOVIRUS

■ DEFINITION

Cytomegalovirus (CMV), which was initially isolated from patients

with congenital cytomegalic inclusion disease, is now recognized as an

important pathogen in all age groups. In addition to inducing severe

birth defects, CMV causes a wide spectrum of disorders in older children and adults, ranging from an asymptomatic subclinical infection

to a mononucleosis syndrome in healthy individuals to disseminated

disease in immunocompromised patients. Human CMV is one of

several related species-specific viruses that cause similar diseases in

various animals. All are associated with the production of characteristic enlarged cells—hence the name cytomegalovirus.

195 Cytomegalovirus and

Human Herpesvirus

Types 6, 7, and 8

Camille Nelson Kotton, Martin S. Hirsch

CMV, a β-herpesvirus, has double-stranded DNA, four species of

mRNA, a protein capsid, and a lipoprotein envelope. Like other herpesviruses, CMV demonstrates icosahedral symmetry, replicates in

the cell nucleus, and can cause either a lytic and productive or a latent

infection. CMV can be distinguished from other herpesviruses by certain biologic properties, such as host range and type of cytopathology.

Viral replication is associated with the production of large intranuclear inclusions and smaller cytoplasmic inclusions. CMV appears to

replicate in a variety of cell types in vivo; in tissue culture it grows

preferentially in fibroblasts. Although there is little evidence that CMV

is oncogenic in vivo, it does transform fibroblasts in rare instances, and

genomic transforming fragments have been identified.

■ EPIDEMIOLOGY

CMV has a worldwide distribution. In many regions of the world,

nearly all adults are seropositive for CMV, whereas only half of adults

in the United States and Canada are seropositive. In regions where the

prevalence of CMV antibody is high, immunocompromised adults are

more likely to undergo reactivation disease rather than primary infection. Data generated in specific regions should be considered in the

context of local seropositivity rates, when appropriate.

Of newborns in the United States, 0.5–2.0% are infected with CMV;

the percentages are higher in less developed regions. Communal living and poor personal hygiene facilitate spread. Perinatal and early

childhood infections are common. CMV may be present in breast

milk, saliva, feces, and urine. Transmission has occurred among young

children in day-care centers and has been traced from infected toddler to pregnant mother to developing fetus. When an infected child

introduces CMV into a household, 50% of susceptible family members

seroconvert within 6 months.

CMV is not readily spread by casual contact but rather requires

repeated or prolonged intimate exposure for transmission. In late

adolescence and young adulthood, CMV is often transmitted sexually,

and asymptomatic carriage in semen or cervical secretions is common.

Antibody to CMV is present at detectable levels in a significant proportion of sexually active men and women, who may harbor several strains

simultaneously. Transfusion of blood products containing viable leukocytes may transmit CMV, with a frequency of 0.14–10% per unit

transfused. Transfusion of leukocyte-reduced or CMV-seronegative

blood significantly decreases the risk of CMV transmission.

Once infected, an individual generally carries CMV for life, similar

to other herpes viruses. The infection usually remains silent. CMV

reactivation syndromes develop more frequently, however, when

T lymphocyte–mediated immunity is compromised—for example,

after organ transplantation, with lymphoid neoplasms and certain

acquired immunodeficiencies (in particular, HIV infection; Chap. 202),

or during critical illness in intensive care units. Most primary CMV

infections in organ transplant recipients (Chap. 143) result from transmission via the graft or blood products. In CMV-seropositive transplant recipients, infection results from reactivation of latent virus in

the recipients or from infection by a new strain from the donor. CMV

infection may be associated with diseases as diverse as coronary artery

stenosis and malignant gliomas, although these associations require

further validation.

■ PATHOGENESIS

Congenital CMV infection can result from either primary or reactivation infection of the mother. However, clinical disease in the fetus or

newborn is related largely to primary maternal infection (Table 195-1).

The major factors determining the severity of congenital infection are

unclear, although a deficient capacity to produce precipitating antibodies and to mount T-cell responses to CMV is associated with relatively

severe disease.

Primary infection with CMV in late childhood or adulthood is

often associated with a vigorous T-lymphocyte response that may

contribute to the development of a mononucleosis syndrome similar

to the sequelae of infection with Epstein-Barr virus (Chap. 194). The

hallmark of such infection is the appearance of atypical lymphocytes

in the peripheral blood; these cells are predominantly activated CD8+

1488 PART 5 Infectious Diseases

and elevated protein levels in cerebrospinal fluid. The prognosis for

severely infected infants is poor, and few survivors escape intellectual

or hearing difficulties later in childhood. The differential diagnosis of

cytomegalic inclusion disease in infants includes syphilis, toxoplasmosis, bacterial sepsis, and infection with a variety of viruses, including

rubella, Zika, or herpes simplex virus.

Most congenital CMV infections are clinically inapparent at birth.

Of asymptomatically infected infants, 7−11% develop sensorineural

hearing loss over a 5-year period.

Perinatal CMV Infection The newborn may acquire CMV at

delivery by passage through an infected birth canal or by postnatal contact with infected breast milk or other maternal secretions. Of infants

who are breast-fed for >1 month by seropositive mothers, 40–60%

become infected. Iatrogenic transmission can result from blood transfusion; use of leukocyte-reduced or CMV-seronegative blood products

for transfusion into low-birth-weight seronegative infants or seronegative pregnant women decreases risk.

The great majority of infants infected at or after delivery remain

asymptomatic. However, protracted interstitial pneumonitis has been

associated with perinatally acquired CMV infection, particularly in

premature infants, and occasionally has been accompanied by infection

with Chlamydia trachomatis, Pneumocystis, or Ureaplasma urealyticum.

Poor weight gain, adenopathy, rash, hepatitis, anemia, and atypical

lymphocytosis may also be found, and CMV excretion often persists

for months or years.

CMV Mononucleosis The most common clinical manifestation

of CMV infection in immunocompetent hosts beyond the neonatal

period is a heterophile antibody–negative mononucleosis syndrome,

which may develop spontaneously or follow transfusion of leukocytecontaining blood products. Although the syndrome occurs at all ages,

it most often involves sexually active young adults. With incubation

periods of 20–60 days, the illness generally lasts for 2–6 weeks. Prolonged high fevers, sometimes with chills, profound fatigue, and malaise, characterize this disorder. Myalgias, headache, and splenomegaly

are common, but in CMV mononucleosis (as opposed to Epstein-Barr

virus mononucleosis), exudative pharyngitis and cervical lymphadenopathy are rare. Occasional patients develop rubelliform rashes, often

after exposure to ampicillin or certain other antibiotics. Less common are interstitial or segmental pneumonia, myocarditis, pleuritis,

arthritis, splanchnic vein thrombosis, and encephalitis. In rare cases,

Guillain-Barré syndrome complicates CMV mononucleosis. The characteristic laboratory abnormality of CMV mononucleosis is relative

lymphocytosis in peripheral blood, with >10% atypical lymphocytes.

Total leukocyte counts may be low, normal, or markedly elevated.

Although significant jaundice is uncommon, serum aminotransferase and alkaline phosphatase levels are often moderately elevated.

Heterophile antibodies are absent; however, transient immunologic

abnormalities are common and may include the presence of cryoglobulins, rheumatoid factors, cold agglutinins, and antinuclear antibodies.

Hemolytic anemia, thrombocytopenia, and granulocytopenia complicate recovery in rare instances.

TABLE 195-1 Cytomegalovirus (CMV) Disease in the Immunocompromised Host

POPULATION RISK FACTORS PRINCIPAL SYNDROME(S) TREATMENT PREVENTION

Fetus Primary maternal infection/

early pregnancy

Cytomegalic inclusion disease Ganciclovir followed by

valganciclovir for symptomatic

neonates

Avoidance of exposure;

education of pregnant women

about risks

Organ transplant recipient Seropositivity of donor

and/or recipient; potent

immunosuppressive regimen;

treatment of rejection

Febrile leukopenia (CMV

syndrome); gastrointestinal

disease; pneumonia

Ganciclovir or valganciclovir, ±

CMV immunoglobulin

Prophylaxis with ganciclovir or

valganciclovir or preemptive

therapy

Hematopoietic stem cell

transplant recipient

Graft-vs-host disease; older

age of recipient; seropositive

recipient; viremia

Pneumonia; gastrointestinal

disease

Ganciclovir or valganciclovir

or foscarnet, ± CMV

immunoglobulin

Prophylaxis with letermovir,

ganciclovir, or valganciclovir or

preemptive therapy

Person with HIV <50 CD4+ T cells/μL; CMV

seropositivity

Retinitis; gastrointestinal

disease; neurologic disease

Ganciclovir, valganciclovir,

foscarnet, or cidofovir

Oral valganciclovir

T lymphocytes. Polyclonal activation of B cells by CMV contributes

to the development of rheumatoid factors and other autoantibodies

during mononucleosis.

Once acquired, CMV persists indefinitely in host tissues. The sites

of persistent infection may include multiple cell types and various

organs. Transmission via blood transfusion or organ transplantation

is due primarily to silent infections in these tissues. If the host’s T-cell

responses become compromised by disease or by iatrogenic immunosuppression, latent virus can reactivate to cause a variety of syndromes.

Chronic antigenic stimulation in the presence of immunosuppression

(for example, after organ transplantation) appears to be an ideal setting

for CMV activation and CMV disease. Certain particularly potent

suppressants of T-cell immunity (e.g., antithymocyte globulin, alemtuzumab) are associated with a high rate of clinical CMV syndromes.

CMV may itself contribute to further T-lymphocyte hyporesponsiveness, which often precedes superinfection with other opportunistic

pathogens such as bacteria, molds, and Pneumocystis.

■ PATHOLOGY

Cytomegalic cells in vivo (presumed to be infected epithelial cells)

are two to four times larger than surrounding cells and often contain

an 8- to 10-μm intranuclear inclusion that is eccentrically placed and

is surrounded by a clear halo, producing an “owl’s eye” appearance.

Smaller granular cytoplasmic inclusions are demonstrated occasionally. Cytomegalic cells are found in a wide variety of organs, including

the salivary gland, lung, liver, kidney, intestine, pancreas, adrenal

gland, and central nervous system.

The cellular inflammatory response to infection consists of plasma

cells, lymphocytes, and monocyte-macrophages. Granulomatous reactions occasionally develop, particularly in the liver. Immunopathologic reactions may contribute to CMV disease. Immune complexes

have been detected in infected infants, sometimes in association with

CMV-related glomerulopathies. Immune-complex glomerulopathy

has also been observed in some CMV-infected patients after renal

transplantation.

■ CLINICAL MANIFESTATIONS

Congenital CMV Infection Fetal infections range from subclinical to severe and disseminated. CMV seroconversion rates during pregnancy range from 1% to 7%. Of infants born to mothers with primary

CMV infections during pregnancy, 5–20% will develop clinical manifestations, with a mortality rate of ~5%. Petechiae, hepatosplenomegaly, and jaundice are the most common presenting features (60–80% of

cases). They can have “blueberry muffin”–like hemorrhagic purpuric

eruptions, which when biopsied show histopathology with dermal

erythropoiesis. Infections during the first trimester are associated with

up to 40−50% of infected neonates developing sensorineural complications. Microcephaly with or without cerebral calcifications, intrauterine growth retardation, and prematurity are reported in 30–50%

of cases. Inguinal hernias and chorioretinitis are less common. Laboratory abnormalities include elevated alanine aminotransferase levels in

serum, thrombocytopenia, conjugated hyperbilirubinemia, hemolysis,

1489CHAPTER 195 Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8

Most patients recover without sequelae, although postviral asthenia may persist for months. The excretion of CMV in urine, genital

secretions, and/or saliva often continues for months or years. Rarely,

CMV infection is fatal in immunocompetent hosts; survivors can have

recurrent episodes of fever and malaise, sometimes associated with

autonomic nervous system dysfunction (e.g., attacks of sweating or

flushing).

CMV Infection in the Immunocompromised Host (Table

195-1) CMV is the most common viral pathogen complicating organ

transplantation (Chap. 143). In recipients of kidney, heart, lung, liver,

pancreas, and vascularized composite (hand, face, other) transplants,

CMV infection may result in a variety of clinical manifestations,

including fever and leukopenia, hepatitis, colitis, pneumonitis, esophagitis, gastritis, and retinitis. CMV disease is an independent risk

factor for both graft loss and death. Without prophylaxis, the period

of maximal risk is between 1 and 4 months after transplantation. Disease likelihood and viral replication levels generally are greater after

primary infection than after reactivation. Molecular studies indicate

that seropositive organ transplant recipients are susceptible to infection with donor-derived, genotypically variant CMV. Reactivation

infection, although common, is less likely than primary infection to

be clinically significant. The overall risk of clinical disease is related to

various factors, such as serologic mismatch (donor seropositive, recipient seronegative), degree of immunosuppression, use of antilymphocyte antibodies, lack of anti-CMV prophylaxis, and co-infection with

other pathogens. The transplanted organ is particularly vulnerable as a

target for CMV infection; thus, there is a tendency for CMV hepatitis

to follow liver transplantation and for CMV pneumonitis to follow lung

transplantation.

CMV viremia occurs in roughly one-third of hematopoietic stem

cell transplant (HSCT) recipients; the risk of severe disease may be

reduced by prophylaxis or preemptive therapy with antiviral drugs. The

risk is greatest in the first 100 days after transplantation, and identified

risk factors include certain types of immunosuppressive therapy, an

allogeneic (rather than an autologous) graft, acute graft-versus-host

disease, older age, and recipient seropositivity prior to transplant.

CMV is an important pathogen in patients with advanced HIV

infection (Chap. 202), in whom it may cause retinitis or disseminated

disease, particularly when peripheral-blood CD4+ T-cell counts fall

below 50/μL. As treatment for underlying HIV infection has improved,

the incidence of serious CMV infections (e.g., retinitis) has decreased.

During the first few weeks after institution of highly active antiretroviral therapy, however, acute flare-ups of CMV retinitis may occur

secondary to an immune reconstitution inflammatory syndrome.

Syndromes produced by CMV in immunocompromised hosts

(“CMV syndrome”) often begin with fatigue, fever, malaise, anorexia,

night sweats, and arthralgias or myalgias. Liver function abnormalities,

leukopenia, thrombocytopenia, and atypical lymphocytosis may be

observed during these episodes. Without treatment, CMV infection

may progress to more severe end-organ disease. The development of

tachypnea, hypoxemia, and nonproductive cough signals respiratory

involvement. Radiologic examination of the lung often shows bilateral

interstitial or reticulonodular infiltrates that begin in the periphery

of the lower lobes and spread centrally and superiorly; localized segmental, nodular, or alveolar patterns are less common. The differential

diagnosis includes Pneumocystis infection; other viral, bacterial, or

fungal infections; pulmonary hemorrhage; and injury secondary to

irradiation or to treatment with cytotoxic drugs.

Gastrointestinal CMV involvement may be localized or extensive

and almost exclusively affects immunocompromised hosts. Colitis is

the most common clinical manifestation in organ transplant recipients.

Ulcers of the esophagus, stomach, small intestine, or colon may result

in bleeding or perforation. Clinicians should be aware that blood tests

such as CMV antigenemia and viral load testing may yield negative

results in the setting of intestinal disease. CMV infection may lead

to exacerbations of underlying ulcerative colitis. Hepatitis occurs frequently, particularly after liver transplantation. Acalculous cholecystitis and adrenalitis also have been described.

CMV rarely causes meningoencephalitis in otherwise healthy individuals. Two forms of CMV encephalitis are seen in people with HIV.

One resembles HIV encephalitis and presents as progressive dementia;

the other is a ventriculoencephalitis characterized by cranial-nerve

deficits, nystagmus, disorientation, lethargy, and ventriculomegaly.

In immunocompromised patients, CMV can also cause subacute progressive polyradiculopathy, which is often reversible if recognized and

treated promptly.

CMV retinitis is an important cause of blindness in immunocompromised patients, particularly patients with advanced AIDS

(Chap. 202). Early lesions consist of small, opaque, white areas of

granular retinal necrosis that spread in a centrifugal manner and are

later accompanied by hemorrhages, vessel sheathing, and retinal edema

(Fig. 195-1). CMV retinopathy must be distinguished from that due

to other conditions, including toxoplasmosis, candidiasis, and herpes

simplex virus infection.

Fatal CMV infections are often associated with persistent viremia

and the involvement of multiple organ systems. Progressive pulmonary infiltrates, pancytopenia, hyperamylasemia, and hypotension are

characteristic features that are frequently found in conjunction with

a terminal bacterial, fungal, or protozoan superinfection. Extensive

adrenal necrosis with CMV inclusions is often documented at autopsy,

as is CMV involvement of many other organs.

■ DIAGNOSIS

CMV infection usually cannot be diagnosed reliably on clinical

grounds alone. Isolation of CMV or detection of its antigens or DNA

in appropriate clinical specimens is the preferred approach. The most

common method of detection is quantitative nucleic acid testing

(QNAT) for CMV by polymerase chain reaction (PCR) technology,

for which blood or other specimens can be used; some centers use

a CMV antigenemia test, an immunofluorescence assay that detects

CMV antigens (pp65) in peripheral-blood leukocytes. Such assays may

yield a positive result several days earlier than culture methods. QNAT

may predict the risk for disease progression, particularly in immunocompromised hosts. CMV DNA in cerebrospinal fluid is useful in the

diagnosis of CMV encephalitis or polyradiculopathy. Recent introduction of an international testing standard has helped reduce variation in

viral load test results.

Virus excretion and/or viremia is readily detected by culture of

appropriate specimens on human fibroblast monolayers. If CMV titers

are high, as is common in congenital disseminated infection and in

AIDS, characteristic cytopathic effects may be detected within a few

days. However, in some situations (e.g., CMV mononucleosis), viral

titers are low, and cytopathic effects may take several weeks to appear.

Many laboratories expedite diagnosis with an overnight tissue-culture

method (shell vial assay) involving centrifugation and an immunocytochemical detection technique employing monoclonal antibodies to

FIGURE 195-1 Cytomegalovirus infection in a patient with AIDS may appear as an

arcuate zone of retinitis with hemorrhages and optic disk swelling. Often CMV is

confined to the retinal periphery, beyond view of the direct ophthalmoscope.