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Haemophagocytic Syndrome
Case presentation and literature review
Case: Mr D.J. Age 81

HPC

Febrile neutropenia
Recent URTI
Drenching night sweats
Weight loss
PHx

Rheumatoid arthritis
Hyperthyroidism (prior radioactive I2)
Hypertension
Mr D.J. Age 81

Medications

MTX 2.5mg weekly
Folate
Ramipril
Indapamide SR
SHx

Living independently with normal performance
status
Ex-smoker
Mr D.J. Age 81

On examination

Febrile (>39oC) with associated episodes of
hypotension & tachycardia
Hypoxic episodes (O2 saturation 93% OA)
No localising signs for infective focus
Moderate hepatosplenomegaly
No lymphadenopathy
Mr D.J. Age 81

Initial investigations:

FBE: Hb 134 Plt 82 WCC 0.69 Nθ 0.4
U&E, LFT normal, LDH 301, β2M 6.3
Septic screen negative
CRP 92, ESR 35
B12 & folate normal, ferritin 6206
RF 34 (ANA & ENA negative)
Differential diagnosis

Methotrexate toxicity
Felty’s syndrome
Lymphoma / T-LGL syndrome
Mr D.J. Age 81

BMAT:
Mr D.J. Age 81

Other investigations

USS: 17cm splenomegaly
CTPA & VQ: multiple acute / subacute PE
CT chest / abdo / pelvis: no lymphadenopathy
Initial management:

Empiric antibiotic therapy
Folinic acid
Intermittent G-CSF
Anticoagulation
Mr D.J. Age 81

Progress:

Oliguric ARF requiring haemodialysis
Ongoing fevers with haemodynamic instability
Delirium
D.I.C (anticoagulation ceased)
Further investigations:

Hyperferritinaemia (86,700ug/L)
Hypertriglyceridemia (6.8mmol/L)
LDH 834 (IU/L)
Mr D.J. Age 81

Working diagnosis

Haemophagocytic syndrome
Treatment (HLH-2004 protocol)

Dexamethasone (tapered from 20mg od)
Etoposide 150mg/m2 (twice weekly)
IVIG 2g/kg
VP-16 etc
Haemophagocytic syndrome

Also known as:

Macrophage activation syndrome &
haemophagocytic lymphohistiocytosis
‘SIRS’ with common features of:

Haemophagocytosis
Hyperferritinaemia
Hypercytokinaemia
Variable cytopenias
Hypofibrinogenaemia
Multi-organ failure &
death
Pathogenesis
Predisposition
Environmental trigger
HLH
Genetic:
Infection:
Macrophage activation
Familial defects of
cytotoxic effector cell
function
Viral (especially EBV)
Cytokine storm
Malignancy
End-organ toxicities
Acquired:
Autoimmune disease
Related depression of
NK cell function
Lymphoma
Other
e.g. drugs interfering
with cytokine networks
Emmenger et al. Swiss Med Wkly 2005; 135: 299-314
Pathogenesis of hypofibrinogenaemia

Profound hypofibrinogenaemia is a notable
feature of HLH
Drop in fibrinogen is disproportionate to
contribution of hepatic dysfunction
Not fully explained by consumptive
coagulopathy / DIC
Consumption of fibrinogen may be a direct
consequence of macrophage activation

CHS:

Autosomal recessive disorder
Oculocutaneous albinism
Abnormal cytoplasmic granules in leucocytes
Immune deficiency syndrome due to reduced
cytotoxic effector cell function (NK- & T- cells)
Terminal accelerated phase is due to HLH
*Blood 1985; 65: 1275 - 1281
Chediak-Higashi Syndrome:

Testing on 8 CHS patients:

All at baseline during chronic course
5 also during accelerated phase
Battery of coagulation tests

APTT, PT, TT
Fibrinogen (Clauss), FDPs
FII, V, VII + X, VIII (chromogenic)
Plasminogen (immunodiffusion & chromogenic)
Fibrinolytic assay (radioassay)
Fibrinolytic activity of single cells (caseinolytic plaque
formation)
*Blood 1985; 65: 1275 - 1281

Accelerated phase:

Severe thrombocytopenia
Variable reductions in FII, V, & VII + X
Low fibrinogen / elevated FDPs
Low plasminogen
AT levels and FVIII normal

Conclusions:

Moderate deficiency in II & VII + X with mild
reduction in V may be consistent with hepatic
dysfunction
Hypofibrinogenaemia and low plasminogen
consistent with increased fibrin(-ogen)olysis
Relatively normal FV, normal FVIII & AT argue
against a major role for DIC
Increased numbers of macrophages with
enhances plasminogen activator activity may be
pathogenesis of hypofibrinogenaemia in HLH
*Blood 1985; 65: 1275 - 1281
Familial HLH

Autosomal recessive disease

Usually manifests in early childhood following
an environmental trigger (e.g. infection)
Rapidly fatal without aggressive treatment

1:50,000 births
CNS involvement common
Multiple genetic lesions identified

All cause defects of cytotoxic effector cell function
*Emmenger et al. Swiss Med Wkly 2005; 135: 299-314
Perforin expression in familial HLH*

Membranolytic protein

Expression in NK/T
cells increases with age

HLH more common in
paediatric population
Low expression in
familial HLH

*Kogawa et al. Blood 2002; 99: 61-66
Granzyme B
Tool for rapid diagnosis
Perforin expression in familial HLH*

(A) Normal adult
(B) Primary HLH, 10 y.o.

Low perforin
(D) EBV associated HLH

*Kogawa et al. Blood 2002; 99: 61-66
Low perforin
Increased perforin
expression but low absolute
numbers of NK cells
Paediatric HLH: treatment

HLH-94 protocol*

113 patients aged less than 15 years recruited
from 21 countries
Familial HLH or persistent non-familial HLH
Treatment strategy:
Initial therapy
Continuation therapy
Stem cell transplant
Obtain remission
Maintenance while
finding BM donor
Cure
*Henter et al. Blood 2002; 100: 2367-73
HLH-94 Protocol
HLH-94: outcome

56% survival at median follow-up of 37.5 months
No familial HLH survived without BMT
Why is etoposide important?

Mode of action:

Excellent initiator of apoptosis
Highly active against monocytes / macrophages
Blockade of EBV DNA synthesis
Protocols utilising etoposide have superior
outcomes

In paediatric HLH1 & young adults2 time to VP-16
use is major prognostic factor
Role in older patients less well defined
1Imashuku
et al. 2001 JCO 19: 2665-2673
2Imashuku
et al. Med Paedr Oncol 2003; 41: 103-9
Adult HLH

HLH less common in adults:

Age dependant perforin expression
Initial EBV infection usually occurs in childhood /
adolescence
Associated with acquired immune deficiency
states:

Rheumatologic diseases (e.g. RA)
HIV infection / AIDS
Malignancies (especially T- & NK- cell NHL)
*Emmenger et al. Swiss Med Wkly 2005; 135: 299-314
Adult HLH: diagnosis
HLH 2004 criteria* (5 or more required):

*
*
*
*
1.
2.
3.
4.
+/- 5.
6.
*
7.
8.
Fever
Splenomegaly
Bicytopenia (Hb < 90g/l, Plt < 100, Nθ < 1.0)
Fasting hypertriglyceridaemia (TG > 3.0mmol/L)
and/or hypofibrinogenaemia (fibrinogen <1.5g/L)
Haemophagocytosis
Low/absent NK cell activity
Hyperferritinaemia (ferritin > 500ug/L)
Increased soluble CD25
*Henter et al. Crit Rev Oncol Haematol 2004; 50:150-157
Adult HLH: diagnosis

Macrophage activation markers: ferritin, β2M,
transcobalamin 2, IFN-γ, TNF-α, IL-12, IL-18
Soluble CD163

Soluble CD25

Haemoglobin-haptoglobin scavenger receptor
Exclusively expressed on monocyte / macrophage
lineage
IL-2 receptor alpha chain
Other

EBV serology & PCR
Supportive care

Cryoprecipitate
Corticosteroids
Avoid G-CSF
IVIG

Immunomodulatory
dose
Infection associated
HLH
Cyclosporin A

Effects on
macrophage & T-cell
function
Reduces VP-16
related neutropenia
Questions?