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Pediatric Cytomegalovirus Infectio

Background

Of all the human herpesviruses described to date, cytomegalovirus (CMV) arguably causes themost morbidity and mortality. Although primary infection with this agent generally does not

produce symptoms in healthy adults, several high-risk groups, including immunocompromised

organ transplant recipients and individuals infected with human immunodeficiency virus (HIV),are at risk of developing life-threatening and sight-threatening cytomegalovirus disease. In

addition, cytomegalovirus has emerged in recent years as the most important cause of congenital

infection in the developed world, commonly leading to mental retardation and developmental

disability.

In 1904, Ribbert first identified histopathological evidence of cytomegalovirus, probably intissues from a congenitally infected infant. Ribbert mistakenly assumed that the large inclusion-

bearing cells he observed at autopsy were from protozoa (incorrectly namedEntamoebamortinatalium). In 1920, Goodpasture correctly postulated the viral etiology of these

inclusions.[1]

Goodpasture used the term cytomegalia to refer to the enlarged, swollen nature ofthe infected cells. Human cytomegalovirus (HCMV) 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;[2]

during the 1970s and 1980s, knowledgeof the role of cytomegalovirus as an important pathogen with diverse clinical manifestations

increased steadily.[3] Although enormous progress has recently been made in defining and

characterizing the molecular biology, immunology, and antiviral therapeutic targets for

cytomegalovirus, considerable work remains in devising strategies for prevention ofcytomegalovirus 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 below).[4]

Pathophysiology

Cytomegalovirus is a member of a family of 8 human herpesviruses, designated as human

herpesvirus 5 (HHV-5). Taxonomically, cytomegalovirus 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. Cytomegalovirus is the largest member of theherpesvirus 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 anicosahedral 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. Cytomegalovirus replicates very slowly in cell


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culture, mirroring its very slow pattern of growth in vivo (in contrast toherpes simplex virus

[HSV] infection, which progresses very rapidly). The replication cycle of cytomegalovirus istemporally 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 majorimmediate early promoter of this region of the cytomegalovirus genome is one of the most

powerful eucaryotic promoters described in nature; this has been exploited in modernbiotechnology as a useful promoter for driving gene expression in gene therapy and vaccination

studies.

Following synthesis of immediate early genes, the early gene products are transcribed. Early

gene products include DNA replication proteins and some structural proteins.

Finally, 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 ofviral 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 ofhost cellmediated 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 UL97gene 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 cytomegalovirus therapy.

[5]

In clinical specimens, one of the classic hallmarks of cytomegalovirus infection is thecytomegalic inclusion cell. These strikingly enlarged cells (the property of "cytomegaly," from

which cytomegalovirus acquires its name) contain intranuclear inclusions that have the

histopathological appearance of owl's eyes. The presence of these cells indicates productiveinfection, although they may be absent even in actively infected tissues. In most cell lines,

cytomegalovirus is difficult to culture in the laboratory; however, in vivo infection seems to

chiefly involve epithelial cells. In severe disseminated cytomegalovirus disease, involvement canbe observed in most organ systems.

Little is known about the molecular mechanisms responsible for the pathogenesis of tissue

damage caused by cytomegalovirus, particularly for congenital cytomegalovirus infection.Although the CNS is the major target organ for tissue damage in the developing fetus, culturing

cytomegalovirus from the cerebrospinal fluid of symptomatic infants with congenital infection is

surprisingly difficult. Because cytomegalovirus can infect endothelial cells, some authors havepostulated that a viral angitis may be responsible for perfusion failure in the developing brain

with resultant maldevelopment. Others have postulated a direct teratogenic effect of

cytomegalovirus on the developing fetus. Observation of cytomegalovirusinduced alternations
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in the cell cycle and cytomegalovirusinduced damage to chromosomes supports this

speculation; however, this hypothesis has been difficult to experimentally verify.

Immunity to cytomegalovirus is complex and involves humoral and cell-mediated responses.

Several cytomegalovirus gene products are of particular importance in cytomegalovirus

immunity. The outer envelope of the virus, which is derived from the host cell nuclearmembrane, 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 cytomegalovirus subunit vaccines; however, although humoral responses are

important in control of severe disease, they are clearly inadequate in preventing transplacentalinfection, which can occur even in women who are cytomegalovirus seropositive.

The generation of cytotoxic T-cell (CTL) responses against cytomegalovirus may be a more

important host immune response in control of infection. In general, these CTLs involve majorhistocompatibility complex (MHC) class I restricted CD8+ responses. Although many viral gene

products are important in generating these responses, most cytomegalovirus

specific CTLstarget an abundant phosphoprotein in the viral tegument, pp65, the product of thecytomegalovirus 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 cytomegalovirusspecific CD8+ T cells that target the cytomegalovirus UL83 gene,which was able to control cytomegalovirus disease.

Recent investigations into the molecular biology of cytomegalovirus have revealed the presenceof many viral gene products, which appear to modulate host inflammatory and immune

responses. Several cytomegalovirus genes interfere with normal antigen processing and

generation of cell-mediated immune responses. To date, 3 viral gene products have been

identified that inhibit MHC class I antigen presentation. One is the US11 gene product, whichexports 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 inhibitspeptide translocation by transporters associated with antigen processing (TAP).

Other viral gene products, the UL33, US27, and US28 genes, are functional homologs of cellularG-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 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 cytomegalovirus toevade host defense. The UL144 open reading frame found in clinical isolates of cytomegalovirus

encodes a structural homolog of the tumor necrosis factor receptor superfamily, which may

contribute to the ability of HCMV 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 thedevelopment of protective immunity to cytomegalovirus infection should enable the design of

improved vaccines.


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Epidemiology

Frequency

United States

Every mammal appears to be infected with its own species-specific cytomegalovirus, and noevidence suggests that infections cross species. Hence, humans are the only natural host for

HCMV infection. Although most adults eventually become infected with cytomegalovirus, the

epidemiology of this infection is complex, and the age at which an individual acquirescytomegalovirus greatly depends on geographic location, socioeconomic status, cultural factors,

and child-rearing practices.

In developing countries, most children acquire cytomegalovirus infection early in life, with adultseroprevalence approaching 100% by early adulthood. In contrast, in developed countries, the

seroprevalence of cytomegalovirus approximates 50% in young adults of middle-upper

socioeconomic status. This observation has important implications for congenitalcytomegalovirus epidemiology because women of childbearing age who are cytomegalovirus

seronegative are at major risk of giving birth to infants with symptomatic congenital infection if

primary infection is acquired during pregnancy.

Transmission of cytomegalovirus infection may occur throughout life, chiefly via contact with

infected secretions.[6]

Acquisition of cytomegalovirus in the newborn period is common.Approximately 1% (range, 0.5-2.5%) of all newborns are congenitally infected with

cytomegalovirus. Most of these infections occur in infants born to mothers with preexisting

immunity and 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. Cytomegalovirus may also be

transmitted perinatally, both by aspiration of cervicovaginal secretions in the birth canal and bybreastfeeding. More than 50% of infants fed with breast milk that contains infectious virus

become infected with cytomegalovirus.[7]

In particular, a recent study reported 5 cases of severe

morbidity and mortality in very low birth weight infants with cytomegalovirus infection acquiredpostnatally through breast milk.[8] Infants who are not infected congenitally or perinatally with

cytomegalovirus are at high risk to acquire infection in daycare centers. According to some

studies, the prevalence of cytomegalovirus infection in children who attend daycare, particularlychildren 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. Such horizontal transmission ofinfection in daycare centers appears to play a major role in the epidemiology of many

cytomegalovirus infections in young parents.

In adulthood, sexual activity is probably the most important route of acquisition of

cytomegalovirus,[9]

although the observation that virus is present in saliva, cervicovaginalsecretions, 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


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cytomegalovirus, and this route of transmission may be responsible for those cases of

heterophile-negative mononucleosis, which are attributable to cytomegalovirus. Kissing appearsto be a way in which cytomegalovirus is transmitted from toddlers to seronegative parents.

Recent work by theCenters 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.

[10]

Other important routes of transmission include blood transfusion and solid organ transplantation.Before screening of blood products, transfusion-associated cytomegalovirus was an important

cause of morbidity and mortality in premature infants; however, the routine use in many neonatal

intensive care units of cytomegalovirusnegative blood products has largely eliminated thisproblem. Posttransfusion cytomegalovirus is still a risk in cytomegalovirusseronegative trauma

and in surgery patients, often manifesting as hepatitis.

International

The risk of congenital cytomegalovirus infection is not well defined in the developing world.Because seroepidemiologic studies indicate that, in many developing countries, seroprevalencefor cytomegalovirus approaches 100% very early in childhood, little attention has been given to

the question of potential morbidities in these populations.

Mortality/Morbidity

Cytomegalovirus is a substantial cause of morbidity in newborns. As the most common so-calledtoxoplasmosis,rubella, cytomegalovirus, and herpes simplex (TORCH) infection in the

developed world, cytomegalovirus accounts for extensive neurodevelopmental morbidity,

including sensorineural deafness in infants. Cytomegalovirus also accounts for substantial

mortality in immunocompromised patients.

Race

The effects of race and genetics on clinical manifestations of cytomegalovirus infection are notwell understood. In some studies in the United States, prevalence of congenital cytomegalovirus

appears to be higher in infants born to black women.[11]

More work is required to understand the

basis for the differences in the epidemiology of cytomegalovirus infection in various ethnicgroups in the United States.

Sex

Both sexes are equally susceptible to infection and morbidity from cytomegalovirus, although

only women are at risk for transplacental transmission of infection.

Age

The annual seroconversion rate for acquisition of cytomegalovirus infection is approximately

1%. However, two age groups have higher rates of acquisition of infection: toddlers who attend
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group daycare and adolescents. Accordingly, these represent two potential groups in which to

implement vaccination.

Pediatric Cytomegalovirus Infection Clinical Presentation

History

The history must be tailored to the specific clinical circumstances and disease category. Specificdisease categories are considered as follows:

Congenital cytomegalovirus (CMV) infection: Current estimates suggest that 30,000-40,000infants are born with congenital cytomegalovirus infection annually in the United States, making

cytomegalovirus by far the most common and important of all congenital infections. The

likelihood of congenital infection and the extent of disease in the newborn depend on maternal

immune status. If primary maternal infection occurs during pregnancy, the average rate of

transmission to the fetus is 40%; approximately 65% of these infants have cytomegalovirus

disease at birth. With recurrent maternal infection (ie, cytomegalovirus infection that occurs inthe context of preconceptual immunity), the risk of transmission to the fetus is lower, ranging

from 0.5-1.5%; most of these infants appear normal at birth (ie, silent infection). Hence,

congenital infection may be classified as symptomatic or asymptomatic in nature (see the image

below).

Epidemiology patterns of congenital cytomegalovirus infection. Approximately 10% of cases of

congenital cytomegalovirus occur in women with primary infection during pregnancy, and 90% of these

infants have neurological sequelae. Although preexisting immunity (eg, maternal recurrent infection)


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protects against severe disease, approximately 15% of these infants have sequelae, particularly

sensorineural hearing loss.\

Cytomegalic inclusion disease (CID)o Approximately 10% of infants with congenital infection have clinical evidence of

disease at birth.[12]

The most severe form of congenital CMV infection is referredto as CID.

o CID almost always occurs in women who have primary cytomegalovirus infectionduring pregnancy, although rare cases are described in women with preexistingimmunity who presumably have reactivation of infection during pregnancy.

o CID is characterized by intrauterine growth retardation, 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, andsensorineural hearing loss are the most common neurological consequences of

CID.o Intracerebral calcifications typically demonstrate a periventricular distribution and

are commonly encountered using CT scanning (see the image below). The findingof intracranial calcifications is predictive of cognitive and audiologic deficits in

later life and predicts a poor neurodevelopmental prognosis.

Cranial CT scan of infant born with symptomatic congenital cytomegalovirus

infection. Neurological involvement is evident, manifest as ventriculomegaly andperiventricular calcifications.

o Most infants who survive symptomatic CID have significant long-termneurological and neurodevelopmental sequelae. Indeed, it has been estimated that

congenital cytomegalovirus may be second only toDown syndromeas anidentifiable cause of mental retardation in children.

Asymptomatic congenital cytomegaloviruso Most infants with congenital cytomegalovirus infection are born to women who

have preexisting immunity to cytomegalovirus. These infants appear clinicallyhealthy at birth; however, although infants with congenital cytomegalovirus

infection appear well, they may have subtle growth retardation compared to

uninfected infants. Although asymptomatic at birth, these infants, nevertheless,are at risk for neurodevelopmental sequelae.
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o The major consequence of inapparent congenital cytomegalovirus infection issensorineural hearing loss. Approximately 15% of these infants will haveunilateral or bilateral deafness. Routine newborn audiologic screening may not

detect cases of cytomegalovirusassociated hearing loss because this deficit may

develop months or even years after birth.[13]

Acquired cytomegalovirus infection: In contrast to congenital infection, acquiredcytomegalovirus infection occurs postnatally. Primary infection in this context is generallyasymptomatic, although cytomegalovirus disease may occur in certain risk groups as follows:

Perinatal infectiono Perinatal acquisition of cytomegalovirus usually occurs secondary to exposure to

infected secretions in the birth canal or via breastfeeding. Most infections are

asymptomatic. Indeed, in some reviews, cytomegalovirus acquired through breast

milk has been referred to as a form of natural immunization.

o Some infants who acquire cytomegalovirus infection perinatally may have signsand symptoms of disease, includinglymphadenopathy, hepatitis, and pneumonitis,which may be severe. Disease secondary to acquisition by breast milk is generallylimited to premature infants with low birth weight. These infants may suffer

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 of long-term neurodevelopmental outcomes of prematureinfants who acquire cytomegalovirus infection perinatally from breast milk are

needed.

Cytomegalovirus mononucleosiso Typical cytomegalovirus mononucleosis is a disease found in young adults.

Although cytomegalovirus mononucleosis may be acquired by blood transfusion

or organ transplantation, cytomegalovirus mononucleosis is usually acquired viaperson-to-person transmission.

o The hallmark symptoms of cytomegalovirus mononucleosis are fever and severemalaise. An atypical lymphocytosis and mild elevation of liver enzymes are

present.

o Clinically differentiating cytomegalovirus mononucleosis fromEpstein-Barr virus(EBV)-induced mononucleosismay be difficult. Cytomegalovirus mononucleosis

is typically associated with lesspharyngitisand less splenomegaly. As with EBVmononucleosis, the use of b-lactam antibiotics in association with

cytomegalovirus mononucleosis may precipitate a generalized morbilliform rash.

Transfusion-acquired cytomegalovirus infectiono

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

o 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).

Cytomegalovirus infections in immunocompromised patients: Cytomegalovirus causes various

clinical syndromes in immunocompromised patients. Disease manifestations vary in severity
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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 marrowtransplant 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.

Cytomegalovirus pneumonitiso Cytomegalovirus 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 marrowtransplant.

o The mortality rate is based on the degree of immunosuppression, with mortalityrates of at least 90% reported in bone marrow transplant recipients. Solid organ

transplant recipients are at risk of developing cytomegalovirus pneumonitis also,although mortality rates are lower.

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

o The illness is an interstitial pneumonitis, with a radiographic appearance ofdiffuse bilateral interstitial infiltrates. Because the differential diagnosis of

pneumonitis is extensive in immunocompromised patients, consider performing abronchoalveolar lavage or open lung biopsy to confirm the diagnosis and direct

appropriate therapy.

Cytomegalovirus GI diseaseo GI tract disease caused by cytomegalovirus can includeesophagitis, gastritis,

gastroenteritis, pyloric obstruction, hepatitis,pancreatitis,colitis, and

cholecystitis. Characteristic signs and symptoms may include nausea, vomiting,

dysphagia, epigastric pain, icterus, and watery diarrhea.

o Stool may be Hemoccult positive or frankly bloody. Endoscopy and biopsy arewarranted, and characteristic cytomegalic inclusion cells may be observed in GI

endothelium or epithelium.

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

o Differentiating cytomegalovirus hepatitis from chronic rejection in liver transplantpatients may be difficult, even with biopsy.

Cytomegalovirus retinitiso Before the advent of highly active antiretroviral therapy (HAART) for HIV

infection, cytomegalovirus retinitis was the most common cause of blindness in

adult patients with acquired immunodeficiency syndrome (AIDS), with an overalllifetime prevalence of more than 90%.

o HIV-associated cytomegalovirus retinitis in children, in contrast to adults, hasbeen relatively rare, probably reflecting overall differences in cytomegalovirusseroprevalence between the populations. Retinitis is less common in transplant

patients.
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o Cytomegalovirus produces a necrotic rapidly progressing retinitis withcharacteristic white perivascular infiltrate with hemorrhage (brushfire retinitis).

o Peripheral lesions may be asymptomatic, and even advanced disease does notcause pain. In children, strabismus or failure to fix and follow objects may be

important clues to the diagnosis.

oThe disease can progress to total blindness and retinal detachment if leftuntreated. Cytomegalovirus chorioretinitis is also observed in symptomatic

infants with congenital infection infants, although the disease does not usually

progress to vision loss. The presence of chorioretinitis in an infant with congenitalinfection infant indicates a poor neurodevelopmental prognosis.

Other cytomegalovirus syndromeso Various syndromes have been attributed to cytomegalovirus infection, although

cause and effect relationships are often difficult to establish.

o Menetrier disease is a rare disorder characterized by hyperplasia and hypertrophyof the gastric mucous glands, which results in massive enlargement of the gastric

folds. Most cases appear to be cytomegalovirus associated, although the

pathogenesis is unknown.o In children with congenital HIV infection, co-infection with cytomegalovirus

appears to accelerate the HIV disease progression and HIV-associatedneurological disease. Accumulating evidence suggests that cytomegalovirus

infection may be a cofactor in the pathogenesis of atherosclerosis. In addition, the

phenomena of posttransplant vascular sclerosis and postangioplasty restenosisappear to be cytomegalovirusinduced lesions.

o The long-term health consequences of cytomegalovirus infection may includeatherosclerosis, immunosenescence, and an increased risk of malignancy. These

associations require further study but provide a potential justification for universalvaccination of both sexes against cytomegalovirus.

Physical

Physical examination findings depend on age, route of acquisition, and immune status of thepatient. Findings are reviewed in a syndrome-specific fashion.


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Causes

Risk factors for cytomegalovirusassociated illness chiefly include age and immunodeficiency.These points are covered in case-by-case fashion in other sections of this article.

Differentials

Enteroviral Infections Herpes Simplex Virus Infection Herpesvirus 6 Infection Lymphocytic Choriomeningitis Virus Rubella Toxoplasmosis

Pediatric Cytomegalovirus Infection Workup

Laboratory Studies

The following laboratory studies may be indicated in patients with cytomegalovirus (CMV)

infection:

Viral cultureo The most important diagnostic study in the evaluation of suspected cytomegalovirus

disease is the viral culture.

o Cytomegalovirus 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.

o The specimen is inoculated onto human cells (usually human foreskin fibroblasts), andthe cell culture is monitored for development of the characteristic cytomegalovirus

associated cytopathic effect.

Shell vial assayo Although culture is highly sensitive, clinical isolates of cytomegalovirus may grow slowly,

requiring as long as 6 weeks of incubation in the virology laboratory. An adaptation of

tissue culture that provides results more rapidly is the centrifugation enhancement

monoclonal-antibody culture technique, which is referred to as the shell-vial assay.

o In this technique, 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 cytomegalovirusspecific antigen, usually an

immediate early gene product.o A positive shell vial culture is presumptive evidence of active cytomegalovirus infection,

and the test is a useful adjunct to traditional viral culture.[15]

Exercise caution when obtaining and interpreting cytomegalovirus diagnostic studies. Takespecial care in interpretation of diagnostic studies in infants. By definition, the diagnosis of

congenital cytomegalovirus 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 age 3 weeks may
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simply represent perinatal or breast milk acquisition and may not be interpreted as evidence of

congenital cytomegalovirus infection.

Although theoretically helpful, cytomegalovirus immunoglobulin M (IgM) assays areunfortunately too nonspecific to reliably diagnose congenital cytomegalovirus. 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 cytomegalovirus infection may be a reasonable future goaland could enable establishment of appropriate anticipatory neurodevelopmental and serial

audiological screening programs.

Outside of the neonatal period, the major caution regarding cytomegalovirus diagnosis is to usediagnostic studies appropriately to differentiate between cytomegalovirus infection and

cytomegalovirus disease.

o Infants and children infected with cytomegalovirus may shed the virus for years, makinga positive urine viral culture difficult to interpret.

o Immunocompromised patients often have reactivation of latent cytomegalovirus withsubsequent viral shedding, even in the absence of overt cytomegalovirus disease. Thus,

the identification of cytomegalovirus by culture in urine or saliva may reflect such

chronic shedding of virus and is difficult to interpret in the evaluation of patients withend-organ disease, such as pneumonitis or hepatitis.

o Lung biopsy or bronchoalveolar lavage may be necessary to confirm the diagnosis ofcytomegalovirus pneumonitis.

o Hepatitis may require liver biopsy for confirmation of the diagnosis, andcytomegalovirus hepatitis and chronic rejection may be a difficult differential diagnosis

in liver transplant recipients, even with a biopsy.

Newer molecular diagnostic studies, including polymerase chain reaction (PCR)[16] andcytomegalovirus antigenemia studies, are also useful and predictive in monitoring

cytomegalovirus disease activity in immunocompromised patients. The magnitude of the viral

load in blood as determined by quantitative PCR in infants with congenital infection may predict

neurodevelopmental outcomes and may be useful in monitoring response to antiviral therapy.

Imaging Studies

The following imaging studies are indicated in patients with cytomegalovirus infection:

Congenitalo The most important study in the diagnostic evaluation of the congenitally infected infant

with cytomegalovirus is head CT scanning (see the image below).
http://refimgshow%282%29/


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Cranial CT scan of infant born with symptomatic congenital cytomegalovirus infection.

Neurological involvement is evident, manifest as ventriculomegaly and periventricular

calcifications.

o A CT scan of the head is required for infants with microcephaly or when congenitalcytomegalovirus 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.

o Evidence suggests that head ultrasonography may be of equal value to CT scanning inevaluation of potential intracranial pathology in the setting of congenital

cytomegalovirus.

o Infants with congenital cytomegalovirus infection may also require abdominal imagingstudies (eg, ultrasonography, CT scanning) for documentation and monitoring of

organomegaly.

Other cytomegalovirus syndromeso Depending on the patient population, radiographic studies are seldom of value in

evaluation of cytomegalovirus disease.

o Exceptions include the rare patient with severe mononucleosis caused by primarycytomegalovirus infection who may require abdominal ultrasound for monitoring ofsplenomegaly or the immunocompromised patient who requires chest radiograph

studies for the possibility of cytomegalovirus pneumonitis.

Other Tests

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

Procedures

Procedures depend on the age of the patient and manifestations of disease syndromes.

For infants, procedures may includelumbar punctureor liver biopsy. For immunocompromised transplant recipients, bronchoalveolar lavage, tissue or organ biopsy,

and lumbar puncture may all be required to evaluate for extent of cytomegalovirusassociated

disease.

For some patients with AIDS who have retinitis, placement of ganciclovir-impregnated

intravitreal implants may be an important ancillary procedure.

Histologic Findings

The classic tissue histological finding in cytomegalic disease is the inclusion cell; however, viralculture, serology, antigenemia, and nucleic acid detection systems (eg, PCR) generally have

much better sensitivity for the diagnosis of cytomegalovirusassociated diseases.

Pediatric Cytomegalovirus Infection Treatment & Management
http://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/1978434-overviewhttp://emedicine.medscape.com/article/1978434-overviewhttp://emedicine.medscape.com/article/1978434-overviewhttp://emedicine.medscape.com/article/80773-overview


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Ganciclovir is commonly used as preemptive therapy in transplant recipients at high risk of

developing disease (eg, a cytomegalovirusseronegative recipient of an organ transplant from acytomegalovirusseropositive donor). Oral and intravenous acyclovir has also been used

successfully as prophylaxis for solid organ transplantation (seronegative recipient); however,

never use acyclovir for cytomegalovirus therapy in active disease. An oral formulation is

approved for use in adult patients infected with HIV who have cytomegalovirus retinitis;however, the bioavailability is poor, and no data support use in children.

Relatively little information concerning the use of ganciclovir in the setting of congenital

cytomegalovirus infection is available. Because some of the neurological sequelae of congenital

cytomegalovirus, particularly sensorineural hearing loss, progress postnatally, the presentation ofresults from a terminated nationwide collaborative trial are of interest. Intravenous ganciclovir

led to improvement or stabilization of hearing in a significant number of 6-month-old infants.

Case reports have suggested the efficacy of ganciclovir for acutely ill neonates with life-

threatening cytomegalovirus disease (eg, pneumonia).

Alternatives to ganciclovir include trisodium phosphonoformate (PFA) and cidofovir. Pediatricexperience with these agents is limited. Although potentially useful in the setting of ganciclovirresistance, 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

cytomegalovirus, high-dose oral acyclovir and valacyclovir have been used for prophylaxis ofcytomegalovirus in high-risk individuals but are not suitable for therapy of active disease. Oral

therapy with valganciclovir is considered to be investigational in children.

View full drug information

Ganciclovir (Cytovene)

First compound licensed for treatment of CMV infections. 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 theproduct of the viral UL97gene, a protein kinase. Resistance may occur with long-term use,

generally because of mutations in UL97. Indicated in immunocompromised children (eg, HIV

infection, posttransplant, other immunocompromised states) when clinical and virologicalevidence 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 (Schleiss, 2004). A studysponsored by the National Institutes of Allergy and Infectious Diseases demonstrated improved

hearing-related outcomes in infants with symptomatic congenital CMV treated with ganciclovir

(Kimberlin, 2003). Therefore, therapy in newborns with documented infection should beconsidered; however, consult an expert.

http://reference.medscape.com/drug/cytovene-ganciclovir-342619#1http://reference.medscape.com/drug/cytovene-ganciclovir-342619#1http://reference.medscape.com/drug/cytovene-ganciclovir-342619#1http://reference.medscape.com/drug/cytovene-ganciclovir-342619#1http://reference.medscape.com/drug/vistide-cidofovir-342606#1http://reference.medscape.com/drug/vistide-cidofovir-342606#1http://reference.medscape.com/drug/vistide-cidofovir-342606#1http://reference.medscape.com/drug/cytovene-ganciclovir-342619#1http://reference.medscape.com/drug/cytovene-ganciclovir-342619#1


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Cidofovir (Vistide)

Nucleotide analog that selectively inhibits viral DNA production in CMV and other herpesviruses.


Foscarnet (Foscavir)

Organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses,

including CMV, HSV-1, and HSV-2. Inhibits viral replication at pyrophosphate-binding site on

virus-specific DNA polymerases.

Immunoglobulins

Class Summary

These agents are used as passive immunization for the prevention of symptomatic

cytomegalovirus disease. This strategy has been useful in the control of cytomegalovirus disease

in immunocompromised patients in the prenucleoside antiviral era. Evidence in pregnancy

suggests that the infusion of cytomegalovirus immune globulin in women with evidence of aprimary cytomegalovirus infection can prevent transmission and improve outcomes in newborns.


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

The observation that random donor IVIG appears to be equal in efficacy to CMVhyperimmunoglobulin suggests that the benefit may be derived from an immunomodulatoryeffect unrelated to virus neutralization.


CMV-Ig (CytoGam)

A CMV hyperimmunoglobulin has been shown to decrease prevalence of CMV disease whenadministered posttransplant to high-risk transplant recipients when administered alone or in

combination with nucleoside antivirals. May be administered therapeutically for CMV disease in

combination with ganciclovir.
http://reference.medscape.com/drug/vistide-cidofovir-342606#1http://reference.medscape.com/drug/vistide-cidofovir-342606#1http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614#1http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614#1http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614#1http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614#1http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138#1http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138#1http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138#1http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138#1http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138#1http://reference.medscape.com/drug/cytogam-cytomegalovirus-immune-globulin-cmv-ig-343128#1http://reference.medscape.com/drug/cytogam-cytomegalovirus-immune-globulin-cmv-ig-343128#1http://reference.medscape.com/drug/cytogam-cytomegalovirus-immune-globulin-cmv-ig-343128#1http://reference.medscape.com/drug/cytogam-cytomegalovirus-immune-globulin-cmv-ig-343128#1http://reference.medscape.com/drug/cytogam-cytomegalovirus-immune-globulin-cmv-ig-343128#1http://reference.medscape.com/drug/cytogam-cytomegalovirus-immune-globulin-cmv-ig-343128#1http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138#1http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138#1http://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138#1http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614#1http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614#1http://reference.medscape.com/drug/vistide-cidofovir-342606#1


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Pediatric Cytomegalovirus Infection Follow-up

Deterrence/Prevention

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 cytomegalovirus vaccine is women of childbearing age.Although immunization is unlikely to prevent all congenital infection, immunization will

hopefully have a significant and major impact on the prevalence of CID.

A vaccine can also be useful in controlling cytomegalovirus disease in organ transplantrecipients. A live attenuated vaccine, the Towne vaccine, showed promise for prevention of

cytomegalovirus disease in studies involving renal transplant recipients reported in the 1980s.

However, the Towne strain of cytomegalovirus 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 betweenTowne virus and a low-passage clinical isolate, the Toledo strain, are currently underinvestigation as the next generation of live-virus cytomegalovirus vaccines.

Subunit vaccine approaches are also being explored. These use molecularly clonedeucaryotically expressed forms of the major immunogenic cytomegalovirus 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 arecombinant cytomegalovirus vaccine (envelope glycoprotein B with MF59 adjuvant). Three

doses of the cytomegalovirus vaccine or placebo were administered at 0, 1, and 6 months to 464

cytomegalovirusseronegative 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 toevaluate the potential for a cytomegalovirus vaccine to decrease maternal and congenital

cytomegalovirus infection.[17]

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

the UL83 gene product.

Until the goal of a cytomegalovirus vaccine is realized, educating women of childbearing ageabout the risks of cytomegalovirus and about 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 environments, may be at particularly high risk.

Cytomegalovirus has been demonstrated to enter epithelial and endothelial cells by differentpathways than those used for entry intro fibroblast, and a complex of cytomegalovirus proteins

(ie, gH/gL/UL128/130/131 complex) is essential for this process. This discovery has provided a

new potential target for vaccines.[18]

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


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Deterrence/Prevention

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

The major target population for a cytomegalovirus vaccine is women of childbearing age.Although immunization is unlikely to prevent all congenital infection, immunization will

hopefully have a significant and major impact on the prevalence of CID.

A vaccine can also be useful in controlling cytomegalovirus disease in organ transplantrecipients. A live attenuated vaccine, the Towne vaccine, showed promise for prevention of

cytomegalovirus disease in studies involving renal transplant recipients reported in the 1980s.

However, the Towne strain of cytomegalovirus 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 betweenTowne virus and a low-passage clinical isolate, the Toledo strain, are currently under

investigation as the next generation of live-virus cytomegalovirus vaccines.

Subunit vaccine approaches are also being explored. These use molecularly clonedeucaryotically expressed forms of the major immunogenic cytomegalovirus 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 arecombinant cytomegalovirus vaccine (envelope glycoprotein B with MF59 adjuvant). Three

doses of the cytomegalovirus vaccine or placebo were administered at 0, 1, and 6 months to 464

cytomegalovirusseronegative 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 cytomegalovirus vaccine to decrease maternal and congenital

cytomegalovirus infection.[17]

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

the UL83 gene product.

Until the goal of a cytomegalovirus vaccine is realized, educating women of childbearing ageabout the risks of cytomegalovirus and about 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 environments, may be at particularly high risk.

Cytomegalovirus has been demonstrated to enter epithelial and endothelial cells by differentpathways than those used for entry intro fibroblast, and a complex of cytomegalovirus proteins

(ie, gH/gL/UL128/130/131 complex) is essential for this process. This discovery has provided a

new potential target for vaccines.[18]

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

Patient Education

Increased awareness of the complications of congenital cytomegalovirus infection is needed.


19/23

With a greater educational effort, women of childbearing age can be better prepared toanticipate risk factors for cytomegalovirus transmission during pregnancy.

[19]

A national cytomegalovirus registry provides education and support for families affected bycongenital cytomegalovirus 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 athttp://www.bcm.tmc.edu/pedi/infect/cmv/.

Better education of the risks of cytomegalovirus infection for young women is a must. TheCDCis also an excellent educational resource.

Other foundations provide education and resources for parents interested in learning moreabout congenital cytomegalovirus, including theCMV Foundation.

The Test

1. How is it used?2. When is it ordered?3. What does the test result mean?4. Is there anything else I should know?

How is it used?

Cytomegalovirus (CMV) testing is used to determine whether someone withsignsandsymptoms

has an active infection. Sometimes it may be ordered to help determine whether someone had aprior infection and is therefore immune to a primary infection.

There are a few different methods of detecting a CMV infection:

Antibody testing

Antibody testing can be used to determine if someone has had recent or past exposure. There aretwo types of CMVantibodiesthat are produced in response to a CMV infection,IgMandIgG,

and one or both may be detected in the blood.

IgM antibodies are the first to be produced by the body in response to a CMV infection. They arepresent in most individuals within a week or two after the initial exposure. IgM antibody

production rises for a short time period and then declines. After several months, the level of

CMV IgM antibody usually falls below detectable levels. Additional IgM antibodies are produced

when latent CMV is reactivated.

IgG antibodies are produced by the body several weeks after the initial CMV infection andprovide protection from primary infections. Levels of IgG rise during the active infection, then

stabilize as the CMV infection resolves and the virus becomes inactive. After a person has been

exposed to CMV, he or she will have some measurable amount of CMV IgG antibody in their

blood for the rest of their life. CMV IgG antibody testing can be used, along with IgM testing, to

help confirm the presence of a recent or previous CMV infection.

CMV antibody testing may be used to determine immunity to primary CMV infections in peopleprior to organ or bone marrow transplantation and in a person diagnosed with HIV/AIDS. Since
http://www.bcm.tmc.edu/pedi/infect/cmv/http://www.bcm.tmc.edu/pedi/infect/cmv/http://www.bcm.tmc.edu/pedi/infect/cmv/http://www.cdc.gov/cmv/index.htmlhttp://www.cdc.gov/cmv/index.htmlhttp://www.cdc.gov/cmv/index.htmlhttp://www.cmvfoundation.org/http://www.cmvfoundation.org/http://www.cmvfoundation.org/http://labtestsonline.org/understanding/analytes/cmv/tab/test#howhttp://labtestsonline.org/understanding/analytes/cmv/tab/test#howhttp://labtestsonline.org/understanding/analytes/cmv/tab/test#whenhttp://labtestsonline.org/understanding/analytes/cmv/tab/test#whenhttp://labtestsonline.org/understanding/analytes/cmv/tab/test#whathttp://labtestsonline.org/understanding/analytes/cmv/tab/test#whathttp://labtestsonline.org/understanding/analytes/cmv/tab/test#ishttp://labtestsonline.org/understanding/analytes/cmv/tab/test#ishttp://labtestsonline.org/glossary/sign/http://labtestsonline.org/glossary/sign/http://labtestsonline.org/glossary/sign/http://labtestsonline.org/glossary/symptom/http://labtestsonline.org/glossary/symptom/http://labtestsonline.org/glossary/symptom/http://labtestsonline.org/glossary/antibodyhttp://labtestsonline.org/glossary/antibodyhttp://labtestsonline.org/glossary/antibodyhttp://labtestsonline.org/glossary/igm/http://labtestsonline.org/glossary/igm/http://labtestsonline.org/glossary/igm/http://labtestsonline.org/glossary/igg/http://labtestsonline.org/glossary/igg/http://labtestsonline.org/glossary/igg/http://labtestsonline.org/understanding/conditions/hivhttp://labtestsonline.org/understanding/conditions/hivhttp://labtestsonline.org/understanding/conditions/hivhttp://labtestsonline.org/understanding/conditions/hivhttp://labtestsonline.org/glossary/igg/http://labtestsonline.org/glossary/igm/http://labtestsonline.org/glossary/antibodyhttp://labtestsonline.org/glossary/symptom/http://labtestsonline.org/glossary/sign/http://labtestsonline.org/understanding/analytes/cmv/tab/test#ishttp://labtestsonline.org/understanding/analytes/cmv/tab/test#whathttp://labtestsonline.org/understanding/analytes/cmv/tab/test#whenhttp://labtestsonline.org/understanding/analytes/cmv/tab/test#howhttp://www.cmvfoundation.org/http://www.cdc.gov/cmv/index.htmlhttp://www.bcm.tmc.edu/pedi/infect/cmv/


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CMV infection is widespread and causes few problems to those with healthy immune systems,

general population screening is rarely done.

Antibody testing and viral CMV detection may be used to help diagnose primary CMV infection

in young adults, pregnant women, and someimmune-compromisedpeople with flu- or

mononucleosis-like symptoms. By comparing the absence or presence of IgG and IgMantibodies in the same sample or the amount of antibody present in samples collected on

different days, the doctor may be able to distinguish between active andlatentCMV.

Testing for IgM antibodies may be used to detect acongenitalinfection in a newborn. Tests that

detect the virus directly must be performed to confirm the diagnosis.

Viral detection

Viral detection involves determining the presence of CMV in a blood, fluid, or tissue sample.This can be done either byculturingthe virus or by detecting the virus's genetic material (CMV

DNA).

Viral culture is the traditional method of virus detection. Presence of the virus (positive cultures)

can often be determined in as little as 1 to 2 days, but cultures that are negative for the virus must

be held for 3 weeks to confirm the absence of CMV because the virus may be present in verylow numbers in the original sample and/or the CMV strain may be slow-growing.

Molecular methods may be used to detect and measure the amount of viral DNA in a person'ssample. Testing can bequalitative, determining the presence or absence of CMV, orquantitative,

measuring the amount of virus present.

The choice of tests and samples collected depends on the age of the person, their general health

status and symptoms, and on the doctor's clinical findings and suspicions of organ involvement.For instance, a newborn's urine may be cultured to detect CMV, while a pregnant woman mayhave IgG and IgM blood testing to identify the presence of antibodies and to distinguish between

a current primary infection and a previous infection.

Immune-compromised people with active CMV may be monitored using a variety of CMV tests.

Often doctors want a quantifiable viral test to be able to track the amount of virus present (viral

load). They can use a quantitative test to monitor a person's response to antiviral therapy.

^ Back to top

When is it ordered?

CMV tests may be ordered, along with tests forinfluenza,mononucleosis (mono), andEBV

(Epstein Barr virus), when a young adult, a pregnant woman, or animmune-compromisedperson

has flu- or mono-likesignsandsymptomssuch as:

Fatigue, weakness Sore throat
http://labtestsonline.org/glossary/immunocompromisedhttp://labtestsonline.org/glossary/immunocompromisedhttp://labtestsonline.org/glossary/immunocompromisedhttp://labtestsonline.org/glossary/latent/http://labtestsonline.org/glossary/latent/http://labtestsonline.org/glossary/latent/http://labtestsonline.org/glossary/congenital/http://labtestsonline.org/glossary/congenital/http://labtestsonline.org/glossary/congenital/http://labtestsonline.org/glossary/culturehttp://labtestsonline.org/glossary/culturehttp://labtestsonline.org/glossary/culturehttp://labtestsonline.org/glossary/dnahttp://labtestsonline.org/glossary/dnahttp://labtestsonline.org/glossary/qualitative-resultshttp://labtestsonline.org/glossary/qualitative-resultshttp://labtestsonline.org/glossary/qualitative-resultshttp://labtestsonline.org/glossary/quantitative-resultshttp://labtestsonline.org/glossary/quantitative-resultshttp://labtestsonline.org/glossary/quantitative-resultshttp://labtestsonline.org/glossary/viral-loadhttp://labtestsonline.org/glossary/viral-loadhttp://labtestsonline.org/glossary/viral-loadhttp://labtestsonline.org/glossary/viral-loadhttp://labtestsonline.org/understanding/analytes/cmv/tab/test#tophttp://labtestsonline.org/understanding/analytes/cmv/tab/test#tophttp://labtestsonline.org/understanding/analytes/fluhttp://labtestsonline.org/understanding/analytes/fluhttp://labtestsonline.org/understanding/analytes/fluhttp://labtestsonline.org/understanding/analytes/monohttp://labtestsonline.org/understanding/analytes/monohttp://labtestsonline.org/understanding/analytes/monohttp://labtestsonline.org/understanding/analytes/ebvhttp://labtestsonline.org/understanding/analytes/ebvhttp://labtestsonline.org/understanding/analytes/ebvhttp://labtestsonline.org/understanding/analytes/ebvhttp://labtestsonline.org/glossary/immunocompromisedhttp://labtestsonline.org/glossary/immunocompromisedhttp://labtestsonline.org/glossary/immunocompromisedhttp://labtestsonline.org/glossary/sign/http://labtestsonline.org/glossary/sign/http://labtestsonline.org/glossary/sign/http://labtestsonline.org/glossary/symptom/http://labtestsonline.org/glossary/symptom/http://labtestsonline.org/glossary/symptom/http://labtestsonline.org/glossary/symptom/http://labtestsonline.org/glossary/sign/http://labtestsonline.org/glossary/immunocompromisedhttp://labtestsonline.org/understanding/analytes/ebvhttp://labtestsonline.org/understanding/analytes/ebvhttp://labtestsonline.org/understanding/analytes/monohttp://labtestsonline.org/understanding/analytes/fluhttp://labtestsonline.org/understanding/analytes/cmv/tab/test#tophttp://labtestsonline.org/glossary/viral-loadhttp://labtestsonline.org/glossary/viral-loadhttp://labtestsonline.org/glossary/quantitative-resultshttp://labtestsonline.org/glossary/qualitative-resultshttp://labtestsonline.org/glossary/dnahttp://labtestsonline.org/glossary/culturehttp://labtestsonline.org/glossary/congenital/http://labtestsonline.org/glossary/latent/http://labtestsonline.org/glossary/immunocompromised


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Swollen lymph nodes Fever Headache Muscle aches

Other less common but more serious symptoms include inflammation of the lungs, eyes, liver,spleen, and/or digestive tract.

One or more CMV tests may be ordered at intervals when a doctor is monitoring theeffectiveness of antiviral therapy.

CMV testing may be done on a newborn withjaundice,anemia, an enlarged spleen and/or liver,

and a small head; or on an infant with hearing and vision problems,pneumonia, seizures, and/or

signs of delayed mental development.

When a person is a candidate for an organ or bone marrow transplant, CMV antibody testing

may be ordered as a screening test to determine if the person has been exposed to CMV in the

past.

^ Back to top

What does the test result mean?

Care must be taken when interpreting the results of CMV testing. The doctor evaluates the

results in conjunction with clinical findings, includingsignsandsymptoms. It can sometimes be

difficult to distinguish between alatent, active or reactivated CMV infection. This is due toseveral reasons, including:

A healthy person who has been infected with CMV at one time will continue to harbor the virus.The CMV can reactivate intermittently, often sub-clinically, shedding small amounts of virus into

body fluids but not causing symptoms.

Animmune-compromisedperson may not have a strong antibody response to the CMVinfection theirIgMandIgGlevels may be lower than expected even though they have an

active case of CMV.

The virus may not be present in sufficient number in the particular fluid or tissue tested to ableto be detected.

Antibody testing

If both CMV IgG and IgM are present in a symptomatic person, then it is likely that he has either

recently been exposed to CMV for the first time or that a previous CMV infection has beenreactivated. This can be confirmed by measuring IgG levels again 2 or 3 weeks later. A high

level of IgG is not as important as a rising level. If there is a 4-fold increase in IgG between thefirst and second sample, then the person has an active CMV infection (primary or reactivated).

If only IgM is present, then the person may have very recently been infected. If someone issymptomatic but has low or undetectable levels of IgG and/or IgM, it may mean that they either
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have a condition other than CMV or that theirimmune systemis not responding normallynot

producing an adequate amount of antibody even if CMV is present.

The following table summarizes possible antibody testing results:

CMV,IgM

CMV, IgG Possible Interpretation

Negative Negative

No current or prior infection; noimmunity, person is susceptible to

primary infection

Symptoms due to another cause OR immune system cannot produce

adequate amount of antibody

(immunocompromised)

Positive Negative

Recent active primary infection OR person re-exposed to CMV OR reactivation of latent CMV

*Result is NOT diagnostic of primary

infection

Positive

Positive (with four fold increase intiter

between first sample and another collected

later (acuteandconvalescentsamples)

Likely active primary or reactivated latent

infection

Negative Positive

Past exposure, person is immune from primary

infection; latent infection

Viral detectionIf a person is symptomatic and the culture is positive for cytomegalovirus, then the person likely

has an active CMV infection. If the culture is negative, then the person's symptoms may be due

to another cause or the amount of CMV virus in the sample is too low to detect.

If a test for CMV DNA is positive, then CMV is present and the person has an active infection.

High levels of viral DNA tend to indicate a more invasive infection accompanied by serious

symptoms while low levels indicate a CMV infection, usually one with no symptoms or ones thatare mild. Like culture, negative results on a DNA test do not rule out CMV infection

the virus

may be present in very low numbers or may not be present in the body sample tested.

When used to monitor effectiveness of treatment, decreasingviral loadsreflect a response to

antiviral treatment. Levels that do not drop in response to antiviral treatment might reflect a

resistance to the therapy being used.
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Is there anything else I should know?

CMV is one of the conditions included in a"TORCH" testing panel. This group of tests screensfor a group of infectious diseases that can cause illness in pregnant women and may cause birth

defects in their newborns. TORCH is an acronym for: Toxoplasmosis, Rubella,

Cytomegalovirus, and Herpes simplex virus.

When blood transfusion is needed, certain patients, such as CMV-negative HIV/AIDS patients

and CMV-negative heart/lung transplant candidates, should receive cellular blood products that

have been tested negative for CMV antibodies (so-called CMV seronegative blood products).

Common Questions

1. How can I tell if my CMV has reactivated?2. If I have or had CMV, can I spread it to others?3. Is there any way to prevent getting CMV?

1. How can I tell if my CMV has reactivated?

If you are a reasonably healthy person, you will probably not have a symptomatic reactivation or may

have mild flu-like symptoms. If you areimmune-compromised, you may have more serious symptoms

associated with your lungs, digestive tract, or eyes. In this case, it is important to talk to your doctor

about your health concerns.

^ Back to top

2. If I have or had CMV, can I spread it to others?

If you have a new or prior infection with CMV, you can spread it to others even if you aren't showing

signs or symptoms. Nevertheless, you must be in close contact with others in order to transmit the virus.

It can be spread through several types of body fluids, including saliva, breast milk, vaginal fluids, semen,

urine, and blood.

^ Back to top

3. Is there any way to prevent getting CMV?

Careful hygiene can help prevent transmission of the virus. But, since CMV is very common, is present in

most body fluids, and is passed through close contact, most people are infected when they are babies. It

has been estimated that as many as 70% of children in daycare have been exposed to CMV.
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pediatric cytomegalovirus infection, word

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