Dilemmas in diagnosis and management of hemophagocytic lymphohistiocytosis in children

  • Xiao-Jun Xu
  • Yong-Min TangEmail author
Review Article



Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening entity which is characterized by severe hyperinflammation. Now the HLH-2004 protocol has been widely accepted and clinically used; however, many questions still remain in clinical practice. In this review, we discuss the dilemmas in the diagnosis and treatment of HLH in children.

Data sources

Original research for articles and literature reviews published in PubMed was carried out using the key term “hemophagocytic lymphohistiocytosis”.


As the gene sequencing technology progresses, the range of causal mutations and primary HLH has been redefined. The monoallelic variants may contribute to the pathogenesis of the disease. Many conditions without defective cytotoxicity of T or NK cells may lead to HLH, such as primary immunodeficiency (PID) and dysregulated immune activation or proliferation (DIAP). HLH shares overlapping clinical and laboratory characteristics with severe sepsis, but usually the single values are more pronounced in HLH than sepsis. H score is another approach to help the diagnosis of secondary HLH. Specific Th1/Th2 cytokine patterns are very helpful tools to differentiate HLH (reactivation of HLH) from sepsis. Moreover, it also has been used successfully to stratify the therapy intensity. The treatment of HLH should consider underlying diseases, triggers and severity. HLH-94 is recommended for patients who need etoposide-based therapy.


Dramatic progress has been made during the past decades in understanding the pathophysiology of HLH. However, diagnosis and treatment of HLH remain with many dilemmas because of the heterogeneous nature of the disease. Better understanding new gene defects and more effective diagnostic approaches and salvage regimens are goals for the future.


Cytokine Hemophagocytic lymphohistiocytosis Sepsis Transplantation 


Author contributions

XJX and YMT designed the manuscript; XJX drafted the article which was revised by YMT; both the two authors approved the final version published.


This study was supported in part by grants from the National Natural Science Foundation of China (No: 81770202) and the Natural Science Foundation of Zhejiang Province (Nos: LY19H080006, LZ12H08001).

Compliance with ethical standards

Conflict of interest

No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.


  1. 1.
    Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. Lancet. 1939;2:194–8.CrossRefGoogle Scholar
  2. 2.
    Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18:29–33.Google Scholar
  3. 3.
    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;48:124–31.CrossRefGoogle Scholar
  4. 4.
    Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140:221–30.CrossRefGoogle Scholar
  5. 5.
    Henter JI, Samuelsson-Horne A, Arico M, Egeler RM, Elinder G, Filipovich AH, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100:2367–73.CrossRefGoogle Scholar
  6. 6.
    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;118:4577–84.CrossRefGoogle Scholar
  7. 7.
    Ehl S, Astigarraga I, von Bahr Greenwood T, Hines M, Horne A, Ishii E, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH steering committee of the histiocyte society. J Allergy Clin Immunol Pract. 2018;6:1508–17.CrossRefGoogle Scholar
  8. 8.
    Otrock ZK, Daver N, Kantarjian HM, Eby CS. Diagnostic challenges of hemophagocytic lymphohistiocytosis. Clin Lymphoma Myeloma Leuk. 2017;17S:S105–S110.CrossRefGoogle Scholar
  9. 9.
    Tang YM, Xu XJ. Advances in hemophagocytic lymphohistiocytosis: pathogenesis, early diagnosis/differential diagnosis, and treatment. Sci World J. 2011;11:697–708.CrossRefGoogle Scholar
  10. 10.
    Meeths M, Chiang SC, Lofstedt A, Muller ML, Tesi B, Henter JI, et al. Pathophysiology and spectrum of diseases caused by defects in lymphocyte cytotoxicity. Exp Cell Res. 2014;325:10–7.CrossRefGoogle Scholar
  11. 11.
    Al-Samkari H, Berliner N. Hemophagocytic lymphohistiocytosis. Annu Rev Pathol. 2018;13:27–49.CrossRefGoogle Scholar
  12. 12.
    Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127:2672–81.CrossRefGoogle Scholar
  13. 13.
    Zhang K, Chandrakasan S, Chapman H, Valencia CA, Husami A, Kissell D, et al. Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. Blood. 2014;124:1331–4.CrossRefGoogle Scholar
  14. 14.
    Sepulveda FE, Garrigue A, Maschalidi S, Garfa-Traore M, Menasche G, Fischer A, et al. Polygenic mutations in the cytotoxicity pathway increase susceptibility to develop HLH immunopathology in mice. Blood. 2016;127:2113–21.CrossRefGoogle Scholar
  15. 15.
    Spessott WA, Sanmillan ML, McCormick ME, Patel N, Villanueva J, Zhang K, et al. Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood. 2015;125:1566–77.CrossRefGoogle Scholar
  16. 16.
    Zhang M, Bracaglia C, Prencipe G, Bemrich-Stolz CJ, Beukelman T, Dimmitt RA, et al. A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis. J Immunol. 2016;196:2492–503.CrossRefGoogle Scholar
  17. 17.
    Rohr J, Beutel K, Maul-Pavicic A, Vraetz T, Thiel J, Warnatz K, et al. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Haematologica. 2010;95:2080–7.CrossRefGoogle Scholar
  18. 18.
    Wysocki CA. Comparing hemophagocytic lymphohistiocytosis in pediatric and adult patients. Curr Opin Allergy Clin Immunol. 2017;17:405–13.CrossRefGoogle Scholar
  19. 19.
    Xu XJ, Wang HS, Ju XL, Xiao PF, Xiao Y, Xue HM, et al. Clinical presentation and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in China: a retrospective multicenter study. Pediatr Blood Cancer. 2017;64(4):e26264.CrossRefGoogle Scholar
  20. 20.
    Chen X, Wang F, Zhang Y, Teng W, Wang M, Nie D, et al. Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: molecular analyses of PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP. Clin Genet. 2018;94:200–12.CrossRefGoogle Scholar
  21. 21.
    Risma KA, Marsh RA. Hemophagocytic lymphohistiocytosis: clinical presentations and diagnosis. J Allergy Clin Immunol Pract. 2019;7:824–32.CrossRefGoogle Scholar
  22. 22.
    Gao L, Dang X, Huang L, Zhu L, Fang M, Zhang J, et al. Search for the potential "second-hit" mechanism underlying the onset of familial hemophagocytic lymphohistiocytosis type 2 by whole-exome sequencing analysis. Transl Res. 2016;170:26–39.CrossRefGoogle Scholar
  23. 23.
    Ammann S, Lehmberg K, Zur Stadt U, Klemann C, Bode SFN, Speckmann C, et al. Effective immunological guidance of genetic analyses including exome sequencing in patients evaluated for hemophagocytic lymphohistiocytosis. J Clin Immunol. 2017;37:770–80.CrossRefGoogle Scholar
  24. 24.
    Schulert GS, Zhang M, Fall N, Husami A, Kissell D, Hanosh A, et al. Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza. J Infect Dis. 2016;213:1180–8.CrossRefGoogle Scholar
  25. 25.
    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;149:133–41.CrossRefGoogle Scholar
  26. 26.
    Weiss ES, Girard-Guyonvarc'h C, Holzinger D, de Jesus AA, Tariq Z, Picarsic J, et al. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood. 2018;131:1442–55.CrossRefGoogle Scholar
  27. 27.
    Chinn IK, Eckstein OS, Peckham-Gregory EC, Goldberg BR, Forbes LR, Nicholas SK, et al. Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis. Blood. 2018;132:89–100.CrossRefGoogle Scholar
  28. 28.
    Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46:1140–6.CrossRefGoogle Scholar
  29. 29.
    Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014;46:1135–9.CrossRefGoogle Scholar
  30. 30.
    Brisse E, Wouters CH, Matthys P. Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities. Br J Haematol. 2016;174:203–17.CrossRefGoogle Scholar
  31. 31.
    Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol. 2019;10:119.CrossRefGoogle Scholar
  32. 32.
    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;10:387–92.CrossRefGoogle Scholar
  33. 33.
    Gagnaire MH, Galambrun C, Stephan JL. Hemophagocytic syndrome: a misleading complication of visceral leishmaniasis in children—a series of 12 cases. Pediatrics. 2000;106:E58.CrossRefGoogle Scholar
  34. 34.
    Haytoglu Z, Yazici N, Erbay A. Secondary hemophagocytic lymphohistiocytosis: do we really need chemotherapeutics for all patients? J Pediatr Hematol Oncol. 2017;39:e106–9.CrossRefGoogle Scholar
  35. 35.
    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.CrossRefGoogle Scholar
  36. 36.
    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;66:2613–20.CrossRefGoogle Scholar
  37. 37.
    Debaugnies F, Mahadeb B, Ferster A, Meuleman N, Rozen L, Demulder A, et al. Performances of the H-Score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients. Am J Clin Pathol. 2016;145:862–70.CrossRefGoogle Scholar
  38. 38.
    Machowicz R, Janka G, Wiktor-Jedrzejczak W. Similar but not the same: differential diagnosis of HLH and sepsis. Crit Rev Oncol Hematol. 2017;114:1–12.CrossRefGoogle Scholar
  39. 39.
    Tang Y, Xu X, Song H, Yang S, Shi S, Wei J, et al. Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome. Br J Haematol. 2008;143:84–91.CrossRefGoogle Scholar
  40. 40.
    Xu XJ, Tang YM, Song H, Yang SL, Xu WQ, Zhao N, et al. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. J Pediatr. 2012;160:984–90.e1CrossRefGoogle Scholar
  41. 41.
    Xu XJ, Luo ZB, Xia T, Song H, Yang SL, Xu WQ, et al. Comparison of interleukin-6, interleukin-10, procalcitonin and C-reactive protein in identifying high-risk febrile illness in pediatric cancer patients: a prospective observational study. Cytokine. 2019;116:1–6.CrossRefGoogle Scholar
  42. 42.
    Xu XJ, Tang YM, Liao C, Song H, Yang SL, Xu WQ, et al. Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock. Intensive Care Med. 2013;39:319–26.CrossRefGoogle Scholar
  43. 43.
    Shen HP, Tang YM, Song H, Xu WQ, Yang SL, Xu XJ. Efficiency of interleukin 6 and interferon gamma in the differentiation of invasive pulmonary aspergillosis and pneumocystis pneumonia in pediatric oncology patients. Int J Infect Dis. 2016;48:73–7.CrossRefGoogle Scholar
  44. 44.
    Kaufman KM, Linghu B, Szustakowski JD, Husami A, Yang F, Zhang K, et al. Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol. 2014;66:3486–95.CrossRefGoogle Scholar
  45. 45.
    Bergsten E, Horne A, Arico M, Astigarraga I, Egeler RM, Filipovich AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130:2728–38.CrossRefGoogle Scholar
  46. 46.
    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;41:103–9.CrossRefGoogle Scholar
  47. 47.
    Gupta AA, Tyrrell P, Valani R, Benseler S, Abdelhaleem M, Weitzman S. Experience with hemophagocytic lymphohistiocytosis/macrophage activation syndrome at a single institution. J Pediatr Hematol Oncol. 2009;31:81–4.CrossRefGoogle Scholar
  48. 48.
    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;61:1257–62.CrossRefGoogle Scholar
  49. 49.
    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;162:376–82.CrossRefGoogle Scholar
  50. 50.
    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;19:2665–73.CrossRefGoogle Scholar
  51. 51.
    Imashuku S. Treatment of Epstein–Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010. J Pediatr Hematol Oncol. 2011;33:35–9.CrossRefGoogle Scholar
  52. 52.
    Gavand PE, Serio I, Arnaud L, Costedoat-Chalumeau N, Carvelli J, Dossier A, et al. Clinical spectrum and therapeutic management of systemic lupus erythematosus-associated macrophage activation syndrome: a study of 103 episodes in 89 adult patients. Autoimmun Rev. 2017;16:743–9.CrossRefGoogle Scholar
  53. 53.
    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;170:539–49.CrossRefGoogle Scholar
  54. 54.
    La Rosee P, Horne A, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133:2465–77.CrossRefGoogle Scholar
  55. 55.
    Marsh RA, Jordan MB, Filipovich AH. Reduced-intensity conditioning haematopoietic cell transplantation for haemophagocytic lymphohistiocytosis: an important step forward. Br J Haematol. 2011;154:556–63.CrossRefGoogle Scholar
  56. 56.
    Horne A, Wickström R, Jordan MB, Yeh EA, Naqvi A, Henter JI, et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010;116:5824–31.CrossRefGoogle Scholar
  57. 57.
    Horne A, Wickström R, Jordan MB, Yeh EA, Naqvi A, Henter JI, et al. How to treat involvement of the central nervous system in hemophagocytic lymphohistiocytosis? Curr Treat Options Neurol. 2017;19:3.CrossRefGoogle Scholar
  58. 58.
    Canna SW, Girard C, Malle L, de Jesus A, Romberg N, Kelsen J, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. 2017;139:1698–701.CrossRefGoogle Scholar
  59. 59.
    Leiding JW, Forbes LR. Mechanism-based precision therapy for the treatment of primary immunodeficiency and primary immunodysregulatory diseases. J Allergy Clin Immunol Pract. 2019;7:761–73.CrossRefGoogle Scholar
  60. 60.
    Tang Y, Liao C, Xu X, Song H, Shi S, Yang S. Th1/Th2 cytokine profiles in G+/G- bacteremia in pediatric hematology/oncology patients. Pediatr Blood Cancer. 2012;58:50–4.CrossRefGoogle Scholar
  61. 61.
    Zhou JM, Ye Q. Utility of assessing cytokine levels for the differential diagnosis of pneumonia in a pediatric population. Pediatr Crit Care Med. 2017;18:e162–6.CrossRefGoogle Scholar

Copyright information

© Children's Hospital, Zhejiang University School of Medicine 2019

Authors and Affiliations

  1. 1.Division of Hematology-Oncology, Children’s Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics of Ministry of EducationZhejiang UniversityHangzhouChina

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