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No evidence for active viral infection in unicentric and idiopathic multicentric Castleman disease by Viral-Track analysisIra Miller 1 , Melanie D. Mumau 1 , Saishravan Shyamsundar 1 , Mateo Sarmiento Bustamante 1 , Pedro Horna 2 , Michael V. Gonzalez 1? & David C. Fajgenbaum 1?Castleman disease (CD) is a rare hematologic disorder characterized by pathologic lymph node changes and a range of symptoms due to excessive cytokine production. While uncontrolled infection with human herpesvirus-8 (HHV-8) is responsible for the cytokine storm in a portion of multicentric CD (HHV-8-associated MCD) cases, the etiology of unicentric CD (UCD) and HHV-8-negative/idiopathic MCD (iMCD) is unknown. Several hypotheses have been proposed regarding the pathogenesis of UCD and iMCD, including occult infection given the precedent established by HHV-8 infection. To investigate potential active infections in UCD and iMCD, we implemented Viral-Track, a computational method that identif i es viral mRNA sequences from next-generation sequencing data. We applied Viral-Track to short sequencing reads from a cohort of UCD (n = 22), iMCD (n = 19), and controls (n = 86). While viral sequences for several unusual viruses were identif i ed in individual CD patients, sequences for the same virus were not found across multiple CD patients or they were not specif i c to CD samples and were also found in non-CD samples. These results suggest that active viral infection is unlikely to be a pathological driver of UCD or iMCD.Keywords Castleman disease, Hyperinf l ammation, Virus detection, Pathogen detection, Viral-TrackCastleman disease (CD) comprises a group of inf l ammatory conditions characterized by enlarged lymph nodes with characteristic histopathological features and a wide range of symptomatology and disease burden. Unicentric CD (UCD) is characterized by a solitary enlarged lymph node with undetectable or mild symptoms; however, in rare cases, UCD can lead to paraneoplastic pemphigus, which is of t en fatal 1,2 . Multicentric CD (MCD) involves generalized lymphadenopathy and in the most severe cases can lead to multi-organ dysfunction and even death. MCD is further subdivided by etiology: caused by uncontrolled infection with Human Herpesvirus-8 (HHV-8-MCD); caused by neoplastic plasma cells in polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS-MCD); or occurring for an unknown cause in HHV-8-negative/idiopathic MCD (iMCD) 3 . Subclassif i cation of CD is critical for diagnostic, prognostic, and treatment purposes. Like iMCD, UCD also has no known cause. However, in UCD, excision of the enlarged lymph node is of t en curative with rare recurrence 4–6 . For patients with POEMS-MCD and HHV-8-MCD, treatment is directed at the monoclonal plasma cells and the HHV-8-infected plasmablasts, respectively, and is highly ef f ective 7 . In iMCD, anti-interleukin-6 (IL-6) therapy with siltuximab is ef f ective in approximately one-third to one-half of cases; limited treatment options exist for non-responders 8 . In order to improve the diagnosis and care of patients with iMCD and UCD, a better understanding of the underlying etiology is gravely needed.Although the pathogenic drivers of UCD and iMCD are unclear, several hypotheses into the mechanistic origin of disease have been proposed including autoimmunity, autoinf l ammation, malignancy, and infection from an as-yet-identif i ed pathogen 8 . A previous study utilizing virome capture sequencing for vertebrate viruses (VirCapSeq-VERT), a probe-based method that detects all 207 viral taxa known to infect vertebrates with a minimum of 90% sequence homology 9,10 , revealed no evidence of an acute viral infection across a small cohort of UCD and iMCD patients 10 . Although this technology captures a wide breadth of known viruses across approximately 2 million probes, the study had several limitations. Th e VirCapSeq-VERT system is constrained to detecting only known viruses. Th us, the platform cannot detect novel viruses (with < 75% sequence identity to 1 Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania, CSTL, 3535 Market Street, Philadelphia, PA 19104, USA. 2 Division of Hematopathology, Mayo Clinic, Rochester, MN 55905, USA. ? email: michael.gonzalez1@pennmedicine.upenn.edu; davidfa@pennmedicine.upenn.eduOPENScientif i c Reports | (2025) 15:1676 1 | https://doi.org/10.1038/s41598-025-85193-xwww.nature.com/scientificreports