Hemophagocytic lymphohistiocytosis

OVERVIEW

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme inflammation

• two forms: sporadic and familial immune dysregulatory disorder of childhood
• sporadic associated with infections, malignancies, or rheumatologic disorders

Diagnosis is difficult and often delayed:

• rare (but may be underdiagnosed; Strauss et al (2004) showed bone marrow findings were present in 65% of a cohort of MICU non-surviviors)
• variable presentation and nonspecific findings
• may mimic severe sepsis syndromes (consider in patients with no identifiable source of sepsis)

PATHOGENESIS

Normal cytotoxic function limits immune activation and thereby mitigates the development of severe immunopathology – HLH involves:

• predisposing immunodeficiency
• excessive immune activation
• characteristic immunopathology

Underlying triggers:

• rheumatological disorders (e.g. macrophage activation syndrome (MAS) seen in SLE and systemic onset juvenile idiopathic arthritis)

DIAGNOSTIC CRITERIA

Require 5 or more of the following 8 criteria (from the HLH-2004 trial):

1. Fever >T38.5
2. Splenomegaly
3. Cytopenia of 2 or more of the 3 cell lines (Hb <90, N <1, plts <100)
4. Either elevated triglycerides or low fibrinogen
5. Evidence of hemophagocytosis (on either bone marrow, spleen or lymph node biopsy)
6. Serum ferritin > 500 mcg/mL (though generally this level is expected to be much higher in HLH)
7. Low or absent NK cell activity (by flow cytometry, IF you have this available)
8. Soluble CD25 > 2400 U/mL (aka α-chain of the IL-2 receptor)

OTHER INVESTIGATIONS

Laboratory

• ferritin level of > 10,000 was 96% specific for the diagnosis of HLH in one pediatric study
• abnormal CSF in 50% (pleocytosis, elevated protein, and/or hemophagocytosis)
• molecular defects may be detected in HLH-associated proteins wher testing is available (perforin, SLAM-associated protein, or X-linked inhibitor of apoptosis protein) or measurement of surface CD107a exposure (indicative of genetic abnormalities affecting degranulation)

Imaging

• MRI (may show discrete lesions, leptomeningeal enhancement, or global edema)

Histopathology

• hemophagocytosis on bone marrow biopsy (25%-100% of the time’ with ∼ 1-10 hemophagocytes per 500 cells in cases reported as positive) )this may not be seen early)
• biopsies showing macrophage infiltration of various organs (e.g. liver, spleen)

Other clinical features

• liver dysfunction is also common: ranging from mild elevations of transaminases to fulminant liver failure
• neurological dysfunction is often present (e.g. seizures, meningismus, decreased level of consciousness, cranial nerve palsy, psychomotor retardation, ataxia, irritability, hypotonia or peripheral neuropathy)
• pyrexia of unknown origin
• may mimic Kawasaki syndrome
• there may be prior episodes
• family history if primary HLH

MANAGEMENT

• monitor inflammatory markers, such as sCD25 or ferritin, to assess response to therapy

References and Links

Journal articles

• Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treathemophagocytic lymphohistiocytosis. Blood. 2011 Oct 13;118(15):4041-52. PMC3204727.
• Strauss R, Neureiter D, Westenburger B, Wehler M, Kirchner T, Hahn EG.Multifactorial risk analysis of bone marrow histiocytic hyperplasia withhemophagocytosis in critically ill medical patients–a postmortemclinicopathologic analysis. Crit Care Med. 2004 Jun;32(6):1316-21. PMID:15187513