CMV IgG Avidity

Cytomegalovirus (CMV) is a common viral pathogen that can cause significant health complications, particularly in pregnant women and immunocompromised individuals. Understanding the timing of a CMV infection is crucial for effective clinical management, which brings into focus the role of CMV IgG avidity testing. This type of testing measures the strength of the bond between CMV IgG antibodies and antigens, providing insights into whether an infection is recent or longstanding. CMV IgG avidity is particularly valuable in scenarios where determining the age of infection can influence clinical decisions, such as preventing congenital transmission or managing post-transplant complications. 

What is CMV?  [3., 5., 6., 7.] 

Cytomegalovirus (CMV) is a highly prevalent virus belonging to the herpesvirus family.  It has the following key characteristics and clinical implications:

Viral Structure and Replication:

CMV is a double-stranded DNA virus with a relatively large genome, enabling it to encode numerous proteins involved in viral replication and immune evasion. 

It replicates slowly and can establish lifelong latent infection within host cells, periodically reactivating under conditions of immunosuppression.

Transmission and Epidemiology:

CMV is transmitted through bodily fluids like saliva, urine, breast milk, semen, and can also cross the placenta during pregnancy.

It is highly prevalent, with seroprevalence rates of 30-100% in different populations worldwide.

Primary CMV infection is most commonly asymptomatic in immunocompetent individuals. 

Clinical Manifestations:

In immunocompetent individuals a primary infection with CMV is typically asymptomatic, though some may develop a mononucleosis-like syndrome.  This syndrome, similar to that caused by Epstein-Barr virus (EBV), includes fever, fatigue, and malaise. 

However, CMV-related mononucleosis more often involves fever, myalgia, and arthralgia, and less frequently causes exudative pharyngitis, splenomegaly, and lymphadenopathy.  

After primary infection, CMV establishes a lifelong latent infection that is usually well-controlled by the immune system.  Severe manifestations of CMV infection in immunocompetent persons are rare and can occur due to either primary infection or reactivation of the latent virus.

However, in babies, CMV is a potentially serious infection.  Congenital CMV infection can lead to severe birth defects like hearing loss, vision impairment, developmental delays, and organ damage.

In immunocompromised patients (transplant recipients, HIV/AIDS), CMV reactivation can cause life-threatening pneumonia, colitis, retinitis, hepatitis, and other end-organ diseases.

Diagnosis of CMV:

CMV infection is typically diagnosed by detecting viral DNA (PCR), antigens (pp65), or IgM/IgG antibodies in blood or other body fluids.

In pregnant women, IgG avidity testing helps distinguish primary from recurrent infection to assess fetal risk for birth defects.

Treatment for CMV:  [14.] 

No treatment is required for healthy individuals with primary CMV infection. 

Antiviral drugs like ganciclovir, valganciclovir, foscarnet are used to treat severe CMV disease in immunocompromised patients and congenital infections. 

New antivirals (letermovir, maribavir) and vaccines are under investigation for prevention and treatment.

In summary, CMV is a ubiquitous herpesvirus that establishes lifelong latent infection. While often asymptomatic in healthy individuals, it can cause severe congenital defects and life-threatening disease in immunocompromised patients, necessitating antiviral treatment and prevention strategies. 

What is CMV IgG?  [9.] 

Immunoglobulins (Ig), or antibodies, are glycoproteins produced by plasma cells in response to specific antigens.  B cells, upon encountering an antigen, differentiate into plasma cells, which produce antibodies targeting that specific antigen. 

The immune system retains memory of these antigens through memory B cells, which can rapidly respond to subsequent exposures.  There are five main types of immunoglobulins: IgG, IgA, IgM, IgD, and IgE.

IgG is the most abundant immunoglobulin in serum, with a concentration of approximately 9 mg/mL.  It is a monomer composed of two heavy chains and two light chains, forming a Y-shaped structure. 

Each IgG molecule has two identical antigen-binding sites, allowing it to effectively neutralize pathogens. IgG plays a critical role in the secondary immune response by playing a crucial role in neutralizing toxins, viruses, and bacteria, opsonizing them for phagocytosis, and activating the complement system.  

IgG antibodies can also activate the classical complement pathway. 

It is unique among immunoglobulins as it can cross the placenta, providing passive immunity to the fetus.

IgG antibodies to the CMV virus typically provide lifelong immunity.  [10.] 

Dangers of CMV Infections in Pregnancy  [4., 15.]

CMV infection during pregnancy can pose risks to the unborn baby, especially if the mother experiences a primary CMV infection.  

The risk of congenital infection is highest following primary maternal infection, varying between 30% in the first trimester and up to 70% in later trimesters.  [4.]

Most infants with congenital CMV do not have symptoms at birth, but some may develop long-term problems such as hearing loss, vision impairment, developmental delays, or intellectual disability.  Specific complications can include low birth weight, microcephaly (small head size), seizures, jaundice, petechiae (small red spots), and enlarged liver and spleen.  

While most congenital CMV infections are asymptomatic, a small percentage of infected babies can experience severe neurodevelopmental consequences, making CMV the leading cause of non-genetic congenital hearing loss.  

Pregnant women with exposure to young children or those working in childcare settings are at higher risk due to increased chances of contracting CMV from bodily fluids like saliva or urine.

CMV IgG Avidity Testing

The presence of CMV IgG antibodies indicates a previous exposure to and immunity against cytomegalovirus (CMV).  

In pregnant women, a positive CMV IgG may indicate previous CMV exposure before conception, or it may indicate a recent exposure during pregnancy.   

Determining a woman’s exposure to the CMV virus is essential because the risk of intrauterine transmission of cytomegalovirus (CMV) to her baby during pregnancy is much greater than for women who had circulating CMV antibodies before conception.

What is CMV IgG Avidity Testing?  [12.] 

CMV avidity testing measures the binding strength or avidity of IgG antibodies against cytomegalovirus (CMV) antigens.  It helps distinguish between recent primary CMV infection and past infection or reactivation. 

The principle behind avidity testing is that IgG antibodies gradually increase their binding strength or avidity to antigens over the course of 6 months following a primary infection.  This test is particularly useful during pregnancy to identify women with recent primary CMV infection, who are at an increased risk for vertical transmission to the fetus.

Low avidity indicates a primary infection within the preceding 3 to 4 months, with an increased risk of intrauterine transmission to the fetus or newborn.  In contrast, high avidity during the first trimester excludes a postconception primary infection and indicates a low risk of intrauterine transmission. 

The avidity assays use protein denaturing agents like urea or guanidine to dissociate low-avidity antibodies from the antigen.  [12.] 

The anti-cytomegalovirus IgG avidity test is currently considered the most reliable investigation to identify primary CMV infection in pregnant women and assess the risk of congenital transmission.  Various commercially available CMV IgG avidity assays from different manufacturers are available, which can be explored in this article. 

Need for IgG Avidity Testing in Pregnancy  [10.] 

A positive CMV IgG in pregnancy does not distinguish between a recent primary infection (higher risk of congenital transmission) or a past infection.  Therefore, following up a positive CMV IgG test with CMV IgG avidity testing is recommended to determine the timing of infection. 

Laboratory Testing for CMV IgG Avidity

Laboratory testing for CMV IgG avidity is a specialized diagnostic tool used to help determine the timing of a CMV infection in pregnant people.

Laboratory Testing, Sample Collection, and Test Preparation 

Laboratory tests for CMV IgG Avidity involve serological assays that detect the binding strength of IgG antibodies against CMV in the blood.  This requires a blood sample acquired through venipuncture. 

No special preparation is typically required, although it is important to consult with the ordering provider, especially if the individual is using certain antiviral medications or supplements.  

Interpreting CMV IgG Avidity Test Results  [12.] 

CMV IgG avidity testing measures the binding strength of IgG antibodies to CMV antigens, helping distinguish recent primary CMV infection from past infection or reactivation. 

Low avidity indicates a recent primary infection within the preceding 3-4 months, suggesting an increased risk of intrauterine transmission to the fetus in pregnant women.  

In contrast, high avidity excludes a primary infection within the past 3-4 months and indicates a lower risk of congenital transmission. 

The specific avidity index cutoffs for low vs high avidity can vary slightly between different commercial assay manufacturers.  

A high avidity result is more clinically meaningful, as it essentially rules out a recent primary infection during pregnancy that could lead to congenital CMV.  

Overall, CMV IgG avidity testing is considered the most reliable tool for estimating the timing of CMV infection and assessing transmission risk, particularly during pregnancy.

Management Strategies for Pregnant Women Who Test Positive for CMV IgG

Management of a CMV IgG positive result in pregnancy involves several strategies to ensure both the mother's and the baby's health. 

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If the test indicates past immunity, regular monitoring may suffice.  However, if there's any indication of a recent infection (suggested by symptoms or a positive CMV IgM test), further diagnostic steps, such as amniocentesis to test for CMV DNA in amniotic fluid, might be necessary.  [2.] 

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The CMV transmission risk to pregnant women is highest in young children.  Preventive measures including hygiene practices like hand washing and avoiding contact with young children's saliva or urine (common sources of CMV), are recommended to minimize the risk of acquiring a new CMV infection.  [3.] 

CMV IgG Avidity Related Biomarkers and Additional Tests

While CMV IgG avidity testing is crucial for determining the timing of CMV infections, it is often part of a broader diagnostic approach. 

• CMV IgM antibody test: to help distinguish between recent/active and past CMV infection, as IgM is produced earlier in the course of infection 

• CMV IgG antibody test: measures IgG antibodies; this test often precedes an IgG avidity test

• CMV PCR or antigen tests: to directly detect and quantify the presence of CMV viral DNA or antigens in blood or body fluids, indicating active viral replication 

• CMV viral culture: to attempt to grow and isolate the virus from samples like blood, urine or amniotic fluid to confirm active infection 

• Amniocentesis for CMV PCR: in pregnant women with suspected primary CMV infection, amniocentesis can detect viral DNA in amniotic fluid to check for congenital infection 

• Complete blood count (CBC): to check for CMV-related cytopenias like anemia or thrombocytopenia 

• Liver function tests: as CMV can cause hepatitis, especially in immunocompromised patients

When to Opt for Additional Testing: Guidelines for Clinicians

Clinicians must decide on additional testing based on the clinical scenario and initial test results.

In cases where CMV IgG avidity suggests recent infection, confirming this with PCR and IgM tests can provide a fuller picture of the current infection status.

In pregnancy, further testing is crucial if there's any indication of a recent infection to prevent congenital transmission.  In transplantation and immunocompromised patients, ongoing monitoring with PCR is recommended to detect and manage CMV reactivation promptly.

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