Hl hing
- 1. Hemophagocytic lymphohistiocytosis ArzuTOPELI ISKIT Hacettepe University Faculty of Medicine, Medical Intensive Care Unit
- 3. HLH Rare, mortal disease 1.2 cases/1,000,000 population Excessive, abnormal inflammation and organ damage due to immune activation by histiocytes and lymphocytes Frequent in childhood (0-18 months), but can be seen at any age Female = male
- 5. Primary HLH (familial erythrophagocytic lymphohistiocytosis) Hereditary (heterogenous transmission; autosomal recessive) (-) Family history in general Consangiunity is frequent Infection as a trigerring factor
- 6. Secondary HLH (acquired HLH) Strong immunologic activation Systemic infection Immune defficiency Cancer (lymphoma …)
- 7. Macrophage activation syndrome (MAS) A form of HLH Reactive hemophagocytic syndrome Secondary to rheumatologic diseases Juvenile idiopathic arthritis (Still disease) …
- 8. Pathophysiology Macrophages Antigen presenting cells to lymphocytes Excessive activation of macrophages in HLH cytokine tissue damage, organ failure Natural killer (NK) cells and cytotoxic lymphocytes (CD8+; CTL) NK: 10-15% of lymphocyte population Destroy infected or damaged macrophages and host cells in response to viral infection or malignancy In HLH, NK/CTL can not eliminate macrophages !
- 9. Pathophysiology Uncontrolled activation of cellular immune system Decreased apoptosis T lymphocyte and macrophage activation Aggressive proliferation of macrophages and histiocytes; and phagocytosis of erythrocytes, leukocytes, platelets, etc. Not a malignant proliferation Not a clonal proliferation (i.e., Langerhans histiocytosis, histiocytosis X)
- 10. Gene mutation Mutation can be seen in genes related with other immune defficiency syndromes. Perforin gene mutation apoptosis ↓ Demonstrated in 20-40% cases with familial HLH Perforin is a membranolytic protein expressed in cytoplasmic granules of NK cells and CTL. It is responsible for establishing a pore in the membrane by translocating granzyme B from cytotoxic cells to target cells. Granzyme B reaches the target nucleus and induces apoptosis. In case of perforin defficiency, there is decreased or no cytolytic effect of CTL and NK cells. Mainly perforin gene mutation
- 12. Another pathophysiological mechanism Toll-like receptor activation Non-antigen-specific receptor on NK cell surface Activated by microorganisms
- 13. Most frequent involvement Spleen Lymph node Bone marrow Liver Skin Meninx Spinal cord
- 14. Cytokine storm Interferon- TNF- IL-6, 10, 12, 16, 18 Soluble IL-2 R (CD25) …
- 15. Triggering/risk factors Immune-activation Viral EBV, CMV, Parvo virus, HSV, VZV, Adenovirus, Influenza, Measles … Bacteria Brucella, gram (-),TB … Parazite Leishmaniasis, malaria … Fungi Immune-defficiency Inherited immune defficiency syndromes Malignancy (50% in adults) Rheumatologic diseases (MAS) Kawasaki disease HIV Transplantation
- 18. Clinical manifestations Ateş Fever (93%) Hepatosplenomegali (95%) Cytopenia (anemia+thrombocytopenia 80%) Lymphadenopathy (33%) Rash (31-65%) Erythroderma, purpura, macule, papule, morbiliform rash Neurologic manifestations (33%) Sepsis + MOF
- 19. American Histiocyte Association diagnostic criteria 1. Fever ≥ 38.5˚C (> 7 days) 2. Splenomegaly 3. Bi-cytopenia (Hb < 9 g/dL; platelets < 100,000 /mcL; absolute neutrophil < 1000 /mcL) 4. Hypertrygliceridemia (fastingTG > 265 mg/dL) and/or hypofibrinogenemia (< 150 mg/dL) 5. Ferritin > 500 ng/mL (3000 ?) 6. Tissue hemophagocytosis 7. Decreased or (-) NK activity 8. sIL-2R (sCD25; age normalized 2SD+; >2400 IU/mL) Diagnosis: ≥ 5/8 criteria
- 20. Other proposed criteria ¾ clinical criteria Fever Splenomegaly Cytopenia Hepatitis ¼ immunologic criteria Hemophagocytosis Hyperferritinemia Hypofibrinogenemia NK activity ↓/(-) sIL-2R
- 21. Diagnostic tests Fever, MOF Ferritin Triglyceride Bone marrow biopsy (hemophagocytosis) Tissue biopsy sIL-2R NK activity sIL-2R/ferritin ratio in lymphoma related HLH Genetic tests Infection screening
- 22. Differential diagnosis MAS Sepsis + MOF Liver failure Encephalitis Drug reactions (DRESS) TTP, HUS TA-GVHD
- 24. Patients 1 2 3 4 5 6 7 8 9 10 Median (min-max) Age (years) 73 42 21 55 53 73 20 21 22 25 33.5 (20-73) Gender F F F M F M F M F F - APACHE II score 15 23 23 22 12 14 24 24 16 37 22.5 (12-37) Admission SOFA score 15 9 10 8 7 8 14 16 8 14 9.5 (12-37) Last SOFA score 20 20 14 18 16 17 14 20 20 16 17.5 (14-20) Co-morbidities HT, DM Breast cancer Optic gliom GP PU CAD, COPD, HT, Hyperthyroid CVID Renal trans CVID, pregnancy Pregnancy, Cholecystitis LOS (ICU) (days) 12 6 55 9 30 17 4 27 9 42 14.5 (4-55) LOS (Hospital) (days) 13 29 56 10 49 50 26 36 40 44 38 (10-56) Viral serology - - - - CMV - Parvo- EBV CMV CMV- EBV CMV Nosocomial infection in all; all ex; only 1 was diagnosed when alive and treatment was given !
- 25. Median (Min-Max) Hb (11.7-15.5 g/dL) 7.2 (5.8-8.8) WBC (4.1-11200 /mm3) 1300 (500-8600) Neutrophil (/mm3) 1050 (500-6900) Platelet (159-388x103 /mm3) 16 (4-49) Triglyceride (<200 mg/dL) 356.5 (94.5-694.6) Fibrinogen (219-403 mg/dL) 150 (63-788) Peak LDH(240-480 U/L) 1216.3 (730.8-2355) Ferritin (ng/mL) 3684.5 (639.8-40316) Soluble IL-2R level (2.5-3.9-median: 3 ng/mL) 20 (8.6-72.4) Median number of diagnostic criteria 5; patient with 7 criteria was treated when alive !
- 26. HLH in 9 (36%) out of 25 patients Mortality in HLH 89% (8 patients); 25% mortality in other 16 patients without HLH Diagnosis after 23 days of beginning of symptoms, after 16 days of ICU admission
- 28. 1998-2009; single center 72 patients 56 complete data
- 31. Can be missed, delay in diagnosis Bi-cytopenia is the most important parameter for awareness Bone marrow biopsy is the most important test for confirmation
- 33. Treatment principles Survival in months without treatment; with treatment > 50% remission for 6 years Early diagnosis and treatment ! The most important barriers: rarity, variable presentation, non-specific symptoms and signs Chemotherapy Steroid, etoposide, cyclosporine, intratechal methotrexate Hematopoietic cell transplantation HLH gene mutation, hematologic malignancy, relaps, CNS symptoms
- 35. Poor prognostic factors Familial HLH/mutation Neurologic manifestations < 6 months of age > 50 years of age No remission High ferritin,AST, LDH Low platelets Malignancy (T cell lymphoma)
- 36. In summary … HLH is an aggressive, life-threatening, immune activation Excessive proliferation and tissue ivasion of T lymphocytes and macrophages leading to MOF Confused with sepsis + MOF INTENSIVISTS SHOULDTHINK OF HLH in cases with MOF with no known cause ! Splenomegaly, hyperferritinemia, hypertriglyceridemia should be searched for. Bone marrow biopsy, immunologic and genetic tests should be done if necessary Primary disease should be treated first in MAS and infection related HLH. Multi-disciplinary approach with intensivist, hematologist and pathologist