Acquired Cytomegaloviral Infections

Stuart P. Adler

Of all the viruses that infect humans, cytomegalovirus (CMV), a member of the herpes family of viruses, has the largest size genome, with approximately 230 kilobases of DNA. CMV is ubiquitous in the human population, and biologically CMV’s interaction with its human host is extremely complex. CMV usually causes little or no disease, but it may induce illness, either after a first or primary infection or among immunocompromised patients after reactivated infection or secondary infection caused by reinfection with a second viral strain. CMV has adapted to the human immune system such that it adequately propagates itself with prolonged viral excretion in nearly all body fluids including urine, saliva, and semen, without a significant impact on the human immune system and inducing little if any disease. Disease associated with CMV infection occurs most often when the immune system is compromised because of immaturity, as occurs in the fetus, because of disease, as occurs in human immunodeficiency virus (HIV) infection, or for iatrogenic causes, as occurs in transplant recipients.

Within a 65-nm inner core of the CMV viral particle resides the large, double-stranded DNA. Included within the CMV genome are more than 200 open-reading frames. The inner core itself is contained within an icosahedral protein capsid composed of 162 capsomeres. This, in turn, is surrounded by a tegument layer and an outer enveloped membrane composed of glycoprotein. The CMV viral particles are structurally similar to those of other human herpesviruses. The CMV DNA encodes for at least 100 proteins, most of which are structural. The envelope glycoproteins are antigenic and are responsible for generating an immune response. Most of the neutralizing antibodies induced by CMV antigens are directed against the major CMV glycoprotein called gB, although a second envelope glycoprotein called gH also contains neutralizing epitopes. Cellular responses such as those generated by cytotoxic T cells are directed primarily against the major tegument protein, pp65.

CMV has only a single serotype; that is, antibodies directed against one viral isolate cross-react with almost all other isolates. Genetically, however, there are probably thousands of different strains. Each unrelated isolate of CMV differs genotypically from all other epidemiologically unrelated isolates. These genotypic differences have been important epidemiologic tools in tracking the virus as it is transmitted from one individual to another.

EPIDEMIOLOGY AND TRANSMISSION

In the United States, approximately 1% to 2% of the population acquires a CMV infection each year, and thus by age 70 years, nearly all individuals become infected with CMV. In many areas of the world, nearly 100% of a population is infected with CMV by age 2 years. Table 200.1 lists some of the modes by which CMV is transmitted among humans. Congenital infection accounts for a minority of acquired CMV infections. Between 1% and 2% of all newborns worldwide are infected with CMV at birth. Newborns are infected in utero either as the result of a primary maternal CMV infection during pregnancy or as a result of recurrent maternal infection that occurs when a mother has had a CMV infection before pregnancy. Recurrent maternal infections occur either following reactivation of latent maternal virus or by reinfection of the mother with a second CMV strain. If a woman’s first CMV infection occurs during pregnancy, the CMV transmission rate from mother to the fetus is about 50%, but for women initially infected with CMV before pregnancy, the transmission rate to the fetus is only 1% to 3%. Congenital CMV disease occurs primarily following a primary maternal infection during pregnancy. This aspect of CMV infection is covered in Chapter 77.

Newborns who are not infected in utero may acquire CMV postnatally from two major sources. Approximately 10% to 13% of seropositive women excrete CMV in cervical or vaginal secretions, and infants delivered of a mother who is excreting CMV will often acquire CMV from this source. Perinatal acquisition of CMV via this mode by full-term healthy newborns causes no apparent disease. CMV transmission from mother to infant also occurs via breast milk. Between 25% and 50% of
seropositive women who breast-feed their infants will transmit CMV to these infants. Infants acquiring CMV via breast milk also have no apparent disease associated with CMV acquisition via this source.

TABLE 200.1. MODES AND FREQUENCY OF CYTOMEGALOVIRUS TRANSMISSION

Mode	Approximate Transmission Rate
Transplacental
Primary maternal	50%
Recurrent maternal	0.5%–1%
Perinatal
Breast milk	25%–50%
Cervical secretion	10%
Postnatal
Day care	10%–70%
Intrafamilial	50%
Sexual
Oral	Unknown
Genital	Unknown
Nosocomial
Transfusion	2%–10% (with unscreened or filtered blood)
Hospital personnel	0%

Infants and children may also acquire CMV either via child-to-child transmission or via intrafamilial transmission. Child-to-child transmission has been studied intensely, particularly in the day-care setting. Of preschool children who attend large day-care centers, an average of 25% (range, 10% to 70%) will acquire a CMV infection from other children in the same day-care center. These children, especially those less than 2 years old, will, in turn, transmit the virus to their caretakers, including both parents and day-care workers. Infection rates for previously uninfected day-care workers are between 10% and 20%/year, compared with an annual infection rate of approximately 2% for the general population. The annual rate of CMV infections among parents who have not had a previous infection (seronegative) and who have a child who is less than 2 years old and is shedding CMV is approximately 50%, or 25-fold higher than for the general population.

Thus, the natural history of CMV transmission in day care is that a child who acquired CMV either congenitally or perinatally enters day care and then transmits the virus to other children, with subsequent transmission from children to seronegative day-care employees and seronegative parents. CMV transmission by young children is facilitated by the prolonged duration of viral excretion in both saliva and urine. For children less than 2 years of age who acquire CMV infection postnatally, CMV is excreted for an average of 18 months with a range of 6 to 40 months. In contrast, for older children and adults who acquire primary CMV infection, viral excretion in urine and saliva usually occurs for only a few days to several weeks, although some individuals may excrete the virus for longer periods.

CMV is excreted not only in urine and saliva but also in other secretions except tears. CMV is in highest concentrations in semen and is highly prevalent in cervical or vaginal secretions. Hence, it is assumed that CMV transmission occurs via sexual activity. CMV infections are associated with increased sexual activity among adolescents and those attending clinics for sexually transmitted diseases. Homosexual men also have very high rates of CMV infection, with nearly 100% having acquired CMV infection presumably via sexual activity.

Nosocomial transmission of CMV within the hospital occurs very infrequently. In numerous studies, CMV transmission from infected patients to hospital personnel has not been observed. Patient-to-patient transmission is rare and occurs only when patients are hospitalized side-by-side for prolonged periods. Thus, CMV seronegative women caring for young children or for other patients who may be excreting CMV can be reassured that there is little or no risk of acquiring CMV from patients. CMV may be transmitted by transfusion of whole blood. CMV is located in the white cell fraction. For immunocompromised patients requiring transfusion, the risk of CMV acquisition from a blood donor is eliminated either by selecting donors who are CMV seronegative or by using blood products with white cells removed.

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