Effectiveness of Immune Checkpoint Inhibitors in Transplant Recipients with Progressive Multifocal Leukoencephalopathy.
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ABSTRACT:
SUBMITTER: Medrano C
PROVIDER: S-EPMC6810212 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Progressive multifocal leukoencephalopathy (PML) is typically associated with minimal inflammation; however, patients may develop an inflammatory response due to immune reconstitution (IRIS). The authors aimed to determine if characteristics and outcomes of PML are altered in those with IRIS. A retrospective records review was performed on 87 patients diagnosed with PML at Johns Hopkins, 27 of which had a syndrome consistent with IRIS. Gadolinium enhancement on MRI occurred in 44.4% of cases of PML-IRIS versus 5.1% in PML (p<0.05), and thus had low diagnostic sensitivity and specificity. In HIV+ cases, CD4 counts were lower in those who later developed IRIS (mean 34.8 vs. 71.7, p<0.05) and was predictive of the development of IRIS (p<0.05). Improved prognosis was seen with higher cerebrospinal fluid (CSF) white blood cell counts and protein levels, but not for gadolinium enhancement and there were no differences in survival for PML versus PML-IRIS.
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Project description:Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is rare even though the proven etiological agent of PML, the polyomavirus JC (JC virus), is ubiquitous within the human population. The common feature of PML cases appears to be underlying immunosuppression, and PML has gained clinical visibility because of its association with human immunodeficiency virus and AIDS and its occurrence as a side effect of certain immunomodulatory drugs. A hypothesis has gained general acceptance that JC virus causes a primary infection in childhood and enters a latent state, after which immunosuppression allows viral reactivation leading to PML. Nonetheless, many important aspects of PML pathogenesis remain unclear, including the molecular bases of latency and reactivation, the site(s) of latency, the relationship of archetype and prototype virus and the mode of virus transmission within the body and between individuals. In this review, we will revisit these areas and examine what the available evidence suggests.
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Project description:We investigated delay in diagnosing progressive multifocal leukoencephalopathy (PML). The median time from initial symptom to diagnosis was 74 days (range 1-1643) in 111 PML patients seen at our institution from 1993 to 2015. Another diagnosis was considered before PML in nearly two-thirds, and more than three-quarters of patients suffered from diagnostic delay greater than 1 month, irrespective of their underlying immunosuppressive condition. Extended diagnostic delay occurred more frequently in patients with possible PML, and among HIV (+) patients with higher CD4(+) T-cell counts at symptom onset. Prompt diagnosis may improve survival of PML in so far as immune reconstitution can be effected, and prevent unnecessary interventions.
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Project description:The fatal CNS demyelinating disease, progressive multifocal leukoencephalopathy (PML), is rare and appears to occur almost always as a consequence of immune dysfunction. Thus, it is associated with HIV/AIDS and also as a side effect of certain immunomodulatory monoclonal antibody therapies. In contrast to the rarity of PML, the etiological agent of the disease, the polyomavirus JC (JCV), is widespread in populations worldwide. In the 40 years since JCV was first isolated, much has been learned about the virus and the disease from laboratory and clinical observations. However, there are many aspects of the viral life cycle and of the pathogenesis of the disease that remain unclear, and our understanding is constantly evolving. In this review, we will discuss our current understanding of the clinical features of PML and molecular characteristics of JCV and of how they relate to each other. Clinical observations can inform molecular studies of the virus, and likewise, molecular findings concerning the life cycle of the virus can guide the development of novel therapeutic strategies.
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Project description:Progressive multifocal encephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), which occurs in immunocompromised individuals. Management of PML relies on restoration of immunity within the CNS. However, when this restoration cannot be readily achieved, PML has a grim prognosis. Innovative strategies have shown promise in promoting anti-JCV immune responses, and include T-cell adoptive transfer or immune checkpoint inhibitor therapies. Conversely, management of immune reconstitution inflammatory syndrome, particularly in iatrogenic PML, remains a major challenge. In this paper, we review recent development in the treatment of PML. ANN NEUROL 2021;90:865-873.
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Project description:Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral disease of the brain-caused by human polyomavirus 2. It affects patients whose immune system is compromised by a corresponding underlying disease or by drugs. Patients with an underlying lymphoproliferative disease have the worst prognosis with a mortality rate of up to 90%. Several therapeutic strategies have been proposed but failed to show any benefit so far. Therefore, the primary therapeutic strategy aims to reconstitute the impaired immune system to generate an effective endogenous antiviral response. Recently, anti-PD-1 antibodies and application of allogeneic virus-specific T cells demonstrated promising effects on the outcome in individual PML patients. This article aims to provide a detailed overview of the literature with a focus on these two treatment approaches.
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Project description:Progressive multifocal leukoencephalopathy is caused by the JC polyomavirus (JCV) and is one of the most feared complications of HIV-1 infection. Unlike other opportunistic infections, this disease can present when CD4 counts are higher than those associated with AIDS and when patients are receiving combined antiretroviral therapy, either shortly after starting or, more rarely, during long term successful treatment. Clinical suspicion of the disease is typically when MRI shows focal neurological deficits and associated demyelinating lesions; however, the identification of JCV in cerebrospinal fluid or brain tissue is needed for a definitive diagnosis. Although no specific treatment exists, the reversal of immunosuppression by combined antiretroviral therapy leads to clinical and MRI stabilisation in 50-60% of patients with the disease, and JCV clearance from cerebrospinal fluid. A substantial proportion of patients treated with combined antiretroviral therapy develop inflammatory lesions, which can be associated with either a favourable outcome or clinical worsening. The reasons for variability in the natural history of progressive multifocal leukoencephalopathy and treatment responses are largely undefined, and more specific and rational approaches to management are needed.
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Project description:Progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain, is typically diagnosed in immunocompromised persons. Here, we describe the diagnostic challenge of PML in an apparently immunocompetent patient. Thorough analyses, including cytokine release assays and whole exome sequencing, revealed a deficit in the antiviral interferon gamma production capacity of this patient and compound heterozygous mutations in BCL-2-associated athanogene 3. Interestingly, both factors are associated with reduced expression of John Cunningham virus T-antigen, a protein that plays a key role in viral replication in infected cells. After validation in other patients, our findings may contribute to novel insights into the etiology and possibly treatment of PML.
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