Pediatric Cytomegalovirus Infection

In 1904, Ribbert first identified histopathological evidence of CMV, probably in tissues from a congenitally infected infant. Ribbert mistakenly assumed that the large inclusion-bearing cells he observed at autopsy were from protozoa (incorrectly named Entamoebamortinatalium). In 1920, Goodpasture correctly postulated the viral etiology of these inclusions.[3] Goodpasture used the term cytomegalia to refer to the enlarged, swollen nature of the infected cells. Human CMV was first isolated in tissue culture in 1956, and the propensity of this organism to infect the salivary gland led to its initial designation as a salivary gland virus.

In 1960, Weller designated the virus cytomegalovirus[4] ; during the 1970s and 1980s, knowledge of the role of CMV as an important pathogen with diverse clinical manifestations increased steadily.[5] Although enormous progress has recently been made in defining and characterizing the molecular biology, immunology, and antiviral therapeutic targets for CMV, considerable work remains in devising strategies for prevention of CMV infection and in understanding the role of specific viral genes in pathogenesis.

Furthermore, development of a vaccine against this virus is a major public health priority (reviewed in Prevention).[6, 3, 7]

As noted, cytomegalovirus (CMV) is a member of a family of 8 human herpesviruses, officially designated as human herpesvirus type 5 (HHV-5). Taxonomically, CMV is referred to as a Betaherpesvirinae, based on its propensity to infect mononuclear cells and lymphocytes and on its molecular phylogenetic relationship to other herpesviruses. CMV is the largest member of the herpesvirus family, with a double-stranded DNA genome of more than 240 kbp, capable of encoding more than 200 potential protein products. The function of most of these proteins remains unclear. As with the other herpesviruses, the structure of the viral particle is that of an icosahedral capsid, surrounded by a lipid bilayer outer envelope.

An understanding of the process of viral replication provides insights into molecular mechanisms of antiviral therapy and protective immunity. The relationship between viral replication and the pathogenesis of infection is the subject of a recent review.[8] CMV replicates very slowly in cell culture, mirroring its very slow pattern of growth in vivo (in contrast to herpes simplex virus [HSV] infection, which progresses very rapidly). The replication cycle of CMV is temporally divided into the following 3 regulated classes: immediate early, early, and late.

Immediate early gene transcription occurs in the first 4 hours following viral infection, when key regulatory proteins that allow the virus to take control of cellular machinery are made. The major immediate early promoter of this region of the CMV genome is one of the most powerful eucaryotic promoters described in nature; this has been exploited in modern biotechnology as a useful promoter for driving gene expression in gene therapy and vaccination studies.

Following the synthesis of immediate early genes, the early gene products are transcribed. Early gene products include DNA replication proteins and some structural proteins.

The late gene products are made approximately 24 hours after infection, and these proteins are chiefly structural proteins that are involved in virion assembly and egress. Synthesis of late genes is highly dependent on viral DNA replication and can be blocked by inhibitors of viral DNA polymerase, such as ganciclovir. The lipid bilayer outer envelope contains the virally encoded glycoproteins, which are the major targets of host neutralizing antibody responses. These glycoproteins are candidates for human vaccine design. The proteinaceous layer between the envelope and the inner capsid, the viral tegument, contains proteins that are major targets of host cell–mediated immune responses. The most important of these tegument proteins is the so-called major tegument protein, UL83 (phosphoprotein 65 [pp65]).

Another clinically important gene product, the UL97 gene product, is a phosphotransferase. Although the function of this protein in the viral life cycle is unknown, this gene is clinically important because a substrate of the kinase is the antiviral drug ganciclovir, which, once phosphorylated, becomes a highly effective CMV therapy.[9]

In clinical specimens, one of the classic hallmarks of CMV infection is the cytomegalic inclusion cell. These strikingly enlarged cells (the property of "cytomegaly," from which CMV acquires its name) contain intranuclear inclusions that have the histopathological appearance of owl's eyes. The presence of these cells indicates productive infection, although they may be absent even in actively infected tissues. In most cell lines, CMV is difficult to culture in the laboratory; however, in vivo infection seems to chiefly involve epithelial cells. In severe disseminated CMV disease, involvement can be observed in most organ systems.

Little is known about the molecular mechanisms responsible for the pathogenesis of tissue damage caused by CMV, particularly for congenital CMV infection. The mechanisms by which CMV injures the fetus are complex and likely include a combination of direct fetal cellular injury (particularly in the fetal brain) induced by pathologic virally encoded gene products, an incomplete maternal immune response incapable of fully controlling infection, and the impact of infection on placental function, including oxygen and substrate transport.

CMV also encodes gene products that function, at both the RNA and the protein level, to interfere with many cellular processes. These include gene products that modify the cell cycle; gene products that interfere with apoptosis; functions that induce an inflammatory response; gene products that mediate vascular injury; proteins that induce site-specific breakage of chromosomes; gene products that promote oncogenesis and dysregulation of cellular proliferation; and, most strikingly, genes that facilitate evasion of host immune responses.[8]

Immunity to CMV is complex and involves humoral and cell-mediated responses. Several CMV gene products are of particular importance in CMV immunity. The outer envelope of the virus, which is derived from the host cell nuclear membrane, contains multiple virally encoded glycoproteins. Glycoprotein B (gB) and glycoprotein H (gH) appear to be the major determinants of protective humoral immunity. Antibody to these proteins is capable of neutralizing virus, and gB and gH are targets of investigational CMV subunit vaccines; however, although humoral responses are important in control of severe disease, they are clearly inadequate in preventing transplacental infection, which can occur even in women who are CMV seropositive.

CMV uses 2 pathways of entry into the cell: (1) a fusion-mediated pathway in fibroblasts and (2) an endocytosis-mediated pathway in epithelial and endothelial cells. CMV proteins that are important in the endocytosis-mediated entry pathway, encoded by the UL128-131 genes, may emerge as particularly useful vaccine candidates in future studies.[10, 11]

The generation of cytotoxic T-cell (CTL) responses against CMV may be a more important host immune response in control of infection. In general, these CTLs involve major histocompatibility complex (MHC) class I restricted CD8+ responses. Although many viral gene products are important in generating these responses,[12] most CMV-specific CTLs target an abundant phosphoprotein in the viral tegument, pp65, the product of the CMV UL83 gene. In passive transfer experiments involving high-risk bone marrow transplant recipients, the value of these responses was dramatically demonstrated using adoptive transfer of CMV-specific CD8+ T cells that target the CMV UL83 gene, which was able to control CMV disease.[13]

Investigations into the molecular biology of CMV have revealed the presence of many viral gene products, which appear to modulate host inflammatory and immune responses.[14] Several CMV genes interfere with normal antigen processing and generation of cell-mediated immune responses, including the US11 gene product, which exports the class I heavy chain from the endoplasmic reticulum (ER) to the cytosol (rendering it nonfunctional). Another is the US3 gene product, which retains MHC molecules in the ER, preventing them from traveling to the plasma membrane. Finally, the US6 protein inhibits peptide translocation by transporters associated with antigen processing (TAP).

Other viral gene products, the UL33, US27, and US28 genes, are functional homologs of cellular G-protein coupled receptors, which may, via molecular mimicry, subvert normal inflammatory responses and, in the process, promote tissue dissemination of the virus and interfere with the host immune response.

The cytomegalovirus genome also encodes a homolog of the cellular major histocompatibility class I gene, which appears to contribute to the ability of CMV to evade host defense. The UL144 open reading frame found in clinical isolates of CMV encodes a structural homolog of the tumor necrosis factor receptor superfamily, and this too may contribute to the ability of human CMV to escape immune clearance. Other cytomegalovirus genes interfere with natural killer (NK) cell responses, including the UL18 gene product. A better understanding of the impact of viral immune evasion genes on the development of protective immunity to CMV infection should enable the design of improved vaccines.[15]

United States statistics

Every mammal appears to be infected with its own species-specific cytomegalovirus (CMV), and no evidence suggests that infections cross species. Hence, humans are the only natural host for human CMV infection. Although most adults eventually become infected with CMV, the epidemiology of this infection is complex, and the age at which an individual acquires CMV greatly depends on geographic location, socioeconomic status, cultural factors, and child-rearing practices.

In developing countries, most children acquire CMV infection early in life, with adult seroprevalence approaching 100% by early adulthood. In contrast, in developed countries, the seroprevalence of CMV approximates 50% in young adults of middle-upper socioeconomic status. This observation has important implications for congenital CMV epidemiology because women of childbearing age who are CMV seronegative are at major risk of giving birth to infants with symptomatic congenital infection if primary infection is acquired during pregnancy.

Transmission of CMV infection may occur throughout life, chiefly via contact with infected secretions.[16] In the developed world, CMV is the most common congenital viral infection. An overall rate of congenital CMV transmission of approximately 1% (ranging from 0.25–2%, depending on the population studied) has been estimated in newborn infants in the developed world in most reviews. This translates to about 80,000 congenital CMV infections per year in the United States and Europe. In the United States, congenital CMV infection occurs in 3-6 of every 1000 infants born each year.[17]

A meta-analysis of published studies concluded that the overall birth prevalence of congenital CMV infection was 0.64%, but noted that rates varied considerably among different study populations.[18] Nonwhite race, low socioeconomic status, premature birth, and neonatal intensive care unit admittance were risk factors for congenital CMV infection; and birth prevalence increased with maternal CMV seroprevalence.

There has been insufficient attention given to congenital CMV infection in the developing world, but the limited data available suggest that CMV may also represent a significant public health concern in these populations.[19] A multicenter study comparing newborn screening by oropharyngeal culture versus polymerase chain reaction (PCR)–based detection of viral DNA in the newborn dried blood spot indentified an overall prevalence of 0.45% in the 7 sites surveyed.[20] Most congenital CMV infections occur in infants born to mothers with preexisting immunity, and these infections are clinically asymptomatic at birth; however, long-term sequelae, including deafness, can occur (see History).

The route of congenital infection is presumed to be transplacental. The transplacental transmission rate after maternal primary infection is about 32%.[21, 22] CMV may also be transmitted perinatally, both by aspiration of cervicovaginal secretions in the birth canal and by breastfeeding. More than 50% of infants fed with breast milk that contains infectious virus become infected with CMV.[23] In particular, a study reported 5 cases of severe morbidity and mortality in very low birth weight infants with CMV infection acquired postnatally through breast milk.[24] Infants who are not infected congenitally or perinatally with CMV are at high risk to acquire infection in daycare centers. According to some studies, the prevalence of CMV infection in children who attend daycare, particularly children younger than 2 years, approximates 80%.

The virus may be readily transmitted to susceptible children via saliva, urine, and fomites; these children, in turn, may transmit infection to their parents.[25, 26] Horizontal transmission of infection in daycare centers appears to play a major role in the epidemiology of many CMV infections in young parents.[27]

In adulthood, sexual activity is probably the most important route of acquisition of CMV,[28] although the observation that virus is present in saliva, cervicovaginal secretions, and semen obscures which route or routes of transmission are primarily responsible for establishment of infection. Saliva alone appears to be sufficient for transmission of CMV, and this route of transmission may be responsible for those cases of heterophile-negative mononucleosis, which are attributable to CMV. Kissing appears to be a way in which CMV is transmitted from toddlers to seronegative parents. Work by the Centers for Disease Control and Prevention (CDC) has emphasized the need for greater public awareness of these risks and for educational interventions for young women of childbearing age.[29]

Other important routes of transmission include blood transfusion and solid organ transplantation. Before screening of blood products, transfusion-associated CMV was an important cause of morbidity and mortality in premature infants; however, the routine use in many neonatal intensive care units of CMV-negative blood products has largely eliminated this problem. Posttransfusion CMV is still a risk in CMV-seronegative trauma and in surgery patients, often manifesting as hepatitis.

International statistics

The risk of congenital CMV infection is not well defined in the developing world. Because seroepidemiologic studies indicate that in many developing countries, seroprevalence for CMV approaches 100% very early in childhood, little attention has been given to the question of potential morbidities in these populations.

Race-, sex-, and age-related demographics

Race

The effects of race and genetics on clinical manifestations of cytomegalovirus (CMV) infection are not well understood. In some studies in the United States, the prevalence of congenital CMV infection appears to be higher in infants born to Black women.[30] More recent studies using the National Health and Nutrition Examination Survey (NHANES) database confirm that substantial differences exist in the prevalence of CMV infection as a function of race in the United States.[25, 26]

Congenital CMV infection, indeed, should be considered a disease of health disparities. More work is required to understand the basis for the differences in the epidemiology of CMV infection in various ethnic groups in the United States.

Sex

Both sexes are equally susceptible to infection and morbidity from cytomegalovirus (CMV), although only women are at risk for transplacental transmission of infection.

Age

The annual seroconversion rate for acquisition of cytomegalovirus (CMV) infection is approximately 1%. However, 2 age groups have higher rates of acquisition of infection: toddlers who attend group daycare and adolescents. Accordingly, these represent 2 potential groups in which to implement vaccination.

A cohort study by Gunkel et al that assessed the neurodevelopment in 356 infants 6 years of age and younger, of which 14% had postnatal cytomegalovirus infection, reported no adverse effect on neurodevelopment in preterm children with postnatal cytomegalovirus infection.[31]

Morbidity/mortality

Cytomegalovirus (CMV) is a substantial cause of morbidity in newborns. As the most common so-called toxoplasmosis, rubella, CMV, and herpes simplex (TORCH) infection in the developed world, CMV accounts for extensive neurodevelopmental morbidity, including sensorineural deafness in infants.

CMV also accounts for substantial mortality in immunocompromised patients. Mortality due to congenital CMV infection is low (about 4% of infants).[21, 22]

Increased awareness of the complications of congenital cytomegalovirus (CMV) infection is needed.

With a greater educational effort, women of childbearing age can be better prepared to anticipate risk factors for CMV transmission during pregnancy.[32]

A national CMV registry provides education and support for families affected by congenital CMV infection. Contact the National Congenital CMV Disease Registry at Feigin Center, Suite 1150, 1102 Bates Street, MC 3-2371, Houston, TX, 77030-2399, (832) 824-4387, or visit the Web site at http://www.bcm.tmc.edu/pedi/infect/cmv/ .

Better education of the risks of CMV infection for young women is a must. The CDC is also an excellent educational resource.

Other foundations provide education and resources for parents interested in learning more about congenital CMV, including the CMV Foundation.

The history must be tailored to the specific clinical circumstances and disease category.

Congenital cytomegalovirus (CMV) infection

The risk of intrauterine transmission is highest when primary infection occurs during pregnancy, with a significantly increased risk of adverse fetal effects if fetal infection occurs during the first half of pregnancy.[33]

Among congenitally infected infants, approximately 10% have signs and symptoms of disease at birth, and these symptomatic infants have been reported to have a 40-90% risk of subsequent neurologic sequelae, including mental retardation, microcephaly, development delay, seizure disorders, and cerebral palsy.[34, 35, 36] Although the remaining 90% of infants are asymptomatic at birth, a range of 7-20% have been reported to subsequently develop permanent sequelae, particularly sensorineural hearing loss.[37, 38, 39]

Congenital CMV infection is the most common cause of nongenetic sensorineural hearing loss. Other complications include cognitive impairment, chorioretinitis, and cerebral palsy. Motor deficits and seizures occur in 23% and 19%, respectively, of pediatric patients with symptomatic congenital CMV infection.[21, 22]

Hence, congenital infection may be classified as symptomatic or asymptomatic in nature (see the image below). Overall, it has been estimated that in a given cohort of 1000 infants with congenital CMV infection, 170-190 will have permanent sequelae, of whom one third are from the symptomatic group and two thirds are from the asymptomatic group.

Cytomegalic inclusion disease (CID)

Approximately 10% of infants with congenital infection have clinical evidence of disease at birth.[40] The most severe form of congenital CMV infection is referred to as CID.

CID almost always occurs in women who have primary CMV infection during pregnancy, although rare cases are described in women with preexisting immunity who presumably have reactivation of infection during pregnancy.

CID is characterized by intrauterine growth restriction, hepatosplenomegaly, hematological abnormalities (particularly thrombocytopenia), and various cutaneous manifestations, including petechiae and purpura (ie, "blueberry muffin baby"). However, the most significant manifestations of CID involve the CNS. Microcephaly, ventriculomegaly, cerebral atrophy, chorioretinitis, and sensorineural hearing loss are the most common neurologic consequences of CID.

Intracerebral calcifications typically demonstrate a periventricular distribution and are commonly encountered using CT scanning (see the image below). The finding of intracranial calcifications is predictive of cognitive and audiologic deficits in later life and predicts a poor neurodevelopmental prognosis.

Most infants who survive symptomatic CID have significant long-term neurologic and neurodevelopmental sequelae. Indeed, it has been suggested that more children have long-term neurodevelopmental handicaps as a result of congenital CMV infection than either Down syndrome or fetal alcohol syndrome.[41]

Asymptomatic congenital CMV

Most infants with congenital CMV infection are born to women who have preexisting immunity to CMV. These infants appear clinically healthy at birth; however, although infants with congenital CMV infection appear well, they may have subtle growth restriction compared with uninfected infants. Although asymptomatic at birth, these infants, nevertheless, are at risk for neurodevelopmental sequelae.

The major consequence of inapparent congenital CMV infection is sensorineural hearing loss. Approximately 15% of these infants have unilateral or bilateral deafness. Routine newborn audiologic screening may not detect cases of CMV-associated hearing loss because this deficit may develop months or even years after birth.[42]

Acquired CMV infection

In contrast to congenital infection, acquired CMV infection occurs postnatally. Primary infection in this context is generally asymptomatic, although CMV disease may occur in certain risk groups.

Perinatal infection

Perinatal acquisition of CMV usually occurs secondary to exposure to infected secretions in the birth canal or via breastfeeding. Most infections are asymptomatic. Indeed, in some reviews, CMV acquired through breast milk has been referred to as a form of natural immunization.

Some infants who acquire CMV infection perinatally may have signs and symptoms of disease, including lymphadenopathy, hepatitis, and pneumonitis, which may be severe. Disease secondary to acquisition by breast milk is generally limited to premature infants with low birth weight. These infants may have considerable morbidity. Whether interventions such as freezing or pasteurization are warranted to decrease the risk of transmission to these high-risk infants is unclear. More studies are needed on the long-term neurodevelopmental outcomes of premature infants who acquire CMV infection perinatally from breast milk.

CMV mononucleosis

Typical CMV mononucleosis is a disease found in young adults. Although CMV mononucleosis may be acquired by blood transfusion or organ transplantation, CMV mononucleosis is usually acquired via person-to-person transmission.[43]

The hallmark symptoms of CMV mononucleosis are fever and severe malaise. An atypical lymphocytosis and mild elevation of liver enzymes are present.

Clinically differentiating CMV mononucleosis from Epstein-Barr virus (EBV)-induced mononucleosis may be difficult. CMV mononucleosis is typically associated with less pharyngitis and less splenomegaly. As with EBV mononucleosis, the use of beta-lactam antibiotics in association with CMV mononucleosis may precipitate a generalized morbilliform rash.

Transfusion-acquired CMV infection

Posttransfusion CMV infection has a presentation similar to that of CMV mononucleosis. Incubation periods range from 20-60 days.

The use of seronegative blood donors, frozen deglycerolized blood, or leukocyte-depleted blood can decrease the likelihood of transmission and is recommended for high-risk patients (eg, neonates, immunocompromised patients).

CMV infections in immunocompromised patients

CMV causes various clinical syndromes in immunocompromised patients. Disease manifestations vary in severity depending on the degree of host immunosuppression. Infection may occur because of reactivation of latent viral infection or may be newly acquired via organ or bone marrow transplantation from a seropositive donor. Infections may also be mixed in nature, with donor and recipient isolates both present. Viral dissemination leads to multiple organ system involvement, with the most important clinical manifestations consisting of pneumonitis, GI disease, and retinitis.

CMV pneumonitis

CMV is a major cause of pneumonitis in immunosuppressed children and adults. This disease may be observed in the setting of HIV infection, congenital immunodeficiency, malignancy, and solid organ or bone marrow transplantation.

The mortality rate is based on the degree of immunosuppression, with mortality rates of at least 90% reported in bone marrow transplant recipients. Solid organ transplant recipients are also at risk of developing CMV pneumonitis, although mortality rates are lower.

The illness usually begins 1-3 months following transplantation and starts with symptoms of fever and dry, nonproductive cough. The illness progresses quickly with retractions, dyspnea, and hypoxia becoming prominent.

The illness is an interstitial pneumonitis, with a radiographic appearance of diffuse bilateral interstitial infiltrates. Because the differential diagnosis of pneumonitis is extensive in immunocompromised patients, consider performing a bronchoalveolar lavage or open lung biopsy to confirm the diagnosis and direct appropriate therapy.

CMV GI disease

GI tract disease caused by CMV can include esophagitis, gastritis, gastroenteritis, pyloric obstruction, hepatitis, pancreatitis, colitis, and cholecystitis. Characteristic signs and symptoms may include nausea, vomiting, dysphagia, epigastric pain, icterus, and watery diarrhea.

Stool may be Hemoccult positive or frankly bloody. Endoscopy and biopsy are warranted, and characteristic cytomegalic inclusion cells may be observed in GI endothelium or epithelium.

Although CMV enteritis does not carry the same ominous prognosis as CMV pneumonitis, antiviral therapy is warranted.

Differentiating CMV hepatitis from chronic rejection in liver transplantation patients may be difficult, even with biopsy.

Evidence of active CMV infection, including viral inclusion–bearing cells, is often observed in patients with exacerbations of inflammatory bowel disease (ulcerative colitis and Crohn disease), although whether this represents a source of active bowel pathology in this setting remains unclear.

CMV retinitis

Before the advent of highly active antiretroviral therapy (HAART) for HIV infection, CMV retinitis was the most common cause of blindness in adult patients with acquired immunodeficiency syndrome (AIDS), with an overall lifetime prevalence of more than 90%.

HIV-associated CMV retinitis in children, in contrast to adults, has been relatively rare, probably reflecting overall differences in CMV seroprevalence between the populations. Retinitis is less common in transplantation patients.

CMV produces a necrotic rapidly progressing retinitis with characteristic white perivascular infiltrate with hemorrhage (brushfire retinitis).

Peripheral lesions may be asymptomatic, and even advanced disease does not cause pain. In children, strabismus or failure to fix and follow objects may be important clues to the diagnosis.

The disease can progress to total blindness and retinal detachment if left untreated. CMV chorioretinitis is also observed in symptomatic infants with congenital infection, although the disease does not usually progress to vision loss. The presence of chorioretinitis in an infant with congenital infection indicates a poor neurodevelopmental prognosis.

Other CMV syndromes

Various syndromes have been attributed to 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, which results in massive enlargement of the gastric folds. Most cases appear to be CMV associated, although the pathogenesis is unknown.

In children with congenital HIV infection, co-infection with CMV appears to accelerate the HIV disease progression and HIV-associated neurological disease. Accumulating evidence suggests that CMV infection may be a cofactor in the pathogenesis of atherosclerosis. In addition, the phenomena of posttransplant vascular sclerosis and postangioplasty restenosis appear to be CMV-induced lesions.

The long-term health consequences of CMV infection may include atherosclerosis, immunosenescence, and an increased risk of malignancy.[2] These associations require further study but provide a potential justification for universal vaccination of both sexes against CMV.

The laboratory studies discussed below may be indicated in patients with cytomegalovirus (CMV) infection.

Viral culture is the most important diagnostic study in the evaluation of suspected CMV disease. CMV may be cultured from virtually any body fluid or organ system. Blood, urine, saliva, cervicovaginal secretions, cerebrospinal fluid (CSF), 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 is monitored for development of the characteristic CMV-associated cytopathic effect.

Shell vial assay is a centrifugation enhancement monoclonal-antibody culture technique that is an adaptation of tissue culture. It provides results more rapidly, which can be advantageous because although culture is highly sensitive, clinical isolates of CMV may grow slowly, requiring as long as 6 weeks of incubation in the virology laboratory. In shell vial assay, the clinical specimen is centrifuged onto a cell monolayer (in effect, concentrating the specimen). Then, following incubation in tissue culture, cells are stained with a monoclonal antibody to a CMV-specific antigen, usually an immediate early gene product. A positive shell vial culture is presumptive evidence of active CMV infection, and the test is a useful adjunct to traditional viral culture.[45]

Polymerase chain reaction (PCR)[46] and CMV antigenemia studies have emerged in recent years as the studies of choice in monitoring the status of CMV replication and establishing the diagnosis of CMV disease in immunocompromised patients. Of these, PCR is most commonly used owing to its convenience and its ability to be processed in automated fashion. The magnitude of the viral load in blood as determined by quantitative PCR in immunocompromised patients is a valuable parameter in making the decision to initiate preemptive therapy, toward the goal of preventing serious CMV end-organ disease.[47, 48] PCR can also be used to make the diagnosis of congenital CMV infection, using blood, urine and saliva as appropriate fluids for study, and quantitative PCR in infected newborns may prove to be useful in monitoring response to antiviral therapy.

Exercise caution when obtaining and interpreting CMV diagnostic studies in young infants. By definition, the diagnosis of congenital CMV infection requires identification of the virus in a culture specimen acquired before age 3 weeks because perinatally acquired infections may also begin to manifest at this time. Hence, a positive viral culture obtained in infants older than 3 weeks may simply represent perinatal or breast milk acquisition and may not be interpreted as evidence of congenital CMV infection.

Although theoretically helpful, CMV immunoglobulin M (IgM) assays are unfortunately too nonspecific to reliably diagnose congenital CMV infection. False-positive results are common; therefore, making the diagnosis of congenital infection outside of the immediate perinatal period is very difficult.

Universal screening for congenital CMV infection may be a reasonable future goal and could enable establishment of appropriate anticipatory neurodevelopmental and serial audiological screening programs. A study demonstrated that, unfortunately, the use of the newborn blood spot to screen for congenital CMV infection is unreliable, because of suboptimal sensitivity.[49] Therefore, alternative approaches to universal CMV screening need to be developed.

Outside of the neonatal period, the major caution regarding CMV diagnosis is to use diagnostic studies appropriately to differentiate between CMV infection (the presence of CMV in blood or body fluids without proof of end-organ damage) and CMV disease.

Infants and children infected with CMV may shed the virus for years, making a positive urine viral culture difficult to interpret.

Immunocompromised patients often have reactivation of latent CMV with subsequent viral shedding, even in the absence of overt CMV disease. Thus, the identification of CMV by culture in urine or saliva may reflect such chronic shedding of virus and is difficult to interpret in the evaluation of patients with end-organ disease, such as pneumonitis or hepatitis.

Lung biopsy or bronchoalveolar lavage may be necessary to confirm the diagnosis of CMV pneumonitis.

Hepatitis may require liver biopsy for confirmation of the diagnosis, and CMV hepatitis and chronic rejection may be a difficult differential diagnosis in liver transplant recipients, even with a biopsy.

Congenital cytomegalovirus (CMV) infection

The most important study in the diagnostic evaluation of the congenitally infected infant with CMV is head CT scanning (see the image below).

A CT scan of the head is required for infants with microcephaly or when congenital CMV infection is suspected because abnormalities in this study, particularly the presence of calcifications, have a strong positive predictive value and can aid in identifying children who need ongoing neurodevelopmental evaluation and therapy.

Evidence suggests that head ultrasonography may be of equal value to CT scanning in evaluation of potential intracranial pathology in the setting of congenital CMV infection.

Infants with congenital CMV infection may also require abdominal imaging studies (eg, ultrasonography, CT scanning) for documentation and monitoring of organomegaly.

Other CMV syndromes

Depending on the patient population, radiographic studies are seldom of value in evaluation of CMV disease.

Exceptions include the rare patient with severe mononucleosis caused by primary CMV infection who may require abdominal ultrasonography for monitoring of splenomegaly or the immunocompromised patient who requires chest radiography studies for the possibility of CMV pneumonitis.

Other tests are indicated, based on the organ systems involved and manifestations of disease syndromes.

Procedures depend on the age of the patient and manifestations of disease syndromes. For infants, procedures may include lumbar puncture or liver biopsy.

For immunocompromised transplant recipients, bronchoalveolar lavage, tissue or organ biopsy, and lumbar puncture may all be required to evaluate for extent of cytomegalovirus (CMV)-associated disease. For some patients with AIDS who have retinitis, placement of ganciclovir-impregnated intravitreal implants may be an important ancillary procedure.

The classic tissue histological finding in cytomegalic disease is the inclusion cell; however, viral culture, serology, antigenemia, and nucleic acid detection systems (eg, PCR) generally have much better sensitivity for the diagnosis of cytomegalovirus (CMV)–associated diseases. Histopathology, therefore, typically is not needed to establish the diagnosis of CMV infection in most settings.

Medical care of cytomegalovirus (CMV) consists of good nutritional support, vigorous supportive care for end-organ syndromes (particularly pneumonia in immunocompromised patients), and specific antiviral therapy in select circumstances.

Some children with congenital cytomegalovirus (CMV) infection require orthopedic interventions (eg, for cerebral palsy) and gastrostomy placement for enteral nutrition.

Depending on the patient and associated risk factors, cytomegalovirus (CMV) disease is encountered by obstetricians, pediatricians, infectious disease specialists, oncologists, critical care physicians, and other healthcare providers. Appropriate consultations with surgeons, developmental specialists, pathologists, otolaryngologists, ophthalmologists, neurologists, and gastroenterologists may be necessary.

Ultimately, control of cytomegalovirus (CMV) infection, particularly the devastating sequelae of congenital cytomegalic inclusion disease (CID), depends on immunization.

The major target population for a CMV vaccine is women of childbearing age. Although immunization is unlikely to prevent all congenital infection, the hope is that immunization can have a significant and major impact on the prevalence of CID.

A vaccine may also be useful in controlling CMV disease in organ transplant recipients. A live-attenuated vaccine, the Towne vaccine, showed promise for prevention of CMV disease in studies involving renal transplant recipients reported in the 1980s. However, the Towne strain of CMV is poorly immunogenic, probably because it has been overly attenuated during the process of tissue culture passage.

Newer technologies using recombinant chimeric viruses that represent genetic hybrids between Towne virus and a low-passage clinical isolate, the Toledo strain, are currently under investigation as the next generation of live-virus CMV vaccines.

Subunit vaccine approaches are also being explored. These use molecularly cloned, eucaryotically expressed forms of the major immunogenic CMV envelope protein, gB, and are being actively investigated in clinical trials.

A phase II, placebo-controlled, randomized, double-blind trial by Pass et al evaluated a recombinant CMV vaccine (envelope glycoprotein B with MF59 adjuvant). Three doses of the CMV vaccine or placebo were administered at 0, 1, and 6 months to 464 CMV-seronegative women within 1 year after they had given birth. After a minimum of 1 year of follow-up, 49 confirmed infections were noted, 18 in the vaccine group and 31 in the placebo group. One congenital infection among infants of the study subjects occurred in the vaccine group, and 3 infections occurred in the placebo group. Ongoing research continues to evaluate the potential for a CMV vaccine to decrease maternal and congenital CMV infection.[50]  Another study of this vaccine in solid organ transplant patients at risk for CMV infection and disease also indicated efficacy in seronegative transplant recipients.[51]

A prospective, multicenter birth-cohort study was conducted to estimate the risk of postnatal CMV transmission from transfusion of CMV-seronegative and leukoreduced blood and also maternal breast milk. The study concluded that transfusion of CMV-seronegative and leukoreduced blood products effectively prevents transmission of CMV to very low-birth-weight (VLBW) infants. The study further concluded that among infants whose care is managed with the transfusion of CMV-seronegative and leukoreduced blood, maternal breast milk is the primary source of postnatal CMV infection.[52]

A vectored vaccine approach in a genetically engineered poxvirus vector, canarypox, is also under evaluation. In addition to gB, this approach targets the major cytotoxic T-cell (CTL) target, the UL83 gene product.

DNA vaccines have also shown promise for prevention of CMV infection, and they have demonstrated some degree of efficacy in the transplantation setting.[53]

CMV has been demonstrated to enter epithelial and endothelial cells by different pathways than those used for entry into fibroblasts, and a complex of CMV proteins (ie, gH/gL/UL128/130/131 complex) is essential for this process. This discovery has provided a new potential target for vaccines.[33]

Until the goal of a CMV vaccine is realized, educating women of childbearing age about the risks of CMV and about how to avoid disease transmission are the only control strategies available. A survey of 726 women aged 18-44 years in Minnesota found that only 20% of the women were aware of congenital CMV infection.[54]

Seronegative women who regularly come in close contact with large numbers of young children, particularly in daycare environments, may be at particularly high risk.

Acquisition of primary cytomegalovirus (CMV) infection during pregnancy is a major concern. Women at high risk include those with extensive daycare contact, particularly individuals who work in large daycare facilities in which repeated exposures are common.[55]

Behaviors known to be associated with transmission of infection, particularly kissing and sharing eating utensils, can be avoided, and careful handwashing after diaper changes should be stressed.

Experience with antiviral agents for cytomegalovirus (CMV) prophylaxis and CMV therapy is limited in children. Administer anti-CMV therapy only after consultation with an expert familiar with dosages and adverse effects. Antiviral agents may be administered therapeutically for established CMV disease or prophylactically (ie, preemptive therapy) when the risk of development of CMV disease is high (eg, in transplant recipients).

Class Summary

Nucleosides are the only true antiviral agents active against cytomegalovirus (CMV), although immunoglobulins may provide some antiviral effect, particularly in combination with these agents. These agents share a common molecular target, namely, the viral DNA polymerase. Biochemically, ganciclovir is an acyclic nucleoside analog, whereas cidofovir is an acyclic nucleoside phosphonate. Each compound must be phosphorylated to a triphosphate form before it can inhibit the CMV polymerase. A viral gene product, the UL97 phosphotransferase, mediates the monophosphorylation step for ganciclovir. In contrast to these 2 agents, foscarnet is not a true nucleoside analog but can also directly inhibit the viral polymerase.

Ganciclovir is commonly used as preemptive therapy in transplant recipients at high risk of developing disease (eg, a CMV-seronegative recipient of an organ transplant from a CMV-seropositive donor). Oral and intravenous acyclovir have also been used successfully as prophylaxis for solid organ transplantation (seronegative recipient); however, never use acyclovir for CMV therapy in active disease. An oral formulation is approved for use in adult patients infected with HIV who have CMV retinitis; however, the bioavailability is poor, and no data support use in children.

Relatively little information is available concerning the use of ganciclovir in the setting of congenital CMV infection. However, one national collaborative prospective study did demonstrate a benefit of intravenous ganciclovir in infants with symptomatic congenital CMV infection. Antiviral treatment in this study led to improvement or stabilization of hearing.[9] Follow-up studies suggested further neurodevelopmental benefits in treated infants. In light of these data, ganciclovir therapy should probably be offered for all infants with symptomatic congenital CMV infection, toward the goal of improving the neurodevelopmental prognosis of these infants. Ganciclovir therapy should also be used in infants with congenital or perinatally acquired infection with severe end-organ disease, such as pneumonia, hepatitis, or viremia. It is unclear at this time if ganciclovir benefits the long-term prognosis of an infant with asymptomatic congenital CMV infection.

Alternatives to ganciclovir include trisodium phosphonoformate (PFA) and cidofovir. Pediatric experience with these agents is limited. Although potentially useful in the setting of ganciclovir resistance, the toxicities of these antivirals are significant. Use these agents only in pediatric patients in exceptional circumstances. Although they have only a modest level of activity against CMV, high-dose oral acyclovir and valacyclovir have been used for prophylaxis of CMV disease in high-risk individuals but are not suitable for therapy of active disease. Oral therapy with valganciclovir is considered investigational in children.

Ganciclovir (Cytovene)

Ganciclovir is the first compound licensed for the treatment of CMV infections. It is a synthetic acyclic nucleotide structurally similar to guanine. Its structure is similar to that of acyclovir; like acyclovir, it requires phosphorylation for antiviral activity. The enzyme responsible for phosphorylation is the product of the viral UL97 gene, a protein kinase. Resistance may occur with long-term use, generally because of mutations in UL97.

It is indicated in immunocompromised children (eg, HIV infection, posttransplantation, other immunocompromised states) when clinical and virological evidence of specific end-organ disease (eg, pneumonitis, enteritis) is present.

In infants, antiviral therapy with ganciclovir may be of benefit in reducing the prevalence of neurodevelopmental sequelae, in particular sensorineural hearing loss. A study sponsored by the National Institutes of Allergy and Infectious Diseases demonstrated improved hearing-related outcomes in infants with symptomatic congenital CMV treated with ganciclovir. Therefore, therapy in newborns with documented infection should be considered; however, consult an expert.

Cidofovir (Vistide)

Cidofovir is a nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viral infections.

Foscarnet (Foscavir)

Foscarnet is an organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at the pyrophosphate-binding site on virus-specific DNA polymerases.

Class Summary

These agents are used as passive immunization for the prevention of symptomatic cytomegalovirus (CMV) disease. This strategy has been useful in the control of CMV disease in immunocompromised patients in the prenucleoside antiviral era. It is controversial whether the infusion of CMV immune globulin in women with evidence of a primary CMV infection during pregnancy can prevent transmission and/or improve neurological outcomes in newborn infants, although this intervention is currently being investigated in several clinical trials.

Immune globulin intravenous (Carimune, Gamimune, Gammagard S/D, Gammar-P, Polygam S/D)

The observation that random donor intravenous immune globulin appears to be equal in efficacy to CMV hyperimmunoglobulin suggests that the benefit may be derived from an immunomodulatory effect unrelated to virus neutralization.

Cytomegalovirus immunoglobulin (CytoGam)

A CMV hyperimmunoglobulin has been shown to decrease the prevalence of CMV disease when administered posttransplantation to high-risk transplant recipients when administered alone or in combination with nucleoside antivirals. It may be administered therapeutically in combination with ganciclovir for CMV disease.