Skip to main content

Advertisement

SpringerLink
Log in

Current Updates on Classification, Diagnosis and Treatment of Hemophagocytic Lymphohistiocytosis (HLH)

  • Review Article
  • Published:
The Indian Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life threatening hyperinflammatory syndrome characterized by excessive activation of macrophages and T cells resulting from defective cytotoxicity. Severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and histiocytes (macrophages) secreting high amounts of inflammatory cytokines threatens the life of the patient and may lead to death unless arrested by appropriate treatment. HLH can be caused either by certain underlying genetic diseases (familial HLH), or may also occur due to particular triggers in patients with no known inherited disorder (acquired HLH). Due to life threatening nature of the disease, early diagnosis and initiation of immunosuppressive therapy is extremely important. HLH diagnosis is based on constellation of clinical manifestations and laboratory parameters which often overlap with those of severe infection or sepsis. Identification of patients with familial HLH and their underlying genetic defects requires specialized laboratory tests and is important for predicting relapses and planning early therapeutic hematopoietic stem cell transplantation (HSCT). A high suspicion and thorough clinical, immunological and genetic work-up is required for diagnosis of HLH. Prompt initiation of adequate treatment is essential for the survival. Substantial progress has been made in exploring the complex cause and pathophysiology of HLH and also in management of HLH patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233–46.

    Article  CAS  PubMed  Google Scholar 

  2. Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80:428–35.

    Article  CAS  PubMed  Google Scholar 

  3. Osugi Y, Hara J, Tagawa S, et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood. 1997;89:4100–3.

    CAS  PubMed  Google Scholar 

  4. Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. Lancet. 1939;234:194–8.

    Article  Google Scholar 

  5. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27:519–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gholam C, Grigoriadou S, Gilmour KC, Gaspar HB. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management. Clin Exp Immunol. 2011;163:271–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematol Am Soc Hematol Educ Program. 2009;127-31.

  8. Waleed A, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014;22:162.

  9. Dufourcq-Lagelouse R, Jabado N, Le Deist F, et al. Linkage of familial hemophagocytic lymphohistiocytosis to 10q21–22 and evidence for heterogeneity. Am J Hum Genet. 1999;64:172–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ohadi M, Lalloz MR, Sham P, et al. Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3–22 by homozygosity mapping. Am J Hum Genet. 1999;64:165–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Feldmann J, Callebaut I, Raposo G, et al. Munc13–4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell. 2003;115:461–73.

    Article  CAS  PubMed  Google Scholar 

  12. Zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14:827–34.

    Article  CAS  PubMed  Google Scholar 

  13. Cote M, Menager MM, Burgess A, et al. Munc18–2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest. 2009;119:3765–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zur Stadt U, Rohr J, Seifert W, et al. Hennies. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18–2 and impaired binding to syntaxin 11. Am J Hum Genet. 2009;85:482–92.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mhatre S, Madkaikar M, Desai M, Ghosh K. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis (FHL) patients in India. Blood Cells Mol Dis. 2015;54:250–7.

    Article  CAS  PubMed  Google Scholar 

  16. Barbosa MD, Barrat FJ, Tchernev VT, et al. Identification of mutations in two major mRNA isoforms of the chediak-higashi syndrome gene in human and mouse. Hum Mol Genet. 1997;6:1091–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Menasche G, Feldmann J, Fischer A, de Saint Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev. 2005;203:165–79.

    Article  CAS  PubMed  Google Scholar 

  18. Griscelli C, Durandy A, Guy-Grand D, Daguillard F, Herzog C, Prunieras M. A syndrome associating partial albinism and immunodeficiency. Am J Med. 1978;65:691–702.

    Article  CAS  PubMed  Google Scholar 

  19. Nagle DL, Karim MA, Woolf EA, et al. Identification and mutation analysis of the complete gene for chediak-higashi syndrome. Nat Genet. 1996;14:307–11.

    Article  CAS  PubMed  Google Scholar 

  20. Enders A, Zieger B, Schwarz K, et al. Lethal hemophagocytic lymphohistiocytosis in hermansky-pudlak syndrome type II. Blood. 2006;108:81–7.

    Article  CAS  PubMed  Google Scholar 

  21. Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in hermansky-pudlak syndrome due to mutations in the beta 3 a subunit of the AP-3 adaptor. Mol Cell. 1999;3:11–21.

    Article  PubMed  Google Scholar 

  22. Shotelersuk V, Dell'Angelica EC, Hartnell L, Bonifacino JS, Gahl WA. A new variant of hermansky-pudlak syndrome due to mutations in a gene responsible for vesicle formation. Am J Med. 2000;108:423–7.

    Article  CAS  PubMed  Google Scholar 

  23. Huizing M, Scher CD, Strovel E, et al. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe hermansky-pudlak syndrome type 2. Pediatr Res. 2002;51:150–8.

    Article  CAS  PubMed  Google Scholar 

  24. Purtilo DT, Cassel C, Yang JP. Letter: fatal infectious mononucleosis in familial lymphohistiocytosis. N Engl J Med. 1974;291:736.

    CAS  PubMed  Google Scholar 

  25. Rigaud S, Fondaneche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444:110–4.

    Article  CAS  PubMed  Google Scholar 

  26. Coffey AJ, Brooksbank RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2- domain encoding gene. Nat Genet. 1998;20:129–35.

    Article  CAS  PubMed  Google Scholar 

  27. Schmid JP, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011;117:1522–9.

    Article  CAS  Google Scholar 

  28. Marsh RA, Villanueva J, Kim MO, et al. Filipovich. Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations. Clin Immunol. 2009;132:116–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nichols KE, Ma CS, Cannons JL, Schwartzberg PL, Tangye SG. Molecular and cellular pathogenesis of X-linked lymphoproliferative disease. Immunol Rev. 2005;203:180–99.

    Article  CAS  PubMed  Google Scholar 

  30. Huck K, Feyen O, Niehues T, et al. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J Clin Invest. 2009;119:1350–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van Montfrans JM, Hoepelman AI, Otto S, et al. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J Allergy Clin Immunol. 2012;129:787–93.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998;12:435–44.

    Article  CAS  PubMed  Google Scholar 

  33. Tiab M, Mechinaud F, Harousseau J-L. Haemophagocytic syndrome associated with infections. Clin Haematol. 2000;13:163–78.

    CAS  Google Scholar 

  34. Rajagopala S, Dutta U, Chandra KS, Bhatia P, Varma N, Kochhar R. Visceral leishmaniasis associated hemophagocytic lymphohistiocytosis—case report and systematic review. J Infect. 2008;56:381–8.

    Article  PubMed  Google Scholar 

  35. Henter JI, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr. 1993;82:369–72.

    Article  CAS  PubMed  Google Scholar 

  36. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118:4041–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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;52:613–9.

    Article  PubMed  Google Scholar 

  38. Ramanan AV, Baildam EM. Macrophage activation syndrome is hemophagocytic lymphohistiocytosis–need for the right terminology. J Rheumatol. 2002;29:1105.

    PubMed  Google Scholar 

  39. Ishii E, Ohga S, Tanimura M, et al. Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH study group. Med Pediatr Oncol. 1998;30:276–83.

    Article  CAS  PubMed  Google Scholar 

  40. Gurgey A, Gogus S, Ozyurek E, et al. Primary hemophagocytic lymphohistiocytosis in Turkish children. Pediatr Hematol Oncol. 2003;20:367–71.

    Article  CAS  PubMed  Google Scholar 

  41. Arico M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the international registry. FHL Leukemia. 1996;10:197–203.

    CAS  PubMed  Google Scholar 

  42. Stinchcombe JC, Griffiths GM. Secretory mechanisms in cell-mediated cytotoxicity. Annu Rev Cell Dev Biol. 2007;23:495–517.

    Article  CAS  PubMed  Google Scholar 

  43. Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol. 2010;6:137–54.

    Article  PubMed  Google Scholar 

  44. Allen M, De Fusco C, Legrand F, et al. Familial hemophagocytic lymphohistiocytosis: how late can the onset be? Haematologica. 2001;86:499–503.

    CAS  PubMed  Google Scholar 

  45. Bhattacharyya M, Ghosh MK. Hemophagocytic lymphohistiocytosis-recent concept. J Assoc Physicians India. 2008;56:453–8.

    PubMed  Google Scholar 

  46. Pinto-Patarroyo GP, Rytting ME, Vierling JM, Suarez-Almazor ME. Haemophagocytic lymphohistiocytosis presenting as liver failure following Epstein-Barr and prior hepatitis a infections. BMJ Case Rep. 2013. doi:10.1136/bcr-2013-008979.

    PubMed  PubMed Central  Google Scholar 

  47. Chandrakasan S, Filipovich AH. Hemophagocytic lymphohistiocytosis: advances in pathophysiology, diagnosis, and treatment. J Pediatr. 2013;163:1253–9.

    Article  PubMed  Google Scholar 

  48. Lin T, Ferlic-Stark L, Allen C, Kozinetz C, McClain K. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer. 2011;56:154–5.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.

    Article  PubMed  Google Scholar 

  50. Schram AM, Campigotto F, Mullally A, et al. Marked hyperferritinemia does not predict for HLH in the adult population. Blood. 2015;125:1548–52.

    Article  CAS  PubMed  Google Scholar 

  51. Shiota Y, Sato T, Ono T. Serum levels of soluble CD25 (soluble interleukin 2 receptor) in asthmatic patients. Arerugi. 1993;42:914–9.

    CAS  PubMed  Google Scholar 

  52. 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;93:821–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen WF, Xu J, Qiu HX, et al. Detection of serum neopterin in patients with hemophagocytic lymphohistiocytosis and its significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013;21:465–8.

    CAS  PubMed  Google Scholar 

  54. Xu XJ, Tang YM, Song H, et al. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. J Pediatr. 2012;160:984–90.

    Article  CAS  PubMed  Google Scholar 

  55. Molleran Lee S, Villanueva J, Sumegi J, et al. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in north American families with haemophagocytic lymphohistiocytosis. J Med Genet. 2004;41:137–44.

    Article  CAS  PubMed  Google Scholar 

  56. Kogawa K, Lee SM, Villanueva J, Marmer D, Sumegi J, Filipovich AH. Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members. Blood. 2002;99:61–6.

    Article  CAS  PubMed  Google Scholar 

  57. Bryceson YT, Pende D, Maul-Pavicic A, et al. A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood. 2012;119:2754–63.

    Article  CAS  PubMed  Google Scholar 

  58. Madkaikar M, Mishra A, Desai M, Gupta M, Mhatre S, Ghosh K. Comprehensive report of primary immunodeficiency disorders from a tertiary care center in India. J Clin Immunol. 2013;33:507–12.

    Article  CAS  PubMed  Google Scholar 

  59. Trottestam H, Horne A, Aricò M. et al; Histiocyte Society. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118:4577–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mahlaoui N, Ouachée-Chardin M, de Saint BG, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics. 2007;120:e622–8.

    Article  PubMed  Google Scholar 

  61. Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60:101–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Milone MC, Tsai DE, Hodinka RL, et al. Nichols. Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy. Blood. 2005;105:994–6.

    Article  CAS  PubMed  Google Scholar 

  63. Sieni E, Cetica V, Piccin A, et al. Familial hemophagocytic lymphohistiocytosis may present during adulthood: clinical and genetic features of a small series. PLoS ONE. 2012;7:e44649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Contributions

MM and SS: Conception, literature review and writing of the manuscript. MM and MD: Critically revising and final approval of the manuscript. MM will act as guarantor for the paper.

Author information

Authors and Affiliations

  1. Department of Pediatric Immunology and Leukocyte Biology, National Institute of Immunohematology (ICMR), 13th floor, Multistoreyed Building, KEM Campus, Parel, Mumbai, 400 012, India

    Manisha Madkaikar & Snehal Shabrish

  2. Division of Immunology, Bai Jerbai Wadia Hospital for Children, Mumbai, India

    Mukesh Desai

Authors
  1. Manisha Madkaikar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Snehal Shabrish
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mukesh Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manisha Madkaikar.

Ethics declarations

Conflict of Interest

None.

Source of Funding

Indian Council of Medical Research (ICMR) and Department of Biotechnology (DBT).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Madkaikar, M., Shabrish, S. & Desai, M. Current Updates on Classification, Diagnosis and Treatment of Hemophagocytic Lymphohistiocytosis (HLH). Indian J Pediatr 83, 434–443 (2016). https://doi.org/10.1007/s12098-016-2037-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12098-016-2037-y

Keywords

Search

Navigation