Hemophagoctic Lymphohistiocytosis – Recent Concept Maitreyee Bhattacharyya*, MK Ghosh** Abstract

Review Article
Hemophagoctic Lymphohistiocytosis – Recent Concept
Maitreyee Bhattacharyya*, MK Ghosh**
Abstract
Hemophagocytic lymphohistiocytosis is a rare condition characterized by highly stimulated but inactive
immune response. The disease may be inherited or acquired due to infections, collagen vascular diseases
and malignancies. The pathological hallmark of the syndrome is aggressive proliferation of macrophages
and histiocytes. Decreased NK cell activity results in increased T cell activation resulting production of
large quantities of interferon γ (IFNγ), tumor necrosis factor α (TNFα) and granulocyte macrophage colony
stimulating factor (GM-CSF). This causes sustained macrophage activation and tissue infiltration as well
as production of interleukin 1 (IL1) and interleukin 6 (IL6).The resulting inflammatory reaction causes
extensive damage and associated symptoms. Patients with HLH commonly present with high fever, anemia
and splenomegaly. Minimal diagnostic parameters are a complete hemogram, liver function test, serum
triglycerides and ferritin, coagulation profile including fibrinogen and bone marrow aspiration. Two highly
sensitive diagnostic marker are an increased plasma concentration of the α chain of soluble IL2 receptor
(CD25) and impaired NK cell activity. Hyperinflammation can be treated with steroid, Cyclosporine prevents
T lymphocytes and immunoglobulin infusion helps to control the infection. Etoposide may be life saving
specially in case of HLH with Ebstein Barr Viruses infection. The Histiocyte Society in 1994 developed a
common treatment protocol (HLH-94). In January 2004 a revised HLH treatment protocol was opened
entitled HLH-2004, which is based on HLH-94 with minor modifications. There is a high remission rate on
the HLH-94 and HLH-2004 treatment protocols. ©
H
INTRODUCTION
-
emophagocytic lymphohistiocytosis (HLH ) is a
rare but potentially life threatening condition
characterized by uncontrolled activation of macrophages
and lymphocytes. Pediatric age group is most commonly
affected but it can occur at any age. It is not a single
disease and can be encountered in association with
a variety of underlying diseases that leads to highly
stimulated but inactive immune response.
Classification :
1. Inherited HLH
Familial HLH (Farquhar disease)
- Known genetic defects (perforin, munc 13-4,
syntaxin 11)
- Unknown genetic defects.
Immune deficiency syndrome
- Chediak Higashi syndrome
- Griscelli syndrome
- X- linked lymphoproliferative syndrome
2. Acquired HLH
Exogenous agents (infectious organisms, toxins)
*Associate Professor, **Professor and Head, Department of
Hematology, N.R.S. Medical College, Kolkata, India.
© JAPI • VOL. 56 • JUNE 2008
Infection – associated hemophagocytic
syndrome (IAHS)
Endogenous products (tissue damage, metabolic
products)
- Rheumatic diseases
- Macrophage activation syndrome (MAS)
Malignant disease
The syndrome, which has also been referred
to as histiocytic medullary reticulosis, was first
described in 1939.1 HLH was initially thought to be
a sporadic disease caused by neoplastic proliferation
of histiocytes. Subsequently, a familial form of the
disease2 (now referred to as familial hemophagocytic
lymphohistiocytosis (FHLH)3 was described. Familial
HLH is an inherited autosomal recessive disorder first
described by Farquhar and Claireaux in 1952,2 estimated
to occur in a frequency of 1 in 50,000 births. The diagnosis
of FHLH is made based on the presence of clinical
criteria and is confirmed by molecular genetic testing.
Four disease subtypes (FHL1, FHL2, FHL3, and FHL4)
are described; three genes have been identified and
characterized: PRF1 (FHL2), UNC13D (FHL3), and
STX11 (FHL4). Molecular genetic testing of the PRF1
(FHL2), UNC13D (FHL3), and STX11 (FHL4) genes is
available on a clinical basis (Table 1).
Secondary HLH (ie acquired HLH) occurs after
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453
strong immunologic activation such as that occur
with a variety of viral, bacterial, fungal, and parasitic
infections, as well as collagen-vascular diseases10-13 and
malignancies, particularly T-cell lymphomas.14-17 The
association between HLH and infection is important
because 1) both sporadic and familial cases of HLH
are often precipitated by acute infections; 2) HLH
may mimic infectious illnesses, such as overwhelming
bacterial sepsis and leptospirosis;18 3) HLH may obscure
the diagnosis of a precipitating, treatable infectious
illness (as reported for visceral leishmaniasis;19 and 4)
a better understanding of the pathophysiology of HLH
may clarify the interactions between the immune system
and infections
The clinical picture of HLH can be induced by
a variety of infectious organisms. The patient in
the original report by Risdull and colleagues were
mostly associated with viral infection following organ
transplantation.20 Subsequently it was clear that it may
be associated with viruses as well as a no of bacteria,
fungi, mycobacteria and parasite and the term Viral
Associated Hemophagocytic Syndrome (VAHS) was
redesigned as Infection Associated Hemophagocytic
Syndrome (IAHS). A review of published cases in
children diagnosed with IAHS before 1996 reported
that more than half of them were from Far East. Ebstein
Barr Virus (EBV) was the triggering virus in 74% of
the children in whom an infectious agent could be
identified.21 Fardet et al reported Human Herpesvirus
8 associated HLH in Human immunodeficiency virus
infected patients.22
HLH in association with malignant disease is well
known entity in adults but rare in children. Most common
malignancy associated with HLH is Lymphoma. In a
recent review of patient with lymphoma associated
hemophagocytic syndrome (LAHS) from Japan EBV
genome was detected from more than 80% of T/NK cell
lymphoma but rarely from B cell lymphoma.23
HLH has also been described in association with
inborn error of metabolism like Lysinuric Protein
Intolerence (LPI).24
Pathophysiology
The pathological hallmark of the syndrome is
aggressive proliferation of macrophages and histiocytes
which phagocytose other blood cells leading to the
clinical symptoms. This uncontrolled growth is nonmalignant and does not appear clonal in contrast to
the lineage of cells in Langerhans cells histiocytosis.
The spleen, lymph nodes, bone marrow, liver, skin
and membranes that surrounds the spinal cord are
preferential site of involvement.25
Over the past 2 decades, the underlying
pathophysiology of HLH has been characterized,
although the processes are not entirely understood.
A current accepted theory involves an inappropriate
immune reaction caused by activated T cells associated
with macrophage activation and inadequate apoptosis of
immunogenic cells.26 Although the precise mechanism is
unclear many research team propose convincing pictures
for the role of perforin or NK cells in the HLH subtypes.2729
NK and cytotoxic T cells kill their targets through
cytolytic granules containing perforins and granzyme.
When activated by challenges NK cells release granules
containing granzymes and perforins which forms pores
in the target cell membrane and causes osmotic lysis
and protein degradation respectively. Patients with
HLH have severe impairment of the cytotoxic function
of NK cells and cytotoxic T lymphocytes. Decreased NK
cell activity results in increased T cell activation and
expansion with resulting production of large quantities
of cytokines, including interferon γ (IFNγ), tumor
necrosis factor α (TNFα) and granulocyte macrophage
colony stimulating factor (GM-CSF). This causes
sustained macrophage activation and tissue infiltration
as well as production of interleukine1 (IL1) and
interleukine 6 (IL6). The resulting inflammatory reaction
causes extensive damage and associated symptoms30
(Fig. 1). Inflammatory cytokines are responsible for
the characteristic disease markers such as cytopenias,
coagulopathy and high triglycerides.
Upon contact between the effector killer cell and
the target cell, an immunological synapses is formed
and cytolytic granules have to traffic the contact site,
dock and fuse with the plasma membrane and release
their content. All known defects in HLH seems to be
involved in this processes. LYST mutations impair
granule secretion, RAB 27α deficiency leads to impaired
docking at the membrane, mutations in UNC13 causes
defective granule priming at the immunologic synapses.
Finally lack of PRF1 leads to loss of cytolytic activity. In
XLP, granule mediated cytotoxicity is defective through
impaired lymphocyte activation.
Factors leading to cytolytic defects in acquired HLH
is less clear. Viruses may interfere with T cell activity
Table 1 : Locus name and genes associated with familial hemophagocytic lymphohistiocytosis
Locus Name
% of FHLH
FHL1
4 inbred Pakistani Families4
FHL2
20-30% worldwide, 50% in
African American families5-7
FHL3
20-30% world wide6,8
FHL4
~ 20% of Turkish/Kurdish
families8,9
454
Mutations
Chromosomal Locus
N/A
9q21.3-q22
>50 distinctive mutations throughout
10q22
the entire coding region
>10 mutations throughout the entire
17q25.1
coding region and splicing sites
3 recurrent mutations
6q24
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Protein name
Unknown
Perforin-1
Unc-13
homolog D
Syntaxin-11
© JAPI • VOL. 56 • JUNE 2008
Table 2 : Clinical signs and laboratory abnormalities
associated with hemophagocytic lymphohistiocytosis
Clinical sign
Fever*
Splenomegaly*
Hepatomegaly
Lymphadenopathy
Rash
Neurologic signs
Laboratory abnormality
Anemia*
Thrombocytopenia*
Neutropenia*
Hypertriglyceridemia*
Hypofibrinogenemia*
Hyperbilirubinemia
Fig. 1 : Schematic representation of possible immunopathologic
mechanisms in infection-associated hemophagocytic lymphohistiocytosis
(HLH). TNF-α = tumor necrosis factor-α ; IFN-γ = interferon-gamma;
IL-1 = interleukin-1; IL-2 = interleukin-2; IL-6 = interleukin-6; IL-18
= interleukin-18; sFasL = soluble Fas ligand; T = T-lymphocyte; M =
macrophage; EBV = Epstein-Barr virus.
Fig. 2 : Overview of the treatment protocol HLH-94.
Dexa = dexamethasone daily [pulses are 10 mg/m2 for 3 days]; VP16 = etoposide 150 mg/m2 intravenously; CSA = cyclosporin A; I.T.
therapy = intrathecal methotrexate [if progressive neurological symptoms
or if an abnormal CSF has not improved].)
by specific proteins or cytokines.31,32
Macrophage activation syndrome (MAS) occurs in
children and adults with autoimmune diseases most
commonly seen in association with systemic onset
juvenile rheumatoid arthritis (sJRA) or adult onset
Still,s disease but also occur rarely with systemic lupus
erythematosus or other entities. 33,34 Clinical picture
and laboratory findings are similar to HLH. Patients
of sJRA was found to have low NK cell function
and perforin expression compared to other form of
rheumatoid arthritis.35 MAS is a grave disorder with
a mortality of about 10-20%. It has been suggested by
some rheumatologists that MAS be classified as a form
of secondary HLH.36,37
Clinical Features
Patients with HLH commonly present with high
fever, anemia and splenomegaly. The fever often
fluctuates with complete remission and recurrences.
Severe fulminant liver failure with coagulopathy or
neurological symptoms may dominate the clinical
© JAPI • VOL. 56 • JUNE 2008
% of patients affected
60-100
35-100
39-97
17-52
3-65
7-47
% of patients affected
89-100
82-100
58-87
59-100
19-85
74
Reference
3,46
3, 46
3,46
3,46
3,46
3,46
Reference
3,44,45
3,44, 45
3,44,46
3,44,46
3,44,46
44
* Proposed diagnostic criterion for HLH2
picture and thereby delay the diagnosis of HLH.
Nearly 75% of patients will show some form of CNS
involvement – including seizures, ataxia, hemiplegia,
altered sensorium. Patient may have even only
neurological manifestations.38,39 About 65% of patients
will have skin rashes40 (Table 2).
The diagnostic criteria set forth by the Histiocytic
Society for inclusion in the international registry41 for
HLH is as follow –
I) Fever as high as 38.5°C for 7 days or more.
II) Splenomegaly – 3 cm below left costal margin
III) Cytopenias –
- Absolute Neutrophils < 1000/µL
- Platelets less than100,000/µL
- Hemoglobin < 9 g/dL
IV) Fibrinogen < 1.5 g/L or fasting triglyceride
>3 mmol/L
V) Hemophagocytosis in spleen, lymph node or Bone
Marrow.
VI) Serum Ferritin > 500 µg/L
VII) sCD25 > 2400 U/L
VIII)Decreased or altered NK cell activity.
Laboratory investigations
In every patient with prolonged fever,
hepatosplenomegaly and pancytopenia, the diagnosis
of HLH should be considered. Minimal diagnostic
parameters are a complete hemogram, liver function
test, serum triglycerides and ferritin, coagulation
profile including fibrinogen. Ferritin has been observed
as a marker of HLH with the serum level paralleling
the course of the disease.26 Altered hepatic function
including hyperbilirubinemia, increased hepatic
enzymes and low albumin has also been reported.42
All patients should undergo bone marrow aspiration,
however, hemophagocytosis may not be present in the
initial bone marrow smears, only increased monocytes
and monohistiocytic cells may be present. In about
50% patients there may be elevated cell count, protein
or both in the CSF even in the absence of clinical
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455
features. Two highly sensitive diagnostic marker are
an increased plasma concentration of the α chain of
soluble IL2 receptor (CD25) and impaired NK cell
activity.43 In October 2002, the Arico group proposed
an approach to the diagnostic work up of a patient
with suspected HLH. The laboratory work-up should
involve perforin expression by NK cell by using flow
cytometry. Patients lacking perforin expression should
be analyzed for the PRFI gene mutation, NK cell activity
helps to differentiate between reactive form of HLH
from familial type. Normal activity is suggestive of the
reactive form rather than familial type. 25 Search for
a triggering infectious agent is important, however it
should be emphasized that with the possible exception
of leishmaniasis, anti-infectious therapy alone is not
sufficient to control HLH (Table 2).
Therapy
The aim of treatment of HLH is to suppress the severe
hyperinflammation and also to control the infection
which has triggered the syndrome. In familial HLH
the ultimate aim should be stem cell transplantation
to replace the defective immune system with normal
functioning immune system.
Hyperinflammation can be treated with steroid,
which is cytotoxic for lymphocytes and inhibit
secretion of various cytokines. Dexamethasone is the
drug of choice since its CSF penetration is better than
prednisolone. Cyclosporine prevents T lymphocytes and
immunoglobulin infusion helps to control the infection
. Emmenegger and others have evidence that IVIG is
effective in the treatment of HLH.47,48 A key finding of
their analysis is the efficacy of IVIG if it is administered
at the beginning (within hours) of the macrophage
activation process and its failure in later stages of the
disease. Etoposide has high activity in monocyte and
histiocytic diseases. Patients who are at low risk may be
treated with only cyclosporine, corticosteroid or IVIG,
only high risk group required etoposide.26 Etoposide
may be life saving specially in case of HLH with
Ebstein Barr Viruses infection.17 CNS reactivation may
occur during treatment, intrathecal Methotrexate plus
Corticosteroid has been found to be beneficial in some
cases. Serum ferritin seems to be a useful emergency
marker for monitoring macrophage activation.
Although symptoms and laboratory features improve
within 2 to 3 weeks in some cases cytopenia may persist.
In these cases bone marrow examination should be
repeated to differentiate between non-response and
myelosuppression due to etoposide. If there is no
response, unlikely to have benefit with treatment. There
is no established salvage regimen. Isolated patient has
responded to Daclizumab, Alemtuzumab or to stem cell
transplantation. Hasegawa et al reported remission of
HLH after syngenic bone marrow transplantation.49 A
recent study has found favorable long –term disease
control in patients who received a reduced-intensity
456
conditioning regimen instead of conventional stem cell
transplant.50
The Histiocyte Society in 1994 developed a common
treatment protocol (HLH-94), primarily designed for
the primary, inherited disease FHL. In January 2004 a
revised HLH treatment protocol was opened entitled
HLH-2004, which is based on HLH-94 with minor
modifications. Cyclosporin A, that in HLH-94 was
introduced at week 9, is instead initiated upfront, and
corticosteroids is now combined with methotrexate
in the intrathecal therapy. The aim is first to achieve
a clinically stable resolution and ultimately to cure
by BMT. The protocols have been widely accepted
internationally and used in more than 25 countries and
on all continents.
There is a high remission rate on the HLH-94 and
HLH-2004 treatment protocols, during which time
a BMT donor usually can be identified. The overall
prognosis with regard to survival improved dramatically
during the last decade. One major problem is that many
children still are diagnosed late, at a stage when they
may have severe and irreversible brain damage. With
regard to long-term survival, the prognosis will be
dependent upon the results of BMT, which also are
increasingly rewarding.
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