Cold agglutinin syndrome secondary to Epstein–Barr virus reactivation during corticosteroid therapy for minimal change nephrotic syndrome in a patient with human immunodeficiency virus infection

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Epstein-Barr virus (EBV), a member of the herpesvirus family, establishes lifelong latency following primary infection and may be reactivated under conditions of immunosuppression. EBV reactivation is classically associated with infectious mononucleosis and Burkitt lymphoma and rarely associated with cold agglutinin syndrome. Here, we describe a case of minimal change nephrotic syndrome complicated by cold agglutinin syndrome secondary to EBV reactivation in the setting of human immunodeficiency virus (HIV) infection and corticosteroid-induced immunosuppression. A 63-year-old man with well-controlled HIV infection owing to antiretroviral therapy was admitted for nephrotic syndrome. He was treated with prednisolone (80 mg/day), and renal biopsy performed on day 9 confirmed minimal change nephrotic syndrome. Complete remission was achieved by day 18; however, the patient subsequently developed hyperbilirubinemia, elevated transaminase and lactate dehydrogenase levels, progressive anemia, and thrombocytopenia, accompanied by pharyngitis, malaise, and fever. Laboratory investigations revealed a positive cold agglutinin test, positive direct Coombs test, reduced haptoglobin level, and positive urine urobilinogen, consistent with cold agglutinin syndrome. CMV reactivation was also suggested by transient CMV antigenemia positivity, although no organ-invasive CMV disease was evident. Although EBV serology indicated a past infection, the EBV DNA load was elevated, which suggested viral reactivation. The patient responded to supportive measures, along with early tapering of the corticosteroid dose to reduce immunosuppression. This case highlights that HIV infection in combination with corticosteroid therapy may create an immunosuppressive milieu, predisposing patients to EBV reactivation and subsequent development of cold agglutinin syndrome. Clinicians should be vigilant for EBV-related complications in patients with minimal change nephrotic syndrome requiring corticosteroid therapy, particularly in those with underlying HIV infection.

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