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Classification, Clinical Manifestations, and Diagnostics of HLH

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Histiocytic Disorders

Abstract

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.

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Abbreviations

ADV:

Adenovirus

CGD:

Chronic granulomatous disease

CHS:

Chediak-Higashi syndrome

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

EBV:

Epstein-Barr virus

FHL:

Familial HLH

HHV:

Human herpes virus

HLH:

Hemophagocytic lymphohistiocytosis

HPS:

Hermansky-Pudlak syndrome

HSCT:

Hematopoietic stem cell transplantation

IFN:

Interferon

MAS:

Macrophage activation syndrome

MRI:

Magnetic resonance imaging

NGS:

Next-generation sequencing

PBMCs:

Peripheral blood mononuclear cells

PCR:

Polymerase chain reaction

PID:

Primary immunodeficiency

SAP:

Signaling lymphocytic activation molecule-associated protein

sJIA:

Systemic juvenile idiopathic arthritis

SLE:

Systemic lupus erythematosus

WES:

Whole-exome sequencing

WGS:

Whole-genome sequencing

XIAP:

X-linked inhibitor of apoptosis

XLP:

X-linked lymphoproliferative syndrome

References

  1. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27(136):519–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program. 2013;2013:605–11.

    PubMed  Google Scholar 

  3. Henter JI, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  6. Pachlopnik Schmid J, et al. Inherited defects in lymphocyte cytotoxic activity. Immunol Rev. 2010;235(1):10–23.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  8. Henter JI, et al. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80(4):428–35.

    Article  CAS  PubMed  Google Scholar 

  9. Stepp SE, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 1238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Menasche G, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000;25(2):173–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. Jessen B, et al. The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2. Blood. 2013;121(15):2943–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bode SF, et al. Hemophagocytic lymphohistiocytosis in imported pediatric visceral leishmaniasis in a nonendemic area. J Pediatr. 2014;165(1):147–53. e1

    Article  PubMed  Google Scholar 

  22. Behrens EM, et al. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol. 2007;34(5):1133–8.

    PubMed  Google Scholar 

  23. Rossi-Semerano L, et al. Macrophage activation syndrome revealing familial Mediterranean fever. Arthritis Care Res (Hoboken). 2011;63(5):780–3.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  25. Canna SW, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46(10):1140–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  27. Wang W, et al. Macrophage activation syndrome in Kawasaki disease: more common than we thought? Semin Arthritis Rheum. 2015;44(4):405–10.

    Article  CAS  PubMed  Google Scholar 

  28. Atteritano M, et al. Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci. 2012;16(10):1414–24.

    CAS  PubMed  Google Scholar 

  29. Ramos-Casals M, et al. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16.

    Article  PubMed  Google Scholar 

  30. Filippone EJ, Farber JL. Hemophagocytic lymphohistiocytosis: an update for nephrologists. Int Urol Nephrol. 2016;48(8):1291.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. e10

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  38. Schultz KA, et al. Familial hemophagocytic lymphohistiocytosis in two brothers with X-linked agammaglobulinemia. Pediatr Blood Cancer. 2008;51(2):293–5.

    Article  PubMed  Google Scholar 

  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. e2

    Article  PubMed  Google Scholar 

  40. Rudman Spergel A, et al. Autoimmune lymphoproliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis. Pediatrics. 2013;132(5):e1440–4.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  42. Duval M, et al. Intermittent hemophagocytic lymphohistiocytosis is a regular feature of lysinuric protein intolerance. J Pediatr. 1999;134(2):236–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  44. Wu S, et al. Cobalamin C disease presenting with hemophagocytic lymphohistiocytosis. Pediatr Hematol Oncol. 2005;22(8):717–21.

    Article  PubMed  Google Scholar 

  45. Gokce M, et al. Secondary hemophagocytosis in 3 patients with organic acidemia involving propionate metabolism. Pediatr Hematol Oncol. 2012;29(1):92–8.

    Article  CAS  PubMed  Google Scholar 

  46. Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher‘s disease. Lancet. 2008;372(9645):1263–71.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  48. Suzuki N, et al. Characteristics of hemophagocytic lymphohistiocytosis in neonates: a nationwide survey in Japan. J Pediatr. 2009;155(2):235–8. e1

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  51. Bechara E, et al. Hemophagocytic lymphohistiocytosis with Munc13-4 mutation: a cause of recurrent fatal hydrops fetalis. Pediatrics. 2011;128(1):e251–4.

    Article  PubMed  Google Scholar 

  52. Malloy CA, et al. Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis. J Perinatol. 2004;24(7):458–60.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  55. Deiva K, et al. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology. 2012;78(15):1150–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  57. Stapp J, et al. Fulminant neonatal liver failure in siblings: probable congenital hemophagocytic lymphohistiocytosis. Pediatr Dev Pathol. 2006;9(3):239–44.

    Article  PubMed  Google Scholar 

  58. Ost A, Nilsson-Ardnor S, Henter JI. Autopsy findings in 27 children with haemophagocytic lymphohistiocytosis. Histopathology. 1998;32(4):310–6.

    Article  CAS  PubMed  Google Scholar 

  59. Seguin A, et al. Pulmonary involvement in patients with Hemophagocytic Lymphohistiocytosis. Chest. 2016;149(5):1294–301.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  62. Trottestam H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sackett K, et al. Extreme Hyperferritinemia: causes and impact on diagnostic reasoning. Am J Clin Pathol. 2016;145(5):646–50.

    Article  PubMed  Google Scholar 

  65. Motley MP, et al. A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. Blood. 2016;127(9):1085–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Osugi Y, et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood. 1997;89(11):4100–3.

    CAS  PubMed  Google Scholar 

  68. Henter JI, et al. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991;78(11):2918–22.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ. 2002;166(8):1056–62.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  74. Quartier P. Current treatments for juvenile idiopathic arthritis. Joint Bone Spine. 2010;77(6):511–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 2015;15(6):388–400.

    Article  CAS  PubMed  Google Scholar 

  79. Vivier E, et al. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10.

    Article  CAS  PubMed  Google Scholar 

  80. Voskoboinik I, et al. Perforin: structure, function, and role in human immunopathology. Immunol Rev. 2010;235(1):35–54.

    Article  CAS  PubMed  Google Scholar 

  81. Orange JS. Natural killer cell deficiency. J Allergy Clin Immunol. 2013;132(3):515–25. quiz 526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Arneson LN, et al. Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity. J Immunol. 2007;179(6):3397–401.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Barbosa MD, et al. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature. 1996;382(6588):262–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  89. Schuster SC. Next-generation sequencing transforms today‘s biology. Nat Methods. 2008;5(1):16–8.

    Article  CAS  PubMed  Google Scholar 

  90. Heather JM, Chain B. The sequence of sequencers: the history of sequencing DNA. Genomics. 2016;107(1):1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  92. Pachlopnik Schmid J, de Saint Basile G. Angeborene hämophagozytische Lymphohistiozytose (HLH). Klin Padiatr. 2010;222(6):345–50.

    Article  CAS  PubMed  Google Scholar 

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Schmid, J.P., Volkmer, B., Ehl, S. (2018). Classification, Clinical Manifestations, and Diagnostics of HLH. In: Abla, O., Janka, G. (eds) Histiocytic Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-59632-7_9

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