Granulomas Gone Wild: Update of Rubella as an Evolving Trigger

Dr. Karolyn Wanat presented information about the discovery, diagnosis, and treatment of rubella virus (RuV)-associated granulomas. RuV is a single-stranded RNA virus typically associated with a mild clinical course. It can persist in immune-privileged sites and cause complications, including encephalitis, uveitis, arthritis, and congenital rubella syndrome (CRS). The RuV vaccine was developed because of the potential severity of CRS for infants. Its demonstrated safety and effectiveness led to the eradication of RuV in the United States by 2004. However, research has identified vaccine-derived and wild type RuV in granulomas among children with inborn errors of immunity (IEI) and adults who are immunosuppressed or immunocompetent, indicating that the RuV vaccine does not induce sterilizing immunity.

First, Wanat provided an overview of granulomas, including clinical presentation and histopathology. Granulomas are aggregates of immune cells with variable histopathology that form in response to inflammation (e.g., infection, foreign object). Suppurative or necrotizing granulomas should raise a high index of suspicion for infection.

Second, Wanat described research leading to the identification of RuV-associated granulomas. Granulomas are a characteristic feature of IEI. Results from high-throughput sequencing of granuloma tissue from 4 children with IEI demonstrated that the granulomas were caused by RuV. The Centers for Disease Control (CDC) subsequently investigated granulomas in children with IEI, finding RuV-associated granulomas in 72% of approximately 100 cases. RuV was found in the skin, liver, brain, gastrointestinal tract, bones and joints, and other organs. The CDC has classified RuV-associated granulomas into 4 inflammatory patterns based on how RuV localizes within specific cell types.

At the Medical College of Wisconsin and University of Pennsylvania, 4 older (aged 49–73 years) immunocompetent patients presented with atypical granulomas on their arms. Clinical features included papules, nodules, indurated plaques, pustules, and scarring; they appeared similar to granulomas in patients with IEI. Histopathology showed granulomatous inflammation with necrosis. Immunohistochemistry identified RuV within macrophages. Three patients had vaccine-derived RuV and 1 had wild type.

This prompted  a retrospective multicenter review of granulomas of unknown etiology and atypical appearance. RuV was identified in ~60.6% of over 100 cases evaluated. Common features of RuV-associated cases included location on the arms and a tuberculoid histological pattern. Most patients were older (average age of onset 50 years) and immunocompetent. Wanat is working to determine whether these cases are vaccine-derived or wild type.

Prospective studies identified vaccine-derived and wild type RuV-associated granulomas. Nasopharyngeal swabs and contact tracing in patients with wild type RuV-associated granulomas showed the virus is not spreading in the community. Wanat described patient cases and encouraged dermatologists with similar cases to submit them for evaluation.

Third, Wanat discussed treatment options for patients with RuV-associated granulomas. For patients with IEI, hematopoietic stem cell transplants are most effective. Other treatment options showed variable results including steroids, mycophenolate mofetil, methotrexate, and tumor necrosis factor inhibitors. For immunocompetent patients, intralesional triamcinolone, infliximab, and dapsone plus adalimumab have showed clinical improvement. Antiviral treatments have not been effective when used alone.

To conclude, Wanat described ongoing studies to evaluate viral and immunologic phenotypes and genetic expression of RuV-associated granulomas.

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