Cytomegalovirus Infections

After completing this article, readers should be able to: Cytomegalovirus (CMV), a member of the herpesvirus family, has the largest genome of all the viruses that infect humans. Because the genome contains about 230 kb of double-stranded DNA and encodes for more than 100 proteins, it is difficult to determine how CMV infection occurs. CMV has adapted to the human immune system and spreads among humans via viral excretion in nearly all body fluids, including urine, saliva, and semen. In most CMV infections, there is no apparent impact on the immune system, and most infected people are disease-free. Disease associated with CMV infection generally occurs when the immune system is compromised, as in patients who have human immunodeficiency virus (HIV) infection or who have received organ transplants. Recent observations suggest that CMV disease associated with congenital infection may be due partly to placental dysfunction caused by CMV infection of the placenta.CMV viral particles are structurally similar to other human herpesviruses. The virus has a 65-nm inner core containing the viral DNA. The inner core is within an icosahedral protein capsid comprised of 162 capsomeres. This structure is surrounded by a tegument layer and an outer enveloped membrane containing glycoproteins. The envelope glycoproteins are antigenic and responsible for triggering an immune response. Most of the neutralizing antibodies induced by CMV antigens are directed against the major CMV glycoprotein gB, although other envelope glycoproteins also induce neutralizing antibodies. Cellular immune responses, such as cytotoxic T-cell response, are directed primarily against the major tegument protein, pp65.In the United States, between 1% and 2% of the population acquires a CMV infection annually. By age 70 years, nearly everyone has been infected with CMV. Table 1lists the modes of CMV transmission. Congenital infections constitute a minority of CMV infections, with CMV infecting fewer than 2% of newborns worldwide at birth. CMV can infect newborns in utero via a primary maternal CMV infection during pregnancy or during CMV reactivation or reinfection in a mother who has a history of primary CMV infection prior to pregnancy. The frequency of CMV reactivation during pregnancy is unknown. If a woman’s first CMV infection occurs during pregnancy, the CMV transmission rate from mother to the fetus is about 50%; for women infected with CMV before pregnancy, the transmission rate to the fetus is only 0.5% to 2%. Congenital CMV disease, therefore, occurs primarily following a primary maternal infection during pregnancy.Newborns not infected in utero acquire CMV postnatally from two sources. Approximately 10% to 13% of seropositive women excrete CMV in cervical and vaginal secretions, and infants delivered of mothers who are excreting CMV often acquire the virus from this source. Perinatal acquisition of CMV via this mode by healthy newborns causes no apparent disease. Between 25% and 50% of seropositive women who breastfeed their infants transmit CMV via human milk to their infants. Term infants acquiring CMV via human milk also have no apparent disease associated with CMV acquisition. However, preterm infants acquiring CMV through human milk can develop symptomatic illness, such as CMV pneumonia.Infants and children acquire CMV either via child-to-child or intrafamilial transmission. Child-to-child transmission has been studied extensively, particularly in child care settings. Of preschool-age children who attend large group child care, 10% to 70% acquire CMV infection from other children in the same facility. Such children, especially those younger than 2 years of age, transmit the virus, in turn, to caretakers, including both parents and child care workers. Infection rates for previously uninfected child care workers range between 10% and 20% per 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 younger than age 2 years shedding CMV is approximately 50% or 25-fold higher than that for the general population.CMV transmission by young children is facilitated by the prolonged duration of viral excretion in both saliva and urine. For children younger than 2 years of age who acquire a CMV infection postnatally, CMV is excreted for an average of 18 months (range, 6 to 40 months). In contrast, viral excretion in urine and saliva of healthy older children and adults who acquire a primary CMV infection usually occurs for only a few days to several weeks, although some individuals may excrete the virus for longer periods.CMV is excreted in all secretions except tears. CMV is concentrated highest in semen and also is present in cervical and vaginal secretions. Hence, it is assumed that CMV transmission can occur via sexual activity. Adolescent serconversion to CMV frequently is associated with increased sexual activity among adolescents and with those adolescents attending clinics for sexually transmitted diseases. Homosexual males also have very high rates of CMV infection, presumably due to sexual activity.Nosocomial transmission of CMV 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 has occurred only when patients are hospitalized in close proximity for prolonged periods. Thus, CMV-seronegative women caring for hospitalized young children or for other patients who may be excreting CMV can be reassured that they have minimal risk of acquiring CMV from patients if they follow standard hospital isolation precautions. CMV may be transmitted by transfusion of whole blood because CMV can reside in the white cell fraction of whole blood. 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 that have had the white cells removed.The precise incubation period for each mode of transmission is not known but generally is believed to be between 1 and 2 months.In summary, person-to-person transmission of CMV is facilitated by prolonged viral excretion (especially among young children) in nearly all body fluids. However, within a population, transmission occurs slowly over time and requires frequent and prolonged “intimate contact,” as can occur among family members, among those engaged in sexual activities, or among children cared for together over prolonged periods in child care. Shared secretions are the key to CMV transmission. Casual transmission of CMV, as might occur in a supermarket, movie theater, or other crowded place, is very unlikely.Most symptomatic congenital infections occur when a mother sustains a primary infection with CMV either during or just prior to pregnancy. Timing of the maternal infection during pregnancy does not appear to affect viral transmission rates, but infections at earlier gestational ages probably result in more severe congenital disease. CMV infections among mothers who already are seropositive are termed recurrent infections because it is unknown whether these episodes are due to reinfection with new CMV strains or to reactivation of latent persistent virus. Although maternal recurrent infections rarely result in symptomatic or severely affected infants, infants of mothers who have recurrent infections also may develop handicaps due to CMV. For example, the frequency of hearing deficit among infants born after a primary maternal infection and the frequency among infants born after a recurrent maternal infection are similar (about 10%), but the frequency of severe or profound and progressive hearing deficit is much greater among infants of mothers who have had a primary infection during pregnancy. Up to 50% of infected fetuses born after a primary maternal infection during pregnancy develop serious and profound handicaps besides hearing loss compared with less than 10% of infected fetuses born of mothers who have a recurrent infection during pregnancy.Among the several risk factors for maternal CMV infection during pregnancy, the primary one is intimate exposure to young children. Toddlers, once infected, shed virus in their saliva and urine for an average of 18 months. Therefore, women of childbearing potential who have young children in the home are more likely to become infected than are women who do not have prolonged contact with young children. At least 50% of women of higher socioeconomic status in the United States are CMV-seronegative. Such seronegative women frequently are exposed to young children in the home and are at high risk for delivering infants who have symptomatic congenital CMV infection if the women sustain a primary infection during pregnancy. Furthermore, women of higher socioeconomic status frequently use child care, which presents a significant risk factor for seronegative women of childbearing potential because of the ubiquitous nature of CMV infection among the young children in these centers.Both maternal cellular and humoral immunity to CMV are important factors in viral transmission during pregnancy. Women who have impaired cellular immune responses to CMV (eg, those who have acquired immune deficiency syndrome [AIDS] or who are receiving immunosuppressive therapy) are more likely to transmit virus to the fetus, and anti-CMV immunoglobulin (Ig)G antibody-neutralizing titers and avidity are correlated inversely with transmission. Avidity is an indirect measure of the “tightness” of antibody binding to a target antigen. Given the reduced disease severity in infants born to mothers who are seropositive for CMV, it is possible that pre-existing immunity reduces or eliminates maternal viremia, thereby protecting the fetus.Diagnosis of primary maternal infection often is difficult if attempted only when signs and symptoms of either maternal infection or fetal disease appear. Symptoms of maternal infection occur in fewer than 10% of infected pregnant women and include a flulike syndrome, myalgia, and asthenia with or without fever. Among the laboratory findings are lymphocytosis (40% of patients) or elevated liver enzyme values (50% of patients). Signs of fetal infection on maternal ultrasonography include growth restriction, microcephaly, echodensities in solid organs or the intestines, and an enlarged placenta.Maternal seroconversion is the gold standard for diagnosing maternal CMV infection, but because universal serologic screening of pregnant or prepregnant women is not standard in the United States, establishing pre- and postinfection serologic status is rare. The detection of IgM antibodies in maternal sera can be helpful but also represents problems. Although IgM antibodies to CMV occur in all primary infections, they also may occur after CMV reactivation or reinfection. Furthermore, IgM remains present for many months after a primary infection. Finding IgM to CMV in a single serum specimen of a pregnant woman does not establish a primary CMV infection during pregnancy.Antibody avidity, a measure of antibody binding to its target antigen, increases in the first weeks after a primary infection. Low-avidity IgG antibodies to CMV persist for up to 20 weeks after a primary CMV infection. Such low-avidity antibodies are replaced by high-avidity antibodies (>60% binding in presence of 5 M urea). Currently, the presence of both anti-CMV IgM antibodies and low-avidity anti-CMV IgG antibodies along with correlating maternal or fetal symptoms is the best combination of factors to diagnose a primary maternal infection.Examination of amniotic fluid may help diagnose maternal CMV infection. Although viral culture of the amniotic fluid may yield false-negative results, polymerase chain reaction (PCR) testing, especially after 21 weeks’ gestation, is both sensitive and specific for fetal infection. A diagnosis of fetal CMV infection alone is insufficient to predict newborn disease. However, fetal abnormalities or placental enlargement noted by ultrasonography are predictive of newborn disease and long-term sequelae.At present, there is no standard therapy for maternal CMV infections diagnosed during pregnancy. A recent observational study demonstrated that administration of CMV hyperimmune globulin to mothers who had a primary CMV infection during pregnancy and whose fetuses had confirmed CMV infection of the amniotic fluid dramatically reduced infant sequelae at birth from 50% to 3%. Also, the administration of CMV hyperimmune globulin to mothers who had a primary CMV infection and did not have amniocentesis was associated with reduced maternal-to-fetal transmission rates from 42% to 16%. Unfortunately, trials of other medical interventions, such as administering antiviral agents (eg, ganciclovir) during pregnancy, are lacking.Behavioral measures are important for preventing or reducing child-to-mother CMV transmission during pregnancy (Table 2). Practices that may prevent transmission include proper handwashing after diaper changes and refraining from mouth-kissing or sharing food with young children. Other interventions, such as a CMV vaccine, are under evaluation.About 10% of infants born with congenital CMV infection demonstrate signs and symptoms at birth; the remaining 90% are asymptomatic. many as 10% of the children develop sequelae in such as progressive hearing most in symptomatic infants include and syndrome, age and Such may placental dysfunction and viral infection of the system Of many of these signs with associated with other congenital viral syndrome is due to due to to and elevated and are responsible for the enlargement in most symptomatic infants. postnatally, which that CMV infection of the causes that fetal and occur in about two of symptomatic newborns and include other and may be due to such as hearing loss or more likely are due to viral and to the fetus because hearing at birth may be but loss may slowly over the first 5 to years after CMV infection should be diagnosed within the first weeks after birth because at diagnosis after this time the of infection due to exposure to CMV in the maternal The gold standard for the diagnosis of congenital CMV infection is detection of the virus in the urine by in This can up to weeks for results, but the after viral infection of can yield in and is sensitive and of diagnosis have been but often are much less or infected infants anti-CMV IgM but this has and and is for diagnosis in the of CMV DNA in the blood by is sensitive and and the of virus in the blood may with the that is for CMV alone is to establish a diagnosis of congenital CMV disease because congenital infection with CMV occurs in up to 2% of all newborns and because to 90% of affected develop In symptomatic infants, also congenital and a congenital CMV infection is a should include of liver and If liver or are the should be over the several months it may for values to appear. A blood should be because some infants develop a and most develop that may range from to which is due to reduced in usually in 1 to 2 and should be The presence of cellular and elevated protein in the fluid or Although are the on other such as or may should be to for possible deficit is associated with congenital CMV infection, and it is that CMV is the of hearing for about of all hearing Given this and the that the hearing loss may be and a should be as as possible after the diagnosis of CMV infection, by hearing for the first few Most children hearing loss within the first 2 years, although some children may develop as as years of The most hearing for of hearing loss are potential or potential who have symptomatic congenital CMV infection have a rate of 10% to who are symptomatic at birth and the period have a high risk of long-term significant including hearing loss that from to who have or and has been some with to findings at the time of diagnosis in the newborn period with long-term and A for a is abnormalities on especially protein of greater than have a significant with including also are of The findings of and of liver and values at birth do not predict long-term Although most infants who have congenital infection rarely severe long-term as many as develop some of hearing The hearing loss associated with congenital CMV infection is or with of loss that can be progressive and develop as as months of For this hearing screening and diagnosis of infection by possible therapy are for the of congenital CMV infection significant of hearing loss with therapy per for 6 in infants who had signs of Unfortunately, therapy requires administration and can usually but also and usually therapy requires of blood and if or of therapy is of is against CMV disease in but this is in children therefore, CMV infections in healthy people are asymptomatic. symptoms are present, they include either flulike symptoms with and or an syndrome with and a Among the less frequent are particularly in the and and particularly in young infants. In previously healthy diagnosis may be difficult because signs and symptoms may be similar to those of such as and A primary CMV infection also may be associated with prolonged without other signs or adults or children who have postnatally acquired CMV infections of symptoms over several days or weeks without who have acquired CMV infections are more likely to have an syndrome or other Although symptoms occur in fewer than 1% of the of CMV should be in older children and adults who have flulike or infections are a frequent of and among immunocompromised for CMV infections are a potential include preterm infants and those who have had organ are for or have The associated with CMV infections in immunocompromised patients are numerous but generally include or infections with either or If immune is severe as occurs with and also are is associated with a CMV infection in immunocompromised to the reactivation of latent CMV. The frequency and severity of CMV disease is to the of Among solid organ latent CMV from the seropositive donor organ more than 90% of the CMV-seronegative patients who have received an organ from a donor are at highest risk for CMV disease. on the immunosuppressive therapy to prevent seropositive of seronegative organs also may reactivation of latent CMV after and develop CMV disease. Among cell CMV after if either the donor or was often is by severe CMV disease, including patients who have very of frequently develop CMV disease, and and CMV disease among patients for is less than among of solid organs or cells or those who have The frequency of CMV disease among those receiving for is to the and duration of induced by the immunocompromised CMV may induce who have CMV have immune responses to a of and The virus also cell activity and in Although CMV infection may in patients and may the risk for infections in is and CMV infections may the rate of organ and disease. CMV both and of human 1 antigens in and CMV infection is in triggering or whether CMV infection is following immune to prevent is unknown. In it is unknown if progressive immunodeficiency the of CMV disease or if CMV disease infections to more to primary CMV infections among patients usually is not difficult if are The diagnosis can be but not confirmed by detection of the virus in urine or For patients who may have a CMV infection, serologic for both IgG and IgM antibodies should be IgG may be or at in the of a primary CMV and should during the 2 to IgG antibodies are by enzyme or 2 to weeks after a primary CMV infection and to high that are for A diagnosis of primary infection among individuals also is possible by IgM or low-avidity IgG antibodies to CMV in the serum using The presence of IgM antibodies per does not a primary infection because they also may occur after reactivation of CMV. Avidity is also a sensitive and specific for a recent primary CMV symptomatic a CMV diagnosis also requires of other causes of of such as virus infection or usually are on the of either or antibodies and a of either IgG or IgM antibodies to immunocompromised it is much more difficult to diagnose CMV disease as to CMV infection. immunocompromised patients often CMV following Thus, the detection of either antibodies to CMV in serum or the detection of virus in body is to diagnose a CMV infection but not to diagnose disease due to CMV. However, CMV or high viral in the of particularly those who have received organ is associated with CMV diagnosis of CMV disease in immunocompromised patients requires two other causes of disease, such as and other or infections, be CMV be in or The presence of CMV in can be by using CMV a in some cells by a if present, high of virus in the infected CMV also can be by in or by both to CMV DNA. However, these are very sensitive and very of which may not with CMV disease. Thus, the presence of in a such as or without is usually for a diagnosis of CMV summary, diagnosing CMV infection and disease in patients is usually but diagnosing CMV disease in immunocompromised patients is more The diagnosis of CMV disease is on CMV or high viral in blood associated with and viral excretion in body a of symptoms with CMV for patients infected with CMV is and no specific therapy is For immunocompromised the is and on the and duration of immune of therapy are antiviral therapy and therapy against CMV should be for immunocompromised patients who therapy of administering that CMV DNA structurally similar to but with greater activity against CMV, is most has been to CMV infections in immunocompromised patients and is for the of severe CMV However, most trials have been trials have for patients who have CMV or for The of for patients who have CMV has been difficult to viral via a similar to that of Cellular to a that is a and of viral DNA without cellular DNA or reduces the of virus excreted in urine and saliva and generally CMV from the blood. This antiviral occurs only when the is receiving the After viral excretion or CMV are among patients who have after and long-term administration often is although therapy frequently can be when immune is of is per in two for 2 to weeks, by 5 to per for also is for administration in but it is from the is primarily to CMV The is 1 per a of is from the is to in the and CMV has been to CMV disease in adults at a of specific of and are for children. The associated with include and which occur for CMV in patients is to per which CMV DNA by a which contains high of IgG antibodies to CMV, is an important therapy for immunocompromised patients who have CMV infection. globulin usually is with particularly for patients who have had cell transplants. For seropositive therapy with hyperimmune globulin reduces the and severity of disease due to by administering hyperimmune immunoglobulin as as to prevent CMV disease following organ CMV vaccine, the to be an for preventing or reducing the of CMV disease among seronegative patients who have received a from a seropositive Unfortunately, this only is on a and is not is in to develop other against CMV. include strains of CMV and that use the major glycoprotein of infections are for most healthy Congenital infections are 10% of which are associated with symptoms at birth. sequelae of congenital infections include infant and hearing that symptomatic infections and severe sequelae are associated with a primary infection during pregnancy but can occur with maternal CMV reinfection or reactivation during pregnancy. Recent observational that maternal infections can be reduced by changes during pregnancy for women who have young children or by administering CMV hyperimmune globulin to women who have a primary infection during pregnancy. from a that to symptomatic infants who have of reduces the severity of hearing deficit associated with congenital infection. CMV infections in immunocompromised patients are often serious and difficult to therapy for such patients of and CMV hyperimmune globulin