Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic brain infection caused by the JC virus, and idiopathic PML is increasingly recognized. Deeper profiling of such patients often reveals occult immune deficiency. We describe a cohort within the National Institutes of Health (NIH) PML Natural History Study with known or suspected inborn errors of immunity (IEIs), aiming to gain insight into PML susceptibility.
The NIH PML Natural History Study (NCT01730131) has enrolled 150 participants to date. Enrollees undergo standardized assessments to characterize immune profiles and disease course. Whole-exome or -genome sequencing (WES, WGS) is conducted in idiopathic cases, with additional targeted deep sequencing of somatic variants and anti-cytokine autoantibody testing in a subset.
Forty-one patients (27%) are included in this cohort. Median age was 55 years, and 56% were male. At enrollment, 9 had a diagnosis of IEI, including CD40LG deficiency, DOCK8 deficiency, STAT1 GOF, FOXN1, and X-SCID. Thirty-two patients had idiopathic PML. Among these, 19 patients had CD4 lymphopenia (median 162 cells/μL) and 14 had CD19 lymphopenia (median 26 cells/μL). Genetic sequencing identified three previously undiagnosed pathogenic variants in RELB, SASH3, and CARMIL2. One patient had previously unrecognized thymoma and Good’s syndrome; one had previously unrecognized T cell lymphoma. Anti-cytokine antibodies, assessed in 16 patients without a genetic diagnosis, revealed only one patient with a suspicious type I IFN autoantibody. Four patients underwent targeted deep sequencing after WES/WGS was nondiagnostic; no pathogenic somatic variants were found. Notably, 13 patients (32%) had spontaneous recovery of PML, 24 (59%) received experimental immunotherapy, and 4 with IEI (10%) underwent hematopoietic stem cell transplantation (CD40LG deficiency, DOCK8 deficiency, and X-SCID). Overall survival was 61%, although four have had <6 months of follow-up to date.
IEIs are an important risk factor for PML. Among patients with idiopathic disease, comprehensive immunologic evaluation can yield definitive diagnoses. It is notable that a substantial fraction of this cohort achieved spontaneous recovery of PML. Understanding the immune pathways involved may guide future therapeutic strategies and improve outcomes.
