search for




 

Review Article
Hemophagocytic Lymphohistiocytosis
Clin Pediatr Hematol Oncol 2017;24:11-20.
Published online April 30, 2017
© 2017 Korean Society of Pediatric Hematology-Oncology and Korean Society for Pediatric Neuro-Oncology

Sun Young Park, M.D. and Jae Min Lee, M.D.

Department of Pediatrics, College of Medicine, Yeungnam University, Daegu, Korea
Correspondence to: Jae Min Lee Department of Pediatrics, Yeungnam University Hospital, 170, Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: +82-53-620-3530 Fax: +82-53-629-2252 E-mail: mopic@yu.ac.kr ORCID ID: orcid.org/0000-0001-6822-1051
Received March 26, 2017; Revised April 7, 2017; Accepted April 21, 2017.
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.
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disease caused by dysregulated immune responses and overwhelming inflammation to infectious or other triggers of the immune system. HLH may be inherited (primary) or may be secondary to any severe infection, malignancy or rheumatologic disease. Clinical progress of HLH is usually rapid and fatal. Early recognition and assessment of potential causes of HLH is critical to improve survival. Urgent treatment is needed for immunosuppression and degradation of the activated antigen. Over the last two decades, research on genetics and pathophysiology of HLH has much improved treatment outcome of the patient. Here, we review recent advances in our understanding of etiology, pathophysiology, diagnosis and treatment of HLH.
Keywords: Hemophagocytic lymphohistiocytosis, Genetics, Pathogenesis, Treatment
References
  1. Chandrakasan S, Filipovich AH. Hemophagocytic lymphohistiocytosis: advances in pathophysiology, diagnosis, and treatment. J Pediatr 2013;163:1253-9.
    Pubmed CrossRef
  2. Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. Lancet 1939;234:194-8.
    CrossRef
  3. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child 1952;27:519-25.
    CrossRef
  4. Gholam C, Grigoriadou S, Gilmour KC, Gaspar HB. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management. Clin Exp Immunol 2011;163:271-83.
    Pubmed KoreaMed CrossRef
  5. Henter JI. Biology and treatment of familial hemophagocytic lymphohistiocytosis: importance of perforin in lymphocyte-mediated cytotoxicity and triggering of apoptosis. Med Pediatr Oncol 2002;38:305-9.
    Pubmed CrossRef
  6. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003;115:461-73.
    CrossRef
  7. Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program 2013;2013:605-11.
  8. Ohadi M, Lalloz MR, Sham P, et al. Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet 1999;64:165-71.
    Pubmed KoreaMed CrossRef
  9. Yoon HS, Kim HJ, Yoo KH, et al. UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis. Haematologica 2010;95:622-6.
    Pubmed KoreaMed CrossRef
  10. Koh KN, Im HJ, Chung NG, et al. Clinical features, genetics, and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in Korea: report of a nationwide survey from Korea Histiocytosis Working Party. Eur J Haematol 2015; 94:51-9.
    Pubmed CrossRef
  11. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet 2014;383:1503-16.
    CrossRef
  12. Allen CE, McClain KL. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program 2015;2015:177-82.
  13. Lehmberg K, Sprekels B, Nichols KE, et al. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol 2015;170:539-49.
    Pubmed CrossRef
  14. O'Brien MM, Lee-Kim Y, George TI, McClain KL, Twist CJ, Jeng M. Precursor B-cell acute lymphoblastic leukemia presenting with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50:381-3.
    Pubmed CrossRef
  15. Atteritano M, David A, Bagnato G, et al. Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci 2012;16:1414-24.
    Pubmed
  16. Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun 2012;13:289-98.
    Pubmed CrossRef
  17. Meeths M, Horne A, Sabel M, Bryceson YT, Henter JI. Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden. Pediatr Blood Cancer 2015;62:346-52.
    Pubmed CrossRef
  18. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991;80:428-35.
    CrossRef
  19. Ishii E, Ohga S, Tanimura M, et al. Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH Study Group. Med Pediatr Oncol 1998; 30:276-83.
    CrossRef
  20. Stinchcombe JC, Griffiths GM. Secretory mechanisms in cell-mediated cytotoxicity. Annu Rev Cell Dev Biol 2007; 23:495-517.
    Pubmed CrossRef
  21. Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 2011;118:5794-8.
    Pubmed KoreaMed CrossRef
  22. Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 2004;104:735-43.
    Pubmed CrossRef
  23. Jessen B, Kögl T, Sepulveda FE, de Saint Basile G, Aichele P, Ehl S. Graded defects in cytotoxicity determine severity of hemophagocytic lymphohistiocytosis in humans and mice. Front Immunol 2013;4:448.
    Pubmed KoreaMed CrossRef
  24. Henter JI, Aricò M, Egeler RM, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Med Pediatr Oncol 1997; 28:342-7.
    CrossRef
  25. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.
    Pubmed CrossRef
  26. Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50:1227-35.
    Pubmed CrossRef
  27. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007;166:95-109.
    Pubmed CrossRef
  28. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood 2011;118:4041-52.
    Pubmed KoreaMed CrossRef
  29. Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood 2011;118:4577-84.
    Pubmed KoreaMed CrossRef
  30. Horne A, Trottestam H, Aricò M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol 2008;140:327-35.
    Pubmed CrossRef
  31. Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983;140:221-30.
    Pubmed CrossRef
  32. Ambruso DR, Hays T, Zwartjes WJ, Tubergen DG, Favara BE. Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer 1980;45:2516-20.
    CrossRef
  33. Fischer A, Virelizier JL, Arenzana-Seisdedos F, Perez N, Nezelof C, Griscelli C. Treatment of four patients with erythrophagocytic lymphohistiocytosis by a combination of epipodophyllotoxin, steroids, intrathecal methotrexate, and cranial irradiation. Pediatrics 1985;76:263-8.
    Pubmed
  34. Henter JI, Elinder G, Finkel Y, Söder O. Successful induction with chemotherapy including teniposide in familial erythrophagocytic lymphohistiocytosis. Lancet 1986;2:1402.
    CrossRef
  35. Lilleyman JS. The treatment of familial erythrophagocytic lymphohistiocytosis. Cancer 1980;46:468-70.
    CrossRef
  36. Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood 2011;118:4577-84.
    Pubmed KoreaMed CrossRef
  37. Mahlaoui N, Ouachée-Chardin M, de Saint Basile G, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics 2007;120:e622-8.
    Pubmed CrossRef
  38. Stéphan JL, Donadieu J, Ledeist F, Blanche S, Griscelli C, Fischer A. Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids, and cyclosporin A. Blood 1993;82:2319-23.
    Pubmed
  39. Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer 2013;60:101-9.
    Pubmed KoreaMed CrossRef
  40. Fischer A, Cerf-Bensussan N, Blanche S, et al. Allogeneic bone marrow transplantation for erythrophagocytic lymphohistiocytosis. J Pediatr 1986;108:267-70.
    CrossRef
  41. Aricò M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996;10:197-203.
    Pubmed
  42. Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002;100:2367-73.
    Pubmed CrossRef
  43. Schechter T, Naqvi A, Weitzman S. Risk for complications in patients with hemophagocytic lymphohistiocytosis who undergo hematopoietic stem cell transplantation: myeloablative versus reduced-intensity conditioning regimens. Expert Rev Clin Immunol 2014;10:1101-6.
    Pubmed CrossRef
  44. Marsh RA, Rao K, Satwani P, et al. Allogeneic hematopoietic cell transplantation for XIAP deficiency: an international survey reveals poor outcomes. Blood 2013;121:877-83.
    Pubmed KoreaMed CrossRef
  45. Marsh RA, Vaughn G, Kim MO, et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood 2010;116:5824-31.
    Pubmed CrossRef
  46. Seo JJ. Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: recent advances and controversies. Blood Res 2015;50:131-9.
    Pubmed KoreaMed CrossRef


October 2019, 26 (2)
Full Text PDF
Citation
Send to a friend
Twitter
Facebook

Cited By Articles
  • CrossRef (0)

Author ORCID Information
  • Jae Min Lee