Clinical Manifestations
Manifestations of acquired human cytomega- lovirus (CMV) infection vary with age and host immunocompetence. Asymptomatic infections are the most common, particularly in children. An infectious mononucleosis-like syndrome with prolonged fever and mild hepatitis, occurring in the absence of hetero- phile antibody production (“monospot nega- tive”), can occur in adolescents and adults.
Pneumonia, colitis, retinitis, and a syndrome characterized by fever, thrombocytopenia, leukopenia, and mild hepatitis can occur in immunocompromised hosts, including people receiving treatment for malignant neoplasms, people infected with HIV, and people receiving immunosuppressive therapy for organ or hematopoietic stem cell transplantation. Less commonly, patients treated with biologic response can exhibit CMV end-organ disease, such as retinitis and hepatitis.
Congenital infection has a spectrum of clinical manifestations but usually is not evident at birth (“clinically silent” congenital CMV infec- tion). Approximately 10% of neonates with congenital CMV infection exhibit clinical findings that are evident at birth (congenital CMV disease), with manifestations including intrauterine growth restriction, jaundice, purpura, hepatosplenomegaly, microcephaly, intracerebral (typically periventricular) calci- fications, and retinitis; developmental delays are common among these neonates in later infancy and early childhood. Death attribut- able to congenital CMV is estimated to occur in 3% to 10% of neonates with congenital dis- ease. Sensorineural hearing loss (SNHL) is the most common sequela following congenital CMV infection, with SNHL occurring in up to 50% of children with congenital disease at birth and up to 15% of those with clinically silent CMV infection. Congenital CMV infection is the leading nongenetic cause of SNHL in chil- dren in the United States. Progressive SNHL can occur following symptomatic or asymp- tomatic congenital CMV infection, with 50%
of affected children continuing to have further
deterioration (progression) of their hearing loss. Between 55% and 75% of clinically appar- ent and clinically silent newborns, respectively, who ultimately develop congenital CMV- associated SNHL will not have hearing loss detectable within the first month of life, illustrating the high frequency of late-onset SNHL in these children. For this reason, tar- geted CMV testing of neonates who fail their uni versal newborn hearing screen will not detect most neonates who are at risk of CMV- associated hearing loss. Approximately 20% of all hearing loss at birth and 25% of all hearing loss at 4 years of age are attributable to congen- ital CMV infection. As such, all children with congenital CMV infection should be regularly evaluated for early detection and intervention as appropriate.
Infection acquired from maternal cervical secretions during the intrapartum period, or in the postpartum period from human milk, is usually not associated with clinical illness in term neonates. In preterm neonates, how- ever, postpartum infection resulting from human milk or from transfusion from CMV- seropositive donors has been associated with systemic infections, including hepatitis, inter- stitial pneumonia, and hematologic abnor- malities, including thrombocytopenia and leukopenia, and a viral sepsis syndrome.
Etiology
Human CMV, also known as human herpes- virus 5, is a double-stranded DNA virus and a member of the herpesvirus family (Herpes- viridae), β-herpesvirus subfamily (Betaherpes- virinae), and Cytomegalovirus genus.
Epidemiology
Cytomegalovirus is highly species specific, and only human CMV has been shown to infect humans and cause disease. The virus is ubiqui- tous and has numerous strain types (exhibits extensive genetic diversity). Transmission occurs horizontally (by direct person-to-person contact with virus-containing secretions), vertically (from mother to neonate before, during, or after birth), and via transfusions of blood, platelets, and white blood cells from infected donors. Cytomegalovirus can also be transmitted with organ or hematopoietic
CyTOmEGALOviruS iNFECTiON 139 stem cell transplantation. Infections have no
seasonal predilection. Cytomegalovirus per- sists in latent form after a primary infection, and intermittent virus shedding and symptom- atic infection can occur throughout the life- time of the infected person, particularly under conditions of immunosuppression. Reinfection with other strains of CMV can occur in sero- positive hosts.
Horizontal transmission is probably the result of exposure to saliva and genital secretions from infected individuals, but contact with infected urine can also have a role. Spread of CMV in households and child care centers is well documented. Excretion rates from urine or saliva in children 1 to 3 years of age who attend child care centers usually range from 30% to 40% but can be as high as 70%. These children frequently excrete high quantities of virus. Young children can transmit CMV to their parents, including mothers who may be pregnant, and other caregivers, including child care staff. In adolescents and adults, sexual transmission occurs, as evidenced by detection of virus in seminal and cervical flu- ids. As such, CMV is considered to be a sexu- ally transmitted infection.
Healthy cytomegalovirus-seropositive people have latent CMV in their leukocytes and tis- sues; hence, blood transfusions and organ transplantation can result in transmission.
Severe CMV disease following transfusion or organ transplantation is more likely to occur if the recipient is immunosuppressed and CMV-seronegative or is a preterm neonate.
In contrast, among nonautologous hemato- poietic stem cell transplant recipients, CMV- seropositive recipients who receive transplants from seronegative donors are at greatest risk of disease when exposed to CMV after trans- plant, perhaps secondary to the failure of transplanted graft to provide immunity to the recipient. Latent CMV can reactivate in immunosuppressed people and result in disease if immunosuppression is severe (eg, patients with AIDS, solid organ or hemato- poietic stem cell transplant recipients).
Vertical transmission of CMV to a neonate occurs in one of the following periods: in utero by transplacental passage of maternal blood- borne virus, at birth by passage through an infected maternal genital tract, or postnatally by ingestion of CMV-positive human milk or by transfusion. Between 0.5% and 1% of all live- born neonates are infected in utero and excrete CMV at birth, making this the most common congenital viral infection in the United States.
In utero fetal infection can occur in women with no preexisting CMV immunity (primary maternal infection) or in women with preexist- ing antibody to CMV (nonprimary maternal infection) by acquisition of a different viral strain during pregnancy or by reactivation of an existing maternal infection. Congenital infection and associated sequelae can occur irrespective of the trimester of pregnancy when the mother is infected, but severe sequelae are more commonly associated with primary maternal infection acquired during the first half of gestation. Damaging fetal infections following nonprimary maternal infection have been reported, and acquisition of a different viral strain during pregnancy in women with preexisting CMV antibody can cause clinically apparent congenital disease with sequelae. It is estimated that more than two-thirds of neo- nates with congenital CMV infection in the United States are born to women with non- primary infection, and the contribution of nonprimary maternal infection as a cause of damaging congenital CMV infection is believed to be common in populations with higher maternal CMV seroprevalence than that of women in the United States. Thus, the definition of protective immunity in congenital CMV infection remains contentious.
Cervical excretion of CMV is common among seropositive women, resulting in exposure of many neonates to CMV at birth. Cervical excretion rates are higher among young moth- ers in lower socioeconomic groups. Similarly, although disease can occur in seronegative neonates fed CMV-infected human milk, most neonates who acquire CMV from ingestion of infected human milk do not develop clinical illness or sequelae, most likely because of the presence of passively transferred maternal
140 CyTOmEGALOviruS iNFECTiON
antibody. Among neonates who acquire infec- tion from maternal cervical secretions or human milk, preterm neonates born before 32 weeks’ gestation are at greater risk of CMV disease than are full-term neonates.
Incubation Period
Horizontally transmitted CMV infections, unknown; 3 to 12 weeks and 1 to 4 months after blood transfusion and organ transplan- tation, respectively.
Diagnostic Tests
The diagnosis of CMV disease is confounded by the ubiquity of the virus, high rate of asymp tomatic excretion, frequency of reacti- vated infections, development of serum immu- noglobulin (Ig) M CMV-specific antibody in some episodes of reactivation, reinfection with different strains of CMV, and concurrent infec- tion with other pathogens.
Virus can be isolated in cell culture from urine, oral fluids, peripheral blood leukocytes, human milk, semen, cervical secretions, and other tissues and body fluids. Recovery of virus from a target organ provides strong evidence that the disease is caused by CMV. Shell vial culture and immunofluorescence antibody stain for immediate early antigen provides results within days. A presumptive diagnosis of CMV infection beyond the neonatal period has been associated with a 4-fold antibody titer increase in paired serum specimens or by demonstra- tion of virus excretion. Viral DNA can be detected by polymerase chain reaction (PCR) assay in tissues and some fluids, such as cere- brospinal fluid, urine, and saliva. Detection of CMV DNA by PCR assay in blood does not indicate acute infection or disease, especially in immunocompetent people. Detection of pp65 antigen or quantification of viral DNA (eg, by quantitative PCR assay) in white blood cells is often used to detect infection in immu- nocompromised hosts. Various serologic assays, including immunofluorescence, latex agglutination, and enzyme, are available for detecting CMV-specific antibodies.
Amniocentesis has been used in several small series of patients to establish the diagnosis of intrauterine infection. Following delivery, proof of congenital infection requires virologic
detection of CMV in urine, oral fluids, respira- tory tract secretions, blood, or cerebrospinal fluid obtained within 2 to 4 weeks of birth. The analytic sensitivity of CMV detection by PCR assay of dried blood spots is low, limiting use of this type of specimen for screening for con- genital CMV infection. A positive PCR assay result from a neonatal dried blood spot con- firms congenital infection, but a negative result does not exclude congenital infection.
Differentiation between intrauterine and peri- natal infection is difficult at later than 2 to 4 weeks of age unless clinical manifestations of the former are present. A strongly positive CMV-specific IgM during early infancy can be suggestive of congenital CMV infection;
however, IgM serologic methods commonly have reduced specificity and frequently result in false-positive results.
Treatment
Intravenous ganciclovir is the drug of choice for induction and maintenance treatment of retinitis caused by acquired or recurrent CMV infection in immunocompromised adult patients, including HIV-infected patients, and for prophylaxis and treatment of CMV disease in adult transplant recipients. Valganci- clovir, the oral prodrug of ganciclovir, is also approved for treatment (induction and mainte- nance) of CMV retinitis in immunocompro- mised adult patients, including HIV-infected patients, and for prevention of CMV disease in kidney, kidney-pancreas, or heart transplant recipients aged 4 months and older at high risk for CMV disease. Ganciclovir and valganciclo- vir are also used to treat CMV infections of other sites (esophagus, colon, lungs) and for preemptive treatment of immunosuppressed adults with CMV antigenemia or viremia.
Oral valganciclovir is available in tablet and powder for oral solution formulations.
Neonates with symptomatic congenital CMV disease with or without central nervous system involvement have improved audiologic and neurodevelopmental outcomes at 2 years of age when treated with oral valganciclovir for 6 months. The dose should be adjusted each month to account for weight gain. Significant neutropenia occurs in one-fifth of neonates treated with oral valganciclovir and in two-
CyTOmEGALOviruS iNFECTiON 141 thirds of neonates treated with parenteral
ganciclovir. Absolute neutrophil counts should be performed weekly for 6 weeks, then at 8 weeks, then monthly for the duration of antiviral treatment; serum aminotransferase concentration should be measured monthly during treatment.
Preterm neonates with intrapartum-acquired CMV infection can have end-organ disease (eg, pneumonitis, hepatitis, thrombocytope- nia). Antiviral treatment has not been studied in this population. In hematopoietic stem cell transplant recipients, the combination of intra- venous immunoglobulin or CMV intravenous immunoglobulin and ganciclovir, adminis- tered intravenously, has been reported to be synergistic in treatment of CMV pneumonia.
Valganciclovir and foscarnet can also be used for treatment and maintenance of CMV retini- tis in adults with AIDS. Foscarnet is more toxic
(with high rates of limiting nephrotoxicity) but may be advantageous for some patients with HIV infection, including people with disease caused by ganciclovir-resistant virus or who are unable to tolerate ganciclovir.
Cytomegalovirus establishes lifelong persis- tent infection, and as such, it is not eliminated from the body with antiviral treatment of CMV disease. Until immune reconstitution is achieved with antiretroviral therapy, chronic suppressive therapy should be administered to HIV-infected patients with a history of CMV end-organ disease (eg, retinitis, colitis, pneu- monitis) to prevent recurrence. All patients who have had anti-CMV maintenance therapy discontinued should continue to undergo regu- lar ophthalmologic monitoring at a minimum of 3- to 6-month intervals for early detection of CMV relapse as well as immune reconstitu- tion uveitis.
Image 40.1
Cells with intranuclear inclusions in the urine of infant with congenital cytomegalovirus disease.
Image 40.2
A 3-week-old with congenital cytomegalovirus infection with purpuric skin lesions and hepatosplenomegaly. Courtesy of Edgar O. Ledbetter, mD, FAAP.
142 CyTOmEGALOviruS iNFECTiON
Image 40.3
A baby girl was delivered prematurely, at 30 weeks’ gestation, by emergency cesarean delivery because of deceleration and no acceleration on fetal heart rate monitoring. in addition, she had severe intrauterine growth restriction, oligohydramnios, and increased peak systolic velocity of the middle cerebral artery on Doppler ultrasonography. The 39-year-old mother (gravida 7, para 5) had been well during pregnancy. On examination, the neonate was found to have respiratory distress, an extensive rash (A), and hepatomegaly. The rash consisted of purple-to-magenta, nonblanching macules that were 0.5 to 1.0 cm in diameter, as well as papules and petechiae covering her entire body. Laboratory investigation revealed anemia (hemoglobin level, 25 g/L [reference range, 121–191 g/L]) and thrombocytopenia (platelet count, 13,000/mm3 [13 x 109/L [reference range, 195,000–450,000/mm3 (195–434 x 109/L)]). results of cytomegalovirus (Cmv) igm and igG tests and serum and plasma DNA polymerase chain reaction assays were positive. Tests for parvovirus B19 and rubella igm antibodies were negative. Despite aggressive care, the child did not survive.
Postmortem examination confirmed disseminated Cmv infection. Extramedullary hematopoiesis was present throughout the body, including the skin (B). Dermal hematopoiesis can occur in utero as a result of severe anemia, congenital rubella, parvovirus infection, or Cmv infection. From The New England Journal of Medicine, Congenital Cytomegalovirus infection, 362, 833. Copyright © 2010.
massachusetts medical Society. reprinted with permission from massachusetts medical Society.
Image 40.4
Cytomegalovirus infection, congenital, with characteristic “blueberry muffin” lesions.
Copyright David Clark.
Image 40.5
This 1-day-old, who was small for gestational age, had microcephaly, hepatomegaly, jaundice, and a “blueberry muffin” rash. The neonate also developed thrombocytopenia and disseminated intravascular coagulation. The neonate died at 48 hours of age. Kidney and lung tissue culture tested positive for cytomegalovirus. Copyright Larry i. Corman.
CyTOmEGALOviruS iNFECTiON 143
Image 40.6
infant with lethal congenital cytomegalovirus disease with purpuric skin lesions and striking hepatosplenomegaly. Courtesy of Edgar O.
Ledbetter, mD, FAAP.
Image 40.7
infant in image 40.6 with lethal cytomegalovirus disease with radiographic changes in long bones of osteitis characterized by fine vertical metaphyseal striations. Courtesy of Edgar O.
Ledbetter, mD, FAAP.
Image 40.8
Widespread “brushfire retinitis” in an infant with congenital cytomegalovirus infection. The perivascular infiltrates and diffuse hemorrhage may result in complete blindness whenever macular involvement occurs. Courtesy of George Nankervis, mD.
Image 40.9
Characteristic white perivascular infiltrates in the retina of an infant with congenital cytomegalo- virus infection. Courtesy of George Nankervis, mD.
144 CyTOmEGALOviruS iNFECTiON
Image 40.11
Cytomegalovirus infection with periventricular calcification. Courtesy of Benjamin Estrada, mD.
Image 40.12
Histopathology of cytomegalovirus infection of brain capillary endothelial cell. Courtesy of Centers for Disease Control and Prevention/
Dr Haraszti.
Image 40.13
Congenital cytomegalovirus encephalitis.
microcephaly and cerebral calcification.
Courtesy of Dimitris P. Agamanolis, mD.
Image 40.14
Histopathologic features of cytomegalovirus infection of the kidney. intranuclear inclusions are surrounded by a halo and the nuclear membrane, giving an “owl eye” appearance. Courtesy of Centers for Disease Control and Prevention/Dr Haraszti.
Image 40.10
Axial T2-weighted magnetic resonance image demonstrates periventricular germinolytic cysts (arrows). Also note the periventricular white matter hyperintensities that are representative of demyelination and gliosis.