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The rare, life-threatening disease you've never diagnosed 1,2

Primary hemophagocytic lymphohistiocytosis (pHLH) is a genetic disease characterized by a dysregulated, hyperinflammatory response 2

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The estimated median survival
time for patients
with pHLH
without treatment is <2 months 3

There are 2 types of HLH

  • pHLH
    (primary HLH)

    • Can present at any age, but is most prevalent in infants (aged <1 year) 1,4

    • Primarily caused by genetic defects that affect immune cell function 1,3

    • Onset of symptoms can be triggered by an infection 1,3

    • Clinical presentation can vary depending on the age of the patient 5,6

  • sHLH
    (secondary, "acquired" HLH) 1

    • Can present at any age 7

    • Typically occurs secondary to uncontrolled infections, malignancies, or rheumatologic diseases; not associated with specific genetic defects 1

    • One retrospective study of patients with undiagnosed HLH secondary to malignancy found that median survival time was 1.5 months 8

HLH often goes undetected due to nonspecific clinical signs and symptoms 3,4

pHLH is caused by genetic defects that result in immune system dysfunction 1,2,9

The immune system relies on T cells and natural killer (NK) cells to destroy harmful pathogens 1,2,9

In patients with pHLH 2 :

1

Failure to eliminate the target cell

Genetic defects in cytotoxic proteins, such as perforin, can prevent T cells and NK cells from effectively eliminating the target cell.

Cytotoxic T cell and target cell
2

Secretion of IFNγ

The inability to destroy the target cell causes an uncontrolled activation of T cells and NK cells, which triggers the release of large amounts of the cytokine interferon gamma (IFNγ).

Cluster of IFNγ molecules
3

Macrophage proliferation
and hyperactivation

IFNγ is responsible for the proliferation, hyperactivation, and systemic recruitment of macrophages, which release additional cytokines.

IL=interleukin; TNF-α=tumor necrosis factor alpha.

Diagram of macrophage proliferation and hyperactivation of target cells
4

Multiorgan damage and dysfunction

Uncontrolled IFNγ production can lead to irreversible multiorgan damage and dysfunction because it perpetuates a continuous inflammatory process.

Liver & Lungs icon

In patients with a healthy immune system 1,9 :

  • Bind to
    target cell

  • Induce
    apoptosis

  • Release
    dying cell

  • Bind to target cell

    T cells and NK cells bind to a target cell (mutated, virally infected, etc).

    Cytotoxic T cell binding to target cell
  • Induce apoptosis

    To induce apoptosis of the target cell, T cells release cytotoxic granules that contain perforin and granzymes.

    T cell releasing granzymes and perforin into target cell
  • Release dying cell

    T cells release the dying target cell to initiate the process again with another target cell.

    T cell beside the dying target cell

Suspect pHLH in your practice?

Downloadable pHLH Guide brochure thumbnail

This guide details what pHLH is and
how to spot its clinical features

Download

Know the initial signs.
Refer to a hematologist/oncologist

References: 1. Esteban YM, de Jong JLO, Tesher MS. An overview of hemophagocytic lymphohistiocytosis. Pediatr Ann . 2017;46(8):e309-e313. doi:10.3928/19382359-20170717-01 2. Vizcaino MA, Eberhart CG, Rodriguez FJ. Hemophagocytic lymphohistiocytosis in adults with intraocular involvement: clinicopathologic features of 3 cases. Ocul Oncol Pathol . 2017;4(1):1-11. doi:10.1159/000475551 3. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med . 2014;5:69-86. doi:10.2147/JBM.S46255 4. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood . 2011;118(15):4041-4052. doi:10.1182/blood-2011-03-278127 5. Jordan MB, Allen CE, Greenberg J, 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. doi:10.1002/pbc.27929 6. Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood . 2011;118(22):5794-5798. doi:10.1182/blood-2011-07-370148 7. Kleynberg RL, Schiller GJ. Secondary hemophagocytic lymphohistiocytosis in adults: an update on diagnosis and therapy. Clin Adv Hematol Oncol . 2012;10(11):726-732. 8. Tamamyan GN, Kantarjian HM, Ning J, et al. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: relation to hemophagocytosis, characteristics, and outcomes. Cancer . 2016;122(18):2857-2866. doi:10.1002/cncr.30084 9. Henter JI, Horne A, Aricò M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer . 2007;48(2):124-131. doi:10.1002/pbc.21039