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 immuno- suppressive/immunomodulatory drugs

HLH Classification

Genetic, primary HLH Acquired, secondary HLH FHLH - Perforin mutations (chr.10) Exogenous agents - infectious organisms, toxins - Chromosom 9 linkage (VAHS, IAHS)

- Unknown mutations HLH Endogenous products - tissue damage - radical stress - Immune deficiencies - metabolic products CHS Griscelli syndrome Rheumatic disorders XLP Malignancies SCID GJ 2002

Leishmaniase

„IAHS“ in Childhood (219 cases from the literature) 1979-1995

Organism Clinical outcome Dead Alive No data

EB Virus 121 72 27 22

Other viruses 28 11 13 4

Bacteria 11 2 9 0

Fungi 2 1 1 0

Protozoae 1 0 1 0 No organism 57 13 33 11

„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

Total 219 103/198 95/198

(52%) (48%)

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

0 20 40 60 80 100

CNS protein

CNS cells >=5/ ul

Natrium < 130 mmol/ l

GPT > 50 U/ l

GOT > 50 U/ l

LDH > 400 U/ l

Triglycerides fasting >= 2mmol/ l

Fibrinogen < 1,5 g/ l

sCD 25 > 5000 U/ ml

NK cell activity negative ordecreased

Hemophagocytosis

Neutrophils < 1.0/ nl

Thrombocytes < 100/ nl

Hb < 90 g/ l

Cytopenia 1 cell line

Cytopenia 2 cell lines

Cytopenia 3 cell lines

Splenomegaly

Fever

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