Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-586b7cd67f-t8hqh Total loading time: 0 Render date: 2024-11-30T20:37:06.913Z Has data issue: false hasContentIssue false

Chapter 27 - Hemophagocytic Lymphohistiocytosis (HLH)

from Section VI - Histiocytic Disorders and Neoplasms

Published online by Cambridge University Press:  25 January 2024

By
Jennifer Picarsic  and
Rebecca Marsh
Edited by
Xiayuan Liang ,
Bradford Siegele  and
Jennifer Picarsic
Xiayuan Liang
Affiliation:
Children’s Hospital of Colorado
Bradford Siegele
Affiliation:
Children’s Hospital of Colorado
Jennifer Picarsic
Affiliation:
Cincinnati Childrens Hospital Medicine Center
Get access

Summary

Hemophagocytic lymphohistiocytosis (HLH) is a complex, life-threatening clinical syndrome of systemic hyperinflammation. The syndrome is often diagnosed based on the presence of clinical signs and symptoms that were included as diagnostic criteria for HLH by the Histiocyte Society in clinical treatment trials (1, 2). The criteria include fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, observation of hemophagocytosis, decreased function of natural killer (NK) cells, elevated ferritin, and elevated soluble interleukin-2 (IL-2) receptor levels (Table 27.1). Other complications of HLH that are not part of the criteria include central nervous system (CNS) involvement in 30–70% of patients (3, 4), as well as hepatitis or acute liver failure. Rarely, isolated CNS disease can also occur (5). The syndrome of HLH can be caused by a wide variety of etiologies, and it is imperative that clinicians bear this in mind when the clinical diagnosis is suspected (6).

Type
Chapter
Information
Pediatric Pathology of Hematopoietic and Histiocytic Disorders , pp. 320 - 329
Publisher: Cambridge University Press
Print publication year: 2024

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Henter, J-I, Samuelsson-Horne, A, Aricò, M, Egeler, RM, Elinder, Gr, Filipovich, AH, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation.Blood. 2002;100(7):2367–73.CrossRefGoogle ScholarPubMed
Bergsten, E, Horne, A, Arico, M, Astigarraga, I, Egeler, RM, Filipovich, AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728–38.Google Scholar
Horne, A, Wickström, R, Jordan, MB, Yeh, EA, Naqvi, A, Henter, J-I, et al. How to treat involvement of the central nervous system in hemophagocytic lymphohistiocytosis? Curr Treat Options Neurol. 2017;19(1):3.CrossRefGoogle ScholarPubMed
Haddad, E, Sulis, M-L, Jabado, N, Blanche, S, Fischer, A, Tardieu, M. Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis. Blood. 1997;89(3):794–800.Google Scholar
Blincoe, A, Heeg, M, Campbell, PK, Hines, M, Khojah, A, Klein-Gitelman, M, et al. Neuroinflammatory disease as an isolated manifestation of hemophagocytic lymphohistiocytosis. J Clin Immunol. 2020;40(6):901–16.Google Scholar
Jordan, MB, Allen, CE, Greenberg, J, Henry, M, Hermiston, ML, Kumar, A, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer. 2019;66(11):e27929.Google Scholar
Rivière, S, Galicier, L, Coppo, P, Marzac, C, Aumont, C, Lambotte, O, et al. Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med. 2014;127(11):1118–25.Google Scholar
Parikh, SA, Kapoor, P, Letendre, L, Kumar, S, Wolanskyj, AP. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc. 2014;89(4):484–92.Google Scholar
Taurisano, R, Maiorana, A, De Benedetti, F, Dionisi-Vici, C, Boldrini, R, Deodato, F. Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation. Eur J Pediatr. 2014;173(10):1391–4.Google Scholar
Sharpe, LR, Ancliff, P, Amrolia, P, Gilmour, KC, Vellodi, A. Type II Gaucher disease manifesting as haemophagocytic lymphohistiocytosis. J Inherit Metab Dis. 2009;32 Suppl 1:S107–10.CrossRefGoogle ScholarPubMed
Ravelli, A, Minoia, F, Davì, S, Horne, A, Bovis, F, Pistorio, A, et al. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2016;75(3):481–9.Google Scholar
Gupta, A, Tyrrell, P, Valani, R, Benseler, S, Weitzman, S, Abdelhaleem, M. The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;51(3):402–4.Google Scholar
Henter, JI, Horne, A, Arico, M, Egeler, RM, Filipovich, AH, Imashuku, S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.Google Scholar
Favara, BE. Hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. Semin Diagn Pathol. 1992;9(1):63–74.Google ScholarPubMed
Emile, JF, Abla, O, Fraitag, S, Horne, A, Haroche, J, Donadieu, J, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127(22):2672–81.Google Scholar
Schulert, GS, Grom, AA. Macrophage activation syndrome and cytokine-directed therapies. Best Pract Res Clin Rheumatol. 2014;28(2):277–92.Google Scholar
Schulert, GS, Yasin, S, Carey, B, Chalk, C, Do, T, Schapiro, AH, et al. Systemic juvenile idiopathic arthritis–associated lung disease: characterization and risk factors. Arthritis Rheumatol. 2019;71(11):1943–54.Google Scholar
Henter, JI, Elinder, G, Ost, A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18(1):29–33.Google Scholar
Macheta, M, Will, AM, Houghton, JB, Wynn, RF. Prominent dyserythropoiesis in four cases of haemophagocytic lymphohistiocytosis. J Clin Pathol. 2001;54(12):961–3.CrossRefGoogle ScholarPubMed
Parizhskaya, M, Youssef, NN, Di Lorenzo, C, Goyal, RK. Clofazimine enteropathy in a pediatric bone marrow transplant recipient. J Pediatr. 2001;138(4):574–6.Google Scholar
Natsheh, SE, Roberts, EA, Ngan, B, Chait, P, Ng, VL. Liver failure with marked hyperferritinemia: “ironing out” the diagnosis. Can J Gastroenterol. 2001;15(8):537–40.Google Scholar
Ost, A, Nilsson-Ardnor, S, Henter, JI. Autopsy findings in 27 children with haemophagocytic lymphohistiocytosis. Histopathology. 1998;32(4):310–6.Google Scholar
Gars, E, Purington, N, Scott, G, Chisholm, K, Gratzinger, D, Martin, BA, et al. Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica. 2018;103(10):1635–41.Google Scholar
Jaffe, R. The histopathology of hemophagocytic lymphohistiocytosis. Cambridge, UK: Cambridge University Press; 2005.Google Scholar
Rosado, FG, Kim, AS. Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol. 2013;139(6):713–27.Google Scholar
Listinsky, CM. Common reactive erythrophagocytosis in axillary lymph nodes. Am J Clin Pathol. 1988;90(2):189–92.Google Scholar
Jawed, SI, Busam, K, Wang, X, Horwitz, S, Querfeld, C. Cutaneous hemophagocytosis after alemtuzumab injection in a patient with Sézary syndrome. JAMA Dermatology. 2014;150(9):1021–3.Google Scholar
Johnson, SM, Gilmour, K, Samarasinghe, S, Bamford, A. Haemophagocytic lymphohistiocytosis complicating visceral leishmaniasis in the UK: a case for detailed travel history, a high index of suspicion and timely diagnostics. BMJ Case Rep. 2019;12(7):e228307.Google Scholar
Favara, BE. Histopathology of the liver in histiocytosis syndromes. Pediatr Pathol Lab Med. 1996;16(3):413–33.Google Scholar
de Kerguenec, C, Hillaire, S, Molinié, V, Gardin, C, Degott, C, Erlinger, S, et al. Hepatic manifestations of hemophagocytic syndrome: a study of 30. Am J Gastroenterol. 2001;96(3):852–7.Google Scholar
Chen, JH, Fleming, MD, Pinkus, GS, Pinkus, JL, Nichols, KE, Mo, JQ, et al. Pathology of the liver in familial hemophagocytic lymphohistiocytosis. Am J Surg Pathol. 2010;34(6):852–67.Google Scholar
Kapelari, K, Fruehwirth, M, Heitger, A, Königsrainer, A, Margreiter, R, Simma, B, et al. Loss of intrahepatic bile ducts: an important feature of familial hemophagocytic lymphohistiocytosi. Virchows Archiv. 2005;446(6):619–25.Google Scholar
Parizhskaya, M, Reyes, J, Jaffe, R. Hemophagocytic syndrome presenting as acute hepatic failure in two infants: clinical overlap with neonatal hemochromatosis. Pediatr Dev Pathol. 1999;2(4):360–6.Google Scholar
Jaffe, R. Liver involvement in the histiocytic disorders of childhood. Pediatr Dev Pathol. 2004;7(3):214–25.Google Scholar
Egan, C, Jaffe, ES. Non-neoplastic histiocytic and dendritic cell disorders in lymph nodes. Semin Diagn Pathol. 2018;35(1):20–33.Google Scholar
Buckley, PJ, O’Laughlin, S, Komp, DM. Histiocytes in familial and infection-induced/idiopathic hemophagocytic syndromes may exhibit phenotypic differences. Pediatr Pathol. 1992;12(1):51–66.Google Scholar
Rekha, TS, Kiran, HS, Nandini, NM, Murthy, S. Cytology of secondary hemophagocytic lymphohistiocytosis masquerading as lymphoma in a nonimmunocompromised adult. J Cytol. 2014;31(4):239–41.Google Scholar
Henter, J-I, Aricò, M, Elinder, G, Imashuku, S, Janka, G. Familial hemophagocytic lymphohistiocytosis: primary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998;12(2):417–33.Google Scholar
Liang, J, Alfano, DN, Squires, JE, Riley, MM, Parks, WT, Kofler, J, et al. Novel NLRC4 mutation causes a syndrome of perinatal autoinflammation with hemophagocytic lymphohistiocytosis, hepatosplenomegaly, fetal thrombotic vasculopathy, and congenital anemia and ascites. Pediatr Dev Pathol. 2017;20(6):498–505.Google Scholar
Valentín, SM, Montalván, E, Sánchez, JL. Perivascular hemophagocytosis: report of 2 cases and review of the literature. Am J Dermatopathol. 2010;32(7):716–9.Google Scholar
Millsop, JW, Ho, B, Kiuru, M, Fung, MA, Sharon, VR. Cutaneous hemophagocytic lymphohistiocytosis: bean bags from the bone. JAMA Dermatology. 2016;152(8):950–2.Google Scholar
Aronson, IK, Worobec, SM. Cytophagic histiocytic panniculitis and hemophagocytic lymphohistiocytosis: an overview. Dermatol Ther. 2010;23(4):389–402.Google Scholar
Pasqualini, C, Jorini, M, Carloni, I, Giangiacomi, M, Cetica, V, Arico, M, et al. Cytophagic histiocytic panniculitis, hemophagocytic lymphohistiocytosis and undetermined autoimmune disorder: reconciling the puzzle. Ital J Pediatr. 2014;40(1):17.Google Scholar
Lee, DE, Martinez-Escala, ME, Serrano, LM, Zhou, XA, Kaplan, JB, Pro, B, et al. Hemophagocytic lymphohistiocytosis in cutaneous T-cell lymphoma. JAMA Dermatology. 2018;154(7):828–31.Google Scholar
Henter, JI, Nennesmo, I. Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis. J Pediatr. 1997;130(3):358–65.Google Scholar
de Saint Basile, G, Ménasché, G, Fischer, A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol. 2010;10(8):568–79.Google Scholar
Dieckmann, NM, Frazer, GL, Asano, Y, Stinchcombe, JC, Griffiths, GM. The cytotoxic T lymphocyte immune synapse at a glance. J Cell Sci. 2016;129(15):2881–6.Google Scholar
Stepp, SE, Dufourcq-Lagelouse, R, Le Deist, F, Bhawan, S, Certain, S, Mathew, PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9.Google Scholar
Duncan, JA, Canna, SW. The NLRC 4 inflammasome. Immunol Rev. 2018;281(1):115–23.Google Scholar
Canna, SW, Marsh, RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. 2020;135(16):1332–43.Google Scholar
Janka, GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140(3):221–30.Google Scholar
Trottestam, H, Horne, A, Aricò, M, Egeler, RM, Filipovich, AH, Gadner, H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577–84.Google Scholar
Locatelli, F, Jordan, MB, Allen, C, Cesaro, S, Rizzari, C, Rao, A, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382(19):1811–22.Google Scholar
Arca, M, Fardet, L, Galicier, L, Rivière, S, Marzac, C, Aumont, C, 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(1):63–8.Google Scholar
Otrock, ZK, Eby, CS. Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol. 2015;90(3):220–4.Google Scholar
Schram, AM, Comstock, P, Campo, M, Gorovets, D, Mullally, A, Bodio, K, et al. Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. Br J Haematol. 2016;172(3):412–9.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×