Laboratory Studies

Because natural killer (NK) cell function or activity is decreased in as many as 90% of patients with hemophagocytic lymphohistiocytosis (HLH), it is one of the most useful laboratory tests. NK cell number is usually not diagnostic.

In addition to pancytopenia, hypofibrinogenemia, and hypertriglyceridemias, other laboratory abnormalities have been linked to HLH. Ferritin has been observed as a marker for hemophagocytic lymphohistiocytosis, with the serum levels paralleling the course of the disease.^[42]A retrospective study evaluated the use of a ferritin value of >500 ng/mL in diagnosing HLH in 344 consecutive patients admitted to the medical intensive care unit. The data suggested that a higher cutoff value of ferritin may have improved utility in the diagnosis of secondary hemophagocytic lymphohistiocytosis in the critical care setting.^[43]

Liver damage has also been reported as evidenced by hyperbilirubinemia (see Bilirubin), hypoalbuminemia (see Albumin), and elevated findings on liver function tests including aspartate aminotransferase (AST) and alanine aminotransferase (ALT).^[44]

The presence of a PRF1 gene mutation can be determined based on flow cytometry by staining perforin contained in lymphocytes.

The finding of a distinctive Th1/Th2 cytokine pattern (significant increase of interferon [IFN]-ƒ× and interleukin-10 [IL-10] with slightly increased or normal level of IL-6) may represent a useful biomarker for the early diagnosis, differential diagnosis, and the monitoring of the disease.^[12]

Imaging Studies

No specific imaging patterns are diagnostic of hemophagocytic lymphohistiocytosis.

Computed tomography (CT) or ultrasonography findings may include ascites, gallbladder wall thickening, increased periportal echogenicity, lymphadenopathy, and pleural effusion.

Magnetic resonance imaging (MRI) may show central nervous system (CNS) involvement, but the diagnosis is clinical and molecular.^[45]

Other Tests

Arico et al proposed an approach to the diagnostic workup of a patient with suspected hemophagocytic lymphohistiocytosis.^[11] A detailed clinical history should be obtained to exclude other associated conditions, such as metabolic disorders or the DiGeorge syndrome. However, if the diagnostic hemophagocytic lymphohistiocytosis criteria are fulfilled, and the findings for associated conditions are negative, initial testing involves perforin expression by NK cells using flow cytometry.

Patients who lack perforin expression should be analyzed for the PRF1 gene mutation. NK cell activity should also be determined to aid in differentiating between the hemophagocytic lymphohistiocytosis subtypes. Normal activity is suggestive of the reactive form of hemophagocytic lymphohistiocytosis rather than the familial type.

DNA samples and fresh cells are suggested to be stored in case of need for future use in familial cases for which no genetic defect can be identified.

Procedures

A skin biopsy can be performed for histologic examination. Lymph node biopsy (see the image below), bone marrow biopsy, or liver biopsy may demonstrate the characteristic hemophagocytosis.

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.

Histologic Findings

A skin biopsy can assist in distinguishing this disorder from other systemic and potentially neoplastic diseases, such as Langerhans cell histiocytosis, myofibrosis, extramedullary hematopoiesis, and leukemia cutis.^{[3, 46]}However, skin biopsy findings are usually not diagnostic and only rarely show hemophagocytosis.

Because hemophagocytosis must be demonstrated in the bone marrow, spleen, or lymph nodes, appropriate specimens should be collected for documentation.^[1]Red blood cells are affected more often than white blood cells or platelets.

Findings in up to two thirds of initial bone marrow aspirates may be nondiagnostic; thus, a negative examination finding may not rule out hemophagocytic lymphohistiocytosis. An additional bone marrow finding includes dyserythropoiesis, which has been observed in the absence of hemophagocytic histiocytes.

Additional studies, including lymph node biopsy, should be performed, and treatment should not be delayed if all other criteria have been met.^[47]

Although problematic in a patient with a coagulopathy, a liver biopsy demonstrating a picture similar to chronic persistent hepatitis can support the diagnosis, as can the presence of mononuclear cells in the cerebrospinal fluid (CSF).

Treatment & Management

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

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.