Cerebrospinal Fluid Positivity in Rubella Virus Associated Multisystem Granulomatous Disease

Summary: Rubella virus (RV) has been considered eliminated from the US since 2004, largely due to widespread implementation of the live-attenuated measles, mumps, rubella (MMR) vaccine. However, several recent cases document wild-type and vaccine-derived rubella virus (VDRV) detection within granulomata of systemic granulomatous disease with active viral shedding from nasopharyngeal secretions, skin lesions and urine. To our knowledge, VDRV detection in cerebrospinal fluid (CSF) has not been reported previously. We present a 41-year-old male with common variable immunodeficiency (CVID) first diagnosed during workup following the development of cutaneous granulomatous disease (CGD) in 2009. Over time his CGD became destructive and extensive, and he developed systemic involvement affecting his skin, eyes, liver, lungs, and central nervous system (CNS), alongside significant inflammatory arthritis. Disease activity stabilized with subcutaneous immunoglobulin, infliximab, methotrexate, hydroxychloroquine, and glucocorticoids. He experienced several years of good control. Unfortunately, following changes to his treatment regimen due to infections and somewhat fragmented care, the patient developed severe disease recurrence. Skin biopsy in 2020 was positive for RuV capsid protein on immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR) confirmed VDRV. Despite resuming granuloma-directed therapy, the patient developed progressive skin, CNS and liver involvement and was hospitalized in 2022 following onset of blindness, severe hearing loss, anosmia, gait and balance issues. Active VDRV shedding was detected via RT-PCR from nasopharyngeal swab, and VDRV was detected in his CSF via metagenomic next-generation sequencing. Despite advancing immunomodulatory therapy with the addition of tofacitinib, and treatment with ribavirin and nitazoxanide, the patient expired in early 2023. Posthumously, the patient was found to have an inactivating mutation in IKZF3 (Aiolos). Both his mother and brother carried the same mutation but without CVID or CGD expression.