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Various immunodeficiencies
Hyperinflammatory but inadequate
immune response
Clinical picture of HLH
Hemophagocytic lymphohistiocytosis (HLH)
Clinical symptoms and findings
High fever, hepatosplenomegaly, pancytopenia
Neurological symptoms, jaundice, edema, lymphadenopathy, rash
High triglycerides, low fibrinogen, coagulopathy
high ferritin, transaminases, bilirubin, LDH
CSF pleocytosis and/or elevated protein
Hemophagocytosis in BM or other organs
Phagocytosing macrophages in HLH
HLH
Variable course of disease
 Rapidly progressive leading to death within weeks
 Transient improvements with unspecific therapies
 Disappearance of symptoms without therapy
 Disappearance of symptoms with immunosuppressive/immunomodulatory drugs
HLH
Classification
Genetic, primary HLH
Acquired, secondary HLH
 FHLH
-
Perforin mutations (chr.10)
-
Chromosom 9 linkage
-
Unknown mutations
Exogenous agents
- infectious organisms, toxins
(VAHS, IAHS)
HLH
 - Immune deficiencies
CHS
Griscelli syndrome
XLP
SCID
Endogenous products
- tissue damage
- radical stress
- metabolic products
Rheumatic disorders
Malignancies
GJ 2002
Leishmaniase
„IAHS“ in Childhood
(219 cases from the literature)
1979-1995
Organism
Clinical outcome
Dead
Alive
No data
121
72
27
22
Other viruses
28
11
13
4
Bacteria
11
2
9
0
2
1
1
0
1
57
0
13
1
33
0
11
EB Virus
Fungi
Protozoae
No organism
„IAHS“ in Childhood
(219 cases from the literature)
(1979-1995)
Age
Clinical outcome
Dead
Alive
No data
< 3 years:
77
40
26
11
> 3 years:
82
29
47
6
„Children“:
60
60
22
4
103/198
95/198
(52%)
(48%)
Total
219
HLH
Diagnostic criteria Histiocyte Society 1991
Clinical
Fever > 38.5
Splenomegaly
Laboratory
Cytopenia of => 2/3 cell lines
Hypertriglyceridemia and/or
hypofibrinogenemia
Histopathology
Hemophagocytosis in bone marrow
or spleen or liver or lymphnode
Strong supportive evidence are spinal fluid pleocytosis, liver histology
resembling chronic persistent hepatitis, low natural killer cell activity
Diagnostic criteria
Fever
Splenomegaly
Cytopenia 3 cell lines
Cytopenia 2 cell lines
Cytopenia 1 cell line
Hb < 90 g/l
Thrombocytes < 100/nl
Neutrophils < 1.0/nl
Hemophagocytosis
NK cell activity negative or
decreased
sCD 25 > 5000 U/ml
Fibrinogen < 1,5 g/l
Triglycerides fasting >= 2mmol/l
LDH > 400 U/l
GOT > 50 U/l
GPT > 50 U/l
Natrium < 130 mmol/l
CNS cells >=5/ul
CNS protein
0
20
40
60
80
100
Percent of cases
At initial presentation
At diagnosis
HLH
Immunological parameters

Hypercytokinemia (TNF, INF, IL 6, IL 8, IL 10),

Increased soluble CD 25 (interleukin 2 receptor -chain)

Increased soluble CD95-ligand

NK-cell activity below 5% lysis

CD2/CD86 positive cells in lymphocyte gate

Phagocytosing dendritic cells in culture
HLH
Therapy
 Cytostatic and immunsuppressive/
immunomodulatory drugs:
Corticosteroids, Cyclosporin A,
Etoposide
Immunoglobulins, Antithymocyte globulin
 Bone marrow transplantation
Prognosis
In 20% no response to therapy
After BMT 60-70% relapse-free survival