Advertisement

Hemophagocytic Lymphohistiocytosis Associated with Malignancies and with Epstein-Barr Virus

  • Kai Lehmberg
  • Fumihiro Ochi
  • Kim E. Nichols
  • Eiichi Ishii
Chapter

Abstract

Hemophagocytic lymphohistiocytosis (HLH) represents an often life-threatening syndrome associated with the uncontrolled activation of immune cells and the overproduction of pro-inflammatory cytokines. HLH can occur as the result of several underlying conditions in which there is excess stimulation of the immune system, in combination with inadequate downregulation of the immune response. Among the stimuli commonly associated with HLH are underlying malignancies, most often lymphomas, and certain viruses, including Epstein-Barr virus (EBV), a member of the herpesvirus family. In recent years, increased awareness has led to improved recognition as well as research into these as yet poorly understood disorders. We discuss current insights into the clinical manifestations, prognostic features, biology, and treatment approaches for malignancy- and EBV-associated HLH.

Keywords

Hemophagocytic lymphohistiocytosis Hemophagocytic syndrome Macrophage activation syndrome Epstein-Barr virus T cell lymphoma Diffuse large B cell lymphoma Hodgkin lymphoma Etoposide Clonality Rituximab 

Abbreviations

CAEBV

Chronic active EBV infection

CMV

Cytomegalovirus

CTL

Cytotoxic T cells

EBNA

Epstein-Barr nuclear antigen

EBV

Epstein-Barr virus

FHL

Familial HLH

FIM

Fulminant mononucleosis

HIV

Human immune deficiency virus

HLH

Hemophagocytic lymphohistiocytosis

HSCT

Hematopoietic stem cell transplantation

IFN

Interferon

IM

Infectious mononucleosis

ITK

Inducible T cell kinase

MAC

Myeloablative conditioning

MAGT1

Magnesium transporter 1

MRI

Magnetic resonance imaging

NK

Natural killer

PBMNC

Peripheral blood mononuclear cells

PTLD

Post-transplantation lymphoproliferative disorder

RIC

Reduced intensity conditioning

sCD25

Soluble IL2 receptor

TBI

Total body irradiation

TCR

T cell receptor

TGF

Transforming growth factor

UCBT

Unrelated donor cord blood transplantation

VCA

Virus capsid antigen

XLP

X-linked lymphoproliferative disease

References

  1. 1.
    Warnke RA, Kim H, Dorfman RF. Malignant histiocytosis (histiocytic medullary reticulosis). I. Clinicopatholigic study of 29 cases. Cancer. 1975;35(1):215–30.PubMedCrossRefGoogle Scholar
  2. 2.
    Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16.PubMedCrossRefGoogle Scholar
  3. 3.
    Lehmberg K, Nichols KE, Henter JI, Girschikofsky M, Greenwood T, Jordan M, et al. Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015;100(8):997–1004.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Al-Hashmi I, Decoteau J, Gruss HJ, Zielenska M, Thorner P, Poon A, et al. Establishment of a cytokine-producing anaplastic large-cell lymphoma cell line containing the t(2;5) translocation: potential role of cytokines in clinical manifestations. Leuk Lymphoma. 2001;40(5–6):599–611.PubMedCrossRefGoogle Scholar
  5. 5.
    Siebert S, Amos N, Williams BD, Lawson TM. Cytokine production by hepatic anaplastic large-cell lymphoma presenting as a rheumatic syndrome. Semin Arthritis Rheum. 2007;37(1):63–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Perez-Encinas M, Villamayor M, Campos A, Gonzalez S, Bello JL. Tumor burden and serum level of soluble CD25, CD8, CD23, CD54 and CD44 in non-Hodgkin’s lymphoma. Haematologica. 1998;83(8):752–4.PubMedGoogle Scholar
  7. 7.
    Janik JE, Morris JC, Pittaluga S, McDonald K, Raffeld M, Jaffe ES, et al. Elevated serum-soluble interleukin-2 receptor levels in patients with anaplastic large cell lymphoma. Blood. 2004;104(10):3355–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Menard F, Besson C, Rince P, Lambotte O, Lazure T, Canioni D, et al. Hodgkin lymphoma-associated hemophagocytic syndrome: a disorder strongly correlated with Epstein-Barr virus. Clin Infect Dis. 2008;47(4):531–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Risdall RJ, McKenna RW, Nesbit ME, Krivit W, Balfour HH Jr, Simmons RL, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979;44(3):993–1002.PubMedCrossRefGoogle Scholar
  10. 10.
    Delavigne K, Berard E, Bertoli S, Corre J, Duchayne E, Demur C, et al. Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy. Haematologica. 2014;99(3):474–80.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Celkan T, Berrak S, Kazanci E, Ozyurek E, Unal S, Ucar C, et al. Malignancy-associated hemophagocytic lymphohistiocytosis in pediatric cases: a multicenter study from Turkey. Turk J Pediatr. 2009;51(3):207–13.PubMedGoogle Scholar
  12. 12.
    Lehmberg K, Sprekels B, Nichols KE, Woessmann W, Müller I, Suttorp M, Bernig T, Beutel K, Bode SFN, Kentouche K, Kolb R, Längler A, Minkov M, Schillign FH, Schmid I, Vieth S, Ehl S, Zur Stadt U, Janka GE. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. B J Haematol. 2015;170(4):539–49.CrossRefGoogle Scholar
  13. 13.
    Riviere S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O, et al. Reactive hemophagocytic syndrome in adults: a multicenter retrospective analysis of 162 patients. Am J Med. 2014;127(11):1118–25.PubMedCrossRefGoogle Scholar
  14. 14.
    Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol. 2007;86(1):58–65.PubMedCrossRefGoogle Scholar
  15. 15.
    Li J, Wang Q, Zheng W, Ma J, Zhang W, Wang W, et al. Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients. Medicine. 2014;93(2):100–5.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Yu JT, Wang CY, Yang Y, Wang RC, Chang KH, Hwang WL, et al. Lymphoma-associated hemophagocytic lymphohistiocytosis: experience in adults from a single institution. Ann Hematol. 2013;92(11):1529–36.PubMedCrossRefGoogle Scholar
  17. 17.
    Han AR, Lee HR, Park BB, Hwang IG, Park S, Lee SC, et al. Lymphoma-associated hemophagocytic syndrome: clinical features and treatment outcome. Ann Hematol. 2007;86(7):493–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Veerakul G, Sanpakit K, Tanphaichitr VS, Mahasandana C, Jirarattanasopa N. Secondary hemophagocytic lymphohistiocytosis in children: an analysis of etiology and outcome. J Med Assoc Thail. 2002;85(Suppl 2):S530–41.Google Scholar
  19. 19.
    Lehmberg K, Sprekels B, Nichols KE, Woessmann W, Muller I, Suttorp M, et al. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol. 2015;170(4):539–49.PubMedCrossRefGoogle Scholar
  20. 20.
    Go RS, Wester SM. Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature. Cancer. 2004;101(6):1404–13.PubMedCrossRefGoogle Scholar
  21. 21.
    Ferreri AJ, Dognini GP, Campo E, Willemze R, Seymour JF, Bairey O, et al. Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions. Haematologica. 2007;92(4):486–92.PubMedCrossRefGoogle Scholar
  22. 22.
    Kelly C, Salvi S, McClain K, Hayani A. Hemophagocytic lymphohistiocytosis associated with precursor B acute lymphoblastic leukemia. Pediatr Blood Cancer. 2011;56(4):658–60.PubMedCrossRefGoogle Scholar
  23. 23.
    Nichols CR, Roth BJ, Heerema N, Griep J, Tricot G. Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med. 1990;322(20):1425–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Chang YH, Lu PJ, Lu MY, Wang JS, Tung CL, Shaw CF. Sequential transplants for respective relapse of Hodgkin disease and hemophagocytic lymphohistiocytosis: a treatment dilemma. J Pediatr Hematol Oncol. 2009;31(10):778–81.PubMedCrossRefGoogle Scholar
  25. 25.
    Shimazaki C, Inaba T, Nakagawa M. B-cell lymphoma-associated hemophagocytic syndrome. Leuk Lymphoma. 2000;38(1–2):121–30.PubMedGoogle Scholar
  26. 26.
    Murase T, Nakamura S, Kawauchi K, Matsuzaki H, Sakai C, Inaba T, et al. An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma associated with haemophagocytic syndrome. Br J Haematol. 2000;111(3):826–34.PubMedGoogle Scholar
  27. 27.
    Stebbing J, Ngan S, Ibrahim H, Charles P, Nelson M, Kelleher P, et al. The successful treatment of haemophagocytic syndrome in patients with human immunodeficiency virus-associated multi-centric Castleman's disease. Clin Exp Immunol. 2008;154(3):399–405.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Hong M, Ko YH, Yoo KH, Koo HH, Kim SJ, Kim WS, et al. EBV-positive T/NK-cell Lymphoproliferative disease of childhood. Korean J Pathol. 2013;47(2):137–47.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kimura H, Ito Y, Kawabe S, Gotoh K, Takahashi Y, Kojima S, et al. EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases. Blood. 2012;119(3):673–86.PubMedCrossRefGoogle Scholar
  30. 30.
    Paik JH, Choe JY, Kim H, Lee JO, Kang HJ, Shin HY, et al. Clinicopathological categorization of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disease: an analysis of 42 cases with an emphasis on prognostic implications. Leuk Lymphoma. 2017;58(1):53–63. Epub 2016 May 9.Google Scholar
  31. 31.
    Aronson IK, Worobec SM. Cytophagic histiocytic panniculitis and hemophagocytic lymphohistiocytosis: an overview. Dermatol Ther. 2010;23(4):389–402.PubMedCrossRefGoogle Scholar
  32. 32.
    Trebo MM, Attarbaschi A, Mann G, Minkov M, Kornmuller R, Gadner H. Histiocytosis following T-acute lymphoblastic leukemia: a BFM study. Leuk Lymphoma. 2005;46(12):1735–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Lackner H, Urban C, Sovinz P, Benesch M, Moser A, Schwinger W. Hemophagocytic lymphohistiocytosis as severe adverse event of antineoplastic treatment in children. Haematologica. 2008;93(2):291–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154–7.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.PubMedCrossRefGoogle Scholar
  36. 36.
    Gupta A, Tyrrell P, Valani R, Benseler S, Weitzman S, Abdelhaleem M. The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;51(3):402–4.PubMedCrossRefGoogle Scholar
  37. 37.
    Tsuji T, Hirano T, Yamasaki H, Tsuji M, Tsuda H. A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol. 2014;93(5):821–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Hayden A, Park S, Giustini D, Lee AY, Chen LY. Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: a systematic scoping review. Blood Rev. 2016;30(6):411–20.PubMedCrossRefGoogle Scholar
  39. 39.
    Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Fardet L, Lambotte O, Meynard JL, Kamouh W, Galicier L, Marzac C, et al. Reactive haemophagocytic syndrome in 58 HIV-1-infected patients: clinical features, underlying diseases and prognosis. AIDS. (London, England). 2010;24(9):1299–306.PubMedCrossRefGoogle Scholar
  41. 41.
    Wang J, Wang D, Zhang Q, Duan L, Tian T, Zhang X, et al. The significance of pre-therapeutic F-18-FDG PET-CT in lymphoma-associated hemophagocytic lymphohistiocytosis when pathological evidence is unavailable. J Cancer Res Clin Oncol. 2016;142(4):859–71.PubMedCrossRefGoogle Scholar
  42. 42.
    Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol. 2012;160(3):275–87.PubMedCrossRefGoogle Scholar
  43. 43.
    Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, et al. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood. 2011;117(1):53–62.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Speckmann C, Lehmberg K, Albert MH, Damgaard RB, Fritsch M, Gyrd-Hansen M, et al. X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis. Clin Immunol. 2013;149(1):133–41.PubMedCrossRefGoogle Scholar
  45. 45.
    Cohen JI. Primary Immunodeficiencies associated with EBV disease. Curr Top Microbiol Immunol. 2015;390(Pt 1):241–65.PubMedGoogle Scholar
  46. 46.
    Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med. 2000;192(5):755–60.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Chia J, Yeo KP, Whisstock JC, Dunstone MA, Trapani JA, Voskoboinik I. Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc Natl Acad Sci U S A. 2009;106(24):9809–14.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Clementi R, Locatelli F, Dupre L, Garaventa A, Emmi L, Bregni M, et al. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood. 2005;105(11):4424–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Santoro A, Cannella S, Trizzino A, Lo Nigro L, Corsello G, Arico M. A single amino acid change A91V in perforin: a novel, frequent predisposing factor to childhood acute lymphoblastic leukemia? Haematologica. 2005;90(5):697–8.PubMedGoogle Scholar
  50. 50.
    Mehta PA, Davies SM, Kumar A, Devidas M, Lee S, Zamzow T, et al. Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the children’s oncology group. Leukemia. 2006;20(9):1539–41.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Lofstedt A, Chiang SC, Onelov E, Bryceson YT, Meeths M, Henter JI. Cancer risk in relatives of patients with a primary disorder of lymphocyte cytotoxicity: a retrospective cohort study. Lancet Haematol. 2015;2(12):e536–42.PubMedCrossRefGoogle Scholar
  52. 52.
    Machaczka M, Klimkowska M, Chiang SC, Meeths M, Muller ML, Gustafsson B, et al. Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations. Haematologica. 2013;98(5):760–4.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Lorenzi L, Tabellini G, Vermi W, Moratto D, Porta F, Notarangelo LD, et al. Occurrence of nodular lymphocyte-predominant hodgkin lymphoma in hermansky-pudlak type 2 syndrome is associated to natural killer and natural killer T cell defects. PLoS One. 2013;8(11):e80131.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Nagai K, Ochi F, Terui K, Maeda M, Ohga S, Kanegane H, et al. Clinical characteristics and outcomes of chediak-Higashi syndrome: a nationwide survey of Japan. Pediatr Blood Cancer. 2013;60(10):1582–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Pagel J, Beutel K, Lehmberg K, Koch F, Maul-Pavicic A, Rohlfs AK, et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood. 2012;119(25):6016–24.PubMedCrossRefGoogle Scholar
  56. 56.
    Yoshida N, Tsuzuki S, Karube K, Takahara T, Suguro M, Miyoshi H, et al. STX11 functions as a novel tumor suppressor gene in peripheral T-cell lymphomas. Cancer Sci. 2015;106(10):1455–62.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Trapani JA, Thia KY, Andrews M, Davis ID, Gedye C, Parente P, et al. Human perforin mutations and susceptibility to multiple primary cancers. Oncoimmunology. 2013;2(4):e24185.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Bryceson YT, Pende D, Maul-Pavicic A, Gilmour KC, Ufheil H, Vraetz T, et al. A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood. 2012;119(12):2754–63.PubMedCrossRefGoogle Scholar
  59. 59.
    Marsh RA, Bleesing JJ, Filipovich AH. Flow cytometric measurement of SLAM-associated protein and X-linked inhibitor of apoptosis. Methods Mol Biol. 2013;979:189–97.PubMedCrossRefGoogle Scholar
  60. 60.
    Johnson TS, Terrell CE, Millen SH, Katz JD, Hildeman DA, Jordan MB. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol. 2014;192(1):84–91.PubMedCrossRefGoogle Scholar
  61. 61.
    Wang Y, Huang W, Hu L, Cen X, Li L, Wang J, et al. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood. 2015;126(19):2186–92.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Arca M, Fardet L, Galicier L, Riviere S, Marzac C, Aumont C, et al. Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide. Br J Haematol. 2014;168(1):63–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Schram AM, Comstock P, Campo M, Gorovets D, Mullally A, Bodio K, et al. Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. Br J Haematol. 2016;172(3):412–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Mizutani S, Kuroda J, Shimura Y, Kobayashi T, Tsutsumi Y, Yamashita M, et al. Cyclosporine A for chemotherapy-resistant subcutaneous panniculitis-like T cell lymphoma with hemophagocytic syndrome. Acta Haematol. 2011;126(1):8–12.PubMedCrossRefGoogle Scholar
  65. 65.
    Maschalidi S, Sepulveda FE, Garrigue A, Fischer A, de Saint Basile G. Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood. 2016;128(1):60–71.PubMedCrossRefGoogle Scholar
  66. 66.
    Das R, Guan P, Sprague L, Verbist K, Tedrick P, An QA, et al. Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood. 2016;127(13):1666–75.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013;162(3):376–82.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Aulagnon F, Lapidus N, Canet E, Galicier L, Boutboul D, Peraldi MN, et al. Acute kidney injury in adults with hemophagocytic lymphohistiocytosis. Am J Kidney Dis. 2015;65(6):851–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Takahashi N, Chubachi A, Kume M, Hatano Y, Komatsuda A, Kawabata Y, et al. A clinical analysis of 52 adult patients with hemophagocytic syndrome: the prognostic significance of the underlying diseases. Int J Hematol. 2001;74(2):209–13.PubMedCrossRefGoogle Scholar
  70. 70.
    Parikh SA, Kapoor P, Letendre L, Kumar S, Wolanskyj AP. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc. 2014;89(4):484–92.PubMedCrossRefGoogle Scholar
  71. 71.
    Tong H, Ren Y, Liu H, Xiao F, Mai W, Meng H, et al. Clinical characteristics of T-cell lymphoma associated with hemophagocytic syndrome: comparison of T-cell lymphoma with and without hemophagocytic syndrome. Leuk Lymphoma. 2008;49(1):81–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Buyse S, Teixeira L, Galicier L, Mariotte E, Lemiale V, Seguin A, et al. Critical care management of patients with hemophagocytic lymphohistiocytosis. Intensive Care Med. 2010;36(10):1695–702.PubMedCrossRefGoogle Scholar
  73. 73.
    Kawa K. Epstein-Barr virus--associated diseases in humans. Int J Hematol. 2000;71(2):108–17.PubMedGoogle Scholar
  74. 74.
    Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481–92.PubMedCrossRefGoogle Scholar
  75. 75.
    Zhang K, Wakefield E, Marsh R. Lymphoproliferative disease, X-Linked. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle;1993.Google Scholar
  76. 76.
    Castillo L, Carcillo J. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/ systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit Care Med. 2009;10(3):387–92.PubMedCrossRefGoogle Scholar
  77. 77.
    Chen J, Wang X, He P, Li Y, Si M, Fan Z, et al. Viral etiology, clinical and laboratory features of adult hemophagocytic lymphohistiocytosis. J Med Virol. 2016;88(3):541–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Imashuku S, Ikushima S, Hibi S, Todo S. Langerhans cell histiocytosis and hemophagocytic syndrome in Japan: epidemiological studies. Int J Pediatr Hematol Oncol. 1994;1:241–6.Google Scholar
  79. 79.
    Kogawa K, Sato H, Asano T, Ohga S, Kudo K, Morimoto A, et al. Prognostic factors of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children: report of the Japan Histiocytosis Study Group. Pediatr Blood Cancer. 2014;61(7):1257–62.PubMedCrossRefGoogle Scholar
  80. 80.
    Koh KN, Im HJ, Chung NG, Cho B, Kang HJ, Shin HY, 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(1):51–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Gurgey A, Secmeer G, Tavil B, Ceyhan M, Kuskonmaz B, Cengiz B, et al. Secondary hemophagocytic lymphohistiocytosis in Turkish children. Pediatr Infect Dis J. 2005;24(12):1116–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Ishii E, Ohga S, Imashuku S, Kimura N, Ueda I, Morimoto A, et al. Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experiences. Crit Rev Oncol Hematol. 2005;53(3):209–23.PubMedCrossRefGoogle Scholar
  83. 83.
    Henter JI, Arico M, Egeler RM, Elinder G, Favara BE, Filipovich AH, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Med Pediatr Oncol. 1997;28(5):342–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Allen CE, McClain KL. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program. 2015;2015:177–82.PubMedGoogle Scholar
  85. 85.
    Ishii E, Ohga S, Tanimura M, Imashuku S, Sako M, Mizutani S, et al. Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH Study Group. Med Pediatr Oncol. 1998;30(5):276–83.PubMedCrossRefGoogle Scholar
  86. 86.
    Kimura H, Hoshino Y, Hara S, Nishikawa K, Sako M, Hirayama M, et al. Viral load in Epstein-Barr virus-associated hemophagocytic syndrome. Microbiol Immunol. 2002;46(8):579–82.PubMedCrossRefGoogle Scholar
  87. 87.
    Yamashita N, Kimura H, Morishima T. Virological aspects of Epstein-Barr virus infections. Acta Med Okayama. 2005;59(6):239–46.PubMedGoogle Scholar
  88. 88.
    Fadeel B, Orrenius S, Henter JI. Familial hemophagocytic lymphohistiocytosis: too little cell death can seriously damage your health. Leuk Lymphoma. 2001;42(1–2):13–20.PubMedCrossRefGoogle Scholar
  89. 89.
    de Saint BG, Sepulveda FE, Maschalidi S, Fischer A. Cytotoxic granule secretion by lymphocytes and its link to immune homeostasis. F1000Res. 2015;4(F1000 Faculty Rev):930.Google Scholar
  90. 90.
    Parvaneh N, Filipovich AH, Borkhardt A. Primary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases. Br J Haematol. 2013;162(5):573–86.PubMedCrossRefGoogle Scholar
  91. 91.
    Zhizhuo H, Junmei X, Yuelin S, Qiang Q, Chunyan L, Zhengde X, et al. Screening the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK gene mutations in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2012;58(3):410–4.PubMedCrossRefGoogle Scholar
  92. 92.
    Dupre L, Andolfi G, Tangye SG, Clementi R, Locatelli F, Arico M, et al. SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood. 2005;105(11):4383–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Kasahara Y, Yachie A, Takei K, Kanegane C, Okada K, Ohta K, et al. Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Blood. 2001;98(6):1882–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Wada T, Kurokawa T, Toma T, Shibata F, Tone Y, Hashida Y, et al. Immunophenotypic analysis of Epstein-Barr virus (EBV)-infected CD8(+) T cells in a patient with EBV-associated hemophagocytic lymphohistiocytosis. Eur J Haematol. 2007;79(1):72–5.PubMedCrossRefGoogle Scholar
  95. 95.
    Toga A, Wada T, Sakakibara Y, Mase S, Araki R, Tone Y, et al. Clinical significance of cloned expansion and CD5 down-regulation in Epstein-Barr Virus (EBV)-infected CD8+ T lymphocytes in EBV-associated hemophagocytic lymphohistiocytosis. J Infect Dis. 2010;201(12):1923–32.PubMedCrossRefGoogle Scholar
  96. 96.
    Beutel K, Gross-Wieltsch U, Wiesel T, Stadt UZ, Janka G, Wagner HJ. Infection of T lymphocytes in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children of non-Asian origin. Pediatr Blood Cancer. 2009;53(2):184–90.PubMedCrossRefGoogle Scholar
  97. 97.
    Chuang HC, Lay JD, Hsieh WC, Wang HC, Chang Y, Chuang SE, et al. Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome. Blood. 2005;106(9):3090–6.PubMedCrossRefGoogle Scholar
  98. 98.
    Nagy N, Matskova L, Kis LL, Hellman U, Klein G, Klein E. The proapoptotic function of SAP provides a clue to the clinical picture of X-linked lymphoproliferative disease. Proc Natl Acad Sci U S A. 2009;106(29):11966–71.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Lay JD, Chuang SE, Rowe M, Su IJ. Epstein-barr virus latent membrane protein-1 mediates upregulation of tumor necrosis factor-alpha in EBV-infected T cells: implications for the pathogenesis of hemophagocytic syndrome. J Biomed Sci. 2003;10(1):146–55.PubMedGoogle Scholar
  100. 100.
    Kawanishi M. Expression of Epstein-Barr virus latent membrane protein 1 protects Jurkat T cells from apoptosis induced by serum deprivation. Virology. 1997;228(2):244–50.PubMedCrossRefGoogle Scholar
  101. 101.
    Kasahara Y, Yachie A. Cell type specific infection of Epstein-Barr virus (EBV) in EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Crit Rev Oncol Hematol. 2002;44(3):283–94.PubMedCrossRefGoogle Scholar
  102. 102.
    Owen G, Webb DK. Evidence of clonality in a child with haemophagocytic lymphohistiocytosis. Br J Haematol. 1995;89(3):681–2.PubMedCrossRefGoogle Scholar
  103. 103.
    Matsuda K, Nakazawa Y, Yanagisawa R, Honda T, Ishii E, Koike K. Detection of T-cell receptor gene rearrangement in children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis using the BIOMED-2 multiplex polymerase chain reaction combined with GeneScan analysis. Clin Chim Acta. 2011;412(17–18):1554–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Braun M, Melchers I, Peter HH, Illges H. Human B and T lymphocytes have similar amounts of CD21 mRNA, but differ in surface expression of the CD21 glycoprotein. Int Immunol. 1998;10(8):1197–202.PubMedCrossRefGoogle Scholar
  105. 105.
    Tabiasco J, Vercellone A, Meggetto F, Hudrisier D, Brousset P, Fournie JJ. Acquisition of viral receptor by NK cells through immunological synapse. J Immunol. 2003;170(12):5993–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Stinchcombe JC, Bossi G, Booth S, Griffiths GM. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity. 2001;15(5):751–61.PubMedCrossRefGoogle Scholar
  107. 107.
    Hatta K, Morimoto A, Ishii E, Kimura H, Ueda I, Hibi S, et al. Association of transforming growth factor-beta1 gene polymorphism in the development of Epstein-Barr virus-related hematologic diseases. Haematologica. 2007;92(11):1470–4.PubMedCrossRefGoogle Scholar
  108. 108.
    Imashuku S, Kuriyama K, Teramura T, Ishii E, Kinugawa N, Kato M, et al. Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol. 2001;19(10):2665–73.PubMedCrossRefGoogle Scholar
  109. 109.
    Imashuku S, Hibi S, Ohara T, Iwai A, Sako M, Kato M, et al. Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Histiocyte Society. Blood. 1999;93(6):1869–74.PubMedGoogle Scholar
  110. 110.
    Imashuku S, Teramura T, Tauchi H, Ishida Y, Otoh Y, Sawada M, et al. Longitudinal follow-up of patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Haematologica. 2004;89(2):183–8.PubMedGoogle Scholar
  111. 111.
    Shiraishi A, Ohga S, Doi T, Ishimura M, Takimoto T, Takada H, et al. Treatment choice of immunotherapy or further chemotherapy for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2012;59(2):265–70.PubMedCrossRefGoogle Scholar
  112. 112.
    Trottestam H, Berglof E, Horne A, Onelov E, Beutel K, Lehmberg K, et al. Risk factors for early death in children with haemophagocytic lymphohistiocytosis. Acta Paediatr. 2012;101(3):313–8.PubMedCrossRefGoogle Scholar
  113. 113.
    Ohga S, Kudo K, Ishii E, Honjo S, Morimoto A, Osugi Y, et al. Hematopoietic stem cell transplantation for familial hemophagocytic lymphohistiocytosis and Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Japan. Pediatr Blood Cancer. 2010;54(2):299–306.PubMedGoogle Scholar
  114. 114.
    Chandrakasan S, Filipovich AH. Hemophagocytic lymphohistiocytosis: advances in pathophysiology, diagnosis, and treatment. J Pediatr. 2013;163(5):1253–9.PubMedCrossRefGoogle Scholar
  115. 115.
    Cooper N, Rao K, Gilmour K, Hadad L, Adams S, Cale C, et al. Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood. 2006;107(3):1233–6.PubMedCrossRefGoogle Scholar
  116. 116.
    Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010;116(26):5824–31.PubMedCrossRefGoogle Scholar
  117. 117.
    Lehmberg K, Albert MH, Beier R, Beutel K, Gruhn B, Kroger N, et al. Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis. Haematologica. 2014;99(1):180–4.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Sawada A, Ohga S, Ishii E, Inoue M, Okada K, Inagaki J, et al. Feasibility of reduced-intensity conditioning followed by unrelated cord blood transplantation for primary hemophagocytic lymphohistiocytosis: a nationwide retrospective analysis in Japan. Int J Hematol. 2013;98(2):223–30.PubMedCrossRefGoogle Scholar
  119. 119.
    Nishi M, Nishimura R, Suzuki N, Sawada A, Okamura T, Fujita N, et al. Reduced-intensity conditioning in unrelated donor cord blood transplantation for familial hemophagocytic lymphohistiocytosis. Am J Hematol. 2012;87(6):637–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Kai Lehmberg
    • 1
  • Fumihiro Ochi
    • 2
  • Kim E. Nichols
    • 3
  • Eiichi Ishii
    • 2
  1. 1.Department of Pediatric Hematology and OncologyUniversity Medical Center Hamburg EppendorfHamburgGermany
  2. 2.Department of PediatricsEhime University Graduate School of MedicineToonJapan
  3. 3.Department of OncologySt. Jude Children’s Research HospitalMemphisUSA

Personalised recommendations