Sections

Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)

Sections Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
Overview
Presentation
DDx
Workup
Treatment
Medication
Follow-up
Questions & Answers
References

Medication

Medication Summary

This life-threatening hyperinflammatory syndrome is difficult to treat.^[54]Initial therapy in patients with hemophagocytic lymphohistiocytosis (HLH) consists of etoposide and dexamethasone for 8 weeks in varying doses as described below.^[55]In the HLH-2004 protocol, cyclosporine is added in the beginning. Intrathecal methotrexate is used only with persistently abnormal cerebrospinal fluid (CSF) or progressive neurologic symptoms.

Resolved nonfamilial hemophagocytic lymphohistiocytosis does not require continuation of the therapy regimen unless disease reactivation occurs after completion of the initial therapy or unless patients are undergoing bone marrow transplantation (BMT). For the remaining children with persistent nonfamilial disease or familial disease, continuation therapy with etoposide intravenous (IV) infusions, dexamethasone pulses, and oral cyclosporine is instituted at week 9 from the start of initial treatment.^[50]

Emapalumab, a monoclonal antibody that binds and neutralizes INF-gamma, was approved by the FDA in 2018. It is indicated for primary HLH in adults and children with refractory, recurrent, or progressive disease or who are intolerant to conventional HLH therapy.^[49]

Alemtuzumab may be an effective salvage agent for refractory HLH, with retrospective trials needed to define optimal dosing.^[54]

Hemophagocytic lymphohistiocytosis associated with malignancies demands prompt therapy directed at the neoplasm.

Class Summary

These agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Etoposide (Toposar, VePesid)

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Also called VP-16. Inhibits topoisomerase II and results in DNA strand breakage causing cell proliferation to arrest in late S or early G2 portion of the cell cycle.

Methotrexate (Trexall)

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Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. Satisfactory response observed 3-6 wk following administration.

Adjust dose gradually to attain satisfactory response.

Class Summary

These agents elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Dexamethasone (Decadron, Hexadrol)

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Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Postulated mechanisms of action of corticosteroids in tumors include reduction in vascular permeability, cytoxic effects on tumors, and inhibition of tumor formation.

Class Summary

These agents may be used in combination with corticosteroids and immune globulin in patients at low risk.

Cyclosporine (Sandimmune, Neoral)

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Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for various organs.

In children and adults, base dosing on ideal body weight.

Class Summary

Elevated interferon-gamma (INF-gamma) is thought to be part of the pathogenesis that causes the hyperinflammation associated with HLH. Controlling the inflammation helps maintain organ function while preparing for hematopoietic stem-cell transplant (HSCT).

Emapalumab (Gamifant, emapalumab-lzsg)

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Human monoclonal antibody that binds to and neutralizes interferon-gamma (IFN-gamma). It is indicated for primary HLH in adults and children (newborn and older) with refractory, recurrent, or progressive disease or who are intolerant to conventional HLH therapy.

Class Summary

Immune globulin is a purified preparation of gamma globulin. It is derived from large pools of human plasma and is comprised of 4 subclasses of antibodies, approximating the distribution of human serum.

Immune globulin, intravenous (Carimune NF, Gamumex, Gammagard)

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Neutralizes circulating myelin antibodies through anti-idiotypic antibodies. Down-regulates proinflammatory cytokines, including INF-γ. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade. Promotes remyelination. May increase CSF IgG (10%).

Follow-up

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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].
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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].
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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)
Overview
Presentation
DDx
Workup
Treatment
Medication
Follow-up
Questions & Answers
References

Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis) Medication

Medication Summary

Antineoplastic agents