Final Diagnosis --Primary Hemophagocytic Lymphohistiocytosis


Primary hemophagocytic lymphohistiocytosis


Hemophagocytic lymphohistiocytosis is a disorder characterized by the persistent activation of cytotoxic T- lymphocytes and natural killer (NK) cells that induce the systemic release of cytokines with ensuing macrophage activation responsible for the main clinical findings. The combined prevalence for primary and secondary forms has been established at around 1 in 100,000 children with a median age of diagnosis of 1.8 years and an incidence of 1 to 225 children per 300,000 live births [3,6].

HLH has been designated to be part of the group of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. It is considered primary if it arises due to specific genetic defects and secondary if it arises due to external triggers such as infections, malignancies or autoimmune disorders. [14]

Five groups of familial HLH have been identified, all related to defects in proteins involved in the cytolytic attack process on the surface of NK-cells and cytotoxic lymphocytes [8]. Primary HLH has also been associated with congenital immunodeficiency disorders and mutations predisposing to Epstein Barr Virus- driven disease [13].

Patients with HLH usually present with fever, organomegaly, neurologic dysfunction, dermatologic manifestations, and signs of liver dysfunction such as jaundice or bruising [1]. The diagnosis of HLH is critical due to its possible life-threatening consequences but is challenging and frequently delayed due to its rare occurrence and nonspecific clinical findings. Initial patient evaluation should include prompt assessment and recognition of the signs of HLH [3].

The diagnosis of HLH can be established if 5 of 8 of the following criteria are present: fever; splenomegaly; cytopenias; hypertriglyceridemia and/ or hypofibrinogenemia; hemophagocytosis in bone marrow, spleen, lymph nodes, or liver; low or absent NK-cell activity; elevated ferritin levels and elevated soluble CD25 [4].

Hemophagocytosis refers to the pathologic finding of engulfment of erythrocytes, platelets or white blood cells within the histiocyte cytoplasm. It is not present at disease onset in all patients and is considered nonsensitive and nonspecific for the diagnosis of HLH, thus, hemophagocytosis by itself should be regarded as a supportive criterion in most instances. [3, 5]

Ferritin is often highly elevated in HLH as an acute-phase reactant whose primary storage site is within tissue macrophages. [9]. A retrospective study found that serum ferritin levels above 10,000 ug/L are 90 % sensitive and 98 % specific for pediatric HLH. [10]

Interleukin 2 is known by its immune-stimulating effects on lymphocyte activation; its receptor has three subunits, ?, ? and ? with only the ? subunit expressed after cell activation. The soluble or alpha subunit of the IL-2 receptor (sCD25) is cleaved from the main protein once T-cells are activated and thus is used as a surrogate marker of T-cell activation [11]. A cutoff point of ?2400 U/mL has been described to have sensitivities ranging from 88 to 93 % for primary and secondary HLH in children [4, 13].

As a result, due to the often nonspecific clinical findings and the high likelihood of clinical deterioration of patients with HLH, besides prompt clinical assessment and recognition of laboratory findings, early assessment of NK functional tests and sCD25 are pivotal to guide further genetic work-up that could lead to a specific diagnosis. The most common genetic defects in primary HLH involve PRF1, MUNC13-4, STXBP2, STX11 and RAB27A [3].

Familiar HLH type 2 is due to mutations in PRF1, a gene located in the long arm of chromosome 10 at position 22.1 that codes for the protein perforin [7,8]. This condition is usually inherited in an autosomal recessive fashion with most mutations being nonsense and causing a complete loss of the protein perforin whose physiologic function is forming membrane pores in target cells and facilitating the entrance of granzymes that ultimately triggers apoptosis [8]. Under pathologic circumstances, the blockade of perforin function results in the inability to clear antigenic stimuli with ensuing immune activation syndrome resulting in high levels of macrophage activation, hemophagocytosis and tissue damage. [8].

Based on the patient's clinical presentation, initial laboratory evaluation, bone marrow results, and genetic testing, she was diagnosed with primary hemophagocytic lymphohistiocytosis and started on cytotoxic chemotherapy with etoposide and dexamethasone which are proapoptotic in HLH. [1] In patients with familial or persistent disease continuation therapy with etoposide, dexamethasone and cyclosporine are recommended until allogeneic HSCT be performed [2].


  1. Fadeel B, Orrenius S, Henter JI. Induction of apoptosis and caspase activation in cells obtained from familial haemophagocytic lymphohistiocytosis patients. BrJ Haematol. 1999;106(2):406- 415.
  2. Trottestam, H., Horne, A. C., Aric̣, M., Egeler, R. M., Filipovich, A. H., Gadner, H., … Henter, J. I. (2011). Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: Long-term results of the HLH-94 treatment protocol. Blood, 118(17), 4577-4584.
  3. Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H., & McClain, K. L. (2011). How I treat hemophagocytic lymphohistiocytosis. Blood, 118(15), 4041-4052.
  4. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for he- mophagocytic lymphohistiocytosis. PediatrBlood Cancer. 2007;48(2):124-131.
  5. Gupta, A., Weitzman, S., & Abdelhaleem, M. (2008). The role of hemophagocytosis in bone marrow aspirates in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatric Blood & Cancer, 50(2), 192-194.
  6. Niece JA, Rogers ZR, Ahmad N, Langevin AM, McClain KL. 2010. Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr. Blood Cancer 54:424-28
  7. Goransdotter EK, Fadeel B, Nilsson-Ardnor S, Soderhall C, Samuelsson A, et al. 2001. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am. J. Hum. Genet. 68:590-97
  8. Al-Samkari, H., & Berliner, N. (2018). Hemophagocytic Lymphohistiocytosis. Annual Review of Pathology: Mechanisms of Disease, 13(1), 27-49.
  9. Cohen LA, Gutierrez L, Weiss A, Leichtmann-Bardoogo Y, Zhang DL, et al. 2010. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 116:1574-84
  10. Allen CE, Yu X, Kozinetz CA, McClain KL. 2008. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 50:1227-35
  11. Lin, M., Park, S., Hayden, A., Giustini, D., Trinkaus, M., Pudek, M., … Chen, L. Y. C. (2017). Clinical utility of soluble interleukin-2 receptor in hemophagocytic syndromes: a systematic scoping review. Annals of Hematology, 96(8), 1241-1251.
  12. Amir A, Ling S, Naqvi A et al (2016) Liver transplantation for children with acute liver failure associated with secondary haemophagocytic lymphohistiocytosis. J Hepatol 64:S295-S296
  13. Chandrakasan S, Filipovich AH. 2013. Hemophagocytic lymphohistiocytosis: advances in pathophysiology, diagnosis, and treatment. J. Pediatr. 163:1253-59
  14. Morimoto, A., Nakazawa, Y., & Ishii, E. (2016). Hemophagocytic lymphohistiocytosis: Pathogenesis, diagnosis, and management. Pediatrics International, 58(9), 817-825.

Contributed by Daniel Martinez, MD and Nidhi Aggarwal, MD.

Case IndexCME Case StudiesFeedbackHome