Chapter 247 Cytomegalovirus Sergio Stagno Human cytomegalovirus (CMV) is widely distributed. Most CMV infections are inapparent, but the virus can cause a variety of clinical illnesses that range in severity from mild to fatal. CMV is the most common cause of congenital infection, which occasionally causes the syndrome of cytomegalic inclusion disease (hepatosplenomegaly, jaundice, petechia, purpura, and microcephaly) in neonates. In immunocompetent adults, CMV infection is occasionally characterized by a mononucleosis-like syndrome. In immunosuppressed persons, including transplant recipients and patients with AIDS, CMV pneumonitis, retinitis, and gastrointestinal disease are common and can be fatal. Primary infection occurs in a seronegative, susceptible host. Recurrent infection represents reactivation of latent infection or reinfection of a seropositive immune host. Disease may result from primary or recurrent CMV infection, but the former is more commonly associated with severe disease. Etiology CMV is the largest of the herpesviruses and has a diameter of 200 nm with a double-stranded DNA viral genome of 240 kb in a 64-nm core enclosed by an icosahedral capsid composed of 162 capsomers. The core is assembled in the nucleus of the host cells. The capsid is surrounded by a poorly defined amorphous tegument, which is itself surrounded by a loosely applied, lipid-containing envelope. The tegument contains the most immunogenic proteins of the virion, including targets of T-lymphocyte and antibody responses. The envelope is acquired during the budding process through the nuclear membrane into a cytoplasmic vacuole, which contains the protein components of the envelope. The envelope glycoproteins induce strong antibody responses, including neutralizing antibodies in the infected host. Mature viruses exit the cells by cell lysis (fibroblasts) or by poorly defined exocytic pathways. Routine serologic tests do not define specific serotypes. In contrast, restriction endonuclease analysis of CMV DNA shows that human strains are not genetically identical unless obtained from epidemiologically related cases. Epidemiology Seroepidemiologic surveys demonstrate CMV infection in every population examined worldwide. The prevalence of infection increases with age and is higher in developing countries and among lower socioeconomic strata of the more developed nations. Transmission sources of CMV include saliva, breast milk, cervical and vaginal secretions, urine, semen, tears, blood products, and organ allographs. The spread of CMV requires very close or intimate contact because it is very labile. Transmission occurs by direct person-to-person contact, but indirect transmission is possible via contaminated fomites. The incidence of congenital CMV infection ranges from 0.2% to 2.2% (average 1%) of all live births, with the higher rates among populations with a lower economic standard of living. The risk for fetal infection is greatest with maternal primary CMV infection (30%) and much less likely with recurrent infection (<1%). In the USA, 1-4% of pregnant women acquire primary CMV infection, and as many as 8,000 newborns have neurodevelopmental sequelae associated with congenital CMV infection. Perinatal transmission is common, accounting for an incidence of 10-60% through the 1st 6 mo of life. The most important perinatal sources of virus are genital tract secretions at delivery and breast milk. Among CMV-seropositive mothers, virus is detectable in breast milk in 96%, with postnatal transmission occurring in approximately 38% of infants, resulting in symptomatic infection in nearly half of very low birthweight infants. Infected infants may excrete virus for years in saliva and urine. After the 1st year of life, the prevalence of infection depends on group activities, with child-care centers contributing to rapid spread of CMV among children. Infection rates of 50-80% during childhood are common. For children who are not exposed to other toddlers, the rate of infection increases very slowly throughout the 1st decade of life. A 2nd peak occurs in adolescence as a result of sexual transmission. Seronegative child-care workers and parents of young children shedding CMV have a 10-20% annual risk of acquiring CMV, in contrast to the risk of 1-3% per year for the general population. Hospital workers are not at increased risk for acquiring CMV infection from patients. With the implementation of universal precautions, the risk of nosocomial transmission of CMV to health care workers is expected to be lower than the risk of acquiring the infection in the community. CMV infection may be transmitted in transplanted organs (kidney, heart, bone marrow). Following transplantation, many patients excrete CMV as a result of infection acquired from the donor organ or from reactivation of latent infection caused by immunosuppression. Seronegative transplant recipients of organs from seropositive donors are at greatest risk for severe disease. Nosocomial infection is a hazard of transfusion of blood and blood products. In a population with a 50% prevalence of CMV infection, the risk has been estimated at 2.7% per unit of whole blood. Leukocyte transfusions pose a much greater risk. Infection is usually asymptomatic, but even in well children and adults there is a risk for disease if the recipient is seronegative and receives multiple units. Immunocompromised patients and seronegative premature infants have a much higher (10-30%) risk for disease. Pathogenesis Clinical CMV disease generally results from a combination of altered cellular immunity, uncontrolled viral replication with increased virus burden, multiorgan involvement, and end-organ disease secondary to direct viral cytopathic effects. Increased levels of virus replication, as ascertained by genome copy numbers, are useful in identifying patients at risk for invasive disease and dissemination of infection. The presence of CMV in areas of inflammation increases the expression of soluble mediators such as cytokines and chemokines, leading to recruitment of inflammatory cells. The interactions between the virus and host inflammatory response seem to lead to persistent viral replication, viral gene expression, and dissemination. Clinical Manifestations The signs and symptoms of CMV infection vary with age, route of transmission, and immunocompetence of the patient. The infection is subclinical in most patients. In infants and young children, primary CMV infection occasionally causes pneumonitis, hepatomegaly, hepatitis, and petechial rashes. In older children, adolescents, and adults, CMV may cause a mononucleosis-like syndrome characterized by fatigue, malaise, myalgia, headache, fever, hepatosplenomegaly, elevated liver enzyme values, and atypical lymphocytosis. The course of CMV mononucleosis is generally mild, lasting 2-3 wk. Clinical presentations include occasionally persistent fever, overt hepatitis, and a morbilliform rash. Recurrent infections are asymptomatic in the immunocompetent host. Immunocompromised Persons The risk of CMV disease is increased in immunocompromised persons, with both primary and recurrent infections (Chapter 171 Only gold members can continue reading. 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Chapter 247 Cytomegalovirus Sergio Stagno Human cytomegalovirus (CMV) is widely distributed. Most CMV infections are inapparent, but the virus can cause a variety of clinical illnesses that range in severity from mild to fatal. CMV is the most common cause of congenital infection, which occasionally causes the syndrome of cytomegalic inclusion disease (hepatosplenomegaly, jaundice, petechia, purpura, and microcephaly) in neonates. In immunocompetent adults, CMV infection is occasionally characterized by a mononucleosis-like syndrome. In immunosuppressed persons, including transplant recipients and patients with AIDS, CMV pneumonitis, retinitis, and gastrointestinal disease are common and can be fatal. Primary infection occurs in a seronegative, susceptible host. Recurrent infection represents reactivation of latent infection or reinfection of a seropositive immune host. Disease may result from primary or recurrent CMV infection, but the former is more commonly associated with severe disease. Etiology CMV is the largest of the herpesviruses and has a diameter of 200 nm with a double-stranded DNA viral genome of 240 kb in a 64-nm core enclosed by an icosahedral capsid composed of 162 capsomers. The core is assembled in the nucleus of the host cells. The capsid is surrounded by a poorly defined amorphous tegument, which is itself surrounded by a loosely applied, lipid-containing envelope. The tegument contains the most immunogenic proteins of the virion, including targets of T-lymphocyte and antibody responses. The envelope is acquired during the budding process through the nuclear membrane into a cytoplasmic vacuole, which contains the protein components of the envelope. The envelope glycoproteins induce strong antibody responses, including neutralizing antibodies in the infected host. Mature viruses exit the cells by cell lysis (fibroblasts) or by poorly defined exocytic pathways. Routine serologic tests do not define specific serotypes. In contrast, restriction endonuclease analysis of CMV DNA shows that human strains are not genetically identical unless obtained from epidemiologically related cases. Epidemiology Seroepidemiologic surveys demonstrate CMV infection in every population examined worldwide. The prevalence of infection increases with age and is higher in developing countries and among lower socioeconomic strata of the more developed nations. Transmission sources of CMV include saliva, breast milk, cervical and vaginal secretions, urine, semen, tears, blood products, and organ allographs. The spread of CMV requires very close or intimate contact because it is very labile. Transmission occurs by direct person-to-person contact, but indirect transmission is possible via contaminated fomites. The incidence of congenital CMV infection ranges from 0.2% to 2.2% (average 1%) of all live births, with the higher rates among populations with a lower economic standard of living. The risk for fetal infection is greatest with maternal primary CMV infection (30%) and much less likely with recurrent infection (<1%). In the USA, 1-4% of pregnant women acquire primary CMV infection, and as many as 8,000 newborns have neurodevelopmental sequelae associated with congenital CMV infection. Perinatal transmission is common, accounting for an incidence of 10-60% through the 1st 6 mo of life. The most important perinatal sources of virus are genital tract secretions at delivery and breast milk. Among CMV-seropositive mothers, virus is detectable in breast milk in 96%, with postnatal transmission occurring in approximately 38% of infants, resulting in symptomatic infection in nearly half of very low birthweight infants. Infected infants may excrete virus for years in saliva and urine. After the 1st year of life, the prevalence of infection depends on group activities, with child-care centers contributing to rapid spread of CMV among children. Infection rates of 50-80% during childhood are common. For children who are not exposed to other toddlers, the rate of infection increases very slowly throughout the 1st decade of life. A 2nd peak occurs in adolescence as a result of sexual transmission. Seronegative child-care workers and parents of young children shedding CMV have a 10-20% annual risk of acquiring CMV, in contrast to the risk of 1-3% per year for the general population. Hospital workers are not at increased risk for acquiring CMV infection from patients. With the implementation of universal precautions, the risk of nosocomial transmission of CMV to health care workers is expected to be lower than the risk of acquiring the infection in the community. CMV infection may be transmitted in transplanted organs (kidney, heart, bone marrow). Following transplantation, many patients excrete CMV as a result of infection acquired from the donor organ or from reactivation of latent infection caused by immunosuppression. Seronegative transplant recipients of organs from seropositive donors are at greatest risk for severe disease. Nosocomial infection is a hazard of transfusion of blood and blood products. In a population with a 50% prevalence of CMV infection, the risk has been estimated at 2.7% per unit of whole blood. Leukocyte transfusions pose a much greater risk. Infection is usually asymptomatic, but even in well children and adults there is a risk for disease if the recipient is seronegative and receives multiple units. Immunocompromised patients and seronegative premature infants have a much higher (10-30%) risk for disease. Pathogenesis Clinical CMV disease generally results from a combination of altered cellular immunity, uncontrolled viral replication with increased virus burden, multiorgan involvement, and end-organ disease secondary to direct viral cytopathic effects. Increased levels of virus replication, as ascertained by genome copy numbers, are useful in identifying patients at risk for invasive disease and dissemination of infection. The presence of CMV in areas of inflammation increases the expression of soluble mediators such as cytokines and chemokines, leading to recruitment of inflammatory cells. The interactions between the virus and host inflammatory response seem to lead to persistent viral replication, viral gene expression, and dissemination. Clinical Manifestations The signs and symptoms of CMV infection vary with age, route of transmission, and immunocompetence of the patient. The infection is subclinical in most patients. In infants and young children, primary CMV infection occasionally causes pneumonitis, hepatomegaly, hepatitis, and petechial rashes. In older children, adolescents, and adults, CMV may cause a mononucleosis-like syndrome characterized by fatigue, malaise, myalgia, headache, fever, hepatosplenomegaly, elevated liver enzyme values, and atypical lymphocytosis. The course of CMV mononucleosis is generally mild, lasting 2-3 wk. Clinical presentations include occasionally persistent fever, overt hepatitis, and a morbilliform rash. Recurrent infections are asymptomatic in the immunocompetent host. Immunocompromised Persons The risk of CMV disease is increased in immunocompromised persons, with both primary and recurrent infections (Chapter 171 Only gold members can continue reading. Log In or Register to continue Share this: Share on X (Opens in new window) X Share on Facebook (Opens in new window) Facebook Related Related posts: Rumination, Pica, and Elimination (Enuresis, Encopresis) Disorders Adolescent Pregnancy Neisseria gonorrhoeae (Gonococcus) Blastomycosis (Blastomyces dermatitidis) Stay updated, free articles. Join our Telegram channel Join Tags: Nelson Textbook of Pediatrics Expert Consult Jun 18, 2016 | Posted by admin in PEDIATRICS | Comments Off on Cytomegalovirus Full access? Get Clinical Tree
