Varicella Zoster Virus (VZV) Serology

Varicella zoster virus (human herpesvirus 3) causes chickenpox (varicella) as primary infection, then persists in dorsal root and cranial nerve ganglia and reactivates as shingles (herpes zoster). Serology measures VZV IgG (immunity) and VZV IgM (recent infection or reactivation) by enzyme immunoassay or chemiluminescence, and IgG avidity in some laboratories.

The fluorescent antibody to membrane antigen (FAMA) test is the reference method for immunity but is rarely used. Diagnosis of active lesions is by PCR of vesicle fluid, scrapings or swab, and CSF PCR for neurological disease.

Before vaccination, varicella affected almost all children by 10 years in temperate regions. In tropical regions a larger proportion of adults remain susceptible, with 10 to 20% of adults non-immune. Varicella in adults, pregnant women and immunocompromised people is severe, with pneumonitis in 5 to 15% of adult cases and mortality of about 10 to 30 times higher than in children.

Herpes zoster affects about 1 in 3 people in their lifetime, rising to half of those reaching 85 years, and postherpetic neuralgia complicates 10 to 20% (up to 30% in those over 70).

Indications. Assessment of immunity in pregnancy, healthcare workers, immunocompromised patients and before transplant or immunosuppressive therapy. Contacts of chickenpox who are pregnant, newborn or immunosuppressed (urgent IgG result to decide on prophylaxis). Diagnosis of atypical or retrospective varicella or zoster, and zoster sine herpete. Congenital or neonatal varicella.

Aseptic meningitis, encephalitis, cerebellitis, vasculopathy or myelitis (CSF antibody and PCR). Pre-vaccination screening.

Specimen. Serum 1 mL, no fasting. Stable for days at 2 to 8 °C. Vesicle fluid or lesion swab in viral transport medium for PCR. CSF 0.5 to 1 mL for PCR and intrathecal antibody index.

Reference values (assay dependent). VZV IgG: negative under 50 to 100 mIU/mL (or index under 0.9), equivocal, positive over 150 to 165 mIU/mL (protective). VZV IgM: negative (index under 0.9). VZV DNA: not detected.

Interpretation.

• A positive IgG in an adult usually indicates immunity, although commercial assays have lower sensitivity for vaccine induced antibody, and a negative result in a vaccinated person does not always mean non-immunity. Two vaccine doses are accepted as evidence of protection.
• A history of chickenpox in adults is a good predictor of immunity (over 97%) and testing is not always required, except in pregnancy and in the immunocompromised.
• IgM may be absent in reactivation and is not reliable, so PCR of lesion or CSF is the test for zoster.
• CSF VZV PCR positive, or intrathecal VZV IgG, with neurological symptoms: VZV meningitis, encephalitis, myelitis or vasculopathy, which can occur without rash.
• In congenital varicella syndrome (maternal infection before 20 weeks), the infant has limb hypoplasia, scarring, chorioretinitis and cortical atrophy, and IgM or PCR is positive.

Critical values and findings needing immediate action.

• Pregnant, immunosuppressed or newborn contact of chickenpox with a negative VZV IgG: urgent prophylaxis with varicella zoster immunoglobulin within 10 days of exposure (the sooner the better), and oral aciclovir or valaciclovir from day 7 after exposure if immunoglobulin is not available.
• Chickenpox in pregnancy, adults or immunosuppressed patients (cough, dyspnoea, hypoxia, haemorrhagic rash): intravenous aciclovir, admission, and chest imaging for pneumonitis.
• Neonate whose mother developed rash between 5 days before and 2 days after delivery: varicella zoster immunoglobulin and aciclovir.
• Herpes zoster involving the ophthalmic division of the trigeminal nerve (including nasal tip, Hutchinson sign): ophthalmology review and antiviral therapy within 72 hours.
• Ramsay Hunt syndrome (ear vesicles, facial palsy, vertigo): antivirals and steroids within 72 hours.
• Disseminated zoster or encephalitis in an immunocompromised patient: intravenous aciclovir.

Interferences and pitfalls.

• Commercial IgG assays are less sensitive for vaccine induced immunity, so a negative result after two documented doses should be interpreted with the vaccine history, and revaccination is not usually needed.
• Passive antibody from blood products or immunoglobulin gives false positive IgG for several weeks to months, so serology is interpreted with the transfusion history.
• Rapid assays (latex agglutination) are quick, with variable sensitivity, and urgent contact management usually needs a laboratory IgG.
• VZV IgM is less reliable than PCR for diagnosis, with false positives from cross-reactivity with herpes simplex virus and Epstein-Barr virus.
• Neonatal and infant (under 12 months) IgG reflects maternal antibody.
• PCR from fresh vesicle is highly sensitive, but scabs and old lesions give lower yield. PCR distinguishes wild type from vaccine strain by sequencing.
• Zoster without rash is diagnosed with PCR or intrathecal antibody, because the clinical picture is nonspecific.
• Live attenuated vaccine is contraindicated in pregnancy and severe immunodeficiency. A non-live recombinant zoster vaccine is available for older adults and the immunocompromised.

Special groups.

• Pregnancy: check immunity at the first antenatal visit when history is uncertain. Non-immune women are vaccinated after delivery and avoid contact in pregnancy. Maternal pneumonitis is a serious risk.
• Neonates: risk is highest when maternal rash occurs from 5 days before to 2 days after delivery.
• Healthcare workers and transplant candidates: confirm immunity, and vaccinate if non-immune before immunosuppression.
• Older adults: zoster and postherpetic neuralgia, and vaccination is offered in many countries from 50 years.
• Regions: in tropical regions varicella commonly occurs in adulthood, and non-immunity among migrants from the tropics and healthcare workers is important.

Follow up tests. VZV PCR (lesion, CSF, blood), CSF cell count, protein and glucose, MRI brain and spine, HIV test, full blood count, liver function tests, chest radiograph for pneumonitis, ophthalmology slit lamp, audiometry in Ramsay Hunt syndrome, foetal ultrasound after maternal infection, and antibody response after vaccination in high risk patients.