Macrophage activation syndrome and post‐transplant microangiopathy following haploidentical bone marrow transplantation for sickle cell anemia
Authors: James O. J. Davies, Alice C. Hart, Josu De La Fuente, Barbara J. Bain
Journal: American Journal of Hematology (2017)

A haploidentical bone marrow transplant was undertaken in this 18-year-old girl with sickle cell anemia complicated by Moya Moya disease and severe cerebrovascular compromise such that the intracranial vessels were only supplied by the posterior circulation. She underwent conditioning with anti-thymocyte globulin, thiotepa, cyclophosphamide, and total body irradiation (2 Gy). Prophylaxis for graft-versus-host disease included post-transplantation cyclophosphamide on day +3 and +4, and mycophenolate mofetil and sirolimus from day +5 onwards. She developed neutropenic fever and was commenced on piperacillin-tazobactam, and gentamicin on day +15, and engrafted on day +17. Following engraftment the fever persisted, the antibiotics were changed to meropenem, and AmBisome (amphotericin B) was added. She developed headaches on day +25 and magnetic resonance imaging of her head showed evidence of meningitis. A lumbar puncture showed a normal white cell count, protein, and glucose. No organisms were detected on culture or by polymerase chain reaction (PCR) for herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein–Barr virus, human herpesvirus 6 (HHV6), JC virus, adenovirus, or enterovirus. The fevers persisted and on day +29 the ferritin rose to 45 123 μg/L, having been 732 μg/L prior to transplantation. Triglycerides were raised to 2.13 g/L, and fibrinogen was borderline low at 1.8 g/L, later falling to 0.6 g/L. A bone marrow aspirate and trephine biopsy were performed, these showing evidence of macrophage activation syndrome (MAS) (top left Image) and increased iron stores (grade 3–4). HHV6 was detected by PCR (496 copies/mL) on the bone marrow aspirate. Cytokine measurements showed interleukin (IL)-10 of 9.40 pg/mL [normal range (NR) <3]; IL-1β of 8.55 pg/mL (NR < 5); IL-6 of 6.18 pg/mL (NR < 6); IL-8 of 288 pg/mL (NR < 70); tumor necrosis factor-alpha 20.1 pg/mL (NR < 3); soluble CD25 728 U/mL (NR 200–500); and lipopolysaccharide binding protein 6.83 µg/mL (NR ≤ 15). She was commenced on dexamethasone, and intravenous immunoglobulin and foscarnet were given to treat the HHV6 reactivation. On day +40 she was converted from sirolimus to ciclosporin and on day +43 she developed renal failure (maximum creatinine 326 μmol/L), confusion, and headaches. This was associated with anemia, leukocytosis, neutrophilia, and thrombocytopenia (Hb 82 g/L, white cell count 19.7 × 109/L; platelets 42 × 109/L on an automated count but on film assessment ∼5 × 109/L). There was evidence of hemolysis—bilirubin 12 μmol/L, lactate dehydrogenase 984 iu/L, haptoglobin 0.364 g/L (NR 0.5-2.4)—with features of a microangiopathic hemolytic anemia on the blood film (top right and bottom Images) consistent with transplant associated microangiopathy (TMA). She had a normal ADAMTS13 with no inhibitor, and complement pathway inherited abnormalities were excluded. Prominent vacuolation of circulating monocytes (bottom Images) was consistent with activation by cytokines. In addition, there were Howell–Jolly bodies and numerous Pappenheimer bodies, reflecting hyposplenism and the mild iron overload demonstrated pre-transplant. TMA was treated with weekly rituximab 375 mg/m2 for four doses and eculizumab 900 mg twice weekly, which resulted in resolution of the neurological symptoms and kidney injury as well as improvement in the platelet count and markers of hemolysis, but she later relapsed requiring two courses of plasma exchange and the infusion of mesenchymal stem cells to abrogate the alloreactivity, resulting in full resolution of the MAS and TMA. HHV6 is a recognized cause of hemophagocytic lymphohistiocytosis/macrophage activation syndrome and we have seen this association in other haploidentical transplant patients. In this patient, the virus was present at a very low level and other pathogenetic mechanisms may have been operating. We postulate that the immunosuppressive regime given pretransplant means that some alloreactive T cells are out of cycle on days +3 and +4 when cyclophosphamide is infused. They thus escape deletion and when there is some degree of immune reconstitution MAS occurs. The peripheral blood film in this patient showed evidence of multiple pathological processes: red cell fragmentation and consumptive thrombocytopenia (indicative of TMA); hyposplenism (resulting from sickle cell anemia); and heavily vacuolated monocytes (reflecting the cytokine-driven MAS, an uncommon observation that may be a clue to this syndrome).