Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome characterized by uncontrolled activation of macrophages and lymphocytes, leading to excessive inflammation and organ damage. It can occur primarily due to genetic mutations or secondarily in association with infections, malignancies, or rheumatologic conditions. The pathophysiology involves defective cytotoxic lymphocyte function and cytokine overproduction. HLH is diagnosed based on clinical and laboratory criteria including prolonged fever, cytopenias, hypertriglyceridemia/hypofibrinogenemia, hyperferritinemia, and hemophagocytosis. Early diagnosis and treatment with chemotherapy, steroids, and hematopoietic stem cell transplantation is needed for survival, as H

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

4. Primary (Familial)
Secondary (Sporadic)

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

11. Apoptosis pathways

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