History

The diagnostic criteria set forth by the Histiocyte Society for inclusion in the International Registry for Hemophagocytic Lymphohistiocytosis (HLH) is as follows.^[1]All 5 criteria must be met to establish a diagnosis of hemophagocytic lymphohistiocytosis:

Fever - Seven or more days of a temperature as high as 38.5°C (101.3°F)
Splenomegaly - A palpable spleen greater than 3 cm below the costal margin
Cytopenia - Counts below the specified range in at least 2 of the following cell lineages:
- Absolute neutrophil count of less than 1000/µL (see Differential Blood Count)
- Platelet count of less than 100,000/µL
- Hemoglobin level of less than 9.0 g/dL
Hypofibrinogenemia or hypertriglyceridemia - (1) Fibrinogen less than 1.5 g/L or levels greater than 3 standard deviations below the age-adjusted reference range value or (2) fasting triglycerides greater than 2 mmol/L or levels greater than 3 standard deviations above the age-adjusted reference range value
Hemophagocytosis - Must have tissue demonstration from lymph node, spleen, or bone marrow without evidence of malignancy

Skin findings are noted in more than half of patients, such as scaly and waxy lesions and rashes on the scalp and behind the ear.^[3] Other findings include swollen or hemorrhagic gums that can result in tooth loss; feeding problems (especially prominent in infants); and abdominal pain, vomiting, diarrhea, and weight loss.

Hemophagocytic lymphohistiocytosis was noted in a boy with Chédiak-Higashi syndrome.^[38] In a sampling from Brazil, 90% of patients with hemophagocytic lymphohistiocytosis had fever and thrombocytopenia, although in adults, hepatomegaly, splenomegaly, and jaundice were less common than in children, and serous cavity effusion was more frequent.^[25]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be a trigger for hemophagocytic lymphohistiocytosis.^[39] Prompt recognition in patients with coronavirus disease 2019 (COVID-19) may improve clinical outcomes. Mortality in patients with hemophagocytic lymphohistiocytosis who have COVID-19 is high.

Physical Examination

Clinical findings, including evidence of infection due to decreased immunity and white cell killing defects, easy bruisability, and pallor, are related to pancytopenia secondary to bone marrow infiltration or splenic sequestration.

Evidence of a coagulopathy with an increased activated partial thromboplastin time (aPTT) is present.

Jaundice is often present due to hyperbilirubinemia.

The skin can be involved in various ways. As many as 65% of patients have a nonspecific rash that is often vaguely termed maculopapular, although it has also been described as ranging from erythroderma to generalized purpuric macules and papules to morbilliform eruptions.^[3]

Hemophagocytic lymphohistiocytosis may be complicated by central nervous system (CNS) involvement. ^[40] One Swedish study described nearly 75% of patients as having some form of CNS involvement, with half showing neurologic symptoms including seizures, ataxia, hemiplegia, mental status changes, or simply irritability.^[41]

Because of the predilection of the disease for certain tissues, lymphadenopathy is frequently found on physical examination. Common constitutional findings are malaise, anorexia with or without weight loss, and failure to thrive.^[1]

Differential Diagnoses

[Guideline] Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991 Feb. 18(1):29-33. [QxMD MEDLINE Link].
Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020 May 7. 382 (19):1811-22. [QxMD MEDLINE Link].
Morrell DS, Pepping MA, Scott JP, et al. Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol. 2002 Sep. 138(9):1208-12. [QxMD MEDLINE Link].
Pasvolsky O, Zoref-Lorenz A, Abadi U, et al. Hemophagocytic lymphohistiocytosis as a harbinger of aggressive lymphoma: a case series. Int J Hematol. 2019 May. 109 (5):553-62. [QxMD MEDLINE Link].
Feldmann J, Le Deist F, Ouachee-Chardin M, et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol. 2002 Jun. 117(4):965-72. [QxMD MEDLINE Link].
Liang J, Qu H, Wang X, et al. Drug reaction with eosinophilia and systemic symptoms associated with reactivation of Epstein-Barr virus and/or cytomegalovirus leading to hemophagocytic syndrome in one of two patients. Ann Dermatol. 2018 Feb. 30 (1):71-4. [QxMD MEDLINE Link].
Rioualen S, Dufau J, Flatres C, Lavenant P, Misery L, Roué JM. [DRESS complicated by hemophagocytic lymphohistiocytosis in an infant treated for congenital toxoplasmosis]. Ann Dermatol Venereol. 2017 Dec. 144 (12):784-7. [QxMD MEDLINE Link].
Ammar H, Azouzi A, Fathallah N, et al. Fatal sulfasalazine-induced DRESS complicated by HHV-6 reactivation and hemophagocytic lymphohistiocytosis. Eur J Clin Pharmacol. 2020 Mar. 76 (3):467-8. [QxMD MEDLINE Link].
Cetica V, Pende D, Griffiths GM, Aricò M. Molecular basis of familial hemophagocytic lymphohistiocytosis. Haematologica. 2010 Apr. 95(4):538-41. [QxMD MEDLINE Link]. [Full Text].
Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952 Dec. 27(136):519-25. [QxMD MEDLINE Link]. [Full Text].
Arico M, Allen M, Brusa S, et al. Haemophagocytic lymphohistiocytosis: proposal of a diagnostic algorithm based on perforin expression. Br J Haematol. 2002 Oct. 119(1):180-8. [QxMD MEDLINE Link].
Tang Y, Xu X. Advances in hemophagocytic lymphohistiocytosis: pathogenesis, early diagnosis/differential diagnosis, and treatment. ScientificWorldJournal. 2011 Mar 22. 11:697-708. [QxMD MEDLINE Link].
Imashuku S, Ueda I, Teramura T, et al. Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients. Eur J Pediatr. 2005 May. 164(5):315-9. [QxMD MEDLINE Link].
Risma KA, Frayer RW, Filipovich AH, Sumegi J. Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J Clin Invest. 2006 Jan. 116(1):182-92. [QxMD MEDLINE Link]. [Full Text].
Katano H, Cohen JI. Perforin and lymphohistiocytic proliferative disorders. Br J Haematol. 2005 Mar. 128(6):739-50. [QxMD MEDLINE Link].
Rieux-Laucat F, Le Deist F, De Saint Basile G. Autoimmune lymphoproliferative syndrome and perforin. N Engl J Med. 2005 Jan 20. 352(3):306-7; author reply 306-7. [QxMD MEDLINE Link].
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 Feb. 203:165-79. [QxMD MEDLINE Link].
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 Mar 15. 14(6):827-34. [QxMD MEDLINE Link]. [Full Text].
Arico M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol. 2001 Sep. 114(4):761-9. [QxMD MEDLINE Link].
Marsh RA, Satake N, Biroschak J, et al. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer. 2010 Jul 15. 55(1):134-40. [QxMD MEDLINE Link].
Gholam C, Grigoriadou S, Gilmour KC, Gaspar HB. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management. Clin Exp Immunol. 2011 Mar. 163(3):271-83. [QxMD MEDLINE Link]. [Full Text].
Koh KN, Im HJ, Chung NG, et al. Clinical features, genetics, and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in Korea: report of a nationwide survey from Korea Histiocytosis Working Party. Eur J Haematol. 2015 Jan. 94 (1):51-9. [QxMD MEDLINE Link].
Toga A, Wada T, Sakakibara Y, et al. Clinical significance of cloned expansion and CD5 down-regulation in Epstein-Barr Virus (EBV)-infected CD8+ T lymphocytes in EBV-associated hemophagocytic lymphohistiocytosis. J Infect Dis. 2010 Jun 15. 201(12):1923-32. [QxMD MEDLINE Link].
Przybylski M, Dzieciatkowski T, Zdunczyk D, Jedrzejczak WW, Luczak M. Microbiological findings and treatment of EBV-associated hemophagocytic lymphohistiocytosis: a case report. Arch Immunol Ther Exp (Warsz). 2010 Jun. 58(3):247-52. [QxMD MEDLINE Link].
Zhang Z, Wang J, Ji B, et al. Clinical presentation of hemophagocytic lymphohistiocytosis in adults is less typical than in children. Clinics (Sao Paulo). 2016 Apr. 71 (4):205-9. [QxMD MEDLINE Link].
Pal P, Giri PP, Ramanan AV. Dengue associated hemophagocytic lymphohistiocytosis: a case series. Indian Pediatr. 2014 Jun. 51(6):496-7. [QxMD MEDLINE Link].
Krithika MV, Amboiram P, Latha SM, Ninan B, Suman FR, Scott J. Neonate with haemophagocytic lymphohistiocytosis secondary to dengue infection: a case report. Trop Doct. 2017 Jul. 47 (3):253-5. [QxMD MEDLINE Link].
Sankhyan N, Saptharishi LG, Sasidaran K, Kanga A, Singhi SC. Clinical profile of scrub typhus in children and its association with hemophagocytic lymphohistiocytosis. Indian Pediatr. 2014 Aug. 51(8):651-3. [QxMD MEDLINE Link].
Akel T, Mobarakai N. Hematologic manifestations of babesiosis. Ann Clin Microbiol Antimicrob. 2017 Feb 15. 16 (1):6. [QxMD MEDLINE Link].
Hanson D, Walter AW, Powell J. Ehrlichia-induced hemophagocytic lymphohistiocytosis in two children. Pediatr Blood Cancer. 2011 Apr. 56(4):661-3. [QxMD MEDLINE Link].
Malloy CA, Polinski C, Alkan S, et al. Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis. J Perinatol. 2004 Jul. 24(7):458-60. [QxMD MEDLINE Link].
Sung L, King SM, Carcao M, et al. Adverse outcomes in primary hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2002 Oct. 24(7):550-4. [QxMD MEDLINE Link].
Ericson KG, Fadeel B, Andersson M, et al. Sequence analysis of the granulysin and granzyme B genes in familial hemophagocytic lymphohistiocytosis. Hum Genet. 2003 Jan. 112(1):98-9. [QxMD MEDLINE Link].
Arico 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 Feb. 10(2):197-203. [QxMD MEDLINE Link].
Gupta AA, Tyrrell P, Valani R, Benseler S, Abdelhaleem M, Weitzman S. Experience with hemophagocytic lymphohistiocytosis/macrophage activation syndrome at a single institution. J Pediatr Hematol Oncol. 2009 Feb. 31(2):81-4. [QxMD MEDLINE Link].
Jenkins RW, Clarke CJ, Lucas JT Jr, et al. Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosis. Am J Hematol. 2013 Nov. 88 (11):E265-72. [QxMD MEDLINE Link].
Filipovich AH. Life-threatening hemophagocytic syndromes: current outcomes with hematopoietic stem cell transplantation. Pediatr Transplant. 2005 Dec. 9 Suppl 7:87-91. [QxMD MEDLINE Link].
Miyamae T, Izaki S, Ikuta K, Yokota S, Yamanaka H. Hemophagocyctic lymphohistiocytosis developed in a Japanese boy with Chédiak-Higashi syndrome. Nihon Rinsho Meneki Gakkai Kaishi. 2013. 36(4):226-32. [QxMD MEDLINE Link].
Yang K, Xing MY, Jiang LY, et al. Infection-associated hemophagocytic syndrome in critically ill patients with COVID-19. Curr Med Sci. 2021 Feb. 41 (1):39-45. [QxMD MEDLINE Link].
Yamashita H, Matsuki Y, Shimizu A, et al. Hemophagocytic lymphohistiocytosis complicated by central nervous system lesions in a patient with dermatomyositis: a case presentation and literature review. Mod Rheumatol. 2013 Mar. 23 (2):386-92. [QxMD MEDLINE Link].
Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991 Apr. 80(4):428-35. [QxMD MEDLINE Link].
Imashuku S, Teramura T, Morimoto A, Hibi S. Recent developments in the management of haemophagocytic lymphohistiocytosis. Expert Opin Pharmacother. 2001 Sep. 2(9):1437-48. [QxMD MEDLINE Link].
Saeed H, Woods RR, Lester J, Herzig R, Gul Z, Monohan G. Evaluating the optimal serum ferritin level to identify hemophagocytic lymphohistiocytosis in the critical care setting. Int J Hematol. 2015 Aug. 102 (2):195-9. [QxMD MEDLINE Link].
Hafsteinsdottir S, Jonmundsson GK, Kristinsson Jr, et al. Findings in familial haemophagocytic lymphohistiocytosis prior to symptomatic presentation. Acta Paediatr. 2002. 91(8):974-7. [QxMD MEDLINE Link].
Clementi R, Emmi L, Maccario R, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. 2002 Sep 15. 100(6):2266-7. [QxMD MEDLINE Link].
Santos-Arroyo A, Barrera-Llaurador J, Sánchez JE, Martín-García R, Sánchez JL. Role of skin biopsies in the diagnosis of hemophagocytic lymphohistiocytosis. Am J Dermatopathol. 2017 Jul. 39 (7):e86-e89. [QxMD MEDLINE Link].
Macheta M, Will AM, Houghton JB, Wynn RF. Prominent dyserythropoiesis in four cases of haemophagocytic lymphohistiocytosis. J Clin Pathol. 2001 Dec. 54(12):961-3. [QxMD MEDLINE Link].
Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol. 2010 Jan. 6(1):137-54. [QxMD MEDLINE Link].
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Media Gallery

A lymph node biopsy is performed. Note that a marking pen has been used to outline the node before removal and that a silk suture has been used to provide traction to assist the removal.

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Author

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Steven K Bergstrom, MD Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland

Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, Children's Oncology Group, American Society of Clinical Oncology, International Society for Experimental Hematology, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Kathleen M Sakamoto, MD, PhD Shelagh Galligan Professor, Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine

Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, International Society for Experimental Hematology, Society for Pediatric Research, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Nicole L Lacz, MD, and Franklin Desposito, MD, to the original writing and development of this article.

Sections Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
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