ABSTRACT
Cytomegalovirus (CMV) is the cause of cytomegalic inclusion disease of the newborn. In common with all herpesviruses, CMV persists for life after primary infection. The site of CMV latency is CD34+ hematopoietic progenitor cells. Virus reactivation occurs upon cellular differentiation into monocytes and dendritic cells. Given the diversity of CMV genotypes, re-infection can also occur. CMV has a broad tropism with two routes of cell entry, an envelope glycoprotein trimer mediates entry into fibroblasts whereas a glycoprotein pentamer mediates entry into epithelial/endothelial and myeloid cells.
After primary infection, virus is shed periodically in saliva and urine. Virus is also found in breast milk, cervical secretions, blood, and semen. In childhood, CMV is acquired by contact with saliva or urine from infected children or on fomites. Later in life, sexual transmission is a major route of infection. CMV passes from mother to child prenatally when virus infects and crosses the placenta and perinatally through cervical secretions, breast milk and saliva. Virus can also be transmitted via organ donation or blood transfusion. Seroprevalence varies according to socioeconomic conditions. In developed countries, only about 40% of adolescents are seropositive and seroprevalence increases by approximately 1% per year thereafter.
The host response to CMV infection starts with innate immunity. The importance of NK cells is demonstrated in that patients with NK-cell deficiencies suffer severe herpesvirus infections. Adaptive immunity in healthy individuals controls viremia, and productive infection in the face of virus reactivation or reinfection. MHC class I restricted CD8+ cytotoxic cells are the most important immune defense to give lifelong control over CMV. CMV encodes more genes for immune evasion than it does to produce the virion and evasion mechanisms are many. Pathology is presumably produced by direct viral cytopathic effects, although indirect effects produced by viral encoded proteins, or the host immune response remain a possibility.
Severe CMV disease is rare in the immunocompetent but young adults with primary CMV infection sometimes present with a mononucleosis syndrome. CMV retinitis due to virus reactivation is most frequent in AIDS but esophagitis and colitis also occur. Seronegative solid-organ transplant recipients (R-) are at risk of primary CMV infection acquired from a CMV seropositive donor (D+). Disease includes esophagitis, colitis, hepatis and rarely interstitial pneumonitis or CMV retinitis. In contrast, allogeneic hematopoietic stem-cell transplant recipients are at high risk of CMV pneumonitis due to CMV reactivation if they are R+ but receive a D- organ. Congenital CMV infection is the most common viral cause of sensorineural hearing loss and neurodevelopmental delay in children. CMV infection acquired by premature infants during birth or early in the perinatal period may develop severe infections with multiorgan disease, including hepatitis, pneumonitis, and sepsis-like syndromes.
Laboratory diagnosis of CMV infection depends on virus isolation, detection of viral antigens or viral nucleic acid, and antibody tests. Accurate quantitative tests: have largely replaced other assays for virologic monitoring of viremia in allogeneic transplant recipients at risk of invasive CMV infection. Other uses of CMV DNA tests include testing for congenital CMV infection of amniotic fluid, or infant’s urine within the first 3 weeks of life. Bronchoalveolar fluid is tested for confirmation of a radiologic diagnosis of CMV pneumonitis. Diagnosis of end-organ disease requires symptoms at the affected site together with tests on a biopsy to demonstrate productively infected cells. CMV-specific IgG antibody tests are used to stratify risk of CMV infection in allograft donors and recipients and to diagnose primary infection in the immunocompetent.
Antiviral agents are used for preemptive therapy or prophylaxis to control CMV infection and disease in allograft recipients, and to treat CMV disease in AIDS, and infants with congenital CMV. Ganciclovir and valganciclovir are the most widely used drugs. Foscarnet is used in the face of ganciclovir resistance, and cidofovir in the case of failure with the other anti-CMV drugs. Letermovir is a recently developed drug licensed for CMV prophylaxis. Fomivirsen is limited to local therapy of CMV retinitis.
Finally, an important priority is for an effective and safe vaccine to reduce congenital CMV infection, but no candidate vaccine has progressed to phase III trials.
