Haemophagocytic lymphohistiocytosis

Reviewed and revised 11 July 2014

OVERVIEW

• Haemophagocytic lymphohistiocytosis (HLH) may be inherited (AR; 5 subtypes, aka familial HLH) or acquired;
• may mimic severe sepsis, consider in apparent sepsis without source
• likely under-diagnosed in ICU
• HLH arising secondary to EBV or other viral infection is commonly termed X-linked lymphoproliferative disease (XLP)

PATHOPHYSIOLOGY

• a hyperimmune state characterised by pathological and uncontrolled macrophage and T-cell activation from cytokine production
• can be primary or secondary (congenital typically presents as shock and acidosis in infancy or early childhood)
• may be triggered by infection, malignancy or rheumatological disease

DIAGNOSTIC CRITERIA

Molecular diagnosis consistent with HLH: pathologic mutations of PRF1,UNC13D, Munc18-2, Rab27a, STX11, SH2D1A, or BIRC4

or

Five of these eight criteria:

• Fever
• Splenomegaly
• Cytopenia of two or more cell lines (i.e. Hb <90 g/L, platelets <100 x 10E9/L, neutrophils <1 x 10E3/L)
• Either elevated triglycerides or low fibrinogen
• Histopathological evidence of hemophagocytosis (on either bone marrow, spleen or lymph node biopsy)
• Serum ferritin > 500 mcg/mL (often much higher in HLH:  ferritin > 3000 ng/mL as concerning for HLH and ferritin > 10 000 as highly suspicious (96% specific))
• Low or absent NK cell activity (by flow cytometry, if available)
• Soluble CD25 > 2400 U/mL

MANAGEMENT

• Treatment of the underlying cause
• Chemotherapy may be required in severe cases (e.g. etoposide, dexamethasone, and cyclosporine)
• Platelet transfusion as indicated
• Supportive care: pneumocystis jiroveci prophylaxis, fungal prophylaxis, intravenous immunoglobulin supplementation, and neutropenic precautions

References and Links

Journal articles

• Allen CE, Yu X, Kozinetz CA, et al. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50:1127–1129. PMID: 18085676
• Besset S, Schnell D, Azoulay E. Hemophagocytic lymphohistiocytosis mimicking septic shock. Chest 2012 Mar;141(3):835. PMID 22396580 [Free Full Text]
• Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL: How I treat hemophagocytic lymphohistiocytosis. Blood 2011, 118:4041–4052. [Free Full Text]
• Raschke RA, and Garcia-Orr R. Original Research. Critical Care. Hemophagocytic Lymphohistiocytosis. A Potentially Underrecognized Association With Systemic Inflammatory Response Syndrome, Severe Sepsis, and Septic Shock in Adults. Chest 2011; 140 (4): 933-938. PMID: 21737492 [Free Full Text]
• Strauss R, Neureiter D, Westenburger B, Wehler M, Kirchner T, Hahn EG (2004) Multifactorial risk analysis of bone marrow histiocytic hyperplasia with hemophagocytosis in critically ill medical patients–a postmortem clinicopathologic analysis. Crit Care Med 32:1316–1321. PMID: 15187513

FOAM and web resources

• Maryland CC Project — HLH… the White Whale of Hematology! (2014)