Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis, diagnosis and treatment

Table 1 List of primary hemophagocytic lymphohistiocytosis

Disease	Molecular abnormalities(chromosome location)
CTL molecule dysfunction
Pore formation
FHL2	Perforin (10q21-2)
Vesicle priming fusion
FHL3	Munc13-4/Unc 13D (17q25)
FHL4	Syntaxin 11 (6q24)
FHL5	STXBP2/Munc18-2 (19p13)
Vesicle docking/trafficking
Chediak-Higashi syndrome	LYST (1q42.1-42.2)
Griscelli syndrome, type 2	Rab27a (15q21)
Hermansky-Pudlak syndrome II	AP-3 (3q24)
EBV-driven
XLP1	SAP/SH2D1A (Xq25)
XLP2 (XIAP)	BIRC4 (Xq24-25)
ITK deficiency1	ITK (5q34)
CD27 deficiency1	CD27 (12p13)
XMEN1	MAGT1 (Xq21.1)

¹Major clinical features in these diseases are not hemophagocytic lymphohistiocytosis (HLH) but Epstein-Barr virus (EBV)-associated lymphoproliferative disease. FHL: Familial hemophagocytic lymphohistiocytosis; XLP: X-linked lymphoproliferative disease; ITK: IL-2-inducible T cell kinase; XMEN: X-linked immunodeficiency with Mg²⁺ defect, EBV infection and neoplasia; MAGT1: Magnesium transporter 1, LYST is also called CHS1 gene. Association of hemophagocytosis was described in some cases.

Table 2 Diagnostic guidelines for hemophagocytic lymphohistiocytosis[38]

The diagnosis of HLH can be established if one of either (1) or (2) below is fulfilled
(1) A molecular diagnosis consistent with HLH
(2) Clinical diagnostic criteria fulfilled for 5 out of the 8 criteria below
Clinical criteria	1 fever
	2 splenomegaly
Routine laboratory criteria	3 bicytopenia (Hb < 90 g/L,
	platelets < 100 × 109/L, neutrophils < 1.0 × 109/L)
	4 Hypertriglyceridemia (> 3.0 mmol/L)
	and/or hypofibrinogenemia (< 1.5 g/L)
Specific histopathological/marker criteria	5 hemophagocytosis
	6 low or absent NK cell activity
	7 hyperferritinemia (> 500 μg/L)
	8 hyper-sIL-2R-nemia (> 2400 U/mL)

HLH: Hemophagocytic lymphohistiocytosis; NK: Natural killer.

Table 3 Poor prognostic factors in Epstein-Barr virus-hemophagocytic lymphohistiocytosis[34]

Persistent increase of cell-free EBV genome copies

Chromosome abnormality

Correlation with chronic active EBV infection (CAEBV)1

In association with primary HLH

Severe organ dysfunction, such as renal failure, CNS hemorrhage

Choice of treatment, such as timing of etoposide use, HSCT

¹CAEBV is often associated with 1 and 2 of the above. CNS: Central nervous system; HSCT: Hematopoietic stem cell transplantation; EBV: Epstein-Barr virus; HLH: Hemophagocytic lymphohistiocytosis.