Annals of Hematology

, Volume 96, Issue 8, pp 1241–1251 | Cite as

Clinical utility of soluble interleukin-2 receptor in hemophagocytic syndromes: a systematic scoping review

  • Molly Lin
  • Sujin Park
  • Anna Hayden
  • Dean Giustini
  • Martina Trinkaus
  • Morris Pudek
  • Andre Mattman
  • Marion Schneider
  • Luke Y.C. Chen
Review Article


The serum-soluble interleukin-2 receptor (sIL-2r) level is considered an important diagnostic test and disease marker in hemophagocytic syndromes/hemophagocytic lymphohistiocytosis (HPS/HLH). However, this cytokine receptor is rarely measured in clinical practice and has been excluded from recent diagnostic/classification criteria such as the HScore and macrophage activation syndrome (MAS) 16. We performed a systematic scoping review of 64 articles (1975–2016) examining the clinical utility of sIL-2r in HPS/HLH. Twenty-two articles describe sIL-2r as a sensitive diagnostic marker for HLH, but only three distinct datasets actually address sensitivity. The original HLH-2004 Guidelines reported sensitivity of 93% and specificity of 100% for sIL-2r ≥ 2400, based on a pediatric dataset (n = 152) which is published for the first time in this review. Two pediatric studies reported sensitivity of 89% for sIL-2r ≥ 2400 in diagnosis of MAS complicating juvenile idiopathic arthritis (JIA) (n = 27) and 88% for secondary HLH in acute liver failure (n = 9). Twenty articles described sIL-2r as a dynamic marker of disease activity that falls with response to treatment, and 15 described high initial sIL-2r levels >10,000 U/mL as a poor prognostic marker. The ability of sIL-2r to distinguish between subtypes of HPS/HLH was inconsistent. This review confirms the importance of soluble IL-2r as a diagnostic and disease marker in HPS/HLH, but also reveals the need for more primary data about its performance characteristics, particularly in adults. More emphasis should be made in including this simple, inexpensive test in clinical practice and studies of HPS/HLH.


Hemophagocytic lymphohistiocytosis Hemophagocytic syndrome Macrophage activation syndrome Soluble interleukin-2 receptor Interleukin-2 receptor alpha subunit Soluble CD25 



Familial hemophagocytic lymphohistiocytosis


Hemophagocytic lymphohistiocytosis


Hemophagocytic syndrome (s)


Infection-associated HPS = IAHS


Juvenile idiopathic arthritis


Lymphoma-associated hemophagocytic syndrome


Macrophage activation syndrome


Malignancy-associated hemophagocytic syndrome


Soluble IL-2 receptor


Soluble IL-2 receptor diagnostic criterion ≥2400 U/mL



This work was supported by the Hal Kettleson Hematology Research Fund.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

277_2017_2993_MOESM1_ESM.doc (220 kb)
ESM 1 (DOC 219 kb)


  1. 1.
    Fujiwara F, Hibi S, Imashuku S (1993) Hypercytokinemia in hemophagocytic syndrome. Am J Pediatr Hematol Oncol 15:92–98PubMedCrossRefGoogle Scholar
  2. 2.
    Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL (2011) How I treat hemophagocytic lymphohistiocytosis. Blood 118:4041–4052PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Henter JI, Elinder G, Soder O, Hansson M, Andersson B, Andersson U (1991) Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 78:2918–2922PubMedGoogle Scholar
  4. 4.
    Bodley SR, Robb-Smith A (1939) Histiocytic medullary reticulocytosis. Lancet 234:194–198CrossRefGoogle Scholar
  5. 5.
    Emile JF, Abla O, Fraitag S et al (2016) Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127:2672–2681PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Lehmberg K, Nichols KE, Henter JI et al (2015) Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica 100:997–1004PubMedPubMedCentralGoogle Scholar
  7. 7.
    Ravelli A, Minoia F, Davi S et al (2016) Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol (68):566–576Google Scholar
  8. 8.
    Hayden A, Park S, Giustini D, Lee AY, Chen LY (2016) Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: a systematic scoping review. Blood Rev 30:411–420PubMedCrossRefGoogle Scholar
  9. 9.
    Kleynberg RL, Schiller GJ (2012) Secondary hemophagocytic lymphohistiocytosis in adults: an update on diagnosis and therapy. Clin Adv Hematol Oncol 10:726–732Google Scholar
  10. 10.
    Janka GE (2012) Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med 63:233–246PubMedCrossRefGoogle Scholar
  11. 11.
    Castillo L, Carcillo J (2009) 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 10:387–392PubMedCrossRefGoogle Scholar
  12. 12.
    Grom AA, Horne A, De Benedetti F (2016) Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol 12:259–268PubMedCrossRefGoogle Scholar
  13. 13.
    Henter JI, Horne A, Arico M et al (2007) HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:124–131PubMedCrossRefGoogle Scholar
  14. 14.
    Fardet L, Galicier L, Lambotte O et al (2014) Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 66:2613–2620PubMedCrossRefGoogle Scholar
  15. 15.
    Ravelli A, Magni-Manzoni S, Pistorio A et al (2005) Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr 146:598–604PubMedCrossRefGoogle Scholar
  16. 16.
    Hejblum G, Lambotte O, Galicier L et al (2014) A web-based Delphi study for eliciting helpful criteria in the positive diagnosis of hemophagocytic syndrome in adult patients. PLoS One 9:e94024PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Tamamyan GN, Kantarjian HM, Ning J et al (2016) Malignancy-associated hemophagocytic lymphohistiocytosis in adults: relation to hemophagocytosis, characteristics, and outcomes. Cancer 122:2857–2866PubMedCrossRefGoogle Scholar
  18. 18.
    Henter JI, Elinder G, Ost A (1991) Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 18:29–33PubMedGoogle Scholar
  19. 19.
    Tsuda H (1997) Hemophagocytic syndrome (HPS) in children and adults. Int J Hematol 65:215–226PubMedCrossRefGoogle Scholar
  20. 20.
    Imashuku S (1997) Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. Int J Hematol 66:135–151PubMedCrossRefGoogle Scholar
  21. 21.
    Takagi S, Masuoka K, Uchida N et al (2009) High incidence of haemophagocytic syndrome following umbilical cord blood transplantation for adults. Br J Haematol 147:543–553PubMedCrossRefGoogle Scholar
  22. 22.
    Olejniczak K, Kasprzak A (2008) Biological properties of interleukin 2 and its role in pathogenesis of selected diseases—a review. Med Sci Monit 14:RA179–RA189PubMedGoogle Scholar
  23. 23.
    Smith KA (1988) Interleukin-2: inception, impact, and implications. Science 240:1169–1176PubMedCrossRefGoogle Scholar
  24. 24.
    Coca A, Bundy KW, Marston B, Huggins J, Looney RJ (2009) Macrophage activation syndrome: serological markers and treatment with anti-thymocyte globulin. Clin Immunol 132:10–18PubMedCrossRefGoogle Scholar
  25. 25.
    Rubin LA, Kurman CC, Fritz ME et al (1985) Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J Immunol 135:3172–3177PubMedGoogle Scholar
  26. 26.
    Rubin LA, Snow KM, Kurman CC, Nelson DL, Keystone EC (1990) Serial levels of soluble interleukin 2 receptor in the peripheral blood of patients with rheumatoid arthritis: correlations with disease activity. J Rheumatol 17:597–602PubMedGoogle Scholar
  27. 27.
    Rubin LA, Nelson DL (1990) The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med 113, 619–627.Google Scholar
  28. 28.
    Tomkinson BE, Wagner DK, Nelson DL, Sullivan JL (1987) Activated lymphocytes during acute Epstein-Barr virus infection. J Immunol 139:3802–3807PubMedGoogle Scholar
  29. 29.
    Monsalve-De CF, Romero TA, Estevez J et al (2002) Concentrations of cytokines, soluble interleukin-2 receptor, and soluble CD30 in sera of patients with hepatitis B virus infection during acute and convalescent phases. Clin Diagn Lab Immunol 9:1372–1375Google Scholar
  30. 30.
    Rudman SA, Walkovich K, Price S et al (2013) Autoimmune lymphoproliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis. Pediatrics 132:e1440–e1444CrossRefGoogle Scholar
  31. 31.
    Komp DM, McNamara J, Buckley P (1989) Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes. Blood 73:2128–2132PubMedGoogle Scholar
  32. 32.
    Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta M, Bosch X (2014) Adult haemophagocytic syndrome. Lancet 383:1503–1516PubMedCrossRefGoogle Scholar
  33. 33.
    Akashi K, Hayashi S, Gondo H et al (1994) Involvement of interferon-gamma and macrophage colony-stimulating factor in pathogenesis of haemophagocytic lymphohistiocytosis in adults. Br J Haematol 87:243–250PubMedCrossRefGoogle Scholar
  34. 34.
    Asano T, Kogawa K, Morimoto A et al (2012) Hemophagocytic lymphohistiocytosis after hematopoietic stem cell transplantation in children: a nationwide survey in Japan. Pediatr Blood Cancer 59:110–114PubMedCrossRefGoogle Scholar
  35. 35.
    Beutel G, Wiesner O, Eder M et al (2011) Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection. Crit Care 15:R80–R87PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Bleesing J, Prada A, Siegel DM et al (2007) The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum 56:965–971PubMedCrossRefGoogle Scholar
  37. 37.
    Bode SFN, Ammann S, Al-Herz W et al (2015) The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis. Haematologica 100:978–988PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Chen Y, Wang Z, Luo Z, Zhao N, Yang S, Tang Y (2016) Comparison of Th1/Th2 cytokine profiles between primary and secondary haemophagocytic lymphohistiocytosis. Ital J Pediatr 42:50PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Duval M, Fenneteau O, Doireau V et al (1999) Intermittent hemophagocytic lymphohistiocytosis is a regular feature of lysinuric protein intolerance. J Pediatr 134:236–239PubMedCrossRefGoogle Scholar
  40. 40.
    Fujiwara F, Hibi S, Imashuku S (1993) Hypercytokinemia in hemophagocytic syndrome. Am J Pediatr Hematol/Oncol 15:92–98CrossRefGoogle Scholar
  41. 41.
    Gao ZY, Li XY, Bhandari V, Li LD, Lan D (2015) Pre-B-cell colony-enhancing factor is markedly elevated in childhood hemophagocytic lymphohistiocytosis. Genet Mol Res 14:5287–5295PubMedCrossRefGoogle Scholar
  42. 42.
    Gorelik M, Fall N, Altaye M et al (2013) Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol 40:1191–1199PubMedCrossRefGoogle Scholar
  43. 43.
    Honda K, Ohga S, Takada H et al (2000) Neuron-specific enolase in hemophagocytic lymphohistiocytosis: a potential indicator for macrophage activation? Int J Hematol 72:55–60PubMedGoogle Scholar
  44. 44.
    Imashuku S, Hibi S, Tabata Y, Todo S, Ohno T (1999) Hemophagocytic syndrome in five patients with Epstein-Barr virus negative B-cell lymphoma. Cancer 85:2298–2299PubMedCrossRefGoogle Scholar
  45. 45.
    Imashuku S, Hibi S, Tabata Y et al (1998) Biomarker and morphological characteristics of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis. Med Pediatr Oncol 31:131–137PubMedCrossRefGoogle Scholar
  46. 46.
    Imashuku S, Hibi S, Sako M et al (1998) Heterogeneity of immune markers in hemophagocytic lymphohistiocytosis: comparative study of 9 familial and 14 familial inheritance-unproved cases. J Pediatr Hematol Oncol 20:207–214PubMedCrossRefGoogle Scholar
  47. 47.
    Imashuku S, Hibi S, Fujiwara F, Todo S (1996) Hyper-interleukin (IL)-6-naemia in haemophagocytic lymphohistiocytosis. Br J Haematol 93:803–807PubMedCrossRefGoogle Scholar
  48. 48.
    Imashuku S, Hibi S, Sako M et al (1995) Soluble interleukin-2 receptor: a useful prognostic factor for patients with hemophagocytic lymphohistiocytosis. Blood 86:4706–4707PubMedGoogle Scholar
  49. 49.
    Imashuku S, Ikushima S, Esumi N, Todo S, Saito M (1991) Serum levels of interferon-gamma, cytotoxic factor and soluble interleukin-2 receptor in childhood hemophagocytic syndromes. Leuk Lymphoma 3:287–292PubMedCrossRefGoogle Scholar
  50. 50.
    Kasama T, Furuya H, Yanai R et al (2012) Correlation of serum CX3CL1 level with disease activity in adult-onset Still’s disease and significant involvement in hemophagocytic syndrome. Clin Rheumatol 31:853–860PubMedCrossRefGoogle Scholar
  51. 51.
    Kounami S, Yoshiyama M, Nakayama K et al (2005) Macrophage activation syndrome in children with systemic-onset juvenile chronic arthritis. Acta Haematol 113:124–129PubMedCrossRefGoogle Scholar
  52. 52.
    Lehmberg K, Pink I, Eulenburg C, Beutel K, Maul-Pavicic A, Janka G (2013) Differentiating macrophage activation syndrome in systemic juvenile idiopathic arthritis from other forms of hemophagocytic lymphohistiocytosis. J Pediatr 162:1245–1251PubMedCrossRefGoogle Scholar
  53. 53.
    Lenert A, Yao Q (2016) Macrophage activation syndrome complicating adult onset Still’s disease: a single center case series and comparison with literature. Semin Arthritis Rheum 45:711–716PubMedCrossRefGoogle Scholar
  54. 54.
    Schneider EM, Lorenz I, Muller-Rosenberger M, Steinbach G, Kron M, Janka-Schaub GE (2002) Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis. Blood 100:2891–2898PubMedCrossRefGoogle Scholar
  55. 55.
    Marsh RA, Allen CE, McClain KL et al (2013) Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer 60:101–109PubMedCrossRefGoogle Scholar
  56. 56.
    Mazodier K, Marin V, Novick D et al (2005) Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood 106:3483–3489PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Mellor-Heineke S, Villanueva J, Jordan MB et al (2013) Elevated granzyme B in cytotoxic lymphocytes is a signature of immune activation in hemophagocytic lymphohistiocytosis. Front Immunol 4:72–79PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Miyahara M, Sano M, Shibata K et al (2000) B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics. Ann Hematol 79:378–388PubMedCrossRefGoogle Scholar
  59. 59.
    Miyazaki T, Kirino Y, Takeno M et al (2010) Serum HO-1 is useful to make differential diagnosis of secondary hemophagocytic syndrome from other similar hematological conditions. Int J Hematol 91:229–237PubMedCrossRefGoogle Scholar
  60. 60.
    Murohashi I, Yoshida K, Ihara N et al (2006) Serum levels of Thl/Th2 cytokines, angiogenic growth factors, and other prognostic factors in young adult patients with hemophagocytic syndrome. Lab Hematol 12:71–74PubMedCrossRefGoogle Scholar
  61. 61.
    Ohno T, Ueda Y, Nagai K-i et al (2003) The serum cytokine profiles of lymphoma-associated hemophagocytic syndrome: a comparative analysis of B-cell and T-cell/natural killer cell lymphomas. Int J Hematol 77:286–294PubMedCrossRefGoogle Scholar
  62. 62.
    Ohno T, Miyake N, Hada S et al (1998) Hemophagocytic syndrome in five patients with Epstein-Barr virus negative B-cell lymphoma. Cancer 82:1963–1972PubMedCrossRefGoogle Scholar
  63. 63.
    Otrock ZK, Gonzalez MD, Eby CS (2015) Ehrlichia-induced hemophagocytic lymphohistiocytosis: a case series and review of literature. Blood Cells Mol Dis 55:191–193PubMedCrossRefGoogle Scholar
  64. 64.
    Otrock ZK, Eby CS (2015) Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 90:220–224PubMedCrossRefGoogle Scholar
  65. 65.
    Reddy VV, Myles A, Cheekatla SS, Singh S, Aggarwal A (2014) Soluble CD25 in serum: a potential marker for subclinical macrophage activation syndrome in patients with active systemic onset juvenile idiopathic arthritis. Int J Rheum Dis 17:261–267PubMedCrossRefGoogle Scholar
  66. 66.
    Schram AM, Campigotto F, Mullally A et al (2015) Marked hyperferritinemia does not predict for HLH in the adult population. Blood 125:1548–1552PubMedCrossRefGoogle Scholar
  67. 67.
    Shiraishi A, Ohga S, Doi T et al (2012) Treatment choice of immunotherapy or further chemotherapy for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 59:265–270PubMedCrossRefGoogle Scholar
  68. 68.
    Sumegi J, Nestheide S, Aronow B et al (2016) MicroRNA activation signature in patients with hemophagocytic lymphohistiocytosis and reversibility with disease-specific therapy. J Allergy Clin Immunol 137:309–312PubMedCrossRefGoogle Scholar
  69. 69.
    Tabata R, Tabata C (2012) Possible prediction of underlying lymphoma by high sIL-2R/ferritin ratio in hemophagocytic syndromes. Ann Hematol 91:63–71Google Scholar
  70. 70.
    Tsuji T, Hirano T, Yamasaki H, Tsuji M, Tsuda H (2014) A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol 93:821–826PubMedCrossRefGoogle Scholar
  71. 71.
    Ueda I, Ishii E, Morimoto A, Ohga S, Sako M, Imashuku S (2006) Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL). Pediatr Blood Cancer 46:482–488PubMedCrossRefGoogle Scholar
  72. 72.
    Wu DX, Wang Z, Wang XL, Lin RR, Liu N, Zhang J (2012) Significance of serum CD25:serum ferritin in the diagnosis of lymphoma-associated hemophagocytic syndrome. J Leuk Lymphoma 31:1–7Google Scholar
  73. 73.
    Yajima N, Wakabayashi K, Odai T et al (2008) Clinical features of hemophagocytic syndrome in patients with dermatomyositis. J Rheumatol 35:1838–1841PubMedGoogle Scholar
  74. 74.
    Yang YQ, Ding CY, Xu J et al (2016) Exploring the role of bone marrow increased FDG uptake on PET/CT in patients with lymphoma-associated hemophagocytic lymphohistiocytosis: a reflection of bone marrow involvement or cytokine storm? Leuk Lymphoma 57:291–298CrossRefGoogle Scholar
  75. 75.
    Yasumi T, Hori M, Hiejima E et al (2015) Laboratory parameters identify familial haemophagocytic lymphohistiocytosis from other forms of paediatric haemophagocytosis. Br J Haematol 170:532–538PubMedCrossRefGoogle Scholar
  76. 76.
    Zhang L, Zhang S, Xu J et al (2011) Significance of soluble interleukin-2 receptor in patients with hemophagocytic lymphohistiocytosis. Leukemia & Lymphoma 52:1360–1362CrossRefGoogle Scholar
  77. 77.
    Buchhorn R, Muller C, Manhardt LB, Willaschek C, Schneider EM, Stuth EA (2010) Beta-blocker therapy and hemophagocytic lymphohistiocytosis: a case report. Cardiol Res Pract 912757–912754Google Scholar
  78. 78.
    DiPaola F, Grimley M, Bucuvalas J (2014) Pediatric acute liver failure and immune dysregulation. J Pediatr 164:407–409PubMedCrossRefGoogle Scholar
  79. 79.
    Faguer S, Vergez F, Peres M et al (2016) Tocilizumab added to conventional therapy reverses both the cytokine profile and CD8+Granzyme+ T-cells/NK cells expansion in refractory hemophagocytic lymphohistiocytosis. Hematol Oncol 34:55–57PubMedCrossRefGoogle Scholar
  80. 80.
    Imashuku S, Okuda T, Yoshihara T, Ikushima S, Hibi S (1991) Cytokine levels in aggressive natural killer cell leukaemia and malignant histiocytosis. Br J Haematol 79:132–133PubMedCrossRefGoogle Scholar
  81. 81.
    Olin RL, Nichols KE, Naghashpour M et al (2008) Successful use of the anti-CD25 antibody daclizumab in an adult patient with hemophagocytic lymphohistiocytosis. Am J Hematol 83:747–749PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Tomaske M, Amon O, Bosk A, Handgretinger R, Schneider EM, Niethammer D (2002) Alpha-CD25 antibody treatment in a child with hemophagocytic lymphohistiocytosis. Med Pediatr Oncol 38:141–142PubMedCrossRefGoogle Scholar
  83. 83.
    Amir A, Ling S, Naqvi A et al (2016) Liver transplantation for children with acute liver failure associated with secondary haemophagocytic lymphohistiocytosis. J Hepatol 64:S295–S296CrossRefGoogle Scholar
  84. 84.
    Cai Q, Huang HQ, Bai B et al (2013) The serum spectrum of cytokines in patients with NK/T-cell lymphoma and its clinical significance in survival. Blood 122:1759Google Scholar
  85. 85.
    Goldberg B, Muscal E, De Guzman M, Allen C (2015) Development of systemic juvenile idiopathic arthritis manifestations following remission of hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 67:2Google Scholar
  86. 86.
    Nanno S, Koh H, Katayama T. et al. (2015) Plasma levels of presepsin (soluble CD14-subtype) as a novel prognostic marker for hemophagocytic syndrome. In 20th Congress of the European Hematology Association Vienna, Austria, Haematologica, 557.Google Scholar
  87. 87.
    Imashuku S (2002) Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol 44:259–272PubMedCrossRefGoogle Scholar
  88. 88.
    Janka GE, Schneider EM (2004) Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol 124:4–14PubMedCrossRefGoogle Scholar
  89. 89.
    Johnson TS, Villanueva J, Filipovich AH, Marsh RA, Bleesing JJ (2011) Contemporary diagnostic methods for hemophagocytic lymphohistiocytic disorders. J Immunol Methods 364:1–13PubMedCrossRefGoogle Scholar
  90. 90.
    Weitzman S (2011) Approach to hemophagocytic syndromes. Hematology 2011:178–183PubMedCrossRefGoogle Scholar
  91. 91.
    Lehmberg K, Ehl S (2013) Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol 160:275–287PubMedCrossRefGoogle Scholar
  92. 92.
    Madkaikar M, Shabrish S, Desai M (2016) Current updates on classification, diagnosis and treatment of hemophagocytic lymphohistiocytosis (HLH). Indian J Pediatr 83:434–443PubMedCrossRefGoogle Scholar
  93. 93.
    Bryceson YT, Pende D, Maul-Pavicic A et al (2012) A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood 119:2754–2763PubMedCrossRefGoogle Scholar
  94. 94.
    Wu JR, Yuan LX, Ma ZG, Chen XX, Gu L, Gao J (2013) GDF15-mediated upregulation of ferroportin plays a key role in the development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 60:940–945PubMedCrossRefGoogle Scholar
  95. 95.
    Jordan MB, Hildeman D, Kappler J, Marrack P (2004) An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 104:735–743PubMedCrossRefGoogle Scholar
  96. 96.
    Zoller EE, Lykens JE, Terrell CE et al (2011) Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med 208:1203–1214PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Bracaglia C, de Graaf K, Pires Marafon D et al (2017) Elevated circulating levels of interferon-gamma and interferon-gamma-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis 76:166–172Google Scholar
  98. 98.
    Schneider EM (2004) Bullfight without killers: interferon rules pathology in HLH. Blood 104:600–601CrossRefGoogle Scholar
  99. 99.
    Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG (2012) Into the eye of the cytokine storm. Microbiol Mol Biol Rev 76:16–32PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    La Rosee P. (2016) Alleviating the storm: ruxolitinib in HLH. Blood 127:1626–1627Google Scholar
  101. 101.
    Canna SW, Behrens EM (2012) Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin N Am 59:329–344CrossRefGoogle Scholar
  102. 102.
    Canna SW, Nigrovic PA (2016) Editorial: 21st century storm chasers: defining macrophage activation syndrome. Arthritis Rheumatol 68:557–560PubMedCrossRefGoogle Scholar
  103. 103.
    Bien E, Balcerska A (2008) Serum soluble interleukin 2 receptor alpha in human cancer of adults and children: a review. Biomarkers 13:1–26PubMedCrossRefGoogle Scholar
  104. 104.
    Witkowska AM (2005) On the role of sIL-2R measurements in rheumatoid arthritis and cancers. Mediat Inflamm 2005:121–130CrossRefGoogle Scholar
  105. 105.
    Kloster BE, John PA, Miller LE et al (1987) Soluble interleukin 2 receptors are elevated in patients with AIDS or at risk of developing AIDS. Clin Immunol Immunopathol 45:440–446PubMedCrossRefGoogle Scholar
  106. 106.
    Prin L, Plumas J, Gruart V et al (1991) Elevated serum levels of soluble interleukin-2 receptor: a marker of disease activity in the hypereosinophilic syndrome. Blood 78:2626–2632PubMedGoogle Scholar
  107. 107.
    Tomita N, Suzuki T, Miyashita K et al (2016) The SIL index is a simple and objective prognostic indicator in diffuse large B-cell lymphoma. Leuk Lymphoma 57:2763–2770PubMedCrossRefGoogle Scholar
  108. 108.
    Yamaguchi M, Suzuki R, Oguchi M et al (2017) Treatments and outcomes of patients with extranodal natural killer/T-cell lymphoma diagnosed between 2000 and 2013: a cooperative study in Japan. J Clin Oncol 35:32–39PubMedCrossRefGoogle Scholar
  109. 109.
    Masaki Y, Dong L, Nakajima A et al (2009) Intravascular large B cell lymphoma: proposed of the strategy for early diagnosis and treatment of patients with rapid deteriorating condition. Int J Hematol 89:600–610PubMedCrossRefGoogle Scholar
  110. 110.
    Umino K, Fujiwara SI, Ito S et al (2017) Serum soluble interleukin-2 receptor level at diagnosis predicts transformation in patients with follicular lymphoma. Leuk Lymphoma 58:316–323PubMedCrossRefGoogle Scholar
  111. 111.
    Bucuvalas J, Filipovich L, Yazigi N et al (2013) Immunophenotype predicts outcome in pediatric acute liver failure. J Pediatr Gastroenterol Nutr 56:311–315PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Johnson TS, Terrell CE, Millen SH, Katz JD, Hildeman DA, Jordan MB (2015) Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol 192:84–91CrossRefGoogle Scholar
  113. 113.
    Mohty M (2007) Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 21:1387–1394PubMedCrossRefGoogle Scholar
  114. 114.
    Hu Y, Turner MJ, Shields J et al (2009) Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 128:260–270PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Novimmune SA (2013) Long-term follow-up of HLH patients who received treatment with NI-0501, an anti-interferon gamma monoclonal antibody. In: [Internet]. Bethesda (MD): National Library of Medicine (US), [cited 2017 Feb 27]. Available from:
  116. 116.
    Children’s Hospital Medical Center (2016) Hybrid immunotherapy for hemophagocytic lympho histiocytosis. In: [internet]. Bethesda (MD): National Library of Medicine (US). [cited 2017 Feb 27]. Available from: Jan 10, 2016.

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© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Molly Lin
    • 1
  • Sujin Park
    • 1
  • Anna Hayden
    • 1
  • Dean Giustini
    • 2
  • Martina Trinkaus
    • 3
  • Morris Pudek
    • 4
  • Andre Mattman
    • 5
  • Marion Schneider
    • 6
  • Luke Y.C. Chen
    • 1
  1. 1.Division of Hematology, Department of MedicineUniversity of British ColumbiaVancouverCanada
  2. 2.Biomedical Branch LibraryUniversity of British ColumbiaVancouverCanada
  3. 3.Division of Hematology, Department of MedicineUniversity of TorontoTorontoCanada
  4. 4.Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada
  5. 5.Adult Metabolic Disease ClinicVancouver General HospitalVancouverCanada
  6. 6.Division of Experimental AnesthesiologyUniversity Hospital UlmUlmGermany

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