Cold Agglutinin Autoimmune Hemolytic Anemia Revealing Undiagnosed Diffuse Large B-cell Lymphoma Following COVID-19 Vaccination

Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma that can be associated with autoimmune hemolytic anemia (AIHA), including the rare cold agglutinin hemolytic anemia (CAHA) subtype. Emerging reports have also suggested a potential link between COVID-19 vaccination and the development of AIHA. We report a case of a 56-year-old male with a history of autoimmune diseases who developed symptomatic hemolytic anemia shortly after receiving an mRNA COVID-19 booster. Laboratory evaluation revealed hemolysis with a positive direct antiglobulin test for C3 and negative for IgG, consistent with CAHA. Imaging demonstrated hepatosplenomegaly and isolated lymphadenopathy, and subsequent biopsies confirmed the diagnosis of DLBCL. Although initiated on steroids for presumed autoimmune hemolysis, the patient's limited response further supported CAHA secondary to underlying lymphoma. While COVID-19 vaccines are widely recognized as safe and effective, rare cases of post-vaccination AIHA have been reported. In this case, it remains unclear whether the CAHA was directly triggered by vaccination, unmasked by underlying DLBCL, or a coincidental occurrence. The temporal association observed highlights the complex interplay between immune activation, vaccination, and hematologic malignancy. This case underscores the importance of maintaining a broad differential diagnosis when evaluating hemolytic anemia following vaccination, particularly in patients with autoimmune backgrounds, and highlights the need for further research to better understand potential immunologic interactions among COVID-19 vaccination, AIHA, and occult lymphoma.