Marzocchetti, A. et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 73, 1551-1558

Division of Viral Pathogenesis, BIDMC, Harvard Medical School, Boston, MA 02215, USA.
Neurology (Impact Factor: 8.29). 11/2009; 73(19):1551-8. DOI: 10.1212/WNL.0b013e3181c0d4a1
Source: PubMed


We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML).
We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood.
Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival.
The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.

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    • "The incidence of PML has increased during the global HIVepidemic in the 1980s (Tan and Koralnik 2010), although the introduction of combination antiretroviral therapy (cART) in the treatment of HIV infection has overturned this trend, with a reduction of PML onset among HIV patients. However, in recent years, PML cases are increasing among patients with immune-mediated diseases treated with monoclonal antibodies (mAb) (Weissert 2011), and as of January 2015, 514 cases of PML had been reported among the 132,600 MS patients treated with natalizumab worldwide, with a fatality rate of about 20–25 % (TYSABRI Safety Update 2015). The estimated risk of natalizumab PML-associated is 11.1 cases per 1000 patients (95 % CI 8.3 to 14.5) when the three main risk factors are present: (1) JCV-specific antibodies, (2) previous use of immunosuppressants, and (3) 25 months of natalizumab treatment (Bloomgren et al. 2012; Sørensen et al. 2012). "
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    ABSTRACT: In the last years, the treatment of multiple sclerosis (MS) patients with natalizumab has been associated with the occurrence of progressive multifocal leukoencephalopathy (PML) caused by human polyomavirus JC (JCV). Here, we have shown a significant correlation between patients with JC viruria and positive JC-specific antibody response and patients without JCV-specific antibodies after 1 year of natalizumab (p = 0.0006). Furthermore, JCV-specific quantitative PCR on urine and plasma samples, collected at the enrollment (t0) and every 4 months (t1, t2, t3) in the first year and at two time points (t4 and t5) in the second year of natalizumab treatment, indicated the prevalence of JC viremia rather than JC viruria only in the second year of treatment (p = 0.04). Moreover, the analysis of JCV non-coding control region (NCCR) sequences in peripheral blood mononuclear cells of patients with JC-specific antibodies after 12 natalizumab infusions (t3) revealed the presence of rearranged sequences, whereas the prevalence of genotypes 1A, 1B, and 4 was detected in these patients by VP1 sequence analysis. In summary, JC viruria evaluation seems to be useful to identify early those patients who do not already develop a humoral immune response against JCV. It may also be interesting to study the JCV NCCR rearrangements since they could give us new insights on the onset of neuro-invasive viral variants.
    Full-text · Article · May 2015 · Journal of NeuroVirology
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    • "It is likely the ability to rapidly restore immunocompetency through accelerated removal of natalizumab by plasma exchange or immunoadsorption that accounts for the remarkably low mortality rate (~22 %) (, 20 June 2013) reported to date in natalizumab-associated PML cases when compared to 1-year mortality rates in organ transport recipients (84 %) (Mateen et al. 2011) and even in HAARTtreated HIV patients (48 %) (Marzocchetti et al. 2009). Virtually , all patients who develop PML following exposure to biological immunomodulatory agents such as natalizumab will also subsequently develop JCV immune reconstitution inflammatory syndrome (IRIS) after drug cessation and accelerated removal (Tan et al. 2011) Understanding how to modulate the adverse effects of IRIS-associated immune-mediated CNS tissue injury without impeding the beneficial effects of immune-mediated JCV clearance will hopefully lead to further reduction in PML morbidity and mortality. "

    Full-text · Article · Aug 2013 · Journal of NeuroVirology
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    • "It is interesting to note that JCV-DNA was never detected in urine samples of our patient despite the severe immunosuppressed status. Studies specifically focused on the pathogenesis of PML suggest that JCV reactivation in the kidney may not be related to PML (Koralnik et al. 1999), and no association between JCV viruria and subject's immunological status has been demonstrated (Marzocchetti et al. 2009). Finally, JCV subtype 1B, the predominant genotype in Southwest Europe (Agostini et al. 2001), was detected, suggesting JCV primary infection as acquired in Italy. "
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    ABSTRACT: John Cunningham virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy (PML), contains a hyper-variable non-coding control region usually detected in urine of healthy individuals as archetype form and in the brain and cerebrospinal fluid (CSF) of PML patients as rearranged form. We report a case of HIV-related PML with clinical, immunological and virological data longitudinally collected. On admission (t0), after 8-week treatment with a rescue highly active antiretroviral therapy (HAART), the patient showed a CSF-JCV load of 16,732 gEq/ml, undetectable HIV-RNA and an increase of CD4+ cell count. Brain magnetic resonance imaging (MRI) showed PML-compatible lesions without contrast enhancement. We considered PML-immune reconstitution inflammatory syndrome as plausible because of the sudden onset of neurological symptoms after the effective HAART. An experimental JCV treatment with mefloquine and mirtazapine was added to steroid boli. Two weeks later (t1), motor function worsened and MRI showed expanded lesions with cytotoxic oedema. CSF JCV-DNA increased (26,263 gEq/ml) and JCV viremia was detected. After 4 weeks (t2), JCV was detected only in CSF (37,719 gEq/ml), and 8 weeks after admission (t3), JC viral load decreased in CSF and JCV viremia reappeared. The patient showed high level of immune activation both in peripheral blood and CSF. He died 4 weeks later. Considering disease progression, combined therapy failure and immune hyper-activation, we finally classified the case as classical PML. The archetype variant found in CSF at t0/t3 and a rearranged sequence detected at t1/t2 suggest that PML can develop from an archetype virus and that the appearance of rearranged genotypes contribute to faster disease progression.
    Full-text · Article · May 2013 · Journal of NeuroVirology
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