Idiopathic thrombocytopenic purpura after influenza vaccination in a bone marrow transplantation recipient

The benefit of influenza vaccination after bone marrow transplantation (BMT) was reported in a recent issue of Bone Marrow Transplantation by Machado et al.1 The authors showed that influenza vaccination played an important role in protecting BMT recipients against influenza in the analysis of a cohort of 177 BMT recipients. With regard to this issue, we present here a case of a BMT recipient who developed idiopathic thrombocytopenic purpura (ITP) after receiving influenza vaccination. A 19-year-old Japanese woman with Philadelphia chromosome-positive acute lymphoblastic leukaemia was transferred to our hospital to receive allogeneic BMT. Although the patient was in second complete remission (CR), allogeneic BMT was considered because of the poor prognosis of the disease. As she did not have a related or unrelated HLA-matched donor, her HLA-haploidentical brother was chosen as a donor for allogeneic BMT.2 The HLA profiles of the patient and donor were as follows: patient A2 B61 Cw8 DRB1*0401/A26 B62 Cw9 DRB1*1406, and donor A2 B61 Cw8 DRB1*0401/A33 B44 Cw- DRB1*0803. The protocol was approved by the institutional review board of Osaka University, and written informed consent was obtained from the patient. The conditioning regimen consisted of fludarabine 30 mg/m2 on days -11 to -8 (total dose 120 mg/m2), cyclophosphamide 60 mg/kg on days -8 and -7 (total dose 120 mg/kg), and fractionated TBI (8 Gy in four fractions on days -3 to -1). GVHD prophylaxis consisted of tacrolimus, a short course of methotrexate (10 mg/m2 on day +1, 7 mg/m2 on day +3), methylprednisolone (mPSL) 2 mg/kg from day +1, and oral mycophenolate mofetil 15 mg/kg/day daily from day +5. The patient received BM containing 3.48 108 nucleated cells/kg without any manipulation. This protocol was well tolerated, and haematopoietic reconstitution was rapid. Although the patient did not develop acute GVHD, the doses of immunosuppressants and steroids were very slowly tapered because BMT from an HLA-haploidentical donor had been performed. Thereafter, the patient continued to be in molecular CR without any GVHD signs or symptoms. On day 388, when the patient received a low dose of tacrolimus (1.7 mg/day) and prednisone (PSL) 7 mg/day, she was given an influenza vaccine (A/New Caledonia/20/99(H1N1), A/New York/55/2004(H3N2), and B/Shanghai/361/2002) for the first time after BMT. However, the platelet count, which was greater than 180 109/l before the influenza vaccination, rapidly decreased to 38 109/l and 10 109/l on days 14 and 17 after the vaccination, respectively (Figure 1). Bone marrow examination revealed hyperplastic megakaryopoiesis, with no evidence of relapse: minor bcr/abl mRNA was not detected (<50 copy/g RNA) in the reverse-transcription polymerase chain reaction analysis. The titer of platelet-associated IgG was 108 ng/107 platelets (normal range, 9–25 ng/107 platelets), anti-HLA antibody test was negative, anti-IIb/IIIa antibody test was positive (in ELISA), and the proportion of reticulated platelets was 22% (normal range, 1.3–9.3%). Based on these data, ITP was diagnosed. 13C urea breath test for Helicobacter pylori (H. pylori) was negative. There were no clinical signs or symptoms of chronic GVHD. There was no severe bleeding tendency except a transient nasal bleeding. As shown in Figure 1, various treatments were performed. The patient first received a high-dose immunoglobulin therapy with no effect. The PSL dose was increased to 25 mg/day, and mPSL 1 g was administered. On day 33 of the vaccination, the platelet count began to rapidly increase although tapering of the PSL dose was initiated. As far as we know, this is the first case of a BMT recipient who developed acute ITP after vaccination. The occurrence of ITP in BMT recipients has been reported in several articles, in which GVHD was considered to play a role in the pathogenesis of ITP.3, 4 In the present case, however, there was no sign of GVHD throughout the clinical course. The platelet count drastically decreased 2 weeks after the influenza vaccination, possibly suggesting that the influenza vaccination caused this complication. Patients with acute ITP usually have a precedent infection: ITP characteristically appears 7–10 days after the primary symptoms of the infection. Common preceding infections are rubella, Epstein–Barr virus, Varicella zoster virus and influenza virus infections, although non-specific viral infections still predominate. Acute ITP may also occur after vaccination.5, 6 Antibodies responsible for the clearance of virus antigens may cross-react with antigens naturally present on platelets. Autoantibodies, predominantly IgM, to platelet surface antigen were transiently detected in a majority of the children with acute ITP.7 Disappearance of IgM antibodies from the circulation may explain the self-limiting nature of acute ITP; spontaneous remissions occur in a majority of patients. Machado et al., in their article, did not describe the adverse effects of influenza vaccine. There were several reports of other adverse effects, including influenza-vaccine-associated Guillan-Barre syndrome8 and a transient production of autoantibodies in patients with SLE.9 Although we appreciate the benefit of influenza vaccination for BMT recipients, since those patients may be in an immune-stimulated condition, we should carefully monitor the inmmunological adverse effects. The authors thank Professor Yuzuru Kanakura (Osaka University Graduate School of Medicine, Japan) for suggestions and support. The authors also thank Machiko Oshida for technical assistance.