Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Clinical features and diagnosis of hemophagocytic lymphohistiocytosis

Kenneth L McClain, MD, PhD
Olive Eckstein, MD
Section Editor
Peter Newburger, MD
Deputy Editor
Alan G Rosmarin, MD


Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. It most frequently affects infants from birth to 18 months of age, but the disease is also observed in children and adults of all ages. HLH can occur as a familial or sporadic disorder, and it can be triggered by a variety of events that disrupt immune homeostasis. Infection is a common trigger both in those with a genetic predisposition and in sporadic cases.

Prompt initiation of treatment is essential for the survival of affected patients. Often the greatest barrier to a successful outcome is a delay in diagnosis, which is difficult because of the rarity of this syndrome, the variable clinical presentation, and the lack of specificity of the clinical and laboratory findings.

The clinical features and diagnosis of HLH and a related disorder, the macrophage activation syndrome (MAS), will be discussed here. The management of patients with these disorders is discussed separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)


Terms used to describe HLH and related syndromes have evolved since the original patient was described as having "familial hemophagocytic reticulosis" in 1952.

Use of the term "primary HLH" to denote the presence of an underlying genetic disorder and "secondary HLH" to denote presence of the HLH phenomenon occurring secondary to another condition has caused a great deal of confusion among clinicians. Both primary and secondary HLH can be triggered by infections or other immunologically activating events, and gene mutations can be found in individuals of any age and with any family history. In practice, distinction between primary and secondary HLH is not essential for the initial diagnosis and management. However, identification of a gene mutation may be useful for subsequent management. (See 'Evaluation and diagnostic testing' below.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jul 2017. | This topic last updated: Jun 20, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Larroche C. Hemophagocytic lymphohistiocytosis in adults: diagnosis and treatment. Joint Bone Spine 2012; 79:356.
  2. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124.
  3. Aricò M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996; 10:197.
  4. Reiner AP, Spivak JL. Hematophagic histiocytosis. A report of 23 new patients and a review of the literature. Medicine (Baltimore) 1988; 67:369.
  5. Clementi R, Emmi L, Maccario R, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood 2002; 100:2266.
  6. Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol 2004; 124:4.
  7. Filipovich A, McClain K, Grom A. Histiocytic disorders: recent insights into pathophysiology and practical guidelines. Biol Blood Marrow Transplant 2010; 16:S82.
  8. Dalal BI, Vakil AP, Khare NS, et al. Abnormalities of the lymphocyte subsets and their immunophenotype, and their prognostic significance in adult patients with hemophagocytic lymphohistiocytosis. Ann Hematol 2015; 94:1111.
  9. Pachlopnik Schmid J, Côte M, Ménager MM, et al. Inherited defects in lymphocyte cytotoxic activity. Immunol Rev 2010; 235:10.
  10. Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr 2012; 24:9.
  11. Egeler RM, Shapiro R, Loechelt B, Filipovich A. Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 1996; 18:340.
  12. Eife R, Janka GE, Belohradsky BH, Holtmann H. Natural killer cell function and interferon production in familial hemophagocytic lymphohistiocytosis. Pediatr Hematol Oncol 1989; 6:265.
  13. Ishii E, Ueda I, Shirakawa R, et al. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood 2005; 105:3442.
  14. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999; 286:1957.
  15. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140:805.
  16. Fall N, Barnes M, Thornton S, et al. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum 2007; 56:3793.
  17. Behrens EM, Canna SW, Slade K, et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest 2011; 121:2264.
  18. Henter JI, Elinder G, Söder O, et al. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 1991; 78:2918.
  19. Osugi Y, Hara J, Tagawa S, et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood 1997; 89:4100.
  20. Aricò M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol 2001; 114:761.
  21. Komp DM, McNamara J, Buckley P. Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes. Blood 1989; 73:2128.
  22. Tang Y, Xu X, Song H, 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.
  23. Takada H, Ohga S, Mizuno Y, et al. Increased IL-16 levels in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 2004; 26:567.
  24. Mazodier K, Marin V, Novick D, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood 2005; 106:3483.
  25. Put K, Avau A, Brisse E, et al. Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ. Rheumatology (Oxford) 2015; 54:1507.
  26. Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic lymphohistiocytosis. Blood 2011; 118:4041.
  27. Parekh C, Hofstra T, Church JA, Coates TD. Hemophagocytic lymphohistiocytosis in children with chronic granulomatous disease. Pediatr Blood Cancer 2011; 56:460.
  28. 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.
  29. Göransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, et al. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet 2001; 68:590.
  30. 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.
  31. 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.
  32. Zhang K, Chandrakasan S, Chapman H, et al. Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. Blood 2014; 124:1331.
  33. Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch Dis Child 2011; 96:688.
  34. Spessott WA, Sanmillan ML, McCormick ME, et al. Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood 2015; 125:1566.
  35. Cetica V, Sieni E, Pende D, et al. Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry. J Allergy Clin Immunol 2016; 137:188.
  36. Kaufman KM, Linghu B, Szustakowski JD, 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.
  37. Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 2011; 118:5794.
  38. Voskoboinik I, Thia MC, Trapani JA. A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. Blood 2005; 105:4700.
  39. Trambas C, Gallo F, Pende D, et al. A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin. Blood 2005; 106:932.
  40. Voskoboinik I, Thia MC, De Bono A, et al. The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. J Exp Med 2004; 200:811.
  41. Meeths M, Chiang SC, Wood SM, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood 2011; 118:5783.
  42. Rudd E, Göransdotter Ericson K, Zheng C, et al. Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. J Med Genet 2006; 43:e14.
  43. Côte M, Ménager 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.
  44. Ménasché G, Pastural E, Feldmann J, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 2000; 25:173.
  45. Rubin CM, Burke BA, McKenna RW, et al. The accelerated phase of Chediak-Higashi syndrome. An expression of the virus-associated hemophagocytic syndrome? Cancer 1985; 56:524.
  46. Arico M, Imashuku S, Clementi R, et al. Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood 2001; 97:1131.
  47. Marsh RA, Madden L, Kitchen BJ, et al. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood 2010; 116:1079.
  48. Li FY, Chaigne-Delalande B, Su H, et al. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood 2014; 123:2148.
  49. Alkhairy OK, Perez-Becker R, Driessen GJ, et al. Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin Immunol 2015; 136:703.
  50. Jessen B, Bode SF, Ammann S, et al. The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2. Blood 2013; 121:2943.
  51. Barilli A, Rotoli BM, Visigalli R, et al. Impaired phagocytosis in macrophages from patients affected by lysinuric protein intolerance. Mol Genet Metab 2012; 105:585.
  52. Nagafuji K, Nonami A, Kumano T, et al. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis. Haematologica 2007; 92:978.
  53. Pagel J, Beutel K, Lehmberg K, et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood 2012; 119:6016.
  54. Lee SM, Sumegi J, Villanueva J, et al. Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation. J Pediatr 2006; 149:134.
  55. Feldmann J, Le Deist F, Ouachée-Chardin M, et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol 2002; 117:965.
  56. Ueda I, Ishii E, Morimoto A, et al. Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL). Pediatr Blood Cancer 2006; 46:482.
  57. Ueda I, Kurokawa Y, Koike K, et al. Late-onset cases of familial hemophagocytic lymphohistiocytosis with missense perforin gene mutations. Am J Hematol 2007; 82:427.
  58. Muralitharan S, Al Lamki Z, Dennison D, et al. An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression. Am J Hematol 2005; 78:59.
  59. Horne A, Ramme KG, Rudd E, et al. Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis. Br J Haematol 2008; 143:75.
  60. 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.
  61. Kostova EB, Beuger BM, Veldthuis M, et al. Intrinsic defects in erythroid cells from familial hemophagocytic lymphohistiocytosis type 5 patients identify a role for STXBP2/Munc18-2 in erythropoiesis and phospholipid scrambling. Exp Hematol 2015; 43:1072.
  62. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991; 80:428.
  63. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, et al. Adult haemophagocytic syndrome. Lancet 2014; 383:1503.
  64. Niece JA, Rogers ZR, Ahmad N, et al. Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer 2010; 54:424.
  65. Shin HJ, Chung JS, Lee JJ, et al. Treatment outcomes with CHOP chemotherapy in adult patients with hemophagocytic lymphohistiocytosis. J Korean Med Sci 2008; 23:439.
  66. Ishii E, Ohga S, Imashuku S, et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol 2007; 86:58.
  67. Ferreri AJ, Dognini GP, Campo E, et al. Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions. Haematologica 2007; 92:486.
  68. Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat 2006; 27:62.
  69. Meeths M, Entesarian M, Al-Herz W, et al. Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood 2010; 116:2635.
  70. Sandrock K, Nakamura L, Vraetz T, et al. Platelet secretion defect in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL-5). Blood 2010; 116:6148.
  71. Ueda I, Morimoto A, Inaba T, et al. Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Br J Haematol 2003; 121:503.
  72. Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood 2011; 118:4577.
  73. Zhao XW, Gazendam RP, Drewniak A, et al. Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations. Blood 2013; 122:109.
  74. Suzuki N, Morimoto A, Ohga S, et al. Characteristics of hemophagocytic lymphohistiocytosis in neonates: a nationwide survey in Japan. J Pediatr 2009; 155:235.
  75. Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis 2003; 36:306.
  76. Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 50:1227.
  77. 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; 61:2101.
  78. Lee WS, McKiernan PJ, Kelly DA. Serum ferritin level in neonatal fulminant liver failure. Arch Dis Child Fetal Neonatal Ed 2001; 85:F226.
  79. Cohen LA, Gutierrez L, Weiss A, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 2010; 116:1574.
  80. Wu JR, Yuan LX, Ma ZG, et al. GDF15-mediated upregulation of ferroportin plays a key role in the development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2013; 60:940.
  81. Stapp J, Wilkerson S, Stewart D, et al. Fulminant neonatal liver failure in siblings: probable congenital hemophagocytic lymphohistiocytosis. Pediatr Dev Pathol 2006; 9:239.
  82. Okamoto M, Yamaguchi H, Isobe Y, et al. Analysis of triglyceride value in the diagnosis and treatment response of secondary hemophagocytic syndrome. Intern Med 2009; 48:775.
  83. Fukaya S, Yasuda S, Hashimoto T, et al. Clinical features of haemophagocytic syndrome in patients with systemic autoimmune diseases: analysis of 30 cases. Rheumatology (Oxford) 2008; 47:1686.
  84. Ost A, Nilsson-Ardnor S, Henter JI. Autopsy findings in 27 children with haemophagocytic lymphohistiocytosis. Histopathology 1998; 32:310.
  85. Jovanovic A, Kuzmanovic M, Kravljanac R, et al. Central nervous system involvement in hemophagocytic lymphohistiocytosis: a single-center experience. Pediatr Neurol 2014; 50:233.
  86. Haddad E, Sulis ML, Jabado N, et al. Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis. Blood 1997; 89:794.
  87. Deiva K, Mahlaoui N, Beaudonnet F, et al. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology 2012; 78:1150.
  88. Feldmann J, Ménasché G, Callebaut I, et al. Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity. Blood 2005; 105:2658.
  89. De Armas R, Sindou P, Gelot A, et al. Demyelinating peripheral neuropathy associated with hemophagocytic lymphohistiocytosis. An immuno-electron microscopic study. Acta Neuropathol 2004; 108:341.
  90. Henter JI, Nennesmo I. Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis. J Pediatr 1997; 130:358.
  91. Horne A, Trottestam H, Aricò M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol 2008; 140:327.
  92. Gratton SM, Powell TR, Theeler BJ, et al. Neurological involvement and characterization in acquired hemophagocytic lymphohistiocytosis in adulthood. J Neurol Sci 2015; 357:136.
  93. McClain K, Gehrz R, Grierson H, et al. Virus-associated histiocytic proliferations in children. Frequent association with Epstein-Barr virus and congenital or acquired immunodeficiencies. Am J Pediatr Hematol Oncol 1988; 10:196.
  94. Mou SS, Nakagawa TA, Riemer EC, et al. Hemophagocytic lymphohistiocytosis complicating influenza A infection. Pediatrics 2006; 118:e216.
  95. Harms PW, Schmidt LA, Smith LB, et al. Autopsy findings in eight patients with fatal H1N1 influenza. Am J Clin Pathol 2010; 134:27.
  96. Yuzurihara SS, Ao K, Hara T, et al. Human parechovirus-3 infection in nine neonates and infants presenting symptoms of hemophagocytic lymphohistiocytosis. J Infect Chemother 2013; 19:144.
  97. Chen TL, Wong WW, Chiou TJ. Hemophagocytic syndrome: an unusual manifestation of acute human immunodeficiency virus infection. Int J Hematol 2003; 78:450.
  98. Fardet L, Blum L, Kerob D, et al. Human herpesvirus 8-associated hemophagocytic lymphohistiocytosis in human immunodeficiency virus-infected patients. Clin Infect Dis 2003; 37:285.
  99. Grossman WJ, Radhi M, Schauer D, et al. Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV-8. Blood 2005; 106:1203.
  100. Hegerova LT, Lin Y. Disseminated histoplasmosis: a cause of hemophagocytic syndrome. Mayo Clin Proc 2013; 88:e123.
  101. Otrock ZK, Eby CS. Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 2015; 90:220.
  102. Huang DB, Wu JJ, Hamill RJ. Reactive hemophagocytosis associated with the initiation of highly active antiretroviral therapy (HAART) in a patient with AIDS. Scand J Infect Dis 2004; 36:516.
  103. Brito-Zerón P, Bosch X, Pérez-de-Lis M, et al. Infection is the major trigger of hemophagocytic syndrome in adult patients treated with biological therapies. Semin Arthritis Rheum 2016; 45:391.
  104. Risdall RJ, Brunning RD, Hernandez JI, Gordon DH. Bacteria-associated hemophagocytic syndrome. Cancer 1984; 54:2968.
  105. Sung PS, Kim IH, Lee JH, Park JW. Hemophagocytic Lymphohistiocytosis (HLH) Associated with Plasmodium vivax Infection: Case Report and Review of the Literature. Chonnam Med J 2011; 47:173.
  106. Falini B, Pileri S, De Solas I, et al. Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood 1990; 75:434.
  107. Okuda T, Sakamoto S, Deguchi T, et al. Hemophagocytic syndrome associated with aggressive natural killer cell leukemia. Am J Hematol 1991; 38:321.
  108. Miyahara M, Sano M, Shibata K, et al. B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics. Ann Hematol 2000; 79:378.
  109. Shimazaki C, Inaba T, Nakagawa M. B-cell lymphoma-associated hemophagocytic syndrome. Leuk Lymphoma 2000; 38:121.
  110. Pastore RD, Chadburn A, Kripas C, Schattner EJ. Novel association of haemophagocytic syndrome with Kaposi's sarcoma-associated herpesvirus-related primary effusion lymphoma. Br J Haematol 2000; 111:1112.
  111. Ménard F, Besson C, Rincé P, et al. Hodgkin lymphoma-associated hemophagocytic syndrome: a disorder strongly correlated with Epstein-Barr virus. Clin Infect Dis 2008; 47:531.
  112. O'Brien MM, Lee-Kim Y, George TI, et al. Precursor B-cell acute lymphoblastic leukemia presenting with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 50:381.
  113. Fox CP, Shannon-Lowe C, Gothard P, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults characterized by high viral genome load within circulating natural killer cells. Clin Infect Dis 2010; 51:66.
  114. Su IJ, Hsu YH, Lin MT, et al. Epstein-Barr virus-containing T-cell lymphoma presents with hemophagocytic syndrome mimicking malignant histiocytosis. Cancer 1993; 72:2019.
  115. Pasqualini C, Minard-Colin V, Saada V, et al. Clinical analysis and prognostic significance of haemophagocytic lymphohistiocytosis-associated anaplastic large cell lymphoma in children. Br J Haematol 2014.
  116. Allory Y, Challine D, Haioun C, et al. Bone marrow involvement in lymphomas with hemophagocytic syndrome at presentation: a clinicopathologic study of 11 patients in a Western institution. Am J Surg Pathol 2001; 25:865.
  117. Shimizu Y, Tanae K, Takahashi N, et al. Primary cutaneous anaplastic large-cell lymphoma presenting with hemophagocytic syndrome: a case report and review of the literature. Leuk Res 2010; 34:263.
  118. Lehmberg K, Sprekels B, Nichols KE, et al. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol 2015; 170:539.
  119. Chang TY, Jaffray J, Woda B, et al. Hemophagocytic lymphohistiocytosis with MUNC13-4 gene mutation or reduced natural killer cell function prior to onset of childhood leukemia. Pediatr Blood Cancer 2011; 56:856.
  120. Davì S, Minoia F, Pistorio A, et al. Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis Rheumatol 2014; 66:2871.
  121. Yokota S, Itoh Y, Morio T, et al. Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis under Treatment with Tocilizumab. J Rheumatol 2015; 42:712.
  122. Ezdinli EZ, Kucuk O, Chedid A, et al. Hypogammaglobulinemia and hemophagocytic syndrome associated with lymphoproliferative disorders. Cancer 1986; 57:1024.
  123. Rohr J, Beutel K, Maul-Pavicic A, et al. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Haematologica 2010; 95:2080.
  124. Enders A, Zieger B, Schwarz K, et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II. Blood 2006; 108:81.
  125. Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome after Kawasaki disease. Pediatr Infect Dis J 2003; 22:663.
  126. Abe Y, Choi I, Hara K, et al. Hemophagocytic syndrome: a rare complication of allogeneic nonmyeloablative hematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29:799.
  127. Ferreira RA, Vastert SJ, Abinun M, et al. Hemophagocytosis during fludarabine-based SCT for systemic juvenile idiopathic arthritis. Bone Marrow Transplant 2006; 38:249.
  128. Karras A, Thervet E, Legendre C, Groupe Coopératif de transplantation d'Ile de France. Hemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of literature. Transplantation 2004; 77:238.
  129. Lladó L, Figueras J, Comí S, et al. Haemophagocytic syndrome after liver transplantation in adults. Transpl Int 2004; 17:221.
  130. George TI, Jeng M, Berquist W, et al. Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: case report and review of the literature. Pediatr Blood Cancer 2005; 44:270.
  131. Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979; 44:993.
  132. Nikiforow S, Berliner N. The unique aspects of presentation and diagnosis of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc Hematol Educ Program 2015; 2015:183.
  133. Hayden A, Park S, Giustini D, et al. Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. Blood Rev 2016; 30:411.
  134. Rosado FG, Rinker EB, Plummer WD, et al. The diagnosis of adult-onset haemophagocytic lymphohistiocytosis: lessons learned from a review of 29 cases of bone marrow haemophagocytosis in two large academic institutions. J Clin Pathol 2016; 69:805.
  135. La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc Hematol Educ Program 2015; 2015:190.
  136. Campo M, Berliner N. Hemophagocytic Lymphohistiocytosis in Adults. Hematol Oncol Clin North Am 2015; 29:915.
  137. Hejblum G, Lambotte O, Galicier L, 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:e94024.
  138. Rivière S, Galicier L, Coppo P, et al. Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med 2014; 127:1118.
  139. Arca M, Fardet L, Galicier L, 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; 168:63.
  140. Parikh SA, Kapoor P, Letendre L, et al. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc 2014; 89:484.
  141. Li J, Wang Q, Zheng W, et al. Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients. Medicine (Baltimore) 2014; 93:100.
  142. Schram AM, Mullally A, Fogerty AE, et al. Hemophagocytic lymphohistiocytosis: The Partners Healthcare experience over the past 8 years. Blood 2014; 124:4104.
  143. Ahn JS, Rew SY, Shin MG, et al. Clinical significance of clonality and Epstein-Barr virus infection in adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 2010; 85:719.
  144. Chen J, Wang X, He P, et al. Viral etiology, clinical and laboratory features of adult hemophagocytic lymphohistiocytosis. J Med Virol 2016; 88:541.
  145. Wong KF, Hui PK, Chan JK, et al. The acute lupus hemophagocytic syndrome. Ann Intern Med 1991; 114:387.
  146. Morris JA, Adamson AR, Holt PJ, Davson J. Still's disease and the virus-associated haemophagocytic syndrome. Ann Rheum Dis 1985; 44:349.
  147. Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003; 49:633.
  148. Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003; 49:633.
  149. Hot A, Toh ML, Coppéré B, et al. Reactive hemophagocytic syndrome in adult-onset Still disease: clinical features and long-term outcome: a case-control study of 8 patients. Medicine (Baltimore) 2010; 89:37.
  150. Tabata R, Tabata C, Terada M, Nagai T. Hemophagocytic syndrome in elderly patients with underlying autoimmune diseases. Clin Rheumatol 2009; 28:461.
  151. Schram AM, Campigotto F, Mullally A, et al. Marked hyperferritinemia does not predict for HLH in the adult population. Blood 2015; 125:1548.
  152. Lim SH, Park S, Jang JH, et al. Clinical significance of bone marrow hemophagocytosis in adult patients with malignancy and non-malignancy-induced hemophagocytic lymphohistiocytosis. Ann Hematol 2016; 95:325.
  153. https://www.cincinnatichildrens.org/service/c/cancer-blood/hcp/clinical-laboratories/diagnostic-lab (Accessed on June 19, 2017).
  154. Schaer DJ, Schleiffenbaum B, Kurrer M, et al. Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. Eur J Haematol 2005; 74:6.
  155. Bleesing J, Prada A, Siegel DM, et al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum 2007; 56:965.
  156. Wang LL, Hu YX, Chen WF, et al. [Significance of soluble interleukin-2 receptor and NK cell activity in patients with hemophagocytic lymphohistiocytosis]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2012; 20:401.
  157. Wang Z, Wang YN, Feng CC, et al. [Diagnostic significance of NK cell activity and soluble CD25 level in serum from patients with secondary hemophagocytic lymphohistiocytosis]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2008; 16:1154.
  158. Imashuku S, Hibi S, Tabata Y, et al. Biomarker and morphological characteristics of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis. Med Pediatr Oncol 1998; 31:131.
  159. 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.
  160. Lee WI, Chen SH, Hung IJ, et al. Clinical aspects, immunologic assessment, and genetic analysis in Taiwanese children with hemophagocytic lymphohistiocytosis. Pediatr Infect Dis J 2009; 28:30.
  161. Mellor-Heineke S, Villanueva J, Jordan MB, et al. Elevated Granzyme B in Cytotoxic Lymphocytes is a Signature of Immune Activation in Hemophagocytic Lymphohistiocytosis. Front Immunol 2013; 4:72.
  162. Tsuji T, Hirano T, Yamasaki H, et al. A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol 2014; 93:821.
  163. Rubin TS, Zhang K, Gifford C, et al. Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH. Blood 2017; 129:2993.
  164. Maruoka H, Inoue D, Takiuchi Y, et al. IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol 2014; 93:393.
  165. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program 2009; :127.
  166. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014; 66:2613.
  167. Nahum E, Ben-Ari J, Stain J, Schonfeld T. Hemophagocytic lymphohistiocytic syndrome: Unrecognized cause of multiple organ failure. Pediatr Crit Care Med 2000; 1:51.
  168. Ben m'rad M, Leclerc-Mercier S, Blanche P, et al. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine (Baltimore) 2009; 88:131.
  169. Rooms L, Fitzgerald N, McClain KL. Hemophagocytic lymphohistiocytosis masquerading as child abuse: presentation of three cases and review of central nervous system findings in hemophagocytic lymphohistiocytosis. Pediatrics 2003; 111:e636.
  170. Rostasy K, Kolb R, Pohl D, et al. CNS disease as the main manifestation of hemophagocytic lymphohistiocytosis in two children. Neuropediatrics 2004; 35:45.
  171. Hymel KP, Abshire TC, Luckey DW, Jenny C. Coagulopathy in pediatric abusive head trauma. Pediatrics 1997; 99:371.
  172. Marzano AV, Berti E, Paulli M, Caputo R. Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma: report of 7 cases. Arch Dermatol 2000; 136:889.
  173. Craig AJ, Cualing H, Thomas G, et al. Cytophagic histiocytic panniculitis--a syndrome associated with benign and malignant panniculitis: case comparison and review of the literature. J Am Acad Dermatol 1998; 39:721.