Classification, Clinical Manifestations, and Diagnostics of HLH

  • J. Pachlopnik Schmid
  • Benjamin Volkmer
  • Stephan Ehl


Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation disease. It can be subdivided into a primary, genetic form and a secondary form that complicates diverse infections, autoimmune or autoinflammatory disorders, and malignancies. Both forms, primary and secondary HLH, present with the same spectrum of non-specific symptoms, making accurate diagnosis and rapid treatment initiation challenging. A prompt diagnosis is crucial for appropriate therapeutic management. Clinical diagnosis of an HLH episode, followed by sequential immunological testing, and genetic diagnosis provide the basis for a rapid decision on hematopoietic stem cell transplantation indicated in patients with primary HLH.


Classification Clinical manifestation Organ involvement Laboratory features Diagnosis Immunological testing Genetic analyses Hemophagocytic lymphohistiocytosis Macrophage activation syndrome 





Chronic granulomatous disease


Chediak-Higashi syndrome


Central nervous system


Cerebrospinal fluid


Epstein-Barr virus


Familial HLH


Human herpes virus


Hemophagocytic lymphohistiocytosis


Hermansky-Pudlak syndrome


Hematopoietic stem cell transplantation




Macrophage activation syndrome


Magnetic resonance imaging


Next-generation sequencing


Peripheral blood mononuclear cells


Polymerase chain reaction


Primary immunodeficiency


Signaling lymphocytic activation molecule-associated protein


Systemic juvenile idiopathic arthritis


Systemic lupus erythematosus


Whole-exome sequencing


Whole-genome sequencing


X-linked inhibitor of apoptosis


X-linked lymphoproliferative syndrome


  1. 1.
    Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27(136):519–25.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program. 2013;2013:605–11.PubMedGoogle Scholar
  3. 3.
    Henter JI, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Ouachee-Chardin M, et al. Hematopoietic stem cell transplantation in hemophagocytic lymphohistiocytosis: a single-center report of 48 patients. Pediatrics. 2006;117(4):e743–50.CrossRefPubMedGoogle Scholar
  5. 5.
    Cesaro S, et al. Hematopoietic stem cell transplantation for hemophagocytic lymphohistiocytosis: a retrospective analysis of data from the Italian Association of Pediatric Hematology Oncology (AIEOP). Haematologica. 2008;93(11):1694–701.CrossRefPubMedGoogle Scholar
  6. 6.
    Pachlopnik Schmid J, et al. Inherited defects in lymphocyte cytotoxic activity. Immunol Rev. 2010;235(1):10–23.CrossRefPubMedGoogle Scholar
  7. 7.
    Pachlopnik Schmid J, 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(5):1522–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Henter JI, et al. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80(4):428–35.CrossRefPubMedGoogle Scholar
  9. 9.
    Stepp SE, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Feldmann J, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell. 2003;115(4):461–73.CrossRefPubMedGoogle Scholar
  11. 11.
    Zur Stadt U, et al. 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(4):482–92.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zur SU, 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(6):827–34.CrossRefGoogle Scholar
  13. 13.
    Cote M, et al. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient disease causing mutations s. J Clin Invest. 2009;119(12):3765–73.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Menasche G, et al. Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1). J Clin Invest. 2003;112(3):450–6.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Menasche G, Fischer A, de Saint Basile G. Griscelli syndrome types 1 and 2. Am J Hum Genet. 2002;71(5):1237–8. author reply 1238CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Menasche G, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000;25(2):173–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Barbosa MD, 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(7):1091–8.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ammann S, et al. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood. 2016;127(8):997–1006.CrossRefPubMedGoogle Scholar
  19. 19.
    Jessen B, et al. The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2. Blood. 2013;121(15):2943–51.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rathnayake PV, et al. Disseminated tuberculosis presenting as hemophagocytic lymphohistiocytosis in an immunocompetent adult patient: a case report. J Med Case Rep. 2015;9:294.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bode SF, et al. Hemophagocytic lymphohistiocytosis in imported pediatric visceral leishmaniasis in a nonendemic area. J Pediatr. 2014;165(1):147–53. e1CrossRefPubMedGoogle Scholar
  22. 22.
    Behrens EM, et al. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol. 2007;34(5):1133–8.PubMedGoogle Scholar
  23. 23.
    Rossi-Semerano L, et al. Macrophage activation syndrome revealing familial Mediterranean fever. Arthritis Care Res (Hoboken). 2011;63(5):780–3.CrossRefGoogle Scholar
  24. 24.
    Ter Haar NM, et al. The phenotype and genotype of mevalonate kinase deficiency: a series of 114 cases from the Eurofever registry. Arthritis Rheumatol. 2016;68(11):2795.CrossRefPubMedGoogle Scholar
  25. 25.
    Canna SW, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46(10):1140–6.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Parodi A, et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis Rheum. 2009;60(11):3388–99.CrossRefPubMedGoogle Scholar
  27. 27.
    Wang W, et al. Macrophage activation syndrome in Kawasaki disease: more common than we thought? Semin Arthritis Rheum. 2015;44(4):405–10.CrossRefPubMedGoogle Scholar
  28. 28.
    Atteritano M, et al. Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci. 2012;16(10):1414–24.PubMedGoogle Scholar
  29. 29.
    Ramos-Casals M, et al. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16.CrossRefPubMedGoogle Scholar
  30. 30.
    Filippone EJ, Farber JL. Hemophagocytic lymphohistiocytosis: an update for nephrologists. Int Urol Nephrol. 2016;48(8):1291.CrossRefPubMedGoogle Scholar
  31. 31.
    Brito-Zeron P, et al. Infection is the major trigger of hemophagocytic syndrome in adult patients treated with biological therapies. Semin Arthritis Rheum. 2016;45(4):391–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Fardet L, 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
  33. 33.
    Bode SF, et al. The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis. Haematologica. 2015;100(7):978–88.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Li FY, et al. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood. 2014;123(14):2148–52.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ghosh S, et al. Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects. J Clin Immunol. 2014;34(8):892–9.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Alkhairy OK, et al. Novel mutations in TNFRSF7/CD27: clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin Immunol. 2015;136(3):703–12. e10CrossRefPubMedGoogle Scholar
  37. 37.
    Pachlopnik Schmid JM, et al. Transient hemophagocytosis with deficient cellular cytotoxicity, monoclonal immunoglobulin M gammopathy, increased T-cell numbers, and hypomorphic NEMO mutation. Pediatrics. 2006;117(5):e1049–56.CrossRefPubMedGoogle Scholar
  38. 38.
    Schultz KA, et al. Familial hemophagocytic lymphohistiocytosis in two brothers with X-linked agammaglobulinemia. Pediatr Blood Cancer. 2008;51(2):293–5.CrossRefPubMedGoogle Scholar
  39. 39.
    Kuijpers TW, et al. Common variable immunodeficiency and hemophagocytic features associated with a FAS gene mutation. J Allergy Clin Immunol. 2011;127(6):1411–4. e2CrossRefPubMedGoogle Scholar
  40. 40.
    Rudman Spergel A, et al. Autoimmune lymphoproliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis. Pediatrics. 2013;132(5):e1440–4.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tesi B, et al. Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-gamma receptor deficiency. J Allergy Clin Immunol. 2015;135(6):1638–41.CrossRefPubMedGoogle Scholar
  42. 42.
    Duval M, et al. Intermittent hemophagocytic lymphohistiocytosis is a regular feature of lysinuric protein intolerance. J Pediatr. 1999;134(2):236–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab. 2012;106(1):12–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Wu S, et al. Cobalamin C disease presenting with hemophagocytic lymphohistiocytosis. Pediatr Hematol Oncol. 2005;22(8):717–21.CrossRefPubMedGoogle Scholar
  45. 45.
    Gokce M, et al. Secondary hemophagocytosis in 3 patients with organic acidemia involving propionate metabolism. Pediatr Hematol Oncol. 2012;29(1):92–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher‘s disease. Lancet. 2008;372(9645):1263–71.CrossRefPubMedGoogle Scholar
  47. 47.
    Dokmanovic L, et al. Extreme hypertriglyceridemia in an infant with Hemophagocytic Lymphohistiocytosis and Hydroxycobalamin deficiency. Srp Arh Celok Lek. 2015;143(11–12):744–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Suzuki N, et al. Characteristics of hemophagocytic lymphohistiocytosis in neonates: a nationwide survey in Japan. J Pediatr. 2009;155(2):235–8. e1CrossRefPubMedGoogle Scholar
  49. 49.
    Arico M, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the international registry. FHL study group of the Histiocyte society. Leukemia. 1996;10(2):197–203.PubMedGoogle Scholar
  50. 50.
    Balta G, et al. Association of nonimmune hydrops fetalis with familial hemophagocytic lymphohistiocytosis in identical twin neonates with perforin His222Arg (c665A>G) mutation. J Pediatr Hematol Oncol. 2013;35(8):e332–4.CrossRefPubMedGoogle Scholar
  51. 51.
    Bechara E, et al. Hemophagocytic lymphohistiocytosis with Munc13-4 mutation: a cause of recurrent fatal hydrops fetalis. Pediatrics. 2011;128(1):e251–4.CrossRefPubMedGoogle Scholar
  52. 52.
    Malloy CA, et al. Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis. J Perinatol. 2004;24(7):458–60.CrossRefPubMedGoogle Scholar
  53. 53.
    Feldmann J, et al. Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity. Blood. 2005;105(7):2658–63.CrossRefPubMedGoogle Scholar
  54. 54.
    Turtzo LC, et al. A neurologic presentation of familial hemophagocytic lymphohistiocytosis which mimicked septic emboli to the brain. J Child Neurol. 2007;22(7):863–8.CrossRefPubMedGoogle Scholar
  55. 55.
    Deiva K, et al. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology. 2012;78(15):1150–6.CrossRefPubMedGoogle Scholar
  56. 56.
    Amir AZ, et al. Liver transplantation for children with acute liver failure associated with secondary hemophagocytic lymphohistiocytosis. Liver Transpl. 2016;22(9):1245–53.CrossRefPubMedGoogle Scholar
  57. 57.
    Stapp J, et al. Fulminant neonatal liver failure in siblings: probable congenital hemophagocytic lymphohistiocytosis. Pediatr Dev Pathol. 2006;9(3):239–44.CrossRefPubMedGoogle Scholar
  58. 58.
    Ost A, Nilsson-Ardnor S, Henter JI. Autopsy findings in 27 children with haemophagocytic lymphohistiocytosis. Histopathology. 1998;32(4):310–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Seguin A, et al. Pulmonary involvement in patients with Hemophagocytic Lymphohistiocytosis. Chest. 2016;149(5):1294–301.CrossRefPubMedGoogle Scholar
  60. 60.
    Tardieu M, et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome. Blood. 2005;106(1):40–2.CrossRefPubMedGoogle Scholar
  61. 61.
    Shimazaki H, et al. Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation. J Neurol Neurosurg Psychiatry. 2014;85(9):1024–8.CrossRefPubMedGoogle Scholar
  62. 62.
    Trottestam H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577–84.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Ravelli A, et al. Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. RMD Open. 2016;2(1):e000161.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Sackett K, et al. Extreme Hyperferritinemia: causes and impact on diagnostic reasoning. Am J Clin Pathol. 2016;145(5):646–50.CrossRefPubMedGoogle Scholar
  65. 65.
    Motley MP, et al. A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. Blood. 2016;127(9):1085–96.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Osugi Y, et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood. 1997;89(11):4100–3.PubMedGoogle Scholar
  68. 68.
    Henter JI, et al. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991;78(11):2918–22.PubMedGoogle Scholar
  69. 69.
    Billiau AD, et al. Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages. Blood. 2005;105(4):1648–51.CrossRefPubMedGoogle Scholar
  70. 70.
    Jenkins MR, et al. Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J Exp Med. 2015;212(3):307–17.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ. 2002;166(8):1056–62.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Lehmberg K, et al. Differentiating macrophage activation syndrome in systemic juvenile idiopathic arthritis from other forms of hemophagocytic lymphohistiocytosis. J Pediatr. 2013;162(6):1245–51.CrossRefPubMedGoogle Scholar
  73. 73.
    Ravelli A, et al. 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
  74. 74.
    Quartier P. Current treatments for juvenile idiopathic arthritis. Joint Bone Spine. 2010;77(6):511–6.CrossRefPubMedGoogle Scholar
  75. 75.
    Bryceson YT, et al. A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood. 2012;119(12):2754–63.CrossRefPubMedGoogle Scholar
  76. 76.
    Stranneheim H, Wedell A. Exome and genome sequencing: a revolution for the discovery and diagnosis of monogenic disorders. J Intern Med. 2016;279(1):3–15.CrossRefPubMedGoogle Scholar
  77. 77.
    Chellapandian D, et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013;162(3):376–82.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 2015;15(6):388–400.CrossRefPubMedGoogle Scholar
  79. 79.
    Vivier E, et al. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10.CrossRefPubMedGoogle Scholar
  80. 80.
    Voskoboinik I, et al. Perforin: structure, function, and role in human immunopathology. Immunol Rev. 2010;235(1):35–54.CrossRefPubMedGoogle Scholar
  81. 81.
    Orange JS. Natural killer cell deficiency. J Allergy Clin Immunol. 2013;132(3):515–25. quiz 526CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Neeft M, et al. Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells. Mol Biol Cell. 2005;16(2):731–41.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Arneson LN, et al. Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity. J Immunol. 2007;179(6):3397–401.CrossRefPubMedGoogle Scholar
  84. 84.
    Bryceson YT, et al. Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood. 2007;110(6):1906–15.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Barbosa MD, et al. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature. 1996;382(6588):262–5.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Dell'Angelica EC, et al. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell. 1999;3(1):11–21.CrossRefPubMedGoogle Scholar
  87. 87.
    Marcenaro S, et al. Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. Blood. 2006;108(7):2316–23.CrossRefPubMedGoogle Scholar
  88. 88.
    Picard C, Fischer A. Contribution of high-throughput DNA sequencing to the study of primary immunodeficiencies. Eur J Immunol. 2014;44(10):2854–61.CrossRefPubMedGoogle Scholar
  89. 89.
    Schuster SC. Next-generation sequencing transforms today‘s biology. Nat Methods. 2008;5(1):16–8.CrossRefPubMedGoogle Scholar
  90. 90.
    Heather JM, Chain B. The sequence of sequencers: the history of sequencing DNA. Genomics. 2016;107(1):1–8.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Schulert GS, 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(7):1180–8.CrossRefPubMedGoogle Scholar
  92. 92.
    Pachlopnik Schmid J, de Saint Basile G. Angeborene hämophagozytische Lymphohistiozytose (HLH). Klin Padiatr. 2010;222(6):345–50.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • J. Pachlopnik Schmid
    • 1
  • Benjamin Volkmer
    • 1
  • Stephan Ehl
    • 2
  1. 1.Division of ImmunologyUniversity Children’s Hospital, University of ZurichZurichSwitzerland
  2. 2.Center for Chronic ImmunodeficiencyUniversity Medical Center Freiburg, University of FreiburgFreiburgGermany

Personalised recommendations