Hypereosinophilia in an Islet Transplant Recipient

Abstract

A 38-year-old male subject, with a 36-year history of type 1 diabetes mellitus, received two allogeneic islet infusions with a steroid-free immunosuppressive therapy (1) resulting in insulin independence for 15 months and partial graft function for the following 7 months. Ten months posttransplant, progressive elevation of eosinophil count occurred reaching a peak value of 6,350 cells/mm3. Clinically he complained of scalp and upper torso itching exacerbated by exercise and hot water (treated with antihistamines) associated with intermittent rash. A skin biopsy demonstrated eosinophilic infiltrate, IgE antibody tests (for allergies) were negative, and thyroid function was normal. There was no weigh loss, upper and lower respiratory tract symtomatology, abdominal pain, or dyspepsia. After commencing immunosuppression, the patient suffered intermittent diarrhea, severe at times. Stool samples were consistently negative for infectious organism except on one occasion when giardia and iodamoeba were detected, successfully treated with metronidazole. A GI biopsy was normal. The diarrhea was presumed secondary to sirolimus. Causes for reactive eosinophilia were sought; infections, parasitic (angiostrongyliasis, capillariasis, fascioliasis, trichinosis), viral (HIV, HTLV, CMV, Parvovirus), and fungal (aspergillosis, candidiasis) were excluded. Malignancy was sought, chest and abdomen CT showed no masses or splenomegaly. Connective tissue diseases were excluded. An echocardiogram was normal. Drug reaction was evaluated by transiently removing all medications other than immunosuppression, no effect on eosinophilia was noted. A bone marrow biopsy demonstrated normocellularity with mild eosinophilia, without immunophenotypic abnormalities or clonality in any cell population. Interleukin-5 levels (an eosinophil growth factor) and serum tryptase (sign of mast cell degranulation) were slightly elevated. In our patient the most likely diagnosis was idiopathic hypereosinophilic syndrome (HES) associated with mast cell activation. Immunosuppressive drugs were discontinued, without alteration in eosinophil levels excluding sensitivity to the medications. The graft was at this point rejected (Fig. 1). Progression of eosinophilia argued against hypereosinophilia secondary to graft rejection.FIGURE 1. White blood cell and eosinophil counts during the clinical follow-up of the patient after transplantation. Important events in the clinical history of the patient is highlighted in the with arrows and relative legends.Eosinophilias can be classified into reactive forms, e.g., secondary to atopy or parasitic infestation, malignancies including lymphomas, connective tissue diseases, GVHD, bone marrow transplantation (2), and graft rejection, and nonreactive forms, e.g., chronic eosinophilic leukemia (CEL), systemic mastocytosis (SM) with eosinophilia, T-cell clonal and non-clonal disease-associated eosinophilia, and HES (3,4). HES is a collective term for those that cannot otherwise be classified, and, while the risk of malignancy is unclear, there is a risk of end-organ damage from the serum eosinophil granule proteins. The recent discovery of cytogenetic abnormality (fusion of the FIP1L1 gene with the platelet-derived growth factor receptor alpha gene) and therapeutic sensitivity to the tyrosine kinase inhibitor Imatinib in some forms of HES is leading to novel therapeutic approaches (5). Treatment with Imatinib mesylate (Gleevec 100 mg increased to 200 mg/day) was initiated and led to rapid remission of clinical signs and near normalization of laboratory abnormalities. Treatment will be continued indefinitely. Chronic (>6 months) hypereosinophilia, skin involvement, and therapeutic response to Imatinib are compatible with a diagnosis of primary HES. Since it developed during immunosuppressive therapy with tacrolimus, sirolimus, and daclizumab, a causal relationship cannot be excluded. Raffaella Poggioli Tatiana Froud David A. Baidal Jacqueline V. Ferreira Muhammad M. Hafiz Camillo Ricordi Diabetes Research Institute and Department of Surgery, University of Miami School of Medicine, Miami, Florida Gerald J. Gleich Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, Utah Rodolfo Alejandro Diabetes Research Institute and Department of Medicine, University of Miami School of Medicine, Miami, Florida