90: Cytomegalovirus

Cytomegalovirus (CMV) is a DNA virus and a member of the herpesvirus group (human herpesvirus 5).

CMV is the most common cause of congenital infection in the United States and occurs in ∼0.2–2.2% of all live births. This results in ∼40,000 new cases in the United States per year.

CMV is a ubiquitous virus that may be transmitted in secretions, including saliva, tears, semen, urine, cervical secretions, blood (white blood cells), and breast milk. The seroprevalence increases with age and is influenced by many factors, such as hygienic circumstances, socioeconomic factors, breast-feeding, and sexual contacts. In addition to transplacental infection, CMV may also be transmitted to the infant intrapartum (through exposure to CMV in cervical secretions), via breast milk, and via blood transfusion of seropositive blood to an infant whose mother is seronegative. CMV infection acquired during delivery or via breast milk has no effect on future neurodevelopmental outcome in full-term infants. There is no definite evidence of CMV transmission among hospital personnel.

In developed countries, CMV seroprevalence varies inversely with socioeconomic status, with 40–80% of women of childbearing age in the United States having serologic evidence of past CMV infection. Seroconversion and initial infection can occur around the time of puberty, and shedding of the virus may continue for a long time. CMV can also become latent in white blood cells and reactivate periodically. In addition, a seropositive individual can be infected by a different strain of CMV.

Maternal reinfection by new strains of CMV has been recognized recently as a major source of congenital infection in a highly CMV-immune maternal population like that of Brazil. Reactivation and reinfection are grouped as a “nonprimary” infection. CMV is capable of penetrating the placental barrier as well as the blood–brain barrier. During early pregnancy, CMV has a teratogenic potential in the fetus. CMV infections may result in neuronal migration disturbances in the brain. Both primary and nonprimary maternal CMV infection can lead to transmission of the virus to the fetus. When primary maternal infection occurs during pregnancy, the virus is transmitted to the fetus in ∼35% of cases. Infection in early pregnancy causes more severe fetal infection with significant CNS sequelae. During nonprimary infection, transmission rate is only 0.2–1.8%. Even though the risk for congenital infection is high after primary maternal infection, nonprimary infection is responsible for 75% of the overall burden of congenital CMV infection.

More than 85% of infants born with CMV have a subclinical infection. Symptomatic infants are usually born to women with a primary infection. Symptomatic infants have a mortality rate of 20–30%. When the placenta becomes infected with CMV after a primary maternal infection, its ability to provide oxygen and nutrients to the developing fetus becomes impaired. This leads to placental enlargement due to viral placentitis and revascularization. Although not completely elucidated, placental tissue damage occurs due to direct tissue injury by persistent CMV replication, ischemic tissue damage due to vasculitis with viral infection of endothelial cells, and tissue damage by immune complex deposition. Eventual fetal viremia leads to fetal multiorgan involvement. The primary target organs are the CNS, eyes, liver, lungs, and kidneys.

Characteristic histopathologic features of CMV include focal necrosis, inflammatory response, formation of enlarged cells with intranuclear inclusions (cytomegalic cells), and the production of multinucleated giant cells. A sepsis-like illness has been described in premature infants.

CMV infection in neonates is associated with nonwhite race, lower socioeconomic status, drug abuse, and neonatal intensive care unit admittance. Premature infants are more often affected than full-term infants. Transfusion with unscreened blood is an additional risk factor for neonatal disease. Risk factors for primary CMV infection during pregnancy include prolonged exposure to young children (daycare workers, multiparous women) and sexual contact (young maternal age, greater numbers of sexual partners, abnormal cervical cytology, and having a sexually transmitted infection during pregnancy).

1. Prenatal presentation. Pregnant women who acquire primary CMV may develop a mononucleosis-like illnesses (<25% of the time). Maternal screening is currently not recommended routinely. Fetal anomalies consistent with congenital CMV infection that can be detected on prenatal ultrasound examination include fetal growth restriction, cerebral periventricular echogenicity or calcifications, cerebral ventriculomegaly, microcephaly, polymicrogyria, cerebellar hypoplasia, hyperechogenic fetal bowel, hepatosplenomegaly, amniotic fluid abnormalities, ascites and/or pleural effusion, and placental enlargement. Prenatal magnetic resonance imaging (MRI), especially to evaluate brain anomalies, is being used increasingly. Amniocentesis to perform polymerase chain reaction (PCR) for CMV DNA in amniotic fluid is the preferred diagnostic approach for identifying an infected fetus. Amniocentesis is most sensitive when done after 21 weeks of gestation and after 6 weeks from maternal infection/exposure.

2. Postnatal presentation

   1. Subclinical infection. Occurs in 85–90% of cases. Despite being asymptomatic at birth, these infants are at risk for sensorineural hearing loss (SNHL) during the first 6 years of life.

   2. Low birthweight. Maternal CMV infection is associated with low birthweight and small for gestational age infants, even when the infant is not infected.

   3. Classic CMV inclusion disease. Occurs in 10–15% of the cases and consists of intrauterine growth restriction, hepatosplenomegaly with jaundice, abnormal liver function tests (LFTs), thrombocytopenia with or without purpura, and severe central nervous system (CNS) involvement (CNS and sensory impairments are seen in 50–90% of symptomatic newborns). Neurologic complications include microcephaly, intracerebral calcifications (most characteristically in the subependymal periventricular area), chorioretinitis, and progressive SNHL (10–20% of cases). Other symptoms include hemolytic anemia and pneumonitis. The most severely affected infants have a mortality rate of ∼30%. Deaths are usually due to hepatic dysfunction, bleeding, disseminated intravascular coagulation, or secondary bacterial infection. Factors associated with poor outcome in symptomatic infants include microcephaly, abnormal findings on head computed tomography (CT), and increased viral load.

   4. Late sequelae. Approximately 10–20% of children with congenital CMV infections, regardless of symptoms, exhibit neurologic damage at follow-up. SNHL occurs in 22–65% of symptomatic and 6–23% of asymptomatic infants. CMV-related SNHL may be present at birth or occur later in childhood. Repeated auditory evaluation during the first 5 years of life is strongly recommended. Visual impairment and strabismus are common in children with clinically symptomatic CMV infection. Visual complications may occur, usually secondary to chorioretinitis, pigmentary retinitis, macular scarring, optic atrophy, and central cortical defects.

1. Laboratory studies

   1. Culture for demonstration of the virus. The gold standard for the diagnosis of congenital CMV is urine or saliva culture obtained before 3 weeks of age. Most urine specimens from infants with congenital CMV are positive within 48–72 hours, especially if shell vial tissue culture techniques are used. Shell vial assay detects CMV-induced antigens by monoclonal antibodies, allowing for identification of the virus within 48 hours compared with the standard tissue culture, which takes 2–4 weeks. Studies evaluating a rapid assay for detection of CMV in saliva as a screening method for congenital infection have shown it to be at least as sensitive a method for detecting congenital infection as for detection of viruria (viruses in the urine). Given that saliva can be collected with less difficulty and expense, it may eventually replace the current use of urine screening.

   2. Polymerase chain reaction (PCR). PCR for CMV DNA is as sensitive as a urine culture for the detection of CMV infection. PCR has been used successfully in retrospective diagnosis of congenital CMV beyond 3 weeks of age through CMV DNA analysis of dried blood spots (Guthrie cards). The sensitivity of CMV DNA detection by PCR assay of dried blood spots is low, limiting use of this type of specimen for widespread screening for congenital CMV. A positive PCR assay result from a neonatal dried blood spot confirms congenital infection, but a negative result does not rule out it out.

   3. Serologic tests. Serologic tests based on the detection of immunoglobulin M (IgM) should not be used to diagnose congenital CMV because they are less sensitive and more subject to false-positive results than culture or PCR. Only 70% of neonates infected with congenital CMV have IgM antibodies at birth.

   4. Other laboratory tests. Other lab tests that are indicated in the workup include complete blood count, LFTs, disseminated intravascular coagulation panel and cerebrospinal fluid analysis, culture, and PCR.

2. Imaging and other studies. Ultrasound or CT scans of the head may demonstrate characteristic periventricular calcifications in addition to other abnormalities (see prenatal presentation earlier). Brain MRI is preferred over other modalities because it is likely to identify most of the brain anomalies associated with congenital CMV.

1. Prevention and treatment of maternal infection during pregnancy. Possible approaches to preventing and treating congenital CMV infections during pregnancy include changes in hygienic behavior for seronegative pregnant women, administration of CMV hyperimmune globulin (HIG) to pregnant women with a primary infection, administering antiviral therapy to women with primary infection, and vaccines administered to girls or women well before pregnancy or during pregnancy. With regard to hygienic measures, epidemiologic studies have shown that instructing mothers who are pregnant on frequent hand washing; wearing gloves for specific child-care tasks; avoiding kissing children under age 6 on the mouth or cheek; not sharing food, drinks, or oral utensils (eg, fork, spoon, toothbrush, pacifier) with young children; and cleaning toys, countertops, and other surfaces that come into contact with children's urine or saliva reduces their chances of acquiring congenital CMV infection. To test the efficacy of HIG, a multicenter nonrandomized study in Italy enrolled pregnant women with primary congenital CMV infection diagnosed before 21 weeks' gestation. The study demonstrated that HIG (100 U/kg) given monthly until delivery reduces congenital infection in the newborn infants (16% vs 40%) compared with mothers who refused therapy. HIG was safe, and therefore this therapy should be considered for mothers diagnosed with primary CMV during the first half of gestation. Use of antiviral therapy for the infected pregnant woman has not been studied in controlled trials. The most effective preventive strategy is developing a vaccine against CMV. Recently, a vaccine targeted toward CMV envelope glycoprotein B, an antigen that typically induces a serum antibody response, was tested in a phase 2 clinical trial. This vaccine has been shown to be immunogenic with an acceptable risk profile. Other trials are underway.

2. Antiviral agents. No antiviral agent is yet approved for treatment of congenital CMV infection. Ganciclovir has been used to treat infants who have symptomatic disease. In a randomized, placebo-controlled, phase III clinical trial in infants with congenital CMV and CNS involvement, treatment with intravenous ganciclovir (6 mg/kg/dose, administered every 12 hours) for 6 weeks at a dose of 6 mg/kg/d resulted in improved hearing compared with controls after 6 months of follow-up. In addition, 68% of controls had deterioration of hearing at 1-year follow-up compared with 21% of treated children. During therapy, the viral excretion in urine decreases but returns to near pretreatment levels after cessation of therapy. The antiviral therapy may suppress virus replication temporarily but may not prevent long-term sequelae. No effect on long-term neurodevelopmental outcome (>2 years) has been reported yet. Ganciclovir was associated with significant side effects, especially neutropenia, which occurred in 60% of the recipients. Based on the results of this study, some experts suggest that ganciclovir therapy may be offered to CMV-infected neonates who manifest CNS disease for prevention of hearing impairment. Another possible indication is chorioretinitis, which involves the macula and may result in blindness. A third possible indication is the critically ill preterm infant who acquires the infection natally (intrapartum) or postnatally. Such infants have life-threatening CMV infection manifested by pneumonitis, hepatitis, or encephalitis, and ganciclovir may modify the course of the disease. Valganciclovir is a prodrug of ganciclovir that is suitable for oral administration. Valganciclovir administered orally to young infants at 16 mg/kg/dose, twice daily, provides the same systemic ganciclovir exposure as does intravenous ganciclovir at 6 mg/kg/dose. Small observational studies from Europe on using valganciclovir to treat congenital CMV are encouraging. In the United States, oral valganciclovir is being evaluated in clinical trials conducted by the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

Congenital CMV is the leading cause of SNHL regardless of the seroprevalence in the population. For symptomatic infants at birth, mortality is up to 30%, and up to 90% will have late complications (intellectual or developmental impairment, hearing loss, spasticity). Factors associated with poor developmental outcome include intrauterine growth restriction, microcephaly, urine and cerebrospinal fluid viral load, and presence of CNS abnormalities on brain imaging studies (CT or MRI). Visual impairment develops in 10–20% of symptomatic newborns. With asymptomatic, congenitally infected infants, the prognosis is uncertain, but they are at a risk for SNHL (up to 20% by 6 years of age).