Cytomegalovirus

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Last modified 09/02/2015

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Cytomegalovirus

Learning Objectives

At the conclusion of this chapter, the reader should be able to:

• Discuss the etiology and epidemiology of acquired, latent, and congenital cytomegalovirus (CMV) infection.

• Explain the signs and symptoms of acquired and congenital CMV infections.

• Describe the immunologic manifestations of CMV.

• Identify and explain the serologic markers and diagnostic evaluation of CMV.

• Discuss the principles and applications of passive latex agglutination and other quantitative determinations of IgM and IgG antibodies.

• Analyze a CMV case study.

• Correctly answer case study related multiple choice questions.

• Be prepared to participate in a discussion of critical thinking questions.

• Describe the principle, reference range, sources of error, limitations, and clinical applications of Latex Agglutination for Antibodies to CMV.

• Describe the principle and clinical applications of antibody detection to CMV.

• Correctly answer end of chapter review questions.

Key Terms

Etiology

Cytomegalovirus (CMV) is a ubiquitous human viral pathogen. The first descriptive report of histologic changes characteristic of those now associated with CMV infection was originally published in 1904, when protozoan-like cells in the lungs, kidneys, and liver of a syphilitic fetus were seen. It was not until 1956 and 1957 that CMV was isolated in the laboratory. Actual isolation of the virus after transfusion, and observation of elevated antibody titers, occurred in 1966.

Human CMV is classified as a member of the herpes family of viruses (herpesviruses). All the herpesviruses are relatively large, enveloped DNA viruses that undergo a replicative cycle involving DNA expression and nucleocapsid assembly within the nucleus. The viral structure gains an envelope when the virus buds through the nuclear membrane, which in turn is altered to contain specific viral proteins.

Although the herpesviruses produce diverse clinical diseases, they share the basic characteristic of being cell associated. The requirements for cell association vary, but herpesviruses may spread from cell to cell, presumably via intercellular bridges and in the presence of antibody in the extracellular phase. CMV spreads to the lymphoid tissues and proceeds to circulate to systemic lymph nodes. The virus finally comes to rest in the epithelial cells of many tissues. This common characteristic may play a role in the ability of these viruses to produce subclinical infections that can be reactivated under appropriate stimuli.

Epidemiology

CMV infection is endemic worldwide, with most urban adults demonstrating evidence of infection; 50% to 80% of U.S. adults are infected with CMV by age 40 years. The prevalence of CMV seropositivity increases steadily with age. CMV is found in all geographic and socioeconomic groups, but in general it is more widespread in developing countries and areas of lower socioeconomic conditions.

CMV is a major health risk because a large proportion of women, particularly white women, entering their childbearing years lack antibody to CMV. Those at greatest risk of infection are fetuses and immunocompromised persons. CMV is the most common virus transmitted to the fetus. Approximately 1 in 150 children is born with congenital CMV infection, and about 8000 children each year suffer permanent disabilities caused by CMV.

Transmission

Transmission of CMV may be by the oral, respiratory, or venereal route. The virus has been isolated in urine, saliva, feces, breast milk, blood, cervical secretions, virus-infected grafts from a donor, semen, vaginal fluid, and respiratory droplets. It may also be transmitted by the transfusion of fresh blood. Transmission of CMV appears to require intimate contact with secretions or excretions. CMV can be transmitted from a pregnant woman to her fetus during pregnancy. Low-birth-weight (LBW) neonates are also at high risk for CMV infection through transfusion of CMV-infected blood products.

Peripheral blood leukocytes and transplanted tissues have been strongly incriminated as sources of CMV. Transmission of CMV by transfusion of blood or blood components containing white blood cells (WBCs) has assumed increased importance in patients with severely impaired immunity who require supportive therapy. In the United States, CMV screening is required for all units of blood collected from donors. Preventive methods in these patients include effective donor screening, leukocyte-depleted or irradiated blood products, and immune globulin containing passively acquired CMV antibodies. The use of irradiated blood products has become more popular.

Once in a person’s body, CMV stays there for life. Most CMV infections are silent, causing no signs or symptoms. Individuals who are CMV-positive (infected with CMV in the past) usually do not have virus in urine or saliva, so the risk of acquiring a CMV infection from casual contact is negligible.

Women who are pregnant or planning a pregnancy should follow hygienic practices (e.g., careful handwashing) to avoid CMV infection. Because young children are more likely to have CMV in their urine or saliva than older children or adults, pregnant women who have or work with young children should be especially careful.

Health care professionals represent a group that has become increasingly concerned about the risks associated with exposure to CMV. Nosocomial transmission from patients to health care workers has not been documented, but observance of good personal hygiene and handwashing offer the best measures for preventing transmission.

Latent Infection

Persistent infections characterized by periods of reactivation are frequently termed latent infections. CMV can persist in a latent state and active infections may develop under a variety of conditions (e.g., pregnancy; immunosuppression; after organ, bone, or stem cell transplantation). Of immunosuppressed patients, only seronegative patients appear to be at a significant risk of developing CMV infection. Patients at the highest risk of mortality from CMV infections are allograft transplant, seronegative patients who receive tissue from a seropositive donor. The great majority of infections in allograft recipients are transmitted by a donated organ or arise from the reactivation of the recipient’s latent virus.

True viral latency is defined by the presence of the genetic information in an unexpressed state in the host cell. An operational definition of latency can include the conditions of a dynamic relationship between the virus and host, along with evidence of latency and reactivation of a latent infection. As with any herpesvirus, CMV reactivation is possible at any time, but rarely manifests in immunocompetent individuals.

Congenital Infection

Primary and recurrent maternal CMV infection can be transmitted in utero. Congenital CMV infection is the most common intrauterine infection, affecting 0.4% to 2.3% of all live births in the United States. The presence of maternal antibody to CMV before conception provides substantial protection against damaging, congenital CMV infection in the newborn.

Primary maternal infection during pregnancy, occurring in 1% to 3% of U.S. women, is associated with more severe sequelae of congenital CMV infection. Infected infants can become severely ill and premature infants may die. Most newborns infected with CMV survive, but they may be mentally impaired or may develop other health problems. Approximately 10% of congenitally infected infants have symptoms at birth and, of the 90% who are asymptomatic, 10% to 15% will develop symptoms over months or even years.

Signs and Symptoms

Acquired Infection

Acquired CMV infection is usually asymptomatic and can persist in the host as a chronic or latent infection. The incubation period is believed to be 3 to 12 weeks.

In most patients, CMV infection is asymptomatic. Occasionally, a self-limited, heterophile-negative, mononucleosis-like syndrome results. CMV hepatitis can also develop.

Symptoms include a sore throat and fever, swollen glands, chills, profound malaise, and myalgia. Lymphadenopathy and splenomegaly may be observed. Infections occurring in healthy immunocompetent individuals usually result in seroconversion. Virus may be excreted in the urine during primary and recurrent CMV infections; it can persist sporadically for months or years. Persons experiencing acquired infection, reinfection with the same or different strains of CMV, or reactivation of a latent infection can excrete the virus in titers as high as 106 infective units/mL in the urine or saliva for weeks or months.

Normal adults and children usually experience CMV infection without serious complications. Infrequent complications of CMV infection in previously healthy individuals, however, include interstitial pneumonitis, hepatitis, Guillain-Barré syndrome, meningoencephalitis, myocarditis, thrombocytopenia, and hemolytic anemia.

CMV infection can be life-threatening in immunosuppressed patients. Infections in these patients may result in disseminated multisystem involvement, including pneumonitis, hepatitis, gastrointestinal (GI) ulceration, arthralgias, meningoencephalitis, and retinitis. Retinitis and encephalitis are common manifestations of disseminated CMV. Ulcerative damage of tissues (e.g., esophagus) is another demonstration of the cytopathic effects of CMV. Interstitial pneumonitis, frequently associated with CMV infection, is a major cause of death after allogeneic bone marrow transplantation. In premature infants, acquired CMV infection can result in atypical lymphocytosis, hepatosplenomegaly, pneumonia, or death.

Transfusion-acquired CMV infections may cause not only mononucleosis-like syndrome, but also hepatitis and increased rejection of transplanted organs. The following three types of CMV infections are possible in blood transfusion recipients:

1. Primary infection occurs when a previously unexposed (seronegative) recipient is transfused with blood from an actively or latently infected donor. This type of infection is accompanied by the presence of virus in the blood and urine, an immediate antibody response, and eventual seroconversion. Patients with primary infections may be symptomatic, but the great majority are asymptomatic.

2. Reactivated infection can occur when a seropositive recipient is transfused with blood from a CMV antibody–positive or –negative donor. Donor leukocytes are thought to trigger an allograft reaction, which in turn reactivates the recipient’s latent infection. These infections may be accompanied by significant increases in CMV-specific antibody. Some reactivated infections exhibit viral shedding as their only manifestation. Reactivated infections are largely asymptomatic.

3. Reinfection can occur by a CMV strain in the donor’s blood that differs from the strain that originally infected the recipient. A significant antibody response is observed and viral shedding occurs. Although it is difficult to differentiate a reactivated infection if the patient and donor are CMV antibody–positive before transfusion, reinfections can be documented if isolates can be obtained from the donor and recipient.

Congenital Infection

About 1 in 750 children in the United States is born with or develops permanent problems due to congenital CMV infection. In the United States, more than 5000 children/year suffer permanent problems caused by CMV infection.

The classic congenital CMV syndrome is manifested by a high incidence of neurologic symptoms, as well as neuromuscular disorders, jaundice, hepatomegaly, and splenomegaly (Fig. 21-1). Petechia is the most common clinical sign, seen in about 50% of CMV-infected infants.

image
Figure 21-1 Four-month-old child with symptomatic congenital cytomegalovirus (CMV) infection manifesting severe failure to thrive, hepatitis with hepatosplenomegaly, bilateral inguinal hernia, and micropenis. (From Katz SL, Gershon AA, Wilfert CM, Krugman S, editors: Infectious diseases of children, ed 9, St Louis, 1992, Mosby.)

Congenitally infected newborns, especially those who acquire CMV during a maternal primary infection, are more prone to develop severe cytomegalic inclusion disease (CID). The severe form of CID may be fatal or can cause permanent neurologic sequelae, such as intracranial calcifications (Fig. 21-2), mental retardation, deafness, vision defects, microcephaly, and motor dysfunction. Psychomotor impairment is seen in 51% to 75% of survivors. Hearing loss is observed in 21% to 50% and visual impairment in 20% of patients. Infants without symptoms at birth may develop hearing impairment and neurologic impairment later.

image
Figure 21-2 Brain of infant with congenital CMV infection.
Note extensive periventricular necrosis and calcification. (From Katz SL, Gershon AA, Wilfert CM, Krugman S, editors: Infectious diseases of children, ed 9, St Louis, 1992, Mosby.)

Immunologic Manifestations

Immune System Alterations

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