Blood Res 2021; 56(S1):
Published online April 30, 2021
https://doi.org/10.5045/br.2021.2020323
© The Korean Society of Hematology
Correspondence to : Dae-Young Kim, M.D., Ph.D.
Department of Internal Medicine, Ewha Womans University College of Medicine, 260 Gonghang-daero, Gangseo-gu, Seoul 07804, Korea
E-mail: drdani@ewha.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of defective apoptosis, a disruption of the regulatory pathway that terminates immune and inflammatory responses. Fever, cytopenia, splenomegaly, and/or hemophagocytosis are typical findings of this syndrome. HLH can be induced by genetic disorders (familial) or secondary causes. Familial HLH is rare, while secondary causes in adults include infection, autoimmunity, and malignancy. HLH in adults tends to be confused with or misdiagnosed as sepsis, mainly due to similar clinical manifestations and laboratory findings, which make it difficult to diagnose HLH rapidly and adopt immunosuppressive agents and/or chemotherapy adequately. Treatment of pediatric HLH using HLH-2004 or multi-agent chemotherapy can be applied in adult patients, although the dose and type of drug need to be adjusted. It is highly recommended that allogenic hematopoietic stem cell transplantation should be used in patients who become reactivated or are refractory to the initial treatment as soon as possible to improve survival. Future clinical trials are warranted to determine more suitable treatments for adult patients with HLH.
Keywords Hemophagocytic lymphohistiocytosis, Hemophagocytic syndrome
Blood Res 2021; 56(S1): S17-S25
Published online April 30, 2021 https://doi.org/10.5045/br.2021.2020323
Copyright © The Korean Society of Hematology.
Yu Ri Kim1, Dae-Young Kim2
1Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, 2Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
Correspondence to:Dae-Young Kim, M.D., Ph.D.
Department of Internal Medicine, Ewha Womans University College of Medicine, 260 Gonghang-daero, Gangseo-gu, Seoul 07804, Korea
E-mail: drdani@ewha.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of defective apoptosis, a disruption of the regulatory pathway that terminates immune and inflammatory responses. Fever, cytopenia, splenomegaly, and/or hemophagocytosis are typical findings of this syndrome. HLH can be induced by genetic disorders (familial) or secondary causes. Familial HLH is rare, while secondary causes in adults include infection, autoimmunity, and malignancy. HLH in adults tends to be confused with or misdiagnosed as sepsis, mainly due to similar clinical manifestations and laboratory findings, which make it difficult to diagnose HLH rapidly and adopt immunosuppressive agents and/or chemotherapy adequately. Treatment of pediatric HLH using HLH-2004 or multi-agent chemotherapy can be applied in adult patients, although the dose and type of drug need to be adjusted. It is highly recommended that allogenic hematopoietic stem cell transplantation should be used in patients who become reactivated or are refractory to the initial treatment as soon as possible to improve survival. Future clinical trials are warranted to determine more suitable treatments for adult patients with HLH.
Keywords: Hemophagocytic lymphohistiocytosis, Hemophagocytic syndrome
Table 1 . Gene mutations associated with hemophagocytic lymphohistiocytosis..
Disease | Genetic mutations |
---|---|
FHL1 | Unknown (9q21.3–2) |
FHL2 | |
FHL3 | |
FHL4 | |
FHL5 |
Abbreviation: FHL, familial hemophagocytic lymphohistiocytosis..
Table 2 . Diagnostic criteria of hemophagocytic lymphohistiocytosis: HLH-2004..
Diagnosis will be established if one of either (1) or (2) is fulfilled |
---|
(1) Molecular diagnosis consistent with HLH |
(2) Diagnostic criteria for HLH fulfilled (5 out of the 8 criteria shown below) |
① Fever ≥38.5°C for ≥7 days |
② Splenomegaly ≥3 finger breadth below the left subcostal margin |
③ Cytopenias affecting ≥2 of 3 lineages in peripheral blood |
Hemoglobin <9 g/L |
Platelets <100×109/L |
Absolute neutrophil count <1.0×109/L |
④ Hypertriglyceridemia and/or hypofibrinogenemia |
Fasting triglycerides ≥265 mg/dL, Fibrinogen ≤1.5 g/L |
⑤ Hemophagocytosis in the bone marrow or spleen or lymph node |
⑥ Low or absent NK cell activity (according to the local laboratory reference) |
⑦ Ferritin ≥500 μg/L |
⑧ Soluble CD25 (sIL-2 receptor) ≥2,400 U/mL |
Abbreviations: HLH, hemophagocytic lymphohistiocytosis; NK, natural killer; sIL-2, soluble interleukin-2..
Table 3 . Results of studies on the treatment of hemophagocytic lymphohistiocytosis in adult patients..
Authors | Characteristics | N | Cause | Treatment | Outcome | Etc |
---|---|---|---|---|---|---|
Imashuku | Early vs. delayed etoposide | 20 | EBV-HLH | Etoposide (within 4 weeks) | Survivor: 5/7 vs. 1/13 | 2.5-yr OS: |
85 vs. 10% | ||||||
Tseng | Non-infectious vs. Infectious | 96 | Non-infection: 66 | Observational study | Mortality: 70% vs. 47% | |
Infectious: 30 | ||||||
Buyse | HLH at ICU | 56 | Tumor: 43 | Etoposide: 45 | Mortality: 29/56 | MAHS |
Non-viral: 13 | Corticosteroid: 31 | Aggressive supportive care | ||||
Viral: 10 | IVIG: 3 | |||||
Park | HLH with hemophagocytosis | 23 | EBV: 16 | HLH-94 or 2004: 13 | Long-term survivor: 6/23 (26%) | 4 survivors received alloHCT |
Idiopathic: 6 | Immunosuppressive therapy: 9 | |||||
Hepatitis A: 1 | ||||||
Yoon | Non malignancy associated HLH | 126 | EEBV, infection, autoimmune | HLH-94 81 (64.3%) | CR: 64.3% | 8-week treatment response is a predictor for survival |
Shin | CHOP-based Tx | 17 | CHOP | CR: 41.2% | 2-year OS rate: 43.9% | |
PR: 17.6% |
Abbreviations: CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; CR, complete remission; EBV, EpsteinBarr virus; HLH, hemophagocytic lymphohistiocytosis; ICU, intensive care unit; IVIG, intravenous immunoglobulin; MAHS, malignancy-associated hemophagocytic syndrome; OS, overall survival; PR, partial remission..
Table 4 . Diagnostic workup to differentiate hemophagocytic lymphohistiocytosis from other diseases..
Differential diagnosis | Tests |
---|---|
Malignancy | Bone marrow aspiration/biopsy |
Neck/chest/abdominopelvic computed tomography | |
Tumor markers | |
Infection | Cytomegalovirus, Epstein–Barr virus, parvovirus |
Hepatitis A, B, C virus | |
Human immunodeficiency virus | |
Immunoglobulin E | |
Parasite-specific antibody | |
Rheumatic disorder | Fluorescence anti-nuclear antibodyanti-double-strand DNA |
C3/C4 | |
Erythrocyte sediment rate | |
Lupus anticoagulant |
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