Progressive multifocal leukoencephalopathy caused by BK virus?

In this issue of the Journal, Daveson and colleagues1 describe a case of progressive multifocal leukoencephalopathy (PML) possibly caused by BK virus rather than JC virus. This finding is potentially very significant. The polyomaviruses BK and JC commonly infect humans and remain latent in immunocomptent individuals. Both are associated with clinical disease in the setting of immunosuppression. However, only JC virus has been causally associated with PML; BK virus has been causally associated with nephropathy, ureteric stenosis and cystitis. There have been previous case reports of BK virus causing a meningoencephalitis and PML as detailed by Daveson et al, but the evidence for causality has been tenuous, largely because of the lack of confirmation in tissue. The data provided by Daveson et al are more convincing, although not definitive.

How could their evidence change clinical practice? First, the significance of PML being caused by BK virus is that the diagnosis of PML has until now only focused on the detection of JC virus.2,3 A large number of patients have or are presumed to have PML as a consequence of immunosuppression from cytotoxic chemotherapy (especially rituximab), from immunodeficiency related to HIV disease, or from immunomodulation related to the multiple sclerosis drug natalizumab.3 In a reasonable number of cases, JC virus is not detected in the cerebrospinal fluid or brain biopsy. This has been considered a consequence of insensitive assay tools, sampling error, or episodes of immune restoration inflammatory syndrome that may reduce viral DNA load before collection of cerebrospinal fluid.2,3 It is now conceivable that some of these PML cases may be caused by BK virus. Such cases would potentially be amenable to therapy: some evidence exists for efficacy with cidofovir, fluoroquinolones such as ciprofloxacin, and leflunomide.4,5 Further, risk stratification for PML in natalizumab-treated patients is currently heavily weighted towards the presence or absence of JC virus on serological testing.6 If BK virus truly can cause PML, such risk stratification strategies would need to include assessment for BK virus antibodies.

Given the potential importance of BK virus causing PML, how robust is the evidence of the causal link in Daveson et al’s report? While the authors did not find evidence for JC virus, it would have been helpful to have negative serology results for JC virus. The presence of enhancing lesions on magnetic resonance imaging is somewhat unusual for PML unless the patient has immune restoration inflammatory syndrome. Nonetheless, it can occur and has been recorded in about 10% of non-natalizumab-treated patients.2 The detection of BK virus in brain tissue, especially in the context of inflammation, raises the possibility that it was imported into the brain in inflammatory cells and that it is an “innocent bystander”. This is certainly possible but, on the other hand, no other cause was found and, in particular, JC virus was not detected by polymerase chain reaction. Further, it would be reassuring to know that the BK virus antibodies did not cross react with JC virus. Last, the case for BK virus causing PML would have been strengthened if there were data showing BK viraemia or viruria. Nonetheless, the BK viral DNA load in the cerebrospinal fluid was high, at 11 975 copies/mL; a level in the plasma of > 10 000 copies/mL is associated with a 93% specificity for presence of BK virus nephropathy.7 This level was quoted in recent guidelines by the Kidney Disease Improving Global Outcomes Transplant Work Group for the diagnosis of BK virus nephropathy.8 Given the implications of this observation, confirmation by an independent laboratory with validated and certified assays for these viruses could be reassuring.

The case for a causal link between BK virus and PML is still not solid, yet the details of the case report are highly suggestive. We consider the implications to be substantial. The report should prompt further research and meticulous analysis of future PML cases with particular attention to the issues we have outlined here.