Autoimmune hemolytic anemia with warm-reactive immunoglobulin M antibody in multicentric Castleman disease

Abstract

Dear Editor, Multicentric Castleman disease (MCD) is accompanied by systemic manifestations [1]. Autoimmune hemolytic anemia (AIHA) resulting from warm-reactive immunoglobulin M (wIgM) autoantibodies is rare and associated with a poor prognosis [2–4]. We report here the first case of MCD in which the clinical course was complicated by AIHA with wIgM and IgG antibodies. A 50-year-old male was admitted to our hospital because of weakness, swelling of multiple lymph nodes, and splenomegaly. Lymph node biopsy demonstrated MCD. He was treated with prednisolone (PSL) (0.5 mg/kg/day) and continued to receive maintenance therapy with PSL (10 mg/day). Three years later, he developed fever and fatigue. Upon hospital admission, he had icterus and severe anemia, but MCD activity was absent. Laboratory findings were: Hb, 3.3 g/dL; WBCs, 9,420/μL; platelets, 298,000/μL; reticulocytes, 11.3 %; total bilirubin, 2.4 mg/dL; D-dimer, 3.46 ng/mL; and CRP, 0.95 mg/dL. Anti-autoantibodies (including antiphospholipid antibody) were all negative, as were blood cultures. RBC histograms indicating the mean corpuscular volume (MCV), by a Blood Cell Counter, revealed several large peaks, suggesting hemagglutination in vivo (Fig. 1a). RBCs showed spontaneous agglutination at 37 °C in vitro and, after washing with physiological saline at 43 °C, hemagglutination was finally resolved. We could not carry out a direct antiglobulin test (DAT) due to undissolved material. After treatment of RBCs with 2mercaptoethanol (2-ME), the DAT for IgG and C3d remained positive. Eluted autoantibodies revealed direct hemagglutination. Finally, we confirmed a large amount of IgM and a small amount of IgG on the surface of RBCs by flow cytometry (FCM) (Fig. 1b). Thus, the patient was diagnosed with AIHA due to a high titer of wIgM and a low titer of IgG. Although he received combination treatment of PSL (1 mg/kg/day) and intravenous Ig, he had ongoing hemolysis, hemagglutination, and severe anemia (Hb, 2.2–4.7 g/dL) and required multiple blood transfusions. Ten days after hospital admission, he developed fluctuant disturbances in consciousness, and multiple cerebral thromboembolism (TE) as diagnosed by magnetic resonance imaging (MRI) of the brain (Fig. 1c). We immediately administered chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab (CHOP-R)) with continuous intravenous infusion of low-molecular-weight heparin. Hb levels gradually increased to 9.9 g/dL, and the large peaks of MCV in the RBC histogram disappeared (Fig. 1a). On follow-up, symptoms including neurological deficits had resolved, and MRI showed recovery from TE. DAT remained weakly positive for IgG and C3d. Sometimes, wIgM antibodies cannot be detected by the DAT. This may be because DAT cannot be carried out due to strong resistant hemagglutination; also, the routine DAT does not contain anti-IgM antibody [5]. The indirect AT is frequently negative or weak because most of the wIgM antibodies are absorbed by RBCs [5]. In our patient, the DAT could not be carried out but the indirect AT revealed K. Tajima (*) Department of Radiation Emergency Medicine, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan e-mail: tajima@nirs.go.jp