key: cord-0987654-63nfye10 authors: Tabata, Shotaro; Hosoi, Hiroki; Murata, Shogo; Takeda, Satomi; Mushino, Toshiki; Sonoki, Takashi title: Severe aplastic anemia after COVID-19 mRNA vaccination: Causality or coincidence? date: 2021-12-14 journal: J Autoimmun DOI: 10.1016/j.jaut.2021.102782 sha: 658f976d164ee435d9e7a3d51d1a7337ecd1547e doc_id: 987654 cord_uid: 63nfye10 The development of various autoimmune diseases has been reported after COVID-19 infections or vaccinations. However, no method for assessing the relationships between vaccines and the development of autoimmune diseases has been established. Aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome. We report a case of severe AA that arose after the administration of a COVID-19 vaccine (the Pfizer-BioNTech mRNA vaccine), which was treated with allogeneic hematopoietic stem cell transplantation (HSCT). In this patient, antibodies against the SARS-CoV-2 spike protein were detected both before and after the HSCT. After the patient's hematopoietic stem cells were replaced through HSCT, his AA improved despite the presence of anti-SARS-CoV-2 antibodies. In this case, antibodies derived from the COVID-19 vaccine may not have been directly involved in the development of AA. This case suggests that the measurement of vaccine antibody titers before and after allogeneic HSCT may provide clues to the pathogenesis of vaccine-related autoimmune diseases. Although causality was not proven in this case, further evaluations are warranted to assess the associations between vaccines and AA. a clinic because of bleeding in the oral cavity after dental therapy. Laboratory tests showed that his 1 white blood cell count (1.6 x 10 9 /l) and platelet count (11 x10 9 /l) were decreased. Four days before his 2 visit to the clinic, he had received a second dose of the Pfizer-BioNTech mRNA vaccine (three weeks 3 after his first dose). He was admitted to our hospital due to progressive pancytopenia (Supplementary 4 Table 1 ). He had no history of COVID-19 infection. The Elecsys ® anti-SARS-CoV-2 immunoassay 5 (Roche, Basel, Switzerland), which is used to detect anti-SARS-CoV-2 nucleocapsid protein 6 antibodies, produced a negative result. Tests for immunoglobulin G against cytomegalovirus and 7 Epstein-Barr virus produced positive results, but were not indicative of virus reactivation. Serological 8 tests for hepatitis B, hepatitis C, and human immunodeficiency virus produced negative results. A 9 bone marrow biopsy revealed a hypocellular marrow (Fig. 1) . The patient was diagnosed with very 10 severe AA [6]. Human leukocyte antigen (HLA) testing showed DRB1 04:05 04:05, which is not 11 associated with a high frequency of AA. The administration of granulocyte-colony stimulating factor 12 had no effect on his neutropenia. In spite of the administration of cyclosporine and eltrombopag, his 13 pancytopenia progressed. 14 He underwent an allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA 15 haploidentical related donor (Fig. 2) . The donor had no history of COVID-19 infection and had not 16 received a SARS-CoV-2 vaccine. The conditioning regimen consisted of 120 mg/m 2 fludarabine, 100 17 mg/kg cyclophosphamide, 2.5 mg/kg anti-thymocyte globulin, and 2 Grays of total body irradiation. 18 1 (GVHD). Post-transplant cyclophosphamide was not administered because the patient's HLA-A, C, 2 and DR were homologous, which would not increase the risk of GVHD. The transplanted cells 3 collected from the donor's bone marrow were transfused into the patient after the removal of red blood 4 cells and plasma. Twenty-one days after the HSCT, neutrophil engraftment was achieved. Chimerism 5 analysis performed on day 29 after the HSCT revealed complete chimerism in the peripheral blood. 6 The patient developed acute GVHD (skin grade 1), which was ameliorated with a topical corticosteroid 7 alone. 8 The titers of antibodies against SARS-CoV-2 were measured before and after the HSCT to 9 examine the association between the SARS-CoV-2 vaccine the patient received and the development 10 of AA. The measurement of anti-SARS-CoV-2 spike protein antibody titers was performed by SRL, 11 Inc. (Tokyo, Japan) using the Elecsys ® anti-SARS-CoV-2 S immunoassay (Roche, Basel, Switzerland). 12 The titers of antibodies against SARS-CoV-2 before the conditioning regimen and 63 days after the 13 HSCT were 540 and 34.9 U/mL (reference range, <0.8 U/mL), respectively (Fig. 2) . These results 14 suggest that the AA was ameliorated by the allogeneic HSCT even though anti-SARS-CoV-2 spike 15 protein antibodies continued to be detected after the HSCT. We report a case in which AA developed after the administration of a SARS-CoV-2 vaccine. 3 No association between new-onset AA and SARS-CoV-2 vaccines has been reported. The patient in 4 this case underwent allogeneic HSCT. In this patient, antibodies against the SARS-CoV-2 spike protein 5 were detected both before and after the HSCT. After the allogeneic HSCT, the patient's AA was 6 ameliorated despite the presence of antibodies against SARS-CoV-2. Our results did not reveal a direct 7 association between antibodies derived from the SARS-CoV-2 vaccine and the development of AA. 8 Further studies are needed to investigate the impairment of hematopoiesis induced by immune 9 reactions after SARS-CoV-2 vaccine administration. 10 One of the most feared adverse reactions to vaccines is the development of autoimmune 11 disease. To the best of our knowledge, only six cases of newly diagnosed acquired AA have been 12 reported after vaccination [7] [8] [9] [10] [11] (Table 1) There are no funding sources associated with the writing of this manuscript. Written consent for 3 publication was obtained from the patient. 4 5 The authors declare that they have no conflicts of interest. 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Postvaccination graft 15 dysfunction/aplastic anemia relapse with massive clonal expansion of autologous CD8+ 16 lymphocytes