HLH in Adults

  • Paul La Rosée
  • Rafal Machowicz


Hemophagocytic lymphohistiocytosis (HLH) in adolescent and adult patients (aHLH) is getting increasing attention due to an assumed rising incidence, a better pathophysiologic understanding, and a growing arsenal of therapeutic ammunition. For many years HLH used to be a domain of pediatrics and was almost totally neglected in adults. Nowadays, with raising awareness (although it is still severely underdiagnosed), more and more physicians face the challenges of diagnosis and treatment of aHLH. The aim of this chapter is to provide information on HLH, specifically in adults. The spectrum of underlying conditions, triggering factors, and genetic predisposition differs in age groups with enrichment of familial disease in children and enrichment of malignant disorders as underlying condition and/or trigger in adults. These differences plus differential tolerance of drugs due to age and comorbidity guide the recommended aHLH treatment approach. Simply copying the pediatric recommendations to adults may have deleterious consequences. Treatment of HLH requires individual tailoring of anti-inflammatory and immunosuppressive treatment components combined with disease-specific treatment such as chemotherapy in malignancy or antimicrobial drugs in infection-triggered HLH. The clinical overlap to sepsis with high risk of missed diagnosis on intensive care units will also be discussed.


HLH Hemophagocytic syndrome Hemophagocytic lymphohistiocytosis Adults MAS Macrophage activation syndrome Criteria Treatment Genetics Sepsis 



adult hemophagocytic lymphohistiocytosis


adult-onset Still’s disease




cyclosporin A


cytotoxic T lymphocyte




European Society of Blood and Marrow transplantation


Epstein-Barr virus


familial HLH


hemophagocytic lymphohistiocytosis


lymphoma-associated HLH


macrophage activation syndrome


multiorgan failure

NK cell

natural killer cell


polyvalent intravenous immunoglobulin


soluble interleukin-2 receptor


  1. 1.
    Scott RBR-S, A.H.T. Histiocytic medullary reticulosis. Lancet. 1939;2(6047):194–8.CrossRefGoogle Scholar
  2. 2.
    Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27(136):519–25. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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. CrossRefPubMedGoogle Scholar
  4. 4.
    Otrock ZK, Eby CS. Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol. 2015;90(3):220–4. CrossRefPubMedGoogle Scholar
  5. 5.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    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. 2010;24(9):1299–306. CrossRefPubMedGoogle Scholar
  7. 7.
    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. Google Scholar
  8. 8.
    Li F, Yang Y, Jin F, Dehoedt C, Rao J, Zhou Y, et al. Clinical characteristics and prognostic factors of adult hemophagocytic syndrome patients: a retrospective study of increasing awareness of a disease from a single-center in China. Orphanet J Rare Dis. 2015;10(1):20. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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. CrossRefPubMedGoogle Scholar
  11. 11.
    Park HS, Kim DY, Lee JH, Lee JH, Kim SD, Park YH, et al. Clinical features of adult patients with secondary hemophagocytic lymphohistiocytosis from causes other than lymphoma: an analysis of treatment outcome and prognostic factors. Ann Hematol. 2012;91(6):897–904. CrossRefPubMedGoogle Scholar
  12. 12.
    Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16. CrossRefPubMedGoogle Scholar
  13. 13.
    Allen M, De Fusco C, Legrand F, Clementi R, Conter V, Danesino C, et al. Familial hemophagocytic lymphohistiocytosis: how late can the onset be? Haematologica. 2001;86(5):499–503. PubMedGoogle Scholar
  14. 14.
    Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9. CrossRefPubMedGoogle Scholar
  15. 15.
    Nagafuji K, Nonami A, Kumano T, Kikushige Y, Yoshimoto G, Takenaka K, et al. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis. Haematologica. 2007;92(7):978–81. CrossRefPubMedGoogle Scholar
  16. 16.
    Wang Y, Wang Z, Zhang J, Wei Q, Tang R, Qi J, et al. Genetic features of late onset primary hemophagocytic lymphohistiocytosis in adolescence or adulthood. PLoS One. 2014;9(9):e107386. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794–8. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program. 2013;2013:605–11.PubMedGoogle Scholar
  19. 19.
    Machaczka M, Vaktnas J, Klimkowska M, Hagglund H. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center. Leuk Lymphoma. 2011;52(4):613–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Meeths M, Horne A, Sabel M, Bryceson YT, Henter JI. Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden. Pediatr Blood Cancer. 2014.Google Scholar
  21. 21.
    Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6):1227–35.CrossRefPubMedGoogle Scholar
  22. 22.
    Janka GE, Lehmberg K. Hemophagocytic syndromes – an update. Blood Rev. 2014;28(4):135–42.Google Scholar
  23. 23.
    Birndt S, Schenk T, Brunkhorst, FM, Maschmeyer, G, Rothmann, F, Weber, T.; Müller, M, Panse, J, Schroers, R, Braess, J, Frickhofen, N, Janka, G, Lehmberg, K, Hochhaus, A, Ernst, T, La Rosée, P. Hemophagocytic Lymphohistiocytosis in adults (aHLH): results from the German HLH registry. Blood. 2016;128:2523 (abstract).Google Scholar
  24. 24.
    Cetica V, Sieni E, Pende D, Danesino C, De Fusco C, Locatelli F, et al. Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry. J Allergy Clin Immunol. 2016;137(1):188–96 e4.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Tesi B, Lagerstedt-Robinson K, Chiang SC, Ben Bdira E, Abboud M, Belen B, et al. Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis. Genome Med. 2015;7:130.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr. 2012;24(1):9–15.CrossRefPubMedGoogle Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med. 2003;31(4):1250–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Zoller EE, Lykens JE, Terrell CE, Aliberti J, Filipovich AH, Henson PM, et al. Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med. 2011;208(6):1203–14.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Strauss R, Neureiter D, Westenburger B, Wehler M, Kirchner T, Hahn EG. Multifactorial risk analysis of bone marrow histiocytic hyperplasia with hemophagocytosis in critically ill medical patients – a postmortem clinicopathologic analysis. Crit Care Med. 2004;32(6):1316–21.CrossRefPubMedGoogle Scholar
  31. 31.
    Francois B, Trimoreau F, Vignon P, Fixe P, Praloran V, Gastinne H. Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. Am J Med. 1997;103(2):114–20.CrossRefPubMedGoogle Scholar
  32. 32.
    Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2004;124(1):4–14.CrossRefPubMedGoogle Scholar
  33. 33.
    Riviere S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O, et al. Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med. 2014;127(11):1118–25.CrossRefPubMedGoogle Scholar
  34. 34.
    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.CrossRefPubMedGoogle Scholar
  35. 35.
    Lehmberg K, McClain KL, Janka GE, Allen CE. Determination of an appropriate cut-off value for ferritin in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2014;61(11):2101–3.CrossRefPubMedGoogle Scholar
  36. 36.
    Schram AM, Campigotto F, Mullally A, Fogerty A, Massarotti E, Neuberg D, et al. Marked hyperferritinemia does not predict for HLH in the adult population. Blood. 2015;125(10):1548–52.CrossRefPubMedGoogle Scholar
  37. 37.
    Machowicz R, Kröger N, Krieger T, Zborowska H, Rejowski S, Gorka M, et al. Hyperferritinemia in adult HLH: the best what we have, so far. Blood. 2014-10-602607v1.Google Scholar
  38. 38.
    Tamamyan GN, Kantarjian HM, Ning J, Jain P, Sasaki K, McClain KL, et al. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: relation to hemophagocytosis, characteristics, and outcomes. Cancer. 2016;31.Google Scholar
  39. 39.
    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.Google Scholar
  40. 40.
    Hejblum G, Lambotte O, Galicier L, Coppo P, Marzac C, Aumont C, et al. A web-based delphi study for eliciting helpful criteria in the positive diagnosis of hemophagocytic syndrome in adult patients. PLoS One. 2014;9(4):e94024.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Trottestam H, Horne A, Arico M, Egeler RM, Filipovich AH, Gadner H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577–84.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    La Rosee P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc Hematol Educ Program. 2015;2015(1):190–6.PubMedGoogle Scholar
  43. 43.
    Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol. 2013;160(3):275–87.CrossRefPubMedGoogle Scholar
  44. 44.
    Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007;7(12):814–22.CrossRefPubMedGoogle Scholar
  45. 45.
    Bode SF, Bogdan C, Beutel K, Behnisch W, Greiner J, Henning S, et al. Hemophagocytic lymphohistiocytosis in imported pediatric visceral leishmaniasis in a nonendemic area. J Pediatr. 2014;165(1):147–53 e1.CrossRefPubMedGoogle Scholar
  46. 46.
    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. 2015;168(1):63–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Imashuku S, Kuriyama K, Sakai R, Nakao Y, Masuda S, Yasuda N, et al. Treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: a report from the HLH study center. Med Pediatr Oncol. 2003;41(2):103–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Berliner N, Kurra C, Chou D, CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 1-2016. An 18-year-old man with fever, abdominal pain, and thrombocytopenia. N Engl J Med. 2016;374(2):165–73.CrossRefPubMedGoogle Scholar
  49. 49.
    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.CrossRefPubMedGoogle Scholar
  50. 50.
    Henter JI, Chow CB, Leung CW, Lau YL. Cytotoxic therapy for severe avian influenza a (H5N1) infection. Lancet. 2006;367(9513):870–3.CrossRefPubMedGoogle Scholar
  51. 51.
    Wang Y, Huang W, Hu L, Cen X, Li L, Wang J, et al. Multi-center study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood. 2015;126(19):2186–92.Google Scholar
  52. 52.
    Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood. 2015;125(19):2908–14.Google Scholar
  53. 53.
    Larroche C, Bruneel F, Andre MH, Bader-Meunier B, Baruchel A, Tribout B, et al. Intravenously administered gamma-globulins in reactive hemaphagocytic syndrome. Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP-HP. Annales de medecine interne. 2000;151(7):533–9.Google Scholar
  54. 54.
    Emmenegger U, Spaeth PJ, Neftel KA. Intravenous immunoglobulin for hemophagocytic lymphohistiocytosis? J Clin Oncol. 2002;20(2):599–601.CrossRefPubMedGoogle Scholar
  55. 55.
    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.Google Scholar
  56. 56.
    Tabata C, Tabata R. Possible prediction of underlying lymphoma by high sIL-2R/ferritin ratio in hemophagocytic syndrome. Ann Hematol. 2012;91(1):63–71.CrossRefPubMedGoogle Scholar
  57. 57.
    Jing-Shi W, Yi-Ni W, Lin W, Zhao W. Splenectomy as a treatment for adults with relapsed hemophagocytic lymphohistiocytosis of unknown cause. Ann Hematol. 2015;94(5):753–60.CrossRefPubMedGoogle Scholar
  58. 58.
    Frimmel S, Schipper J, Henschel J, Yu TT, Mitzner SR, Koball S. First description of single-pass albumin dialysis combined with cytokine adsorption in fulminant liver failure and hemophagocytic syndrome resulting from generalized herpes simplex virus 1 infection. Liver Transpl. 2014;20(12):1523–4.PubMedGoogle Scholar
  59. 59.
    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.CrossRefPubMedGoogle Scholar
  60. 60.
    Marsh RA, Allen CE, McClain KL, Weinstein JL, Kanter J, Skiles J, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60(1):101–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Strout MP, Seropian S, Berliner N. Alemtuzumab as a bridge to allogeneic SCT in atypical hemophagocytic lymphohistiocytosis. Nat Rev Clin Oncol. 2010;7(7):415–20.CrossRefPubMedGoogle Scholar
  62. 62.
    Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, 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. Ann Rheum Dis. 2016;75(3):481–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Schulert GS, Grom AA. Macrophage activation syndrome and cytokine-directed therapies. Best Pract Res Clin Rheumatol. 2014;28(2):277–92.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology. 2011;50(2):417–9.CrossRefPubMedGoogle Scholar
  65. 65.
    de Kerguenec C, Hillaire S, Molinie V, Gardin C, Degott C, Erlinger S, et al. Hepatic manifestations of hemophagocytic syndrome: a study of 30 cases. Am J Gastroenterol. 2001;96(3):852–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Hande KR, Wolff SN, Greco FA, Hainsworth JD, Reed G, Johnson DH. Etoposide kinetics in patients with obstructive jaundice. J Clin Oncol. 1990;8(6):1101–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Halacli B, Unver N, Halacli SO, Canpinar H, Ersoy EO, Ocal S, et al. Investigation of hemophagocytic lymphohistiocytosis in severe sepsis patients. J Crit Care. 2016;35:185–90.CrossRefPubMedGoogle Scholar
  68. 68.
    Machowicz R, Janka G, Wiktor-Jedrzejczak W. Your critical care patient may have HLH (hemophagocytic lymphohistiocytosis). Crit Care. 2016;20(1):215.Google Scholar
  69. 69.
    Machowicz RJ, Janka G, Wiktor-Jedrzejczak, W. Similar but not the same: differential diagnosis of HLH and sepsis. submitted for publication. Crit Rev Oncol Hematol. 2017;114:1–12.Google Scholar
  70. 70.
    Feig JA, Cina SJ. Evaluation of characteristics associated with acute splenitis (septic spleen) as markers of systemic infection. Arch Pathol Lab Med. 2001;125(7):888–91.Google Scholar
  71. 71.
    Berbee JF, van der Hoogt CC, de Haas CJ, van Kessel KP, Dallinga-Thie GM, Romijn JA, et al. Plasma apolipoprotein CI correlates with increased survival in patients with severe sepsis. Intensive Care Med. 2008;34(5):907–11.Google Scholar
  72. 72.
    von Muller L, Klemm A, Durmus N, Weiss M, Suger-Wiedeck H, Schneider M, et al. Cellular immunity and active human cytomegalovirus infection in patients with septic shock. J Infect Dis. 2007;196(9):1288–95.Google Scholar
  73. 73.
    Cho E, Lee JH, Lim HJ, Oh SW, Jo SK, Cho WY, et al. Soluble CD25 is increased in patients with sepsis-induced acute kidney injury. Nephrology. 2014;19(6):318–24.Google Scholar
  74. 74.
    Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637.Google Scholar
  75. 75.
    Annane D. Corticosteroids for severe sepsis: an evidence-based guide for physicians. Ann Intensive Care. 2011;1(1):7.Google Scholar
  76. 76.
    Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275–81.Google Scholar
  77. 77.
    Lachmann G, La Rosee P, Schenk T, Brunkhorst FM, Spies C. Hemophagocytic lymphohistiocytosis: a diagnostic challenge on the ICU. Der Anaesthesist. 2016;65(10):776–86.Google Scholar
  78. 78.
    Sieni E, Cetica V, Piccin A, Gherlinzoni F, Sasso FC, Rabusin M, et al. Familial hemophagocytic lymphohistiocytosis may present during adulthood: clinical and genetic features of a small series. PLoS One. 2012;7(9):e44649.Google Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Klinik für Innere Medizin II, Klinikstr. 11Schwarzwald-Baar-KinikumVillingen-SchwenningenGermany
  2. 2.Department of Hematology, Oncology and Internal DiseasesMedical University of WarsawWarsawPoland

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