Various immunodeficiencies Hyperinflammatory but inadequate immune response Clinical

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 - Immune deficiencies CHS Griscelli syndrome XLP SCID Exogenous agents - infectious organisms, toxins (VAHS, IAHS) HLH 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 Fungi 2 1 1 0 Protozoae 1 0 57 13 33 11 EB Virus 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 4 219 103/198 95/198 (52%) (48%) Total

HLH Diagnostic criteria Histiocyte Society 1991 Clinical Laboratory Fever > 38. 5 Splenomegaly 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

At initial presentation At diagnosis

HLH Immunological parameters Hypercytokinemia (TNF , IL 6, IL 8, IL 10), Increased soluble CD 25 (interleukin 2 receptor -chain) Increased soluble CD 95 -ligand NK-cell activity below 5% lysis CD 2/CD 86 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