Rudolph's Pediatrics, 22nd Ed.

CHAPTER 310. Cytomegalovirus

Mark R. Schleiss

Cytomegalovirus (CMV) is one of the family of eight human herpesviruses, designated as human herpesvirus type 5 (HHV-5) (Table 309-1). Taxonomically, it is referred to as a betaherpesvirus, based on its propensity to infect mononuclear cells and lymphocytes and on its molecular phylogenetic relationship to human herpesvirus type 6 (HHV-6) and human herpesvirus type 7 (HHV-7).  The proteinaceous layer between the envelope and the inner capsid, the viral tegument, contains proteins that are targets of host cell-mediated immune responses.


Although most adults eventually become infected with cytomegalovirus (CMV), the epidemiology of this infection is complex, and the age at which an individual acquires CMV depends greatly on geographic location, socioeconomic status, cultural factors, and child-rearing practices.5-7 In developing countries, most children acquire CMV infection early in life, whereas in developed countries, the seroprevalence of CMV may be well below 50% in young adults of middle-upper socioeconomic status.

Transmission of CMV infection may occur throughout life, chiefly via contact with infected secretions. CMV infections in newborns are common, and most are subclinical. Approximately 1% (range 0.5–2.5%) of all newborns are congenitally infected with CMV. Most infections occur in infants born to mothers with preexisting immunity, and although clinically silent at birth, infection can lead to long-term sequelae, most notably, sensorineural hearing loss (SNHL).8 Additional information about congenital CMV infection is presented in Chapter 231. The route of acquisition of CMV infection acquired in utero is believed to be transplacental.9 CMV may also be transmitted perinatally, both by aspiration of cervicovaginal secretions in the birth canal and by breast-feeding.10 Toddlers are at high risk to acquire infection in daycare centers and may in turn transmit infection to their parents.11-13 In adults, sexual activity is a common mode of transmission.14 Although generally asymptomatic, heterophile-negative mononucleosis can be a presentation of primary infection in adulthood, as described later in this chapter.15 Blood transfusion-associated CMV was once an important cause of morbidity and mortality, notably in premature infants, but the routine use of leukofiltration has largely eliminated the problem of posttransfusion CMV.16


In clinical specimens, one of the classic hallmarks of cytomegalovirus (CMV) infection is the cytomegalic inclusion cell. These massively enlarged cells (the property of “cytomegaly” from which CMV acquires its name) contain intranuclear inclusions that histopathologically have the appearance of “owl’s eyes” (Fig. 310-1). The presence of these cells indicates productive infection in vivo, chiefly in epithelial cells.

FIGURE 310-1. Characteristic cytomegalovirus (CMV) inclusion body in biopsy from congenitally infected infant. Classic “owl’s eyes” CMV-associated inclusion body noted in renal biopsy of infant with congenital CMV infection and (unrelated) renal disease. Viral inclusion found within renal tubule (arrowhead) in infant with high-grade DNAemia, viruria, and sensorineural hearing loss. Infant had no other stigmata of congenital CMV infection.

Little is known about the molecular mechanisms responsible for the pathogenesis of tissue damage caused by CMV, particularly for congenital CMV infection. Because CMV can infect endothelial cells, it has been postulated that a viral angiitis may be responsible for perfusion failure of developing brain with resultant maldevelopment. Others have postulated a direct teratogenic effect of CMV on the developing fetus. Observation of CMV-induced alternations in the cell cycle and damage to chromosomes support this speculation, although this hypothesis has been difficult to experimentally verify.17

Immunity to CMV is complex and involves both humoral and cell-mediated responses (reviewed in 18). As noted, envelope glycoproteins and tegument phosphoproteins are important in humoral and cellular immunity, respectively. More recent investigations into the molecular biology of CMV have revealed the presence of many genes that modulate the host immune responses (reviewed in 19). These include genes that inhibit MHC class I antigen presentation, homologs of cellular G-protein-coupled receptors, a homolog of the cellular major histocompatibility class I gene, homologs of chemokines, and a homolog of the tumor necrosis factor receptor super-family. These genes may contribute to the ability of CMV to escape immune clearance.


Congenital CMV Infection

Current estimates suggest that 30,000 to 40,000 infants in the United States are born annually with congenital cytomegalovirus (CMV) infection. Approximately 10% of infants have clinical evidence of disease at birth (Fig. 310-2). The most severe form of congenital CMV infection is referred to as “cytomegalic inclusion disease” (CID), characterized by intrauterine growth retardation, hepatosplenomegaly, hematologic abnormalities (particularly thrombocytopenia), and cutaneous manifestations such as petechiae and purpura (so-called “blueberry muffin” baby).20,21 The most disabling manifestations of CID involve the central nervous system.22 Microcephaly, ventriculomegaly, periventricular calcifications, cerebral atrophy, polymicrogyria, cortical dysplasia, chorioretinitis, and sensorineural hearing loss are among the neurologic consequences (eFig. 310.1 ). Additional information on congenital CMV infection is presented in Chapter 231.

The majority of infants with congenital CMV infection are born to women who have preexisting immunity to CMV. These infants generally are clinically normal at birth but are at risk for neurodevelopmental sequelae, particularly sensorineural hearing loss. Routine newborn hearing screening may miss cases of CMV-associated hearing loss because hearing loss may not be evident until months or years after birth.23,24 Thus, a case can be made for universal newborn screening for congenital CMV infection.25-27

FIGURE 310-2. Disease outcome profile of congenital cytomegalovirus (CMV) infection. Approximately 10% of cases of congenital CMV infections occur in women with primary infection during pregnancy, and 60% to 90% of these infants have neurologic sequelae. Most infections occur in women with preconception immunity (due to recurrent infection), and although this immunity protects against severe disease in the newborn, approximately 15% of these infants still have sequelae, chiefly, sensorineural hearing loss.

Acquired CMV Infection

Perinatal Infection

Perinatal acquisition of cytomegalovirus (CMV) usually occurs secondary to exposure to infected secretions in the birth canal or via breast-feeding. Most infections are asymptomatic. Indeed, breast milk-acquired CMV infection in term babies has been referred to in some reviews as a form of “natural immunization.”10 However, premature infants who acquire CMV infection perinatally via breast milk may have signs and symptoms of disease, including lymphadenopathy, hepatitis, and pneumonitis, which may, on occasion, be severe. There is no evidence that these infections in premature infants carry any risk of long-term neurologic or neurodevelopmental sequelae, although this issue requires further study.

CMV Mononucleosis

Typical cytomegalovirus (CMV) mononucleosis is a disease of young adults. Although it may be acquired by blood transfusion or organ transplantation, it is most commonly acquired via person-to-person transmission. The hallmark symptoms of CMV mononucleosis are fever and severe malaise.13 An atypical lymphocytosis is present, as is mild elevation of liver enzymes. It may be difficult to clinically differentiate CMV mononucleosis from Epstein-Barr virus (EBV)-induced mononucleosis. As with EBV mononucleosis, the use of β-lactam antibiotics in association with CMV mononucleosis may precipitate a generalized morbilliform rash.

Transfusion-Acquired CMV Infection

Posttransfusion cytomegalovirus (CMV) infection has a presentation similar to that of CMV mononucleosis. Incubation periods range from 20 to 60 days. The use of leukocyte-depleted blood has virtually eliminated the risk of transmission via this mechanism.16

CMV in Immunocompromised Patients

Cytomegalovirus (CMV) causes a variety of clinical syndromes in immunocompromised patients.28,29 CMV is a major cause of pneumonitis in immunosuppressed children and adults. This disease may be seen in the setting of HIV infection, congenital immunodeficiency, malignancy, and solid organ or bone marrow transplant. The illness usually begins 1 to 3 months following transplantation, and begins with symptoms of fever and dry, nonproductive cough. The illness progresses quickly, with retractions, dyspnea, and hypoxia becoming prominent. Gastrointestinal tract disease due to CMV can include esophagitis, gastritis, gastroenteritis, pyloric obstruction, hepatitis, pancreatitis, colitis, and cholecystitis. Characteristic signs and symptoms can include nausea, vomiting, dysphagia, epigastric pain, icterus, and watery diarrhea. Endoscopy and biopsy are warranted. CMV retinitis was a common disease, particularly in HIV-infected individuals, prior to the advent of highly active antiretroviral therapy (HAART), with an overall lifetime prevalence of > 90%. CMV produces a necrotic, rapidly progressing retinitis, with characteristic white perivascular infiltrate with hemorrhage (“brushfire retinitis”). Strabismus or failure to fix and follow objects may be important clues to the diagnosis in children. Untreated, the disease can progress to total blindness and retinal detachment.

Other CMV Syndromes

A variety of other syndromes have been attributed to cytomegalovirus (CMV) infection, although cause-and-effect relationships are often difficult to establish. Menetrier disease is a rare disorder characterized by hyperplasia and hypertrophy of the gastric mucous glands that results in massive enlargement of the gastric folds (Chapter 409). The majority of cases appear to be CMV associated, although the pathogenesis is unknown.30 Evidence is accumulating that suggests that CMV infection may be a cofactor in the pathogenesis of atherosclerosis, posttransplant vascular sclerosis, postangioplasty restenosis, immunosenescence, and malignancies.31


The most important diagnostic study in the evaluation of suspected CMV disease is the viral culture. CMV may be cultured from virtually any body fluid or organ system. Blood, urine, saliva, cervicovaginal secretions, cerebrospinal fluid, bronchoalveolar lavage fluid, and tissues from biopsy specimens are all appropriate specimens for culture. The specimen is inoculated onto human cells (usually human foreskin fibroblasts), and the cell culture monitored for the development of the characteristic CMV-associated cytopathic effect. CMV may grow slowly in culture, requiring up to 6 weeks of incubation. Culture identification is enhanced by centrifugation techniques, followed by monoclonal-antibody detection, referred to as the “shell-vial” assay.

Polymerase chain reaction (PCR) amplification of CMV DNA from clinical specimens is a useful adjunct to culture techniques. The information derived from PCR not only helps establish the diagnosis of CMV infection, but help predict neurodevelopmental outcomes in infants with congenital CMV, and may be useful in monitoring response to antiviral therapy.

Particular care must be taken in diagnosis of congenital CMV in the infant. Antibody titers in the infant (so-called “TORCH” titers) are seldom of value in establishing the diagnosis of congenital CMV, and can often be misleading. Culture is mandatory. Cultures obtained after age 3 weeks may represent perinatal CMV acquisition rather than congenital CMV infection. Outside of the neonatal period it must be recognized that CMV can be shed from urine for years after infection so differentiation of CMV infection and CMV disease requires clinical judgement. Lung biopsy or bronchoalveolar lavage may be required for definitive diagnosis of CMV pneumonia, and liver biopsy for diagnosis of CMV hepatitis.


Nucleoside analogs and other types of viral polymerase inhibitors are available for the treatment of cytomegalovirus (CMV) infection. Currently, four antiviral therapies are approved by the US Food and Drug Administration for the prophylaxis and/or therapy of systemic CMV infection (also see Chapter 245). Experience with these agents is limited in pediatrics, however, and anti-CMV therapy in general should be administered only after consultation with an expert familiar with dosage and side effects.

Ganciclovir was the first compound licensed for treatment of CMV infections. Its use is indicated in immunocompromised children (HIV infection, transplant recipients, other immunocompromised states) when there is clinical and virologic evidence of specific end-organ disease (pneumonitis, enteritis, etc). Ganciclovir is myelosuppressive, often a dose-limiting toxicity in immunocompromised patients. Ganciclovir is also commonly used as preemptive therapy in transplant patients at high risk of developing disease (eg, a CMV-seronegative recipient of an organ from a CMV-seropositive donor).

There is relatively little information concerning the use of ganciclovir in the setting of congenital CMV infection. A trial sponsored by the Collaborative Antiviral Study Group (CASG) demonstrated that ganciclovir therapy begun in the neonatal period in symptomatically infected infants with congenital CMV infection involving the central nervous system prevented hearing deterioration at 6 months and that the benefits appeared to persist at or beyond 1 year of age.35,36 Based on this study, ganciclovir therapy should probably be offered to any infant with congenital CMV infection with any evidence of central nervous system (CNS) involvement, including sensorineural hearing loss.

More recently, the valine ester of ganciclovir, valganciclovir, has been licensed. In contrast to oral ganciclovir, oral valganciclovir has a substantially improved bioavailability. There is clinical experience with valganciclovir in treatment and prophylaxis against CMV infection and disease in oncology patients, but little pediatric experience. Ideally, the use of oral valganciclovir would obviate the need for prolonged central venous access. This strategy is currently under study by the CASG.37

Alternatives to ganciclovir include forcarnet (trisodium phosphonoformate) and cidofovir (HPMPC). Pediatric experience with these agents is limited. Although potentially useful in the setting of ganciclovir resistance, the toxicities of these antivirals are significant, and these agents should be used only in exceptional circumstances.

Immunoglobulins have also been useful in the control of CMV disease. A CMV hyperimmunoglobulin (CytoGam) has been shown to decrease the incidence of CMV disease when administered posttransplant to high-risk transplant recipients. A more recent uncontrolled study was conducted using high-titer CMV immune globulin therapy of pregnant women with primary CMV infections and evidence by amniocentesis of fetal infection. High-titer CMV immune globulin was safe, and was associated with a significant reduction in CMV disease compared to a no treatment group.38


Ultimately, control of cytomegalovirus (CMV) infection, particularly the devastating sequelae of congenital cytomegalic inclusion disease (CID), will depend on immunization.39 The major target population for a CMV vaccine would be women of childbearing age. Although immunization would be unlikely to prevent all congenital infection, there is hope that it would have a significant and major impact on the incidence of CID. Until the goal of a CMV vaccine is realized, education of young women of childbearing age about the risks of CMV and how to avoid disease transmission are the only control strategies available. Seronegative women who regularly come in close contact with large numbers of young children, particularly in daycare center environments, may be at particularly high risk. Behaviors known to be associated with transmission of infection, particularly kissing and sharing eating utensils, can be avoided, and careful hand-washing after diaper changes can be stressed.13