Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis) Questions & Answers

1. [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].

2. 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].

3. Morrell DS, Pepping MA, Scott JP, et al. Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol. 2002 Sep. 138(9):1208-12. [QxMD MEDLINE Link].

4. 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].

5. 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].

6. 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].

7. 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].

8. 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].

9. 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].

10. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952 Dec. 27(136):519-25. [QxMD MEDLINE Link]. [Full Text].

11. 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].

12. 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].

13. 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].

14. 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].

15. Katano H, Cohen JI. Perforin and lymphohistiocytic proliferative disorders. Br J Haematol. 2005 Mar. 128(6):739-50. [QxMD MEDLINE Link].

16. 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].

17. Menasche G, Feldmann J, Fischer A, de Saint Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev. 2005 Feb. 203:165-79. [QxMD MEDLINE Link].

18. 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].

19. Arico M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol. 2001 Sep. 114(4):761-9. [QxMD MEDLINE Link].

20. 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].

21. 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].

22. 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].

23. 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].

24. 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].

25. 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].

26. Pal P, Giri PP, Ramanan AV. Dengue associated hemophagocytic lymphohistiocytosis: a case series. Indian Pediatr. 2014 Jun. 51(6):496-7. [QxMD MEDLINE Link].

27. 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].

28. 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].

29. Akel T, Mobarakai N. Hematologic manifestations of babesiosis. Ann Clin Microbiol Antimicrob. 2017 Feb 15. 16 (1):6. [QxMD MEDLINE Link].

30. 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].

31. 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].

32. 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].

33. 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].

34. 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].

35. 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].

36. 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].

37. 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].

38. 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].

39. 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].

40. 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].

41. 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].

42. 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].

43. 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].

44. 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].

45. 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].

46. 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].

47. 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].

48. 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].

49. Locatelli F, Jordan MB, Allen CE, et al. Safety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis (abstract LBA-6). Presented at the American Society of Hematology (ASH) Annual Meeting. December 4, 2018. San Diego, CA. [Full Text].

50. Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002 Oct 1. 100(7):2367-73. [QxMD MEDLINE Link].

51. Emmenegger U, Spaeth PJ, Neftel KA. Intravenous immunoglobulin for hemophagocytic lymphohistiocytosis?. J Clin Oncol. 2002 Jan 15. 20(2):599-601. [QxMD MEDLINE Link].

52. Thompson PA, Allen CE, Horton T, Jones JY, Vinks AA, McClain KL. Severe neurologic side effects in patients being treated for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2009 May. 52(5):621-5. [QxMD MEDLINE Link].

53. Cooper N, Rao K, Gilmour K, et al. Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood. 2006 Feb 1. 107(3):1233-6. [QxMD MEDLINE Link].

54. Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013 Jan. 60 (1):101-9. [QxMD MEDLINE Link].

55. Parrott J, Shilling A, Male HJ, Holland M, Clark-Ganheart CA. Hemophagocytic lymphohistiocytosis in pregnancy: a case series and review of the current literature. Case Rep Obstet Gynecol. 2019. 2019:9695367. [QxMD MEDLINE Link].

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.

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.

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.

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.

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.

• Print this section
• Print the entire contents of
• Print the entire contents of article