How should I interpret cytomegalovirus (CMV) serology results (immunoglobulin M and immunoglobulin G), and when are IgG‑avidity testing or quantitative polymerase chain reaction (PCR) needed?

CMV Serology Interpretation

Direct Answer

Interpret CMV serology based on IgG and IgM patterns: positive IgG alone indicates past exposure/immunity, while positive IgM requires IgG avidity testing to distinguish primary infection from false-positive results or reactivation. 1

Basic Interpretation Framework

IgG Positive, IgM Negative

• Indicates past CMV exposure with established immunity 1
• Over 90% of adults have positive CMV IgG, representing prior infection 1
• In pregnant women, this pattern suggests immunity with low risk of congenital CMV 1
• For transplant risk stratification, document both donor and recipient IgG status 1

IgG Positive, IgM Positive

• IgM has poor positive predictive value and requires IgG avidity testing for accurate interpretation 2, 3
• IgM positivity in asymptomatic pregnant women has only 16.4% positive predictive value for primary infection 2
• IgM positivity with clinical symptoms or ultrasound abnormalities increases positive predictive value to 35-37% 2
• False-positive IgM occurs frequently with Epstein-Barr virus infection and other immune activation states 1, 3

IgG Negative, IgM Positive or Negative

• Indicates no prior CMV exposure (seronegative status) 1
• Critical for transplant risk assessment when recipient is seronegative 1

When IgG Avidity Testing Is Essential

Mandatory Situations

• Any pregnant woman with positive IgM must have IgG avidity testing 1, 4, 2
• Pregnant women with fetal ultrasound abnormalities and positive IgM 2, 5
• Immunocompetent adults hospitalized with acute illness and positive IgM 3

Avidity Interpretation

• Low IgG avidity confirms primary infection within the past 3-4 months 4, 2, 6
• High IgG avidity excludes primary infection in the preceding 3-4 months 4, 6
• High CMV IgM antibody titer strongly predicts low IgG avidity (primary infection) 6
• Avidity testing failed to date infection in only 1% of cases when combined with IgM, versus 26% when used alone 4

When Quantitative PCR Is Required

Immunocompromised Patients

• CMV DNA quantitative PCR is the preferred test instead of serology for immunocompromised patients and transplant recipients 1
• Serology is unreliable in immunocompromised hosts because IgM may be absent despite active infection 1
• Weekly screening with CMV DNA PCR from day 10 to day 100 post-transplant enables preemptive treatment 1
• Initiate treatment when ≥2 consecutive PCR tests are positive or any antigenemia is detected 1

Suspected End-Organ Disease

• Order CMV DNA PCR from the affected site: cerebrospinal fluid for CNS disease, respiratory specimens for pneumonitis, colon biopsy tissue for colitis 1
• Positive blood CMV DNA indicates infection but not necessarily end-organ disease—tissue diagnosis required 1

Pregnancy with Suspected Fetal Infection

• Amniotic fluid CMV DNA testing is required when fetal infection is suspected, regardless of maternal IgM status 5
• Negative maternal IgM does not exclude fetal CMV infection—ultrasound abnormalities warrant amniocentesis 1, 5

Neonatal Diagnosis

• Real-time PCR on neonatal urine or saliva is the gold standard for diagnosing congenital CMV with 100% sensitivity 1

Clinical Algorithm by Population

Immunocompetent Patients

1. Order CMV IgM and IgG as first-line test 1
2. If IgM positive, immediately order IgG avidity testing 4, 2
3. Low avidity = primary infection; high avidity = false-positive IgM or reactivation 4, 6
4. If symptomatic with positive IgM, consider CMV DNA PCR in blood to confirm active viremia 3

Pregnant Women

1. Screen with IgM and IgG 1
2. If IgM positive, IgG avidity is essential regardless of symptoms 1, 2
3. If ultrasound abnormalities present, perform amniocentesis for CMV DNA even if IgM negative 1, 5
4. Positive IgG alone = immunity, low risk of congenital CMV 1

Transplant Recipients

1. Do not use serology for monitoring—use CMV DNA quantitative PCR 1
2. Pre-transplant: document IgG status of donor and recipient for risk stratification 1
3. Post-transplant: weekly CMV DNA PCR or pp65 antigenemia from day 10-100 1
4. Treat when viral load exceeds institutional threshold (typically 4,000-10,000 IU/mL) or ≥2 consecutive positive PCRs 1

Inflammatory Bowel Disease Patients

1. Consider CMV testing in ulcerative colitis resistant to immunosuppressants 1
2. Obtain colon biopsy with immunohistochemistry (IHC)—gold standard for tissue-based CMV disease with 78-93% sensitivity and 92-100% specificity 1, 7
3. Serum CMV DNA PCR >250 copies/mL has 87.9% specificity but only 44.3% sensitivity 1

Critical Pitfalls to Avoid

• Never interpret positive IgM as definitive evidence of primary infection without IgG avidity testing 2, 3
• Never assume negative IgM excludes fetal CMV infection in pregnancy—maternal reactivation can occur with negative IgM 1, 5
• Never rely on serology alone in immunocompromised patients—viral load testing is essential 1
• Never delay amniocentesis in pregnant women with fetal abnormalities based on negative maternal IgM 1
• Never use a single positive PCR to initiate treatment—require ≥2 consecutive positive tests or correlate with clinical findings 1
• Never assume positive tissue PCR alone confirms CMV disease—correlation with histology/IHC and blood PCR is necessary to distinguish disease from colonization 1