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The boundaries between PML and PML-IRIS: difficult to define, pathology may predict
Jiamin Chen1, Yanni Du2, Lei Sun1
1Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Insights
Progressive multifocal leukoencephalopathy (PML) in AIDS patients shows a more severe inflammatory response than previously reported, especially after antiretroviral therapy (ART). This suggests PML and PML-immune reconstitution inflammatory syndrome (IRIS) may be part of a continuous spectrum.
Area of Science:
- Neurology
- Immunology
- Infectious Diseases
Background:
- Progressive multifocal leukoencephalopathy (PML) is a critical neurological complication in individuals with AIDS-related immunosuppression.
- JC virus reactivation is the causative agent of PML.
- This study analyzed 19 confirmed PML cases in an AIDS cohort.
Purpose of the Study:
- To conduct a clinicopathological analysis of PML cases in an AIDS cohort.
- To investigate the characteristics of PML that deviate from classic presentations.
- To explore the relationship between PML, immune reconstitution, and potential therapeutic strategies.
Main Methods:
- Clinicopathological analysis of 19 AIDS-related PML cases.
- Neuropathological evaluation including immunohistochemistry (SV40, NF, NeuN, P53, Ki-67, GFAP, Oligo-2, CD68) and myelin staining (Luxol fast blue).
- Molecular diagnostics: quantitative JC viral load PCR and metagenomic next-generation sequencing (mNGS).
Main Results:
- Significant correlations were found between mass effect and CD4+ T-cell counts and CSF protein levels.
- HIV diagnosis duration correlated positively with inflammatory infiltration and plasma cell infiltration.
- PML cases exhibited increased MRI enhancement and a more severe inflammatory response, particularly in patients on ART.
Conclusions:
- PML and PML-immune reconstitution inflammatory syndrome (IRIS) may represent a continuous pathological spectrum with an intermediate stage.
- This transitional phase highlights synergistic mechanisms of viral oncogenesis and immune reconstitution.
- Findings could redefine therapeutic strategies for this emerging PML variant.
Background:
Progressive multifocal leukoencephalopathy (PML), caused by John Cunningham (JC) virus reactivation, represents a critical neurological complication in AIDS-related immunosuppression. This single-center study conducted a clinicopathological analysis of 19 confirmed PML cases in an AIDS cohort (16 biopsy; 3 surgical specimens), employing comprehensive neuropathological evaluation. Immunohistochemical testing included SV40, NF, NeuN, P53, Ki-67, GFAP, Oligo-2, and CD68. Myelin architecture was evaluated through Luxol fast blue staining, complemented by molecular diagnostics incorporating quantitative JC viral load PCR and metagenomic next-generation sequencing (mNGS).
Results:
Notably, 63.2% (12/19) of them had blood CD4+ T-cell counts < 200 cells/μl, and 36.8% (7/19) had ≥ 200 cells/μl. 52.9% (9/17) of the patients had elevated CSF protein, 5.3% (1/19) had decreased CSF glucose. Statistical analysis revealed significant correlations between mass effect and both blood CD4+ T-cell counts (P = 0.022) and CSF protein levels (P < 0.001). It also demonstrated significant positive correlations between the duration of HIV diagnosis and the degree of inflammatory infiltration (P = 0.038) and perivascular inflammatory infiltration (P = 0.005), as well as plasma cell infiltration (P = 0.011). The degree of inflammatory infiltration was significantly positively correlated with antiretroviral therapy (ART) (P = 0.036). The degree of inflammatory infiltration, the presence of plasma cells, and perivascular lymphocytic cuffing were significantly associated with contrast enhancement on imaging studies (P = 0.044, P = 0.011, and P = 0.018, respectively). These cases display characteristics that deviate from the classic PML previously reported, exhibiting a tendency towards MRI enhancement and histologically indicating a more severe inflammatory response, especially for patients following ART treatment.
Conclusion:
Our findings suggest that PML and PML-immune reconstitution inflammatory syndrome (IRIS) represent a continuous pathological spectrum, potentially bridged by an intermediate stage with distinct clinicopathological features. This transitional phase may constitute a critical link in the continuum between classic PML and fully developed PML-IRIS. Importantly, it implicates synergistic mechanisms of viral oncogenesis and immune reconstitution, which could redefine therapeutic strategies for this emerging PML variant.
