Cytomegalovirus (CMV) Infection

Picture of owl eye inclusion bodies in kidney cells of an individual with cytomegalovirus infection; SOURCE: CDC/Dr. Haraszti

Cytomegalovirus (pronounced si-to-MEG-a-lo-virus), or CMV, is a virus that belongs to the Herpesviridae family, hence its older name, "human herpesvirus 5 (HHV 5)". Other members of this family include herpes simplex viruses (which cause cold sores and genital herpes), varicella-zoster virus (which causes chickenpox and shingles), and Epstein-Barr virus (which causes infectious mononucleosis, also known as "mono"). After primary infection, this group of viruses can infect many-body systems and remain dormant in those cells for life. This is called "latent" infection. Latent infection can "reactivate" later in life to cause disease again. Primary infection with CMV is common and may be asymptomatic. Primary CMV is one of the common causes of mononucleosis, or flu-like syndrome, including fever, fatigue, tiredness, malaise, and other symptoms. Primary infection with CMV has been referred to as "heterophile-negative" mononucleosis because it causes an illness similar to the Epstein-Barr virus, but the results of the heterophile antibody test for EBV will be negative.

CMV infection occurs in people of all ages worldwide. Experts estimate that more than half of the adult population in the United States has been infected with CMV, and 80% of adults have had the infection by the time they are 40 years old. About one in 150 children is born with CMV infection (congenital cytomegalovirus).

Most women (about 30% of cases) who have infants with congenital cytomegalovirus infection pass it to the baby when their latent CMV reactivates (becomes active in the blood) during pregnancy. Only about 1%-7% of women are infected for the first time with CMV (primary CMV) during pregnancy, but 30%-40% of those will pass it on to the baby (congenital CMV). Congenital cytomegalovirus infection causes more complications the earlier in pregnancy that the virus is passed from the mother. About 10%-15% of babies with it will have symptoms at birth, and up to 60% of these will have serious complications later in life. Of babies who are infected but born without symptoms of CMV, some may develop deafness in the months after birth. Although infections are the minority of cases of miscarriage or pregnancy loss, CMV is the leading infection to cause miscarriages.

Direct contact with body fluids from an infected person exposes an individual to CMV. Most healthy children and adults do not experience any symptoms after infection with CMV. However, CMV may cause serious disease in people with a weakened immune system (such as those with HIV/AIDS or those taking medications that suppress immunity). CMV can cause retinitis (blurred vision and blindness), painful swallowing (dysphagia), pneumonia, diarrhea (colitis), and weakness or numbness in the legs.

Those at risk for CMV include young children and adults who work closely with them, people who undergo blood transfusions, people who have multiple sex partners, and previously uninfected people who receive a CMV-infected organ or bone marrow transplant.

People at risk for complications from CMV infection include pregnant women and their fetus (congenital cytomegalovirus infection) and those with a weakened immune system, such as people who are HIV-infected, individuals who are recent organ transplant recipients, cancer patients, or those who are taking medications that might suppress their immune system. Cell-mediated immunity is particularly important in preventing CMV reactivation and opportunistic infections.

CMV is contagious to individuals who have not been infected with it previously, but it is not especially easy to get infected. It is weakly contagious.

Infection with CMV is relatively common, but CMV does not spread very easily or through casual contact. Transmission requires direct contact with body fluids (such as saliva, urine, blood, semen, vaginal secretions, or breast milk) from an infected person. People may become infected with CMV through kissing, breastfeeding, sexual contact, injection drug use (sharing needles), or organ and bone marrow transplantation. CMV can be shed in body fluids for months and intermittently for life, especially in people with compromised immunity such as HIV disease, and it may not cause any symptoms. Transfusion-transmitted CMV is possible and may pose a risk to very immunosuppressed patients. For those at high risk who need a blood transfusion, CMV-negative or "leukoreduced" blood (in which white blood cells are filtered out) may be given. However, this does not eliminate all risks.

The incubation period between the time of getting the virus and the time that symptoms develop ranges from three to 12 weeks in cases of documented CMV infection after a transfusion of infected blood. CMV infection is usually benign, and there is no public health or medical reason to screen for it routinely. In addition, CMV may be shed intermittently for a very long time. This makes it difficult to say what the incubation period maybe with the commoner forms of transmission, such as contact with saliva, urine, and genital fluids.

The contagious period when the virus is being shed in body fluids may last for months in an infected individual, and the virus may be shed without symptoms at intermittent periods throughout life.

CMV transmission can occur during pregnancy through the placenta from the mother's blood or vaginal secretions at delivery. This may cause congenital CMV infection in the newborn. Approximately 1%-7% of women who have never been infected with CMV will have their primary (first) infection during pregnancy. Approximately one-third of them will pass the CMV infection to the baby.

Breastfeeding can transmit CMV to the baby after birth, but there is no need to avoid breastfeeding unless the baby is premature and the doctor recommends avoiding it. Freezing and pasteurization of breast milk can lower the risk of transmission but do not eliminate it.

Most people infected with CMV do not report a history of symptoms or complications and do not recall any contact with an infected person, so most people are unaware they have been infected. Acute CMV infection may mimic flu or infectious mononucleosis caused by Epstein-Barr virus or liver infection by hepatitis A, B, or C. Mono-like symptoms may include fever, malaise (feeling unwell), enlarged lymph nodes, sore throat, muscle aches, loss of appetite, enlarged liver or spleen, and fatigue. Hepatitis-like symptoms and signs may include appetite loss, yellow eyes (jaundice), nausea, and diarrhea.

In people with suppressed immune systems, CMV infection can attack different organs of the body and may cause blurred vision and blindness (CMV retinitis), lung infection (pneumonia), painful swallowing (esophagitis), diarrhea (colitis), inflammation of the liver (hepatitis), or inflammation of the brain (encephalitis), which may cause behavioral changes, seizures, or coma.

Infants with CMV infection at birth (congenital CMV) have no symptoms at birth, however, up to 20% of those without symptoms at birth will go on to develop deafness. Only about 10% of infants with congenital CMV show signs and symptoms of the infection or develop complications. Signs and symptoms of CMV at birth may include deafness, yellow skin, and eyes (jaundice), skin rash, premature birth, low birth weight, pneumonia, enlarged liver and spleen, microcephaly, or seizures.

Specialists usually become involved in the care of complicated cases of CMV or when preventive treatment is needed. Most complicated cases are in individuals who have weakened immune systems, usually due to HIV, cancer chemotherapy, or bone and organ transplantation. Because CMV may affect any organ system, multiple specialists may take part in the management, such as gastroenterologists (digestive system specialists) or pulmonologists (lung specialists). An infectious-disease specialist is often consulted as part of the care team to assist with monitoring, preventive antivirals, diagnosis, or treatment of active infection. Pediatric infectious-disease specialists may manage the care of infants with congenital CMV.

Most CMV infections go undiagnosed because the virus usually causes little to no symptoms. When a person is infected with CMV, antibodies (proteins) to the virus called IgM and/or IgG anti-CMV antibodies develop and stay in the body for the rest of the person's life. A blood test to detect the antibodies will be positive if the person has had a CMV infection. If the antibody test is negative, the person is considered to be uninfected with CMV.

If a "definitive" diagnosis of active CMV infection is necessary, the virus can be found in bodily fluids (such as blood, saliva, or urine) or body tissues by culturing (growing) the virus or detecting its DNA or specific protein called pp65 antigen by PCR tests. These tests are done if a person has signs and symptoms consistent with an active CMV infection. The virus can become reactivated from its latent state (latent infection) when a person's immune system has weakened. Tissue biopsy of affected body systems may sometimes show clumps of CMV in the cells, called "inclusion bodies." CMV inclusion bodies make the infected cell look like an "owl's eye" under the microscope.

These tests may be done if a woman develops symptoms of CMV infection during pregnancy in order to provide counseling and possible treatment for congenital CMV. They may also be done to diagnose a congenital CMV infection if CMV is detected in a newborn's urine, saliva, blood, or other body tissues within two to three weeks after birth.

There is no cure for CMV, and treatment for CMV infection is not necessary for healthy children and adults. Those at very high risk of developing severe CMV infection may be placed on antiviral medication to help prevent CMV disease. This pretreatment is called prophylaxis. This method has helped reduce the number of CMV infections in these patients.

The antiviral medications against CMV include the following:

• Ganciclovir (Cytovene) is the first antiviral medication approved for the treatment of CMV infection. Ganciclovir, given intravenously, is the drug of choice for the treatment of CMV infection. Side effects include fever, rash, diarrhea, anemia, and low white blood cell and platelet counts.
• Valganciclovir (Valcyte) is an oral medication that is activated to ganciclovir in the body and is widely used to prevent CMV infection (prophylaxis). It is used in selected patients for the treatment of CMV infection and is as effective as intravenous ganciclovir in milder cases.
• Foscarnet (Foscavir) is active against CMV by a different mechanism than ganciclovir and is used to treat infections with CMV that are resistant to ganciclovir. It is a second-line therapy for patients who do not tolerate ganciclovir treatment. Foscarnet is toxic to the kidneys and can cause seizures due to an imbalance of minerals and electrolytes.
• Cidofovir (Vistide) is an alternative therapy for patients who have failed ganciclovir and foscarnet treatment. Its use is limited due to toxicity to the kidneys. It is used mainly for the treatment of CMV infection of the eye (retinitis) in patients with acquired immune deficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV).
• CMV immune globulin contains antibodies (proteins) that are specific to CMV. It may be prescribed to prevent CMV infection in high-risk lung transplant patients when given in addition to ganciclovir. It is also used with ganciclovir to treat CMV pneumonia.

No antiviral drug is currently available for the prevention of congenital CMV infection. However, some infants who have infections involving the central nervous system (brain and spinal cord) may benefit from treatment. Some evidence shows that ganciclovir may prevent hearing loss and developmental problems in infants who have severe symptoms of congenital CMV infection. Because of the serious side effects of ganciclovir, a pediatric infectious-disease specialist should be consulted.

There are no home remedies proven to be effective in treating CMV infection.

CMV rarely causes complications in healthy people. The risk of complications is higher in individuals with weakened immune systems (see above sections). CMV can infect the stomach and intestines, causing fever, abdominal pain, blood in the stool, and inflammation of the colon (colitis). Inflammation can also occur in the liver (hepatitis), lung (pneumonitis), and brain (encephalitis). Infection in the eye (retinitis) can cause blindness. Newborns with congenital CMV infection can develop hearing and vision loss, mental disability, and seizures.

Along with influenza viruses, Campylobacter, and other pathogens, CMV is one of the infections associated with Guillain-Barré syndrome.

Latent CMV infection only rarely reactivates in healthy adults. Adults at risk for life-threatening reactivation with CMV disease include those who are immunosuppressed due to advanced HIV disease, those who receive intensive chemotherapy or immune-suppressing drugs, or those who receive organ or bone marrow transplants.

There is increasing evidence from both animal and human studies that CMV-induced inflammation in blood vessels may play a role in atherosclerosis, or "hardening of the arteries." Atherosclerosis may cause heart disease and stroke. Ischemic heart disease has been observed to occur more often in human and animal organ transplant recipients with CMV.

There is some debate, but CMV seems to be associated with severe exacerbations of ulcerative colitis (UC), which is a condition that may require anti-inflammatory and immune-suppressing drugs. Some studies have found CMV in the colon tissue of up to 40% of those with severe UC that is not responding to corticosteroid anti-inflammatory treatment. People with steroid-resistant UC may need total removal of the colon (colectomy). It is not clear whether CMV is an innocent bystander in those with UC, although there is some evidence antiviral treatment may reduce colectomy in steroid-resistant cases. In these cases, CMV is found in high quantity: CMV DNA detected by PCR is often > 250 copies/mg of tissue.

Most healthy children and adults who develop symptoms will recover without any complications. Fatigue may last for several months after the asymptomatic infection is over. Prognosis depends on how severe the CMV infection is and the person's underlying immune system. Giving antiviral medication to people who have a very weak immune system, such as bone marrow transplant recipients, improves prognosis.

Approximately 80% of infants with congenital CMV infection grow up healthy without complications and do not need treatment with antiviral medication. However, one in five infants born with CMV infection will have permanent hearing loss and developmental disabilities. Children diagnosed with congenital CMV infection should have regular vision and hearing screenings because early detection can improve outcomes.

Because CMV is a common virus, it is not always possible to prevent infection. Pregnant women should take precautions to prevent congenital CMV infection. Steps to reduce the risk of CMV infection include the following:

• Washing hands frequently for 15-20 seconds, especially when in contact with young children, changing diapers, and handling toys, or when exposed to oral secretions
• Avoiding sharing food, drinks, and eating utensils with others
• Avoiding contact with saliva when kissing a child
• Cleaning toys, countertops, and surfaces that come into contact with a child's urine or saliva
• Using condoms during sexual contact

There is no available vaccine for preventing congenital CMV infection or CMV disease in individuals with suppressed immune systems. However, researchers are studying experimental vaccines in humans. It may be a number of years before there is a Food and Drug Administration (FDA)-approved CMV vaccine.

In those with HIV/AIDS, CMV most often reactivates when the T cell count (T helper cells, or CD4 cells) drops below 50 cells/microL. One of the most common types of CMV disease in people with advanced HIV/AIDS is CMV retinitis, which may cause permanent blindness. Once highly active antiretroviral therapy (HAART, or ART) was introduced in 1996, the incidence of CMV retinitis dropped by almost 90%. However, some individuals still develop CMV. Some are not able to tolerate ART or develop resistance, or simply do not adhere to treatment. CMV retinitis is a marker for 60% increased overall mortality in patients with HIV. For those whose T cell count remains low, overall mortality is 100%. In those whose T cells are under 100/microL, a dilated eye exam is recommended every six months for CMV; if T cells are under 50/microL, screening should occur every three months. CMV reactivation in these patients is not limited to the eye and may be difficult to diagnose. Other manifestations of CMV in advanced HIV disease include encephalitis, peripheral nerve damage, and disease of the gastrointestinal tract (esophagitis, enteritis, or colitis).

In organ and marrow transplant recipients, CMV is a common cause of disease. Bone marrow recipients require more intensive chemotherapy and immune suppression for both cure of the disease in patients requiring the transplant and to prevent rejection of the new bone marrow. They are thus at greater risk of serious CMV disease than are other organ recipients. The likelihood of CMV disease in solid organ transplants ranges from 10%-30% depending on the type of organ, the level of immune suppression, and "CMV mismatch" (see below). In bone marrow transplants, allogeneic (another person as donor) transplants have a 30% likelihood of CMV disease, while autologous (self as donor) transplants have a 5% likelihood. Transplant recipients are screened for the presence of CMV-specific antibodies, which indicate whether they have a latent infection (seropositive) or have never had it (seronegative).

CMV may cause acute primary disease if the recipient never had CMV and acquires it after transplantation. The acute primary disease may also occur if the recipient is "CMV-seronegative" and the transplanted tissue or marrow contains latent CMV (the donor was "CMV-seropositive"). CMV-positive to CMV-negative transplantation may be referred to as "CMV mismatch" or "CMV D+/R-." A CMV-positive recipient's latent CMV may reactivate during the first three to six months of intensive immune suppression therapy.

CMV may cause either a viral syndrome or tissue invasive disease in these patients. CMV syndrome occurs within the first four months and includes fever, malaise, and upper gastrointestinal pain most commonly. Less often, diarrhea (enterocolitis) may occur. Suppression of bone marrow with decreased white blood cells (leukopenia) and platelets is common. Elevated liver enzymes (hepatitis) may occur, as well. Tissue invasive disease may include CMV pneumonia, which can be severe. Unlike HIV, CMV neurologic disease and retinitis are very unlikely in the transplant setting.

CMV also has been associated with ischemic heart disease in organ transplant recipients.

Donor blood and organs are screened for CMV antibodies as part of the donor screening process. Screening and antiviral therapy (for prevention or treatment of active disease) may be necessary after CMV D+/R- transplantation. Screening for CMV is performed by regular testing for CMV DNA in the blood. While CMV may be found in the blood even without active infection, its presence in these patients, especially with a rising trend, suggests active infection. If the invasive disease is suspected, CMV DNA can be sought in lung fluid (pneumonia), and tissue can be stained for the CMV virus. CMV can often be detected in tissue by the way the virus particles (inclusion bodies) give cells a characteristic "owl eye" appearance.