CMV – cytomegalovirus

How is it tested?
CMV testing is done to find out whether a person has a current or recent CMV infection. It can also be done to find out whether someone has ever been exposed to the virus. CMV testing includes either measuring anti-CMV antibodies, immune proteins produced in response to exposure to the virus, or detecting the virus itself. The virus is detected during active infection by CMV culture or by detecting the virus’s genetic material (its DNA).
In the United States 50-85% of adults have been infected with CMV; in Italy the estimate is about 80%. Most people are infected as children or young adults without any significant symptoms or health problems. During active infection CMV is found in many body fluids, including saliva, urine, blood, breast milk, semen, cervical secretions and cerebrospinal fluid. It is easily spread by direct physical contact or by contact with infected objects such as nappies or toys. After the primary infection has resolved, CMV remains dormant or latent, like the other members of the herpesvirus family. Cytomegalovirus remains in a person for the rest of their life without causing any symptoms, but it can reactivate if the immune system is weakened.

CMV can cause different problems in the following three situations:

In young adults, primary infection can cause a flu-like illness or an illness similar to mononucleosis. This causes symptoms such as severe tiredness, fever, chills, muscle aches and/or headache, which usually resolve within a few weeks.

In newborn babies, primary infection can cause serious physical and developmental problems. If the mother catches a primary infection during pregnancy, she passes it on to the baby across the placenta. Most infected babies (about 90%) appear perfectly normal at birth but may develop sight and hearing problems, pneumonia, seizures and/or delayed mental development a few months later. Some babies may be stillborn, while others may have symptoms at birth such as jaundice, anaemia, an enlarged spleen or liver and a small head. Some of these signs and symptoms will resolve over time, but others may persist.

In patients with a weakened immune system, CMV can cause serious illness and death. This includes people with HIV/AIDS, people who have had a solid organ or bone marrow transplant, and patients having chemotherapy for cancer. Patients with a weakened immune system who are infected for the first time may have more severe symptoms, and the CMV infection may remain active. Those previously exposed to CMV may have a reactivation of the earlier infection. This can damage their eyes (causing inflammation of the retina that can lead to blindness), their intestinal tract (causing bloody diarrhoea and abdominal pain), their lungs (causing pneumonia with a dry cough and shortness of breath) and their brain (causing encephalitis). The spleen and liver may also be involved, and in patients who have had an organ or bone marrow transplant this can cause a degree of rejection.
Active CMV also further suppresses the immune system, making other, so-called secondary infections, such as fungal infections, more likely.

How is the sample collected for testing?
The sample required depends on the patient’s state of health and on the type of test to be done: detecting antibodies or detecting the virus itself. The antibody test requires a blood sample, obtained by inserting a needle into a vein in the arm. The virus can instead be detected in a variety of samples such as urine, blood or sputum. Some samples may need a special collection procedure, such as amniotic fluid, duodenal fluid, cerebrospinal fluid or body tissue (biopsy).

Is any preparation needed to ensure the quality of the sample?
No preparation is needed

How is it used?
How is the virus detected?
When is it requested?
What does the result mean?

How is it used?
There are several methods for identifying cytomegalovirus (CMV) infection:

Antibody tests
Two different types of anti-CMV antibodies can be found in the blood: IgM and IgG. IgM antibodies are the first produced by the body in response to CMV infection. They are present in most people one to two weeks after first exposure to the virus. IgM production rises for a short time and then falls. After a few months the level of anti-CMV IgM usually falls below detectable levels. New IgM is produced when latent CMV reactivates. IgG antibodies, on the other hand, are produced a few weeks after the infection starts, to provide long-term protection. IgG levels rise during active infection and stabilise when the infection resolves and the virus becomes inactive. After first exposure to CMV, IgG antibodies remain measurable in the blood for life. The anti-CMV IgG test can be used together with the IgM test to confirm the presence of the virus or a recent or past CMV infection.

The anti-CMV antibody test can be used to determine the degree of immunity to the virus in pregnant women, in patients before an organ or bone marrow transplant and in people diagnosed with HIV/AIDS. Since CMV infection is very widespread and causes few problems in people with an intact immune system, general population screening is rarely done.

Anti-CMV IgM and IgG testing and viral detection of CMV can be used to diagnose primary CMV infection in young adults, pregnant women and patients with a weakened immune system who have mononucleosis-like or flu-like symptoms. By comparing the absence or presence of IgM and IgG in the same sample, the doctor can distinguish between primary infection, latent infection and reactivation of CMV in patients with symptoms.

How is the virus detected?
Viral detection involves looking for CMV in a sample of blood, body fluid or tissue. This can be done by growing the virus in a suitable environment (culture) or by detecting the virus’s genetic material (CMV DNA).

Viral culture is the traditional method of detecting the virus. It involves inoculating cultures of human cells with the patient’s sample and incubating the culture in a suitable environment. Positive cultures can often be seen in less than 2 or 3 days, while negative ones must be kept for 3 weeks to confirm the absence of CMV, because the virus may be present in small amounts in the original sample and/or the specific strain of CMV may grow slowly.

There are other methods for detecting and measuring the amount of viral DNA in a patient’s sample. The test can be qualitative, showing whether CMV is present or absent, or quantitative, measuring how much virus is present.

The choice of test and of the samples to use depends on the patient’s age, symptoms and general state of health, the doctor’s clinical findings and whether organ involvement is suspected. For example, a newborn baby’s urine can be used for CMV culture and detection, while in a pregnant woman a blood test for IgG and IgM may be done to detect antibodies and distinguish between a current primary infection and a past infection. A second IgG test on a sample taken 2 or 3 weeks after the first (called a convalescent sample) is done to see whether antibody levels are rising or falling, which would indicate a recent CMV infection.

Immunocompromised patients with active CMV can be monitored with a variety of CMV tests. Most doctors prefer a quantitative test that allows the amount of virus present (viral load) to be monitored. They may also use a quantitative test to monitor the patient’s response to antiviral treatment.

When is it requested?
The CMV test may be requested, together with tests for flu, mononucleosis and EBV (Epstein-Barr virus), when a young adult, a pregnant woman or an immunocompromised patient has flu-like or mononucleosis-like symptoms, such as tiredness, swollen lymph nodes and fever. It may be done when the doctor suspects that the patient may have an active primary CMV infection or a reactivation of the virus.
CMV tests may be requested when a person is immunocompromised and there are signs of infection of the lungs, eyes, liver, spleen and/or gut; they are also requested to assess the effectiveness of antiviral treatment.

The CMV test may also be done on a newborn baby who has jaundice, anaemia, an enlarged spleen and/or liver and a small head, or on a newborn with sight or hearing problems, pneumonia, seizures and/or signs of delayed mental development.

A patient who is to have a solid organ or bone marrow transplant has anti-CMV IgG and IgM testing to establish whether they have ever been exposed to CMV in the past.

What does the result mean?
Great care must be taken in interpreting CMV test results, and the doctor assesses them in the light of the clinical findings. Sometimes it can be difficult to distinguish between active and latent infection. This is for several reasons, including:

A healthy person who has been infected with CMV will continue to carry the virus for life. CMV can reactivate repeatedly, often subclinically, releasing small amounts of virus into body fluids but without causing symptoms.
A newborn baby and an immunocompromised person may not have a strong antibody response after CMV infection: their IgG and IgM levels may be lower than expected during active CMV infection.
The virus may not be present in large enough numbers, particularly in a given fluid or tissue, to be detected.

Antibody tests
If both IgG and IgM are present in a patient with symptoms, it may be a recent primary infection or a reactivation of a past infection. This can be confirmed by measuring IgG levels again two or three weeks later. A high IgG level is not as important as a rising level. A 4-fold increase between the first and second samples indicates active CMV infection (primary or reactivation).

If only IgM is present, the patient may indeed have been infected recently. If a newborn baby has IgM antibodies, this indicates congenital CMV infection. If a patient has symptoms but low or undetectable IgG and/or IgM levels, the condition may not be linked to CMV, or the patient’s immune system may not be responding properly and not producing enough antibodies even though CMV is present.

Viral detection
If the patient has symptoms and the culture is positive for cytomegalovirus, the patient may have an active CMV infection. A negative culture indicates that the patient’s symptoms are due to a cause other than CMV.

If a CMV DNA test is positive, the virus is currently present. High levels of viral DNA indicate active infection; low levels still indicate CMV infection, but it may be a condition without symptoms. A falling concentration (falling viral load) indicates that the body is responding to antiviral treatment. Levels that do not fall during antiviral treatment may indicate resistance to the treatment used. Negative results do not rule out CMV infection: the virus may be present in very small numbers or may not be present in the sample tested.