Shouichi Ohga

Familial hemophagocytic lymphohistiocytosis (FHL) is a disorder of immune homeostasis characterized by fever, cytopenias, hepatosplenomegaly, and coagulopathy. We studied the outcomes of 13 FHL patients who underwent the first unrelated cord blood transplantation (UCBT) after non‐myeloablative conditionings. The major regimen consisted of fludarabine (FLU; n = 12)+melphalan (MEL; n = 11)±low‐dose total body irradiation (TBI 2‐4 Gy; n = 6). The median age at presentation and period to UCBT were 6 and 5 months, respectively. Central nervous system (CNS) disease developed in one infant at diagnosis, and in two others until UCBT. HLH activity was controlled in all but one at the time of UCBT. Ten patients had early engraftment on median day 21 with no grade >2 treatment‐related toxicity and two controllable grade >2 acute GVHD. Two patients with early rejection successfully underwent subsequent UCBT after myeloablative conditioning. Two others had late graft failure following mixed donor chimerism. Two deaths occurred from HLH; early liver failure and late CNS disease. Of 11 FLU+MEL‐conditioned patients, the frequency of disease‐free complete engraftment was higher for MEL (≥120 mg/m²)+TBI, or high‐dose MEL (180 mg/m²) than for others (83% vs. 25%, p = 0.036). The FLU+MEL‐based non‐myeloablative regimen was acceptable for FHL infants undergoing UCBT, although further studies will be needed for confirmation. Am. J. Hematol. 87:637–639, 2012.

Background Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis (EBV‐HLH) leads to an aggressive and often fatal course without appropriate treatment. Etoposide therapy is crucial for the better prognosis, although it remains unknown what patients need cytotoxic agents. Since we have complied with step‐up strategy in a tertiary center, treatment outcomes were studied to search predictors for disease course. Methods The study enrolled 22 EBV‐HLH patients treated between 1999 and 2010 in Kyushu University. Immunotherapy, chemotherapy and stem cell transplantation (SCT) proceeded in stages unless patients attained a consecutive >21 days‐afebrile remission. Clinical and laboratory data and outcomes were retrospectively analyzed. Results Median age of 9 males and 13 females was 5 years (range: 9 months–41 years). Sixteen patients (73%) presented at age 5 copies/ml of peripheral blood (range: 200–5 × 10⁷). T‐cells were exclusively targeted (94%; 15/16 examined) often with EBV/T‐cell receptor clonality. EBV status indicated 19 primary infections and 3 reactivations. Either death occurred in EBV‐reactivated patients who underwent chemotherapy ± SCT. Age at primary infection in pediatric patients increased in the last 5 years. Patients having prolonged fever (P = 0.017) or high soluble CD25 levels (P = 0.017) at diagnosis were at higher risk for requiring chemotherapy assessed by multivariate analyses. Conclusions No cytotoxic agents were needed for >60% of EBV‐HLH patients. Early immunotherapy may modulate T‐cell activation and reduce the chance of unnecessary chemotherapy. Pediatr Blood Cancer 2012;59:265–270.

Background: Post‐transplant outcomes of hemophagocytic lymphohistiocytosis (HLH) patients were analyzed in Japan where Epstein–Barr virus (EBV)‐associated severe forms are problematic.Methods: Fifty‐seven patients (43 familial HLH [12 FHL2, 11 FHL3, 20 undefined], 14 EBV‐HLH) who underwent stem cell transplantation (SCT) between 1995 and 2005 were enrolled based on the nationwide registration.Results: Fifty‐seven patients underwent 61 SCTs, including 4 consecutive SCTs. SCTs were employed using allogeneic donors in 93% of cases (allo 53, twin 1, auto 3). Unrelated donor cord blood transplantation (UCBT) was employed in half of cases (21 FHL, 7 EBV‐HLH). Reduced intensity conditioning was used in 26% of cases. The 10‐year overall survival rates (median ± SE%) were 65.0 ± 7.9% in FHL and 85.7 ± 9.4% in EBV‐HLH patients, respectively. The survival of UCBT recipients was >65% in both FHL and EBV‐HLH patients. Three out of four patients were alive with successful engraftment after second UCBT. FHL patients showed a poorer outcome due to early treatment‐related deaths (P = 0.02). The risk of death for FHL patients having received an unrelated donor bone marrow transplant was marginally higher than that for a related donor SCT (P = 0.05) and that for UCBT (P = 0.07).Conclusions: EBV‐HLH patients had a better prognosis after SCT than FHL patients. FHL patients showed either an equal or better outcome even after UCBT compared with the recent reports. UCB might therefore be acceptable as an alternate SCT source for HLH patients, although the optimal conditioning remains to be determined. Pediatr Blood Cancer 2010;54:299–306.

A 7‐y‐old girl presented with prolonged fever, arrhythmia and cardiomegaly during the treatment course of group A β‐haemolytic streptococcal pharyngitis. The isolated rheumatogenic strain M1 suggested the diagnosis of rheumatic fever. However, serous pericardial effusion contained high levels of Epstein‐Barr virus (EBV) DNA. Clonally proliferating EBV⁺ T cells were determined in the circulation. The atypical carditis without valvitis was then complicated by coronary artery dilatations. Four months after the start of prednisolone plus antiviral/bacterial therapy, EBV⁺ T‐cell lymphoma developed in the thigh.Conclusion: Atypical carditis may be a notable and life‐threatening presentation of chronic active EBV infection to be differentiated from rheumatic fever.

An 11‐year‐old boy with severe chronic active Epstein‐Barr virus infection (CAEBV) underwent successful cord blood transplantation (CBT) after consecutive failure of peripheral blood and bone marrow transplantation from his HLA‐mismatched mother. CB cells from an unrelated donor were infused after conditioning with total body irradiation (12 Gy), melphalan (120 mg/m²), and etoposide (600 mg/m²). Complete remission without circulating EBV‐DNA has continued for 15 months after a delayed hematologic recovery. This is the first successful report of CBT for CAEBV. CB may therefore be an alternate source of stem cells for the curative treatment of CAEBV, despite the absence of EBV‐specific cytotoxic T lymphocytes. Am. J. Hematol. 80:207–212, 2005.

We report a case of juvenile xanthogranuloma (JXG) having progressive pancytopenia for 6 months until the proliferating skin lesions. A 2‐month‐old infant presented recurrent fever, anemia, and hepatosplenomegaly mimicking hemophagocytic lymphohistiocytosis (HLH) or juvenile myelomonocytic leukemia (JMML). At 8 months of age, the biopsy of a growing papule on the elbow made the diagnosis. Bone marrow (BM) specimens showed clustering foamy cells including hemophagocytosis by histiocytes. Treatment with etoposide followed by vinblastine plus prednisolone (PSL) therapy improved the disease. Although JXG is a benign non‐Langerhans cell histiocytosis, the multisystem‐visceral form should be considered as a potential aggressive disease when associated with BM failure in early infancy.

Chronic active Epstein–Barr virus (EBV) infection is a chronic mononucleosis syndrome associated with clonal proliferation of EBV‐carrying T‐/natural killer (NK)‐cells. High levels of circulating EBV and activated T‐cells are sustained during the prolonged disease course, whereas it is not clear how ectopic EBV infection in T‐/NK‐cells has been established and maintained. To assess the biological role of activated T‐cells in chronic active EBV infection (CAEBV), EBV DNA and cellular gene expressions in peripheral T‐cells were quantified in CAEBV and infectious mononucleosis (IM) patients. In CAEBV, HLA‐DR⁺ T‐cells had higher viral load and larger amounts of IFNγ, IL‐10, transforming growth factor‐beta (TGFβ), and cytotoxic T lymphocyte antigen‐4 (CTLA4) mRNA than HLA‐DR⁻T‐cells. HLA‐DR⁺ T cells of IM patients transcribed more IFNγ and IL‐10 than their HLA‐DR⁻T cells. Expression levels of IFNγ and forkhead box p3 (Foxp3) in CAEBV HLA‐DR⁺ T‐cells were higher than in IM HLA‐DR⁺ T‐cells. The effective variables to discriminate the positivity of HLA‐DR were IL‐10, IFNγ, CTLA4, TGFβ, and IL‐2 in the order of statistical weight. EBV load in CAEBV T‐cells correlated with the expression levels of only IL‐10 and TGFβ. These results suggest that CAEBV T‐cells are activated to transcribe IFNγ, IL‐10, and TGFβ excessively, and the latter two genes are expressed preferentially in the EBV‐infected subsets. The dominant expression of regulatory cytokines in T‐cells may imply a viral evasion mechanism in the disease. J. Med. Virol. 74:449–458, 2004.