HLH‐2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis

Henter, Jan‐Inge; Horne, AnnaCarin; Aricò, Maurizio; Egeler, R. Maarten; Filipovich, Alexandra H.; Imashuku, Shinsaku; Ladisch, Stephan; McClain, Kenneth L.; Webb, David; Winiarski, Jacek; Janka, Gritta

doi:10.1002/pbc.21039

Cited by 4,127 publications

(4,504 citation statements)

References 52 publications

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“…The diagnosis of FHL2 and FHL3 was completed by the established method using flow-cytometry (perforin, Munc13-4, or CD107a), Western blotting analysis (Munc13-4) and/or direct DNA sequencing [19,20]. After 2006, the screening using flow-cytometry was used even for infants who did not fulfill the clinical criteria of the HLH guidelines [18].…”

Section: Methodsmentioning

confidence: 99%

Reduced‐intensity conditioning in unrelated donor cord blood transplantation for familial hemophagocytic lymphohistiocytosis

et al. 2012

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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 5 12) 1 melphalan (MEL; n 5 11) ± low-dose total body irradiation (TBI 2-4 Gy; n 5 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 FLU1MEL-conditioned patients, the frequency of disease-free complete engraftment was higher for MEL ( 120 mg/m 2 )1TBI, or high-dose MEL (180 mg/m 2 ) than for others (83% vs. 25%, p 5 0.036). The FLU1MEL-based non-myeloablative regimen was acceptable for FHL infants undergoing UCBT, although further studies will be needed for confirmation.Hemophagocytic lymphohistiocytosis (HLH) is a disorder of immune homeostasis characterized by fever, cytopenias, hepatosplenomegaly, hyperferritinemia, and disseminated intravascular coagulopathy [1]. The lifethreatening condition arises from uncontrolled activation of proliferating lymphocytes, hemophagocytosing macrophages, and hypercytokinemia. The genetic basis of primary HLH resides in the defective cytotoxicity of Tcells and natural killer cells, although secondary HLH can occur in patients with infection, malignancy, or autoimmune disease. Familial HLH (FHL) is an autosomal recessive disease. Affected patients develop HLH mostly in childhood as the sole phenotype of the disease and require allogeneic hematopoietic stem cell transplantation (SCT) for a complete cure. The causal genes of FHL account for the structure, function, and metabolism of cytotoxic granules, such as PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5) [2]. A potential risk of developing HLH is also a part of the clinical expressions of X-linked lymphoproliferative disease (XLP1 and XLP2), Chediak-Higashi syndrome, and Griscelli syndrome [3].Recent advances in SCT procedures have improved the survival rate of patients with FHL who undergo SCT after myeloablative conditioning, which now range from 45 to 65% [4][5][6][7][8][9][10][11]. However, there remain critical problems with SCT for FHL; early death from treatment-related events often associated with venoocclusive disease, and neurological sequelae in survivors. The early age at diagnosis also raises a clinical dilemma concerning the timing, preparative regimen, and al...

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Section: Methodsmentioning

confidence: 99%

Reduced‐intensity conditioning in unrelated donor cord blood transplantation for familial hemophagocytic lymphohistiocytosis

et al. 2012

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“…The disease onset was during early infancy in all patients except for patient P4. Patient P2 did not respond to the HLH-2004 treatment protocol [12], and died at 12 days of age. Patients P1, P3, P4 and P5 underwent stem cell transplantation at the ages of 5 mo, 2 yr, 5 mo and 5 mo, respectively [13].…”

Section: Patientsmentioning

confidence: 99%

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

et al. 2013

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Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of T cells and macrophages with overproduction of cytokines. Familial HLH type2 (FHL2) is the most common form of primary HLH and is caused by mutations in PRF1. We have recently described a significant increase in the subpopulation of CD8 + T cells with clonal expansion and CD5 down-regulation in Epstein-Barr virus associated-HLH, which represented a valuable tool for its diagnosis. However, this unusual phenotype of CD8 + T cells has not been investigated fully in patients with FHL2. We performed immunophenotypic analysis of peripheral blood and measured serum proinflammatory cytokines in 5 patients with FHL2. All patients showed significantly increased subpopulations of activated CD8 + T cells with down-regulation of CD5, which were negligible among normal controls. Analysis of T-cell receptor Vβ repertoire suggested the reactive and oligoclonal expansion of these cells. The proportion of the subset declined after successful treatment concomitant with reduction in the serum levels of cytokines in all patients except one who continued to have a high proportion of the subset and died. These findings suggest that down-regulation of CD5 on activated CD8 +

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“…During hospitalization, hemophagocytic lymphohistiocytosis (HLH) was diagnosed based on the HLH‐2004 criteria 15. Leukoerythroblastosis in a peripheral blood (PB) smear was defined as the presence of nucleated erythrocytes and immature myeloid cells 16, 17, 18…”

Section: Methodsmentioning

confidence: 99%

Primary bone marrow lymphoma: A hematological emergency in adults with fever of unknown origin

et al. 2018

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Primary bone marrow lymphoma (PBML) represents non‐Hodgkin lymphoma (NHL) that primarily arises in the bone marrow (BM) without lymphadenopathy. This condition has various definitions and can be masked by prolonged fever, leading to delayed diagnosis. We aimed to identify clinical features and risk indicators of PBML. We enrolled 269 adults with fever of unknown origin (FUO) who underwent a BM study for potential PBML. Thirty patients were diagnosed with PBML (26 and 4 patients in the training and validation cohort, respectively), and 20 patients (67%) showed initial manifestation of hemophagocytic lymphohistiocytosis (HLH). Among PBML patients in the training cohort, their median overall survival is short (8 days), with pneumonia being the most common direct cause of early mortality, followed by life‐threatening HLH. Despite extremely poor prognoses, some B‐cell PBML patients who survived 30 days after BM studies achieved long‐term survival with rituximab‐based treatment. To assist general practitioners in early PBML diagnosis when approaching adults with naïve FUO, we identified several risk indicators, including elevated serum alkaline‐phosphate levels, lowered serum immunoglobulin‐G levels, cytopenia in ≥2 lineages, and peripheral blood leukoerythroblastosis. Our recently published scoring system, which can predict hematological BM disease in FUO adults, showed excellent ability in recognizing PBML early, with high sensitivity and specificity. We conclude that PBML is a specific “clinical” phenotype of NHL; moreover, we have identified diagnostic clues for early identification of FUO adults with underlying PBML, which should be considered a hematological emergency once suspected in any adult with FUO.

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HLH‐2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis

Cited by 4,127 publications

References 52 publications

Reduced‐intensity conditioning in unrelated donor cord blood transplantation for familial hemophagocytic lymphohistiocytosis

Reduced‐intensity conditioning in unrelated donor cord blood transplantation for familial hemophagocytic lymphohistiocytosis

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

Primary bone marrow lymphoma: A hematological emergency in adults with fever of unknown origin

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