Case Report: Severe mixed autoimmune hemolytic anemia associated with acute cytomegalovirus infection in an immunocompetent adult

Background Cytomegalovirus (CMV)-associated hemolytic anemia (HA) is rare in immunocompetent hosts and may present with heterogeneous serologic phenotypes, including direct antiglobulin test (DAT)-negative hemolysis, warm autoimmune hemolytic anemia (AIHA), cold antibody-mediated AIHA, and rarely mixed AIHA. Because mixed AIHA requires evidence of both warm autoantibodies and clinically significant cold autoantibody activity, this phenotype may be underrecognized without comprehensive immunohematologic testing. Case presentation We report a case of CMV-associated HA that was diagnosed as mixed AIHA by comprehensive immunohematologic assessment and successfully managed with combination therapy. A 59-year-old immunocompetent man presented with a 7-day history of fever, sore throat, and fatigue. Initial evaluation revealed marked hepatocellular and cholestatic liver injury, positive CMV IgM with negative CMV IgG, and serum CMV DNA of 2.28 × 10 5 IU/mL. After exclusion of common viral and autoimmune causes, acute CMV hepatitis was clinically diagnosed. On hospital day 4, he developed dark brown urine, with hemoglobin falling to 40 g/L and laboratory evidence of acute hemolysis. Extended DAT revealed IgG, IgA, IgM, and C3d coating of erythrocytes, and cold agglutinin testing identified an IgM cold agglutinin with a titer of 1:128 and thermal amplitude extending to 37 °C, supporting severe CMV-associated mixed AIHA. After antiviral therapy, immunomodulatory and supportive treatment, hemolysis was controlled, and hemoglobin stabilized without further transfusion. Conclusions CMV-associated HA may rarely present as severe mixed AIHA in immunocompetent adults. In severe or atypical cases, comprehensive immunohematologic evaluation beyond routine DAT, including extended DAT, cold agglutinin titration, and thermal amplitude testing, is essential for accurate subtyping. In severe cases, early integrated therapy targeting both CMV replication and immune-mediated hemolysis may be required.