What is the JC virus and what disease does it cause?

This is definitely an interesting pathogen, but one that many healthcare providers may not be familiar with. John Cunningham or JC virus (JCV) is a non-enveloped, double-stranded DNA virus that, following primary infection, undergoes latency in tonsillar tissue, renal tubular cells, bone marrow, or the brain. Seroprevalence studies suggest that >50% of adults over the age of 20 have been exposed to it (Ann Neurol 2015;77:560–70).

Although infection with JCV is typically mild or subclinical in immunocompetent patients, reactivation of latent virus may result in progressive multifocal leukoencephalopathy (PML) in patients who are immunocompromised (such as AIDS patients) or taking immune-modulating therapy. PML is a serious, and often fatal, neurologic disease characterized by progressive demyelination of the white matter of the brain resulting in cognitive decline, gait abnormalities, and seizures.

With the widespread use of highly active antiretroviral therapy in AIDS patients, the incidence of PML has dropped significantly (J Infect Dis 2009;199:77–83). However, over the past decade, cases of PML have been identified in individuals taking immune-modulatory drugs used to treat conditions such as multiple sclerosis (MS) or Crohn’s disease. This has led to a renewed interest in JCV and the laboratory methods used to diagnose this viral infection.

What lab tests can be used to diagnose JCV?

Although JCV can be recovered from primary human cells (e.g., embryonic cells) and peripheral blood mononuclear cells, routine viral cell culture for the diagnosis of JCV is not commonly performed in clinical laboratories. The laboratory methods that are routinely used include histopathology, in situ hybridization (ISH), real-time PCR, and serology.

Should serology be ordered as a non-invasive means of diagnosing PML?

This is an important question. Serology tests designed to detect anti-JCV antibodies should not be used to diagnose PML. This is because >50% of adults have been exposed to JCV and will be positive for IgG-class antibodies to this virus (Eur J Neurol 2014;21:299–304), even though the vast majority will never experience any symptoms. In other words, a positive serology only suggests prior exposure to JCV, and not necessarily that the virus is causing an illness in the patient.

However, serology is useful in screening patients for exposure to JCV prior to initiating certain immune-modulating therapies, such as natalizumab. Recently, an enzyme-linked immunoassay from Focus Diagnostics (Stratify JCV DxSelect) was cleared by the Food and Drug Administration for screening MS patients receiving or considering natalizumab therapy. The results of this test are used as an aid in risk stratification for the development of PML. Simply put, a positive result for anti-JCV antibodies indicates increased risk for possible development of PML in individuals being treated with natalizumab. In contrast, a negative result implies that an individual has not been exposed to JCV and is not at risk for developing PML unless exposed to the virus at a later time.

If serology is not recommended for the diagnosis of PML, what test(s) should be performed if PML is suspected?

Patients with progressive neurological symptoms who are immunosuppressed or on immune-modulatory therapy should have a brain MRI to assess for characteristic features of PML, such as high signal intensity in the cerebral gray-white matter junction. If these radiologic features are present, cerebrospinal fluid should be collected and tested by a validated JCV real-time PCR assay. If the result of the PCR is positive, the diagnosis of PML would be confirmed. However, if the JCV PCR is negative, a full workup for other potential etiologies such as malignancy should be completed. If the results of all tests are negative, a brain biopsy may be performed for histopathology and ISH using JCV-specific probes (Neurology 2013;80:1430–8).

Matthew J. Binnicker, PhD, D(ABMM), is director of clinical virology in the Division of Clinical Microbiology at the Mayo Clinic in Rochester, Minnesota.
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