Pediatric Annals

Cytomegalovirus Infection

Abstract

Cytomegalovirus (CMV) is a ubiquitous virus that can have a devastating effect on the fetus. It belongs to the herpes group of viruses, all of which have a propensity for latency. Infection with CMV is typically subtle, silent, and underreported. Yet it is the most frequently occurring of all known maternal infections that can affect the fetus, such as rubella and toxoplasmosis, and is the one most likely to cause defects in the baby. When rubella is not epidemic, CMV is probably the most common congenital infectious cause of mental retardation, central-nervous-system (CNS) disorders, and deafness. It produces a wide range of disease manifestations affecting many organs. Often these are inapparent or mild, but sometimes they are so severe that they lead to serious developmental impairment, irreversible damage, and neonatal death.

In the newborn, infection is usually detectable only by the presence of cytomegaloviruria, and most infants are without symptoms. The only physical findings may be failure to thrive or increased irritability. However, at the other clinical extreme, CMV can cause abortion, stillbirth, or postnatal death from hemorrhage, anemia, or extensive hepatic or CNS damage. Infants with severe but nonfatal disease often have low birth weight and develop fever, hepatitis with jaundice, microcephaly, purpura, hydrocephalus, areas of calcification in the brain, damage to the retina of the eye, or an enlarged liver or spleen. Any or all of these symptoms may be present. The disease is complex, variable, unpredictable, indescribable.

About 3 per cent of newborns are infected. Perhaps 5 per cent of these will have some damage associated with the infection, but rarely in severe form. The most common manifestations are mental retardation and hightone hearing loss, which may not be apparent until a child is several years old. The number of infants infected with diffuse and disseminated disease is estimated at 3,000 to 6,000 per year in the United States.

In the population at large the lifetime incidence of CMV infection is very high; 60-90 per cent of adults have experienced infection, characteristically without symptoms or consequences. It is estimated that 5 to 6 per cent of pregnant women become infected. Because the virus can persist in the vagina for a long time, an infection existing before pregnancy can be transmitted to the baby. Moreover, the virus that invades the unborn child can persist in the fetal and neonatal organism.

The real clinical and epidemiologic importance of CMV infection lies in one vital area - pregnancy. It is to the period of pregnancy that the National Institute of Child Health and Human Development has directed its interest and support of research on CMV. The ultimate aim, of course, is prevention through the development of a vaccine.

It is not an easy task. The human CMV meets few of the conditions that make successful immunization possible. The infection and its disease are not easy to either identify or detect. The virus has many strains and causes a wide variety of disease manifestations rather than a single one - like measles. The virus infection recurs; one infection does not confer lifelong immunity. The virus is latent; its effects may not appear until many months or years later. Maternal immunity may not protect the fetus, and whether the mother's infection is primary or recurrent is often impossible to learn.

Charles Alford, at the University of Alabama, has been one of the pioneers in research on the epidemiology, virology, immunology, clinical aspects, and silent nature of CMV. He, with David Reynolds, Sergio Stagno, and others of his team, is currently focusing on subclinical infection and low-grade deficits that follow. This group has…

Cytomegalovirus (CMV) is a ubiquitous virus that can have a devastating effect on the fetus. It belongs to the herpes group of viruses, all of which have a propensity for latency. Infection with CMV is typically subtle, silent, and underreported. Yet it is the most frequently occurring of all known maternal infections that can affect the fetus, such as rubella and toxoplasmosis, and is the one most likely to cause defects in the baby. When rubella is not epidemic, CMV is probably the most common congenital infectious cause of mental retardation, central-nervous-system (CNS) disorders, and deafness. It produces a wide range of disease manifestations affecting many organs. Often these are inapparent or mild, but sometimes they are so severe that they lead to serious developmental impairment, irreversible damage, and neonatal death.

In the newborn, infection is usually detectable only by the presence of cytomegaloviruria, and most infants are without symptoms. The only physical findings may be failure to thrive or increased irritability. However, at the other clinical extreme, CMV can cause abortion, stillbirth, or postnatal death from hemorrhage, anemia, or extensive hepatic or CNS damage. Infants with severe but nonfatal disease often have low birth weight and develop fever, hepatitis with jaundice, microcephaly, purpura, hydrocephalus, areas of calcification in the brain, damage to the retina of the eye, or an enlarged liver or spleen. Any or all of these symptoms may be present. The disease is complex, variable, unpredictable, indescribable.

About 3 per cent of newborns are infected. Perhaps 5 per cent of these will have some damage associated with the infection, but rarely in severe form. The most common manifestations are mental retardation and hightone hearing loss, which may not be apparent until a child is several years old. The number of infants infected with diffuse and disseminated disease is estimated at 3,000 to 6,000 per year in the United States.

In the population at large the lifetime incidence of CMV infection is very high; 60-90 per cent of adults have experienced infection, characteristically without symptoms or consequences. It is estimated that 5 to 6 per cent of pregnant women become infected. Because the virus can persist in the vagina for a long time, an infection existing before pregnancy can be transmitted to the baby. Moreover, the virus that invades the unborn child can persist in the fetal and neonatal organism.

The real clinical and epidemiologic importance of CMV infection lies in one vital area - pregnancy. It is to the period of pregnancy that the National Institute of Child Health and Human Development has directed its interest and support of research on CMV. The ultimate aim, of course, is prevention through the development of a vaccine.

It is not an easy task. The human CMV meets few of the conditions that make successful immunization possible. The infection and its disease are not easy to either identify or detect. The virus has many strains and causes a wide variety of disease manifestations rather than a single one - like measles. The virus infection recurs; one infection does not confer lifelong immunity. The virus is latent; its effects may not appear until many months or years later. Maternal immunity may not protect the fetus, and whether the mother's infection is primary or recurrent is often impossible to learn.

Charles Alford, at the University of Alabama, has been one of the pioneers in research on the epidemiology, virology, immunology, clinical aspects, and silent nature of CMV. He, with David Reynolds, Sergio Stagno, and others of his team, is currently focusing on subclinical infection and low-grade deficits that follow. This group has established that infected infants have a 17 per cent chance of developing incapacitating hearing loss as they get older. Some observations suggest a trend toward lower IQs and various perceptual and learning problems, particularly among children of low-income families. There is also evidence suggesting that reactivation rather than primary infection in the mother may be the major cause of congenital CMV and that maternal immunity may not protect the fetus.

The development of animal models to serve as tools for the study of human CMV has been pursued by several investigators. Kenneth Johnson, at the University of California, San Francisco, has produced CMV infections in two strains of guinea pigs. They are transmitted across the placental barrier, occur most commonly in the second trimester of pregnancy, and are usually inapparent.

David Lang, at Duke University, has demonstrated that venereal transmission of CMV is possible in the mouse, that the virus is evident and persistent in semen in humans and animals, and that it does not inhibit fertilization. Dr. Lang also conducts clinical studies among pregnant adolescents and their offspring. In both, the incidence of CMV is high.

Gueh-Djen Hsiung, at Yale University, is working with guinea pigs and monkeys, with special emphasis on intrauterine infection and transplacental transmission. Her work has demonstrated that transplacental transmission occurs only during acute primary maternal infection and that sexual contact among guinea pigs is a more efficient means of spreading CMV than environmental contact. Dr. Hsiung also has been comparing methods for in-vivo and in-vitro assays for detection.

Anne Yeager, of Stanford University, and others have established that there is a significant increase of prevalence of CMV in infants who receive blood transfusions. Currently Dr. Yeager is studying the possible benefits of ascertaining CMV-antibody status among blood donors and eliminating antibody-positive blood for use with sick newborns. The study also includes follow-ups of infected infants and susceptible family members. She is also engaged in simplifying the technical aspects of tests to determine antibody status.

The seriousness of CMV as a public health problem is unquestioned. The NICHD supports these studies in the belief that new knowledge will lead to better understanding of the infection and will encourage the development of effective preventive measures.

Material for this column has been prepared by the staff of the National Institute of Child Health and Human Development, National Institutes of Health.

10.3928/0090-4481-19790101-09

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