Anaphylactic transfusion reaction in homozygous haptoglobin deficiency detected by CD203c expression on basophils

Abstract

To the Editor: It has been reported that the incidence of anhaptoglobinemia who are homozygous for Hpdel is very rare in Africans or European-Africans. However, it is relatively high incidence in East Asian; 1/4,000 in Japan, 1/1,500 in Korea, and 1/1,000 in China 1. Some patients with anhaptoglobinemia develop anaphylactic or allergic transfusion reactions related to antihaptoglobin (Hp) antibodies 2. However, if anti-Hp IgE antibody is negative, it is difficult to elucidate an anaphylactic reaction. Flow cytometric basophil activating test (BAT) based on upregulation of the cell degradation/activation marker CD203c has been developed for monitoring the clinical course of patients with allergic diseases 3, 4. Here, we describe that BAT was a useful tool for diagnosing anaphylactic transfusion reaction associated with anti-Hp antibody. This case was an 8-year-old Japanese boy with acute lymphoblastic leukemia receiving intensive chemotherapy required transfusion. He was transfused with 14 units of leukocyte-reduced red cell concentrates (RCCs) and 150 units of leukocyte-reduced platelet concentrates for chemotherapy-induced anemia and thrombocytopenia without any transfusion-related reactions. However, immediately after starting the next infusion of RCCs, he developed dyspnea, urticaria, and hypotension. Screening tests for nonhemolytic transfusion reactions (NHTRs) were performed at the Japanese Red Cross. Serum analysis by nephelometry revealed Hp deficiency and their PCR method 1 showed complete absence of the Hp gene. He was diagnosed as having anhaptoglobinemia due to homozygous allelic Hpdel. Although anti-Hp IgG antibody was detected by ELISA and Western blotting, IgE antibody against Hp was not detected by ELISA or the IgE crosslinking-induced luciferase expression (EXiLE) test 5. To address the mechanism of this anaphylactic reaction, we performed BAT. As a control, a healthy adult and five age-matched children with severe egg allergy who had histories of food-induced anaphylaxis were examined. A commercial kit (Allergenicity Kit; Beckman Coulter, Fullerton, CA) was used for quantifying basophil CD203c expression 4. Upregulation of CD203c on basophils was determined using a threshold that was defined by the fluorescence of unstimulated cells and expressed as CD203c high % 6. CD203c high % was 23% for the patient and 4.38 ± 0.53% for the control, respectively (Table I). Haptoglobin induced enhancement of CD203c expression in the patient, but not in the control. Since basophils express high-affinity IgE receptors, it is reasonable to assume that the haptoblobin-induced basophil activation observed in the patient was mediated by haptoglobin-specific IgE bound to basophils. We did not detect antihaptoglobin IgE by the ELISA or EXiLE methods, but it is possible that the serum IgE concentration was too low to be detected, whereas the amount of cell-bound IgE was sufficient to induce anaphylaxis. Another possibility is that haptoglobin-specific IgG induced basophil activation. An IgG-mediated systemic anaphylactic reaction involving FcγRs, basophils, and platelet-activating factor was reported in a murine system 7, although it remains unclear whether such an IgG-mediated pathway also exists in humans. Our findings indicate that BAT may be useful for assessing the cause of NHTRs, especially anaphylactic reactions via high-affinity IgE receptors on basophils, leading to development of type I hypersensitivity response when no IgE can be detected in serum. The authors thank Yumi Tanaka, MSc (Blood Transfusion Service, Mie University Hospital) for kindly blood supplies. This work was supported by a Research Grant for Allergic Disease and Immunology (H20-015) from the Japanese Ministry of Health, Labor, and Welfare. Shotaro IwamotoMD, PHD, Takahiro YonekawaMD, Eiichi AzumaMD, PHD Pediatrics Unit, Mie University School of Medicine, Mie, Japan Takao FujisawaMD, PHD, Mizuho NagaoMD, PHD Clinical Research Unit, Mie National Hospital, Mie, Japan Eiko ShimadaMSC Central Blood Institute Unit, Blood Service Headquarters Japanese Red Cross Society, Tokyo, Japan Ryosuke NakamuraPHD, Reiko TeshimaPHD, Novel Foods and Immunochemistry Unit, National Institute of Health Sciences, Mie, Japan Kohshi OhishiMD, PHD Blood Transfusion Service Unit, Mie University Hospital, Mie, Japan Hidemi ToyodaMD, PHD, Yoshihiro KomadaMD, PHD Pediatrics Unit, Mie University School of Medicine, Mie, Japan