Abstract Introduction Hepatitis C virus (HCV) infection is a known cause of mixed cryoglobulinemic vasculitis (CryoVas), though clinical disease is uncommon compared to the high prevalence of circulating cryoglobulins. Only 10–15% of patients with detectable cryoglobulins develop systemic manifestations such as glomerulonephritis, neuropathy, or diffuse alveolar hemorrhage (DAH). Direct-acting antivirals (DAAs) have reduced CryoVas incidence, making recurrence after viral clearance rare. Management of severe CryoVas often requires antiviral therapy combined with immunosuppression. Rituximab is first-line, while cyclophosphamide is less commonly used; concurrent therapy is rare. We present a patient with recurrent HCV complicated by mixed CryoVas manifesting as DAH and rapidly progressive glomerulonephritis, requiring both rituximab and cyclophosphamide, highlighting the interplay between viral relapse, immunosuppression, and end-organ complications. Case Summary 51-year-old man with end-stage renal disease on dialysis and a history of intravenous drug use presented with recurrent DAH and rapidly progressive glomerulonephritis from mixed CryoVas and recurrent HCV. His history included recurrent enterococcal prosthetic mitral valve endocarditis requiring two prior mitral valve replacements and HCV eradication with DAAs. He was admitted with hemoptysis and hypoxemic respiratory failure requiring ICU care. Workup confirmed recurrent HCV and cryoglobulinemia. He was treated with high-dose corticosteroids, plasmapheresis, rituximab, and cyclophosphamide, along with sofosbuvir/velpatasvir/voxilaprevir for viral relapse. His course was complicated by methicillin-resistant Staphylococcus epidermidis prosthetic valve endocarditis, requiring a third mitral valve replacement. Discussion CryoVas is an uncommon extrahepatic manifestation of HCV, often involving kidneys and lungs; severe forms such as DAH and rapidly progressive glomerulonephritis are rare. Although DAAs have reduced HCV-related CryoVas, relapse can occur.Recurrent HCV is particularly concerning in immunocompromised patients. Immunosuppressive therapy, including rituximab, depletes B-cells and alters immune surveillance, while cyclophosphamide adds further immunosuppression, increasing the risk of viral reactivation. In this patient, severe CryoVas reemerged after DAA therapy, highlighting the need for viral monitoring during immunosuppression.Rituximab is widely used in refractory HCV-related CryoVas, whereas cyclophosphamide is less common due to infection risk. Concurrent use of both agents is rare; reports are limited and mostly involve non-HCV cryoglobulinemia. No prior case describes dual rituximab and cyclophosphamide therapy in a patient with recurrent HCV after DAA treatment complicated by DAH and renal failure, highlighting the novelty of this case.The patient’s course was further complicated by recurrent prosthetic mitral valve endocarditis, illustrating the balance between infection control and immunosuppression. This case underscores the importance of multidisciplinary care, viral monitoring, and individualized immunosuppressive strategies in managing complex overlapping autoimmune and infectious conditions. This abstract is funded by: None
Liu et al. (Fri,) studied this question.