Hemophagocytic lymphohistiocytosis

Surapon Wiangnon

Faculty of Medicine

Mahasarakham University

KKU

Histiocytes are myeloid origin hematopoietic cells that populate at tissues

Cell Origins of Histiocytic Diseases

Stem cell

Monocyte

CD11cCD68

CD14+

CD1 ndash

HLADR+

DCSIGN

Fxllla

int

Interstitial

CD14+DC

CD68

CD68

CD163

CD11c

CD206

Macrophage

Mesenchymal

Precursor cell

CD21

CD23

CD35

Follicular

DC

Macrophage

DC Precursor

Myeloid

DC Precursor

CD205

CD1a

intDermal

CD1a+DC

CD207

CD1a

High

S100

Langerhans cell

LCH LCH ECD JXG HLHRDD Malignant Histiocytosis

DC dendritic cell JXG juvenile xanthogranuloma ECD Edheim Chester disease

RDD Rosai-Dorfman disease HLH hemophagocytic lymphohistiocytosis

CD1+

CD14+

HLADR+

Dendritic cell (histiocyte) proliferation

- Langerhans cell histiocytosis (LCH)

- Juvenile xanthogranulomas (JXG) amp related disorders

- Solitary histiocytomas of various DC phenotype

Macrophage proliferation

- Hemophagocytic lymphohistiocytosis (HLH)

- Sinus histiocytosis with massive lymphadenopathy (SHML Rosai-Dorfman disease)

- Solitary histiocytoma of macrophage phenotype

Histiocytosis syndrome

ICD-10 Langerhans cell histiocytosis C960

Hemophagocytic lymphohistiocytosis D761

Malignant histiocytosis C968

HLH มกลมยอยดงน Familial Hemophagocytic Lymphohistiocytosis

Infectious-associated hemophagocytosis (IAHS)

Malignant-associated hemophagocytosis (MAHS)

Macrophage Activation Syndrome (MAS) refractory

to steroid

Int J Hematol 2007

Hyperinflammatory disorder hypercytokinemia and excessively activated lymphocytes and histiocytescharacterized by cytopenia hepatosplenomegaly DIC hyperferritinemia and hemophagocytosis

Primary Secondary

Infection auto-immuneinflammatory

lymphoma post-SCT

Genetic disease

HLH

Familial HLH FHL

Hemophagocytic lymphohistiocytosis HLH

Epidemiology of HLH

12 M or 150000 live-birth (FHLH Swedish registry)

80 of FHL onset in the first year of life

Likely to be under-diagnosed

ThaiPOG 2003-5

2031000000

MF = 11

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Number

1 sex

Male 45 517

Female 42 483

2 age at diagnosis (year)

lt1 16 1860

1-4 37 4302

5-9 19 2209

10-14 13 1512

3 basis of diagnosis

Histology 75 8621

Hist Mets 6 690

Hematology 1 115

X-ray 2 230

Clinical 3 345

Variable Number

4 subtype

Langerhan cell histiocytosis 59 6782

Hemophagocytic syndrome 23 2644

Malignant 4 460

41 Langerhan cell histiocytosis

9751 Langerhan cell histiocytosis NOS 11 186

9752 Langerhan cell histiocytosis unifocal 13 220

9753 Langerhan cell histiocytosis multifocal 20 339

9754 Langerhan cell histiocytosis disseminated 14 237

9999 not specify 1 17

42 Hemophagocytic syndrome

Familial erythrophagocytic lymphohistiocytosis 1 44

Sinus histiocytosis with massive lymphadenopathy 1 44

Hemophagocytosis with infection associated 5 217

Hemophagocytosis NOS 16 696

5 final status

Alive 60 690

Death 20 230

Unknown 7 81

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Histiocytes are myeloid origin hematopoietic cells that populate at tissues

Cell Origins of Histiocytic Diseases

Stem cell

Monocyte

CD11cCD68

CD14+

CD1 ndash

HLADR+

DCSIGN

Fxllla

int

Interstitial

CD14+DC

CD68

CD68

CD163

CD11c

CD206

Macrophage

Mesenchymal

Precursor cell

CD21

CD23

CD35

Follicular

DC

Macrophage

DC Precursor

Myeloid

DC Precursor

CD205

CD1a

intDermal

CD1a+DC

CD207

CD1a

High

S100

Langerhans cell

LCH LCH ECD JXG HLHRDD Malignant Histiocytosis

DC dendritic cell JXG juvenile xanthogranuloma ECD Edheim Chester disease

RDD Rosai-Dorfman disease HLH hemophagocytic lymphohistiocytosis

CD1+

CD14+

HLADR+

Dendritic cell (histiocyte) proliferation

- Langerhans cell histiocytosis (LCH)

- Juvenile xanthogranulomas (JXG) amp related disorders

- Solitary histiocytomas of various DC phenotype

Macrophage proliferation

- Hemophagocytic lymphohistiocytosis (HLH)

- Sinus histiocytosis with massive lymphadenopathy (SHML Rosai-Dorfman disease)

- Solitary histiocytoma of macrophage phenotype

Histiocytosis syndrome

ICD-10 Langerhans cell histiocytosis C960

Hemophagocytic lymphohistiocytosis D761

Malignant histiocytosis C968

HLH มกลมยอยดงน Familial Hemophagocytic Lymphohistiocytosis

Infectious-associated hemophagocytosis (IAHS)

Malignant-associated hemophagocytosis (MAHS)

Macrophage Activation Syndrome (MAS) refractory

to steroid

Int J Hematol 2007

Hyperinflammatory disorder hypercytokinemia and excessively activated lymphocytes and histiocytescharacterized by cytopenia hepatosplenomegaly DIC hyperferritinemia and hemophagocytosis

Primary Secondary

Infection auto-immuneinflammatory

lymphoma post-SCT

Genetic disease

HLH

Familial HLH FHL

Hemophagocytic lymphohistiocytosis HLH

Epidemiology of HLH

12 M or 150000 live-birth (FHLH Swedish registry)

80 of FHL onset in the first year of life

Likely to be under-diagnosed

ThaiPOG 2003-5

2031000000

MF = 11

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Number

1 sex

Male 45 517

Female 42 483

2 age at diagnosis (year)

lt1 16 1860

1-4 37 4302

5-9 19 2209

10-14 13 1512

3 basis of diagnosis

Histology 75 8621

Hist Mets 6 690

Hematology 1 115

X-ray 2 230

Clinical 3 345

Variable Number

4 subtype

Langerhan cell histiocytosis 59 6782

Hemophagocytic syndrome 23 2644

Malignant 4 460

41 Langerhan cell histiocytosis

9751 Langerhan cell histiocytosis NOS 11 186

9752 Langerhan cell histiocytosis unifocal 13 220

9753 Langerhan cell histiocytosis multifocal 20 339

9754 Langerhan cell histiocytosis disseminated 14 237

9999 not specify 1 17

42 Hemophagocytic syndrome

Familial erythrophagocytic lymphohistiocytosis 1 44

Sinus histiocytosis with massive lymphadenopathy 1 44

Hemophagocytosis with infection associated 5 217

Hemophagocytosis NOS 16 696

5 final status

Alive 60 690

Death 20 230

Unknown 7 81

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Cell Origins of Histiocytic Diseases

Stem cell

Monocyte

CD11cCD68

CD14+

CD1 ndash

HLADR+

DCSIGN

Fxllla

int

Interstitial

CD14+DC

CD68

CD68

CD163

CD11c

CD206

Macrophage

Mesenchymal

Precursor cell

CD21

CD23

CD35

Follicular

DC

Macrophage

DC Precursor

Myeloid

DC Precursor

CD205

CD1a

intDermal

CD1a+DC

CD207

CD1a

High

S100

Langerhans cell

LCH LCH ECD JXG HLHRDD Malignant Histiocytosis

DC dendritic cell JXG juvenile xanthogranuloma ECD Edheim Chester disease

RDD Rosai-Dorfman disease HLH hemophagocytic lymphohistiocytosis

CD1+

CD14+

HLADR+

Dendritic cell (histiocyte) proliferation

- Langerhans cell histiocytosis (LCH)

- Juvenile xanthogranulomas (JXG) amp related disorders

- Solitary histiocytomas of various DC phenotype

Macrophage proliferation

- Hemophagocytic lymphohistiocytosis (HLH)

- Sinus histiocytosis with massive lymphadenopathy (SHML Rosai-Dorfman disease)

- Solitary histiocytoma of macrophage phenotype

Histiocytosis syndrome

ICD-10 Langerhans cell histiocytosis C960

Hemophagocytic lymphohistiocytosis D761

Malignant histiocytosis C968

HLH มกลมยอยดงน Familial Hemophagocytic Lymphohistiocytosis

Infectious-associated hemophagocytosis (IAHS)

Malignant-associated hemophagocytosis (MAHS)

Macrophage Activation Syndrome (MAS) refractory

to steroid

Int J Hematol 2007

Hyperinflammatory disorder hypercytokinemia and excessively activated lymphocytes and histiocytescharacterized by cytopenia hepatosplenomegaly DIC hyperferritinemia and hemophagocytosis

Primary Secondary

Infection auto-immuneinflammatory

lymphoma post-SCT

Genetic disease

HLH

Familial HLH FHL

Hemophagocytic lymphohistiocytosis HLH

Epidemiology of HLH

12 M or 150000 live-birth (FHLH Swedish registry)

80 of FHL onset in the first year of life

Likely to be under-diagnosed

ThaiPOG 2003-5

2031000000

MF = 11

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Number

1 sex

Male 45 517

Female 42 483

2 age at diagnosis (year)

lt1 16 1860

1-4 37 4302

5-9 19 2209

10-14 13 1512

3 basis of diagnosis

Histology 75 8621

Hist Mets 6 690

Hematology 1 115

X-ray 2 230

Clinical 3 345

Variable Number

4 subtype

Langerhan cell histiocytosis 59 6782

Hemophagocytic syndrome 23 2644

Malignant 4 460

41 Langerhan cell histiocytosis

9751 Langerhan cell histiocytosis NOS 11 186

9752 Langerhan cell histiocytosis unifocal 13 220

9753 Langerhan cell histiocytosis multifocal 20 339

9754 Langerhan cell histiocytosis disseminated 14 237

9999 not specify 1 17

42 Hemophagocytic syndrome

Familial erythrophagocytic lymphohistiocytosis 1 44

Sinus histiocytosis with massive lymphadenopathy 1 44

Hemophagocytosis with infection associated 5 217

Hemophagocytosis NOS 16 696

5 final status

Alive 60 690

Death 20 230

Unknown 7 81

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Dendritic cell (histiocyte) proliferation

- Langerhans cell histiocytosis (LCH)

- Juvenile xanthogranulomas (JXG) amp related disorders

- Solitary histiocytomas of various DC phenotype

Macrophage proliferation

- Hemophagocytic lymphohistiocytosis (HLH)

- Sinus histiocytosis with massive lymphadenopathy (SHML Rosai-Dorfman disease)

- Solitary histiocytoma of macrophage phenotype

Histiocytosis syndrome

ICD-10 Langerhans cell histiocytosis C960

Hemophagocytic lymphohistiocytosis D761

Malignant histiocytosis C968

HLH มกลมยอยดงน Familial Hemophagocytic Lymphohistiocytosis

Infectious-associated hemophagocytosis (IAHS)

Malignant-associated hemophagocytosis (MAHS)

Macrophage Activation Syndrome (MAS) refractory

to steroid

Int J Hematol 2007

Hyperinflammatory disorder hypercytokinemia and excessively activated lymphocytes and histiocytescharacterized by cytopenia hepatosplenomegaly DIC hyperferritinemia and hemophagocytosis

Primary Secondary

Infection auto-immuneinflammatory

lymphoma post-SCT

Genetic disease

HLH

Familial HLH FHL

Hemophagocytic lymphohistiocytosis HLH

Epidemiology of HLH

12 M or 150000 live-birth (FHLH Swedish registry)

80 of FHL onset in the first year of life

Likely to be under-diagnosed

ThaiPOG 2003-5

2031000000

MF = 11

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Number

1 sex

Male 45 517

Female 42 483

2 age at diagnosis (year)

lt1 16 1860

1-4 37 4302

5-9 19 2209

10-14 13 1512

3 basis of diagnosis

Histology 75 8621

Hist Mets 6 690

Hematology 1 115

X-ray 2 230

Clinical 3 345

Variable Number

4 subtype

Langerhan cell histiocytosis 59 6782

Hemophagocytic syndrome 23 2644

Malignant 4 460

41 Langerhan cell histiocytosis

9751 Langerhan cell histiocytosis NOS 11 186

9752 Langerhan cell histiocytosis unifocal 13 220

9753 Langerhan cell histiocytosis multifocal 20 339

9754 Langerhan cell histiocytosis disseminated 14 237

9999 not specify 1 17

42 Hemophagocytic syndrome

Familial erythrophagocytic lymphohistiocytosis 1 44

Sinus histiocytosis with massive lymphadenopathy 1 44

Hemophagocytosis with infection associated 5 217

Hemophagocytosis NOS 16 696

5 final status

Alive 60 690

Death 20 230

Unknown 7 81

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

ICD-10 Langerhans cell histiocytosis C960

Hemophagocytic lymphohistiocytosis D761

Malignant histiocytosis C968

HLH มกลมยอยดงน Familial Hemophagocytic Lymphohistiocytosis

Infectious-associated hemophagocytosis (IAHS)

Malignant-associated hemophagocytosis (MAHS)

Macrophage Activation Syndrome (MAS) refractory

to steroid

Int J Hematol 2007

Hyperinflammatory disorder hypercytokinemia and excessively activated lymphocytes and histiocytescharacterized by cytopenia hepatosplenomegaly DIC hyperferritinemia and hemophagocytosis

Primary Secondary

Infection auto-immuneinflammatory

lymphoma post-SCT

Genetic disease

HLH

Familial HLH FHL

Hemophagocytic lymphohistiocytosis HLH

Epidemiology of HLH

12 M or 150000 live-birth (FHLH Swedish registry)

80 of FHL onset in the first year of life

Likely to be under-diagnosed

ThaiPOG 2003-5

2031000000

MF = 11

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Number

1 sex

Male 45 517

Female 42 483

2 age at diagnosis (year)

lt1 16 1860

1-4 37 4302

5-9 19 2209

10-14 13 1512

3 basis of diagnosis

Histology 75 8621

Hist Mets 6 690

Hematology 1 115

X-ray 2 230

Clinical 3 345

Variable Number

4 subtype

Langerhan cell histiocytosis 59 6782

Hemophagocytic syndrome 23 2644

Malignant 4 460

41 Langerhan cell histiocytosis

9751 Langerhan cell histiocytosis NOS 11 186

9752 Langerhan cell histiocytosis unifocal 13 220

9753 Langerhan cell histiocytosis multifocal 20 339

9754 Langerhan cell histiocytosis disseminated 14 237

9999 not specify 1 17

42 Hemophagocytic syndrome

Familial erythrophagocytic lymphohistiocytosis 1 44

Sinus histiocytosis with massive lymphadenopathy 1 44

Hemophagocytosis with infection associated 5 217

Hemophagocytosis NOS 16 696

5 final status

Alive 60 690

Death 20 230

Unknown 7 81

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Int J Hematol 2007

Hyperinflammatory disorder hypercytokinemia and excessively activated lymphocytes and histiocytescharacterized by cytopenia hepatosplenomegaly DIC hyperferritinemia and hemophagocytosis

Primary Secondary

Infection auto-immuneinflammatory

lymphoma post-SCT

Genetic disease

HLH

Familial HLH FHL

Hemophagocytic lymphohistiocytosis HLH

Epidemiology of HLH

12 M or 150000 live-birth (FHLH Swedish registry)

80 of FHL onset in the first year of life

Likely to be under-diagnosed

ThaiPOG 2003-5

2031000000

MF = 11

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Number

1 sex

Male 45 517

Female 42 483

2 age at diagnosis (year)

lt1 16 1860

1-4 37 4302

5-9 19 2209

10-14 13 1512

3 basis of diagnosis

Histology 75 8621

Hist Mets 6 690

Hematology 1 115

X-ray 2 230

Clinical 3 345

Variable Number

4 subtype

Langerhan cell histiocytosis 59 6782

Hemophagocytic syndrome 23 2644

Malignant 4 460

41 Langerhan cell histiocytosis

9751 Langerhan cell histiocytosis NOS 11 186

9752 Langerhan cell histiocytosis unifocal 13 220

9753 Langerhan cell histiocytosis multifocal 20 339

9754 Langerhan cell histiocytosis disseminated 14 237

9999 not specify 1 17

42 Hemophagocytic syndrome

Familial erythrophagocytic lymphohistiocytosis 1 44

Sinus histiocytosis with massive lymphadenopathy 1 44

Hemophagocytosis with infection associated 5 217

Hemophagocytosis NOS 16 696

5 final status

Alive 60 690

Death 20 230

Unknown 7 81

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Epidemiology of HLH

12 M or 150000 live-birth (FHLH Swedish registry)

80 of FHL onset in the first year of life

Likely to be under-diagnosed

ThaiPOG 2003-5

2031000000

MF = 11

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Number

1 sex

Male 45 517

Female 42 483

2 age at diagnosis (year)

lt1 16 1860

1-4 37 4302

5-9 19 2209

10-14 13 1512

3 basis of diagnosis

Histology 75 8621

Hist Mets 6 690

Hematology 1 115

X-ray 2 230

Clinical 3 345

Variable Number

4 subtype

Langerhan cell histiocytosis 59 6782

Hemophagocytic syndrome 23 2644

Malignant 4 460

41 Langerhan cell histiocytosis

9751 Langerhan cell histiocytosis NOS 11 186

9752 Langerhan cell histiocytosis unifocal 13 220

9753 Langerhan cell histiocytosis multifocal 20 339

9754 Langerhan cell histiocytosis disseminated 14 237

9999 not specify 1 17

42 Hemophagocytic syndrome

Familial erythrophagocytic lymphohistiocytosis 1 44

Sinus histiocytosis with massive lymphadenopathy 1 44

Hemophagocytosis with infection associated 5 217

Hemophagocytosis NOS 16 696

5 final status

Alive 60 690

Death 20 230

Unknown 7 81

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Number

1 sex

Male 45 517

Female 42 483

2 age at diagnosis (year)

lt1 16 1860

1-4 37 4302

5-9 19 2209

10-14 13 1512

3 basis of diagnosis

Histology 75 8621

Hist Mets 6 690

Hematology 1 115

X-ray 2 230

Clinical 3 345

Variable Number

4 subtype

Langerhan cell histiocytosis 59 6782

Hemophagocytic syndrome 23 2644

Malignant 4 460

41 Langerhan cell histiocytosis

9751 Langerhan cell histiocytosis NOS 11 186

9752 Langerhan cell histiocytosis unifocal 13 220

9753 Langerhan cell histiocytosis multifocal 20 339

9754 Langerhan cell histiocytosis disseminated 14 237

9999 not specify 1 17

42 Hemophagocytic syndrome

Familial erythrophagocytic lymphohistiocytosis 1 44

Sinus histiocytosis with massive lymphadenopathy 1 44

Hemophagocytosis with infection associated 5 217

Hemophagocytosis NOS 16 696

5 final status

Alive 60 690

Death 20 230

Unknown 7 81

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Variable Number

4 subtype

Langerhan cell histiocytosis 59 6782

Hemophagocytic syndrome 23 2644

Malignant 4 460

41 Langerhan cell histiocytosis

9751 Langerhan cell histiocytosis NOS 11 186

9752 Langerhan cell histiocytosis unifocal 13 220

9753 Langerhan cell histiocytosis multifocal 20 339

9754 Langerhan cell histiocytosis disseminated 14 237

9999 not specify 1 17

42 Hemophagocytic syndrome

Familial erythrophagocytic lymphohistiocytosis 1 44

Sinus histiocytosis with massive lymphadenopathy 1 44

Hemophagocytosis with infection associated 5 217

Hemophagocytosis NOS 16 696

5 final status

Alive 60 690

Death 20 230

Unknown 7 81

Histiocytosis ThaiPOG 2003-5 N= 87

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Variable Yes Virus 16 696Bacteria 3

130Fungus 2 87Parasites 4 174

Infectious agents (IAHS) (N=23)

ThaiPOG 2003-5

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Pathogenesis of primary HLH

Incomplete exclusion of infected cells

Postulated mechanisms

Incomplete fratricide killing of activated T cells

Persistent stimulation of antigens (PAMPDAMP)

Perforin amp Granzyme

Production of cytotoxic granules

Trafficking and sorting

Docking priming fusion and

degranulation

Endoplasmic reticulumGolgi-

complex

FHL2

Chediak-Higashi Hermansky-Pudlak

FHL3-5Griscelli

Immune synapse

Target cells

Infected cells

CD8+T cell CD56+NK cells

Effector cells

lysosome Activated T cells

(CTL Th)

IL-1

21

8

Antigen presenting cells (APC) Macrophage

IFNg

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

The Dx of HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular Dx consistent with HLH

(2) Dx criteria for HLH fulfilled (5 out of 8 criteria below)

① Fever

② Splenomegaly

③ Cytopenias (affecting ge2 of 3 lineages in PB)Hgb lt90 gL (in infants lt4 weeks Hgb lt100 gL)

Platelets lt100ⅹ109L

Neutrophils lt10ⅹ109L

④ Hypertriglyceridemia andor hypofibrinogenemiaFasting triglycerides ge30 mmolL (ie ge265 mgdl)

Fibrinogen le15 gL

⑤ Hemophagocytosis in BM or spleen or LN

⑥ Low or absent NK-cell activity

⑦ Ferritin ge500 mgL

⑧ Soluble CD25 (sIL-2 receptor) ge2400 Uml

HLH-2004 Dx Guidelines

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Hemophagocytosis

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Classification of HLH

Primary genetic Secondary acquired

FHLHChromosome 9 linkage (FHL1)PRF1 mutations (FHL2)UNC13D mutations (FHL3) STX11 mutations (FHL4)STXBP2 mutations (FHL5)

Albinism syndromesLYST mutations (Chediak-Higashi syndrome)RAB27A mutations(Griscelli syndrome)

Other immunodeficienciesSH2D1A mutations (XLP1)XIAP mutations (XLP2)ITK (IL-2-inducible T-cell kinase) deficiency

Infection associatedvirus (EBVCMVHSVVSV)bacteria (mycoplasma)parasite fungus

Autoimmune associatedsJIA SLE IBD Kawasaki AOSD

Malignancy associatedT-cell lymphoma

Metabolic disease associatedGaucher diseaseLysinuric protein intolerance

Post organ transplantation

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Secondary hemophagocytic lymphohistiocytosis in children an

analysis of etiology and outcome

Veerakul G J Med Assoc Thai 2002

bull N =52 1989 -1998

bull IAHSN=15

bull MAHS N = 25 (NHL 15 leukemia 7 MDS 1 LCH 1 histiocytic sarcoma 1)

bull idiopathic HLH = 12

bull Causative organisms for IAHS Salmonella (3) Staphylococcus (2)

Enterobactor (2) dengue virus (3) malaria (2) EBV (1)

Serratia marcesens (1) Penicillium maneffei (1)

bull 15 (288) - died during the acute phase and other 4 died of their subseque

nt malignant diseases

bull poorer prognosis and patients age lt 3 years or MAHS (p=0005)

Principles of HLH Treatment

1 Suppression of hyperinflammation

- Corticosteroids IVIG Cyclosporin ATG

Anticytokine agents

2 Elimination of activated immune cells and

(infected) APCs (CTLs histiocytes)

- Corticosteroids Etoposide T-cell Ab (Alemtuzumab

ATG) Rituximab

3 Elimination of trigger - Anti-infectious therapy

4 Replacement of defective immune system

- Hematopoietic stem cell transplantation

1994

2004

HLH 942004 Protocol

Backbone VP-16 + Dexa + CSA

bull Etoposide potent selective deletion of activated T-cell

efficient suppression of inflammatory cytokine

production

bull CSA inhibit gamma-IFN

bull Dexa Long half life CSF

bull Non-verified FLH with complete resolution of disease

stop Tx after 8 weeks

bull IVIG (for IAHS only)

2600 develop cancer Blood 2017

Indication of HSCT for HLH (Flow-sheet of HLH-2004)

Patientswith HLH

Start Initial

8 weeks

chemotherapy

Genetically verified orfamilialdisease

PersistentNon-familialnon-genetically verified

ResolvedNon-familialNon-geneticallyverified

Continuation therapy until SCT

Continuation therapy until SCT

Continuation therapy until SCT

Stoptherapy

Reactivation

1994 2004 (N=369)

5 yr survival () 54 (CI 48-60) 61 (CI 56-67)W 59 (CI 52-67)

Wo 64 (CI 57-71)

Pre-HSCT mortality ()p= 064

27 19

5yr-Survival post HSCT 66 67

IT+ steroid Upfront CSAVS late neuro Sequele

22 17

Blood 2017

Withwithout genetically verified

Hyperferritinemia

Pediatr Blood Cancer 20081227

Maximum ferritin over 10000 mgL

Survival HLH 2004 Post HSCT

Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 06)

HLH-2004 may be improved by risk-group

stratification less therapy reduction weeks

7 to 8 for verified FHL patients and earlier

HSCT

Key points HLH 2004

Blood 2017

1994

2004

HLH 942004 Protocol

Backbone VP-16 + Dexa + CSA

bull Etoposide potent selective deletion of activated T-cell

efficient suppression of inflammatory cytokine

production

bull CSA inhibit gamma-IFN

bull Dexa Long half life CSF

bull Non-verified FLH with complete resolution of disease

stop Tx after 8 weeks

bull IVIG (for IAHS only)

2600 develop cancer Blood 2017

Indication of HSCT for HLH (Flow-sheet of HLH-2004)

Patientswith HLH

Start Initial

8 weeks

chemotherapy

Genetically verified orfamilialdisease

PersistentNon-familialnon-genetically verified

ResolvedNon-familialNon-geneticallyverified

Continuation therapy until SCT

Continuation therapy until SCT

Continuation therapy until SCT

Stoptherapy

Reactivation

1994 2004 (N=369)

5 yr survival () 54 (CI 48-60) 61 (CI 56-67)W 59 (CI 52-67)

Wo 64 (CI 57-71)

Pre-HSCT mortality ()p= 064

27 19

5yr-Survival post HSCT 66 67

IT+ steroid Upfront CSAVS late neuro Sequele

22 17

Blood 2017

Withwithout genetically verified

Hyperferritinemia

Pediatr Blood Cancer 20081227

Maximum ferritin over 10000 mgL

Survival HLH 2004 Post HSCT

Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 06)

HLH-2004 may be improved by risk-group

stratification less therapy reduction weeks

7 to 8 for verified FHL patients and earlier

HSCT

Key points HLH 2004

Blood 2017

HLH 942004 Protocol

Backbone VP-16 + Dexa + CSA

bull Etoposide potent selective deletion of activated T-cell

efficient suppression of inflammatory cytokine

production

bull CSA inhibit gamma-IFN

bull Dexa Long half life CSF

bull Non-verified FLH with complete resolution of disease

stop Tx after 8 weeks

bull IVIG (for IAHS only)

2600 develop cancer Blood 2017

Indication of HSCT for HLH (Flow-sheet of HLH-2004)

Patientswith HLH

Start Initial

8 weeks

chemotherapy

Genetically verified orfamilialdisease

PersistentNon-familialnon-genetically verified

ResolvedNon-familialNon-geneticallyverified

Continuation therapy until SCT

Continuation therapy until SCT

Continuation therapy until SCT

Stoptherapy

Reactivation

1994 2004 (N=369)

5 yr survival () 54 (CI 48-60) 61 (CI 56-67)W 59 (CI 52-67)

Wo 64 (CI 57-71)

Pre-HSCT mortality ()p= 064

27 19

5yr-Survival post HSCT 66 67

IT+ steroid Upfront CSAVS late neuro Sequele

22 17

Blood 2017

Withwithout genetically verified

Hyperferritinemia

Pediatr Blood Cancer 20081227

Maximum ferritin over 10000 mgL

Survival HLH 2004 Post HSCT

Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 06)

HLH-2004 may be improved by risk-group

stratification less therapy reduction weeks

7 to 8 for verified FHL patients and earlier

HSCT

Key points HLH 2004

Blood 2017

Indication of HSCT for HLH (Flow-sheet of HLH-2004)

Patientswith HLH

Start Initial

8 weeks

chemotherapy

Genetically verified orfamilialdisease

PersistentNon-familialnon-genetically verified

ResolvedNon-familialNon-geneticallyverified

Continuation therapy until SCT

Continuation therapy until SCT

Continuation therapy until SCT

Stoptherapy

Reactivation

1994 2004 (N=369)

5 yr survival () 54 (CI 48-60) 61 (CI 56-67)W 59 (CI 52-67)

Wo 64 (CI 57-71)

Pre-HSCT mortality ()p= 064

27 19

5yr-Survival post HSCT 66 67

IT+ steroid Upfront CSAVS late neuro Sequele

22 17

Blood 2017

Withwithout genetically verified

Hyperferritinemia

Pediatr Blood Cancer 20081227

Maximum ferritin over 10000 mgL

Survival HLH 2004 Post HSCT

Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 06)

HLH-2004 may be improved by risk-group

stratification less therapy reduction weeks

7 to 8 for verified FHL patients and earlier

HSCT

Key points HLH 2004

Blood 2017

1994 2004 (N=369)

5 yr survival () 54 (CI 48-60) 61 (CI 56-67)W 59 (CI 52-67)

Wo 64 (CI 57-71)

Pre-HSCT mortality ()p= 064

27 19

5yr-Survival post HSCT 66 67

IT+ steroid Upfront CSAVS late neuro Sequele

22 17

Blood 2017

Withwithout genetically verified

Hyperferritinemia

Pediatr Blood Cancer 20081227

Maximum ferritin over 10000 mgL

Survival HLH 2004 Post HSCT

Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 06)

HLH-2004 may be improved by risk-group

stratification less therapy reduction weeks

7 to 8 for verified FHL patients and earlier

HSCT

Key points HLH 2004

Blood 2017

Hyperferritinemia

Pediatr Blood Cancer 20081227

Maximum ferritin over 10000 mgL

Survival HLH 2004 Post HSCT

Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 06)

HLH-2004 may be improved by risk-group

stratification less therapy reduction weeks

7 to 8 for verified FHL patients and earlier

HSCT

Key points HLH 2004

Blood 2017

Survival HLH 2004 Post HSCT

Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 06)

HLH-2004 may be improved by risk-group

stratification less therapy reduction weeks

7 to 8 for verified FHL patients and earlier

HSCT

Key points HLH 2004

Blood 2017

Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 06)

HLH-2004 may be improved by risk-group

stratification less therapy reduction weeks

7 to 8 for verified FHL patients and earlier

HSCT

Key points HLH 2004

Blood 2017