Hemophagocytic Lymphohistiocytosis (HLH, Hemophagocytic Syndrome)

Classification of Histiocytic Disorders

Benign Disorders with Variable Biologic Behavior

Dendritic Cell-Related Disorders

Langerhans Cell Histiocytosis (LCH) (see Langerhans Cell Histiocytosis)
Erdheim-Chester Disease (ECD)
Juvenile Xanthogranuloma (JXG)
Solitary Histiocytomas with Juvenile Xanthogranuloma Phenotype
Secondary Dendritic Cell Disorders

Macrophage-Related Disorders

Hemophagocytic Lymphohistiocytosis (HLH) (Primary Hemophagocytic Syndrome)
- Familial: accounts for approximately 25% of all HLH cases (J Intensive Care Med, 2015) [MEDLINE]
- Sporadic
Secondary Hemophagocytic Syndrome
- Infection: infection (especially viral infection) is a common precipitant of hemophagocytic syndrome
  - Adenovirus (see Adenovirus)
  - Brucellosis (see Brucellosis): less commonly associated with hemophagocytic lymphohistiocytosis
  - Candida (see Candida)
  - Cryptococcosis (see Cryptococcosis)
  - Cytomegalovirus (CMV) (see Cytomegalovirus)
  - Dengue Hemorrhagic Fever (see Dengue Virus)
  - Hepatitis A Virus (see xxxx)
  - Hepatitis B Virus (see xxxx)
  - Hepatitis C Virus (see xxxx)
  - Herpes Simplex Virus (HSV) (see Herpes Simplex Virus)
  - Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
  - Human Herpesvirus 6 (see Human Herpesvirus 6)
  - Human Herpesvirus 8 (see Human Herpesvirus 8)
  - Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
    - Hemophagocytic lymphohistiocytosis has also been reported after initiation of antiretroviral therapy (see Immune Reconstitution Inflammatory Syndrome)
  - Infectious Mononucleosis (Epstein-Barr Virus, EBV) (see Epstein-Barr Virus)
    - EBV is the Infection Most Commonly Associated with HLH (and Which Has Been the Best Studied)
  - Influenza A Virus (see Influenza Virus): antigenic type H1N1
  - Leishmaniasis (see Leishmaniasis): less commonly associated with hemophagocytic lymphohistiocytosis
  - Malaria (see Malaria): less commonly associated with hemophagocytic lymphohistiocytosis
  - Measles Virus (see Measles Virus)
  - Merkel Cell Polyomavirus
  - Mumps Virus (see Mumps Virus)
  - Mycobacteria (see Mycobacterium)
    - Tuberculosis (see Tuberculosis,): less commonly associated with hemophagocytic lymphohistiocytosis
  - Mycoplasma (see Mycoplasma)
  - Parainfluenza Virus (see Parainfluenza Virus): type III
  - Parechovirus
  - Parvovirus B19 (see Parvovirus B19)
  - Pneumocystis Jirovecii (see Pneumocystis Jirovecii)
  - Rubella Virus (see Rubella Virus)
  - Toxoplasmosis (see Toxoplasmosis)
  - Tuberculosis (Disseminated) (see Tuberculosis) (NEJM, 2020) [MEDLINE]
  - Varicella-Zoster Virus (VZV) (see Varicella-Zoster Virus)
- Malignancy: hemophagocytic lymphohistiocytosis has been most commonly associated with lymphoid malignancies (although cases associated with myeloid malignancies and solid tumors have been reported)
  - Acute Erythroid Leukemia
  - Acute Lymphoblastic Leukemia
  - Aggressive NK Cell Leukemia (ANKL) (see NK Cell Leukemia)
  - Anaplastic Large Cell Lymphoma (see Lymphoma)
  - Extranodal NK/T-Cell Lymphoma, Nasal Type (ENKL) (see Extranodal NK/T-Cell Lymphoma, Nasal Type)
  - Hepatocellular Carcinoma (see Hepatocellular Carcinoma)
  - Hodgkin Lymphoma (see Hodgkin Lymphoma)
  - Lung Cancer (see Lung Cancer)
  - Prostate Cancer (see Prostate Cancer)
- Primary Immunodeficiency
  - Chediak-Higashi Syndrome (see Chediak-Higashi Syndrome)
  - Di George/del (22q11) Syndrome
  - Griscelli Syndrome (Type 2)
  - Hermansky-Pudlak Syndome (Type 2)
  - Severe Combined Immunodeficiency (SCID) (see Severe Combined Immunodeficiency)
  - Wiskott-Aldrich Syndrome
  - XLP-Types 1 and 2
- Secondary Immunodeficiency
  - Hematopoietic Stem Cell Transplant (HSCT) (Bone Marrow Transplant) (see Hematopoietic Stem Cell Transplant)
  - Liver Transplant (see Liver Transplant)
  - Renal Transplant (see Renal Transplant): appears to be associated with antithymocyte globulin (ATG) and splenectomy
- Autoimmune/Macrophage Activation Syndrome (MAS)
  - Adult-Onset Still’s Disease (see Adult-Onset Still’s Disease)
  - Ankylosing Spondylitis (see Ankylosing Spondylitis)
  - Antiphospholipid Antibody Syndrome (see Antiphospholipid Antibody Syndrome)
  - Hashimoto’s Thyroiditis (see Hashimotos Thyroiditis)
  - Inflammatory Bowel Disease (see Inflammatory Bowel Disease)
  - Juvenile Rheumatoid Arthritis (JRA)/Systemic-Onset Juvenile Idiopathic Arthritis (SoJIA)
  - Kawasaki Disease (see Kawasaki Disease)
  - Mixed Connective Tissue Disease (MCTD) (see Mixed Connective Tissue Disease)
  - Polyarteritis Nodosa (PAN) (see Polyarteritis Nodosa)
  - Polydermatomyositis (see Polydermatomyositis)
  - Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis)
  - Sarcoidosis (see Sarcoidosis)
  - Scleroderma (see Scleroderma)
  - Sjogren’s Syndrome (see Sjogren’s Syndrome)
  - Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus)
  - Vasculitis (see Vasculitis)
- Drugs
  - Etanercept (Enbrel) (see Etanercept) (Intern Med, 2011) [MEDLINE]
  - Tocilizumab (Actemra) (see Tocilizumab): where used to treat systemic juvenile idiopathic arthritis (sJIA)

Other

Rosai-Dorfman Disease (RD): sinus histiocytosis with massive lymphadenopathy
Solitary Histiocytoma of Macrophage Phenotype

Malignant Disorders

Monocyte-Associated
- Leukemias
  - Acute Monocytic Leukemia (M5A, M5B)
  - Acute Myelomonocytic Leukemia (M4)
  - Chronic Myelomonocytic Leukemia
- Extramedullary Monocytic Tumor or Sarcoma
Dendritic Cell-Related Histiocytic Sarcoma: localized or disseminated
Macrophage-Related Histiocytic Sarcoma: localized or disseminated

Epidemiology

History

Hemophagocytic Lymphohistiocytosis was First Clinically Described in 1939 [Histiocytic medullary reticulosis. Lancet 1939;ii:194e8)]

Association with Other Diseases

Infection: 41% of cases (Am J Hematol, 2015) [MEDLINE]
- Both Sporadic and Familial HLH May Be Precipitated by Acute Infection
- HLH May Mimic Severe Sepsis and Leptospirosis
- HLH May Obscure the Diagnosis of a Precipitating, Treatable Infection (as Has Been Reported for Visceral Leishmaniasis)
Malignancy: 28.8% of cases (Am J Hematol, 2015) [MEDLINE]
Idiopathic: 17.8% of cases (Am J Hematol, 2015) [MEDLINE]
Autoimmune Disease: 6.8% of cases (Am J Hematol, 2015) [MEDLINE]
Solid Organ Transplant: 2.7% of cases (Am J Hematol, 2015) [MEDLINE]
Primary Immunodeficiency: 1.4% of cases (Am J Hematol, 2015) [MEDLINE]

Demographics

Age
- Average Age: 51 y/o (Range: 18-82 y/o) (Am J Hematol, 2015) [MEDLINE]
  - In a Large Review (n = 775 Adult Cases), Mean Age was 49.03 y/o (Range: 41-67 y/o) (Lancet, 2014) [MEDLINE]
Sex
- Male Sex: 56.2% of cases
  - In a Large Review (n = 775 Adult Cases), Males Represented 63% of Cases (Lancet, 2014) [MEDLINE]

Etiology

Categorization of Hemophagocytic Lymphohistiocytosis (HLH) (Best Pract Res Clin Rheumatol, 2020) [MEDLINE]

Familial-Hemophagocytic Lymphohistiocytosis (F-HLH)

Demographics
- Children < 1 y/o
Susceptibility
- Genetic Defects in Cytotoxicity
  - Type 1 (F-HLH 1): Gene 9q21.3-q22 -> Unknown Protein
    - Unknown Defect
  - Type 2 (F-HLH 2): Gene PRF1 -> perforin Protein
    - Defect in Cytolytic Pore Formation
  - Type 3 (F-HLH 3): Gene UNC13D -> Unc-13 Homolog D Protein
    - Defect in Cytolytic Vesicle Priming
  - Type 4 (F-HLH 4): Gene STX11 -> Syntaxin 11 Protein
    - Defect in Cytolytic Vesicle Fusion
  - Type 5 (F-HLH 5): Gene STXBP2 -> Syntaxin Binding Protein 2
    - Defect in Cytolytic Vesicle Fusion
Triggers
- Presumed Viral Infection
Diagnosis
- HLH-2004
Unique Laboratory/Clinical Features
- Consanguinity
- Family History
- Prominent Central Nervous System Involvement
- Severe/Fulminant Disease

Rheumatologic Hemophagocytic Lymphohistiocytosis (Rh-HLH)

Demographics
- Children
  - Kawasaki Disease (see Kawasaki Disease)
  - Systemic Juvenile Idiopathic Arthritis (sJIA): high risk
  - Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus): strong association
- Adults
  - Adult-Onset Still’s Disease (see Adult-Onset Still’s Disease): strong association
  - Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus): strong association
  - Inflammatory Bowel Disease (IBD)
  - Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis)
  - Vasculitis (see Vasculitis)
Susceptibility
- Chronic Inflammation (Especially IL-18)
Triggers
- Unknown
  - Possible Toll-Like Receptor (TLR) Stimulation
Diagnosis
- H-Score
- MS Score (for Systemic Juvenile Idiopathic Arthritis/sJIA)
Unique Laboratory/Clinical Features
- Leukopenia and/or Thrombocytopenia (see Leukopenia and Thrombocytopenia)
- Transformation of Quotidian to Persistent Fever (see Fever)

Hemophagocytic Lymphohistiocytosis with Immunocompromised State (IC-HLH)

Demographics
- Immunocompromised Child/Adult
  - Chemotherapy for Cancer
  - Immunosuppressive Therapy for Inflammatory Bowel Disease (IBD), etc
- Children with Select Primary Immunodeficiency Syndromes: due to altered host susceptibility to the triggering infection and an abnormal immune response to the pathogen
  - Chediak-Higashi Syndrome (see Chediak-Higashi Syndrome): strong association
  - Griscelli Syndrome Type 2: strong association
  - Hermansky-Pudlak Syndrome Type 2: strong association
  - Autoimmune Lymphoproliferative Syndrome
  - Chronic Granulomatous Disease (CGD) (see Chronic Granulomatous Disease)
  - DiGeorge Syndrome
  - Severe Combined Immunodeficiency (SCID)
  - Wiskott-Aldrich Syndrome
  - X-linked Agammaglobulinemia
Susceptibility
- Defective Cytotoxicity (Genetic or Acquired)
- Immunocompromised State
  - Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant)
  - Renal Transplant (see Renal Transplant)
Triggers (Lancet, 2014) [MEDLINE] (Best Pract Res Clin Rheumatol, 2020) [MEDLINE]
- Viral Infection
  - General Comments
    - Viral Infection (Either Primary infection in a Healthy Patient or After Reactivation in an Immunocompromised Patient) is the Most Common Trigger of Hemophagocytic Lymphohistiocytosis (HLH) (Lancet, 2014) [MEDLINE]
    - Herpes Viruses Account for 62% of Adult Virus-Associated Cases of Hemophagocytic Lymphohistiocytosis (HLH) Cases (Lancet, 2014) [MEDLINE]
  - Epstein-Barr Virus (EBV) (see Epstein-Barr Virus): strong association
    - Epstein-Barr Virus (EBV) is the Most Common Infectious Trigger of Hemophagocytic Lymphohistiocytosis (HLH)
    - Epstein-Barr Virus (EBV)-Associated Hemophagocytic Lymphohistiocytosis (HLH) Occurs Mostly in Children and Adolescents, Often in the Context of Familial Hemophagocytic Lymphohistiocytosis (F-HLH) or Primary Immunodeficiency (Best Pract Res Clin Rheumatol, 2020) [MEDLINE]
    - In Adults, Hemophagocytic Lymphohistiocytosis (HLH) is More Frequently Triggered by Epstein-Barr Virus (EBV) Reactivation in the Setting of Immunocompromised State (Best Pract Res Clin Rheumatol, 2020) [MEDLINE]
  - Cytomegalovirus (CMV) (see Cytomegalovirus): strong association
  - Adenovirus (see Adenovirus)
  - Hepatitis A Virus (Acute) (see Hepatitis A Virus)
  - Hepatitis B Virus (HBV) (see Hepatitis B Virus)
    - Hepatitis B Virus (HBV) Can Trigger Hemophagocytic Lymphohistiocytosis (HLH) During the Acute or Chronic Phase of Infection
  - Hepatitis C Virus (HCV) (see Hepatitis C Virus)
    - Hepatitis C Virus (HCV) Can Trigger Hemophagocytic Lymphohistiocytosis (HLH) During the Acute or Chronic Phase of Infection
  - Herpes Simplex Virus (HSV) (see Herpes Simplex Virus)
  - Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
    - Human Immunodeficiency Virus (HIV) Can Trigger Hemophagocytic Lymphohistiocytosis (HLH) During the Acute or Chronic Phase of Infection
  - Influenza Virus (see Influenza Virus)
  - Respiratory Syncytial Virus (RSV) (see Respiratory Syncytial Virus)
  - Rotavirus (see Rotavirus)
  - Parvovirus B19 (see Parvovirus B19)
- Bacterial Infection
  - Mycobacterium Tuberculosis (see Tuberculosis): intracellular pathogen
  - Escherichia Coli (see Escherichia Coli)
  - Rickettsia (see Rickettsia)
  - Staphylococcus (see Staphylococcus)
- Fungal Infection
  - Histoplasmosis (see Histoplasmosis)
  - Pneumocystis Jirovecii (see Pneumocystis Jirovecii): intracellular pathogen
- Parasitic Infection
  - Leishmaniasis (see Leishmaniasis)
  - Malaria (see Malaria): Plasmaodium is an intracellular pathogen
  - Toxoplasmosis (see Toxoplasmosis)
- Pregnancy (see Pregnancy)
Diagnosis
- H-Score
Unique Laboratory/Clinical Features
- Children with Primary Immunodeficiency Disease
  - Bleeding
  - Partial Albinism
  - Recurrent Infections

Hemophagocytic Lymphohistiocytosis with Malignancy (M-HLH)

General Comments
- Malignancy Plays a Role in Approximately 50% of All Adult Hemophagocytic Lymphohistiocytosis (HLH) Cases (Best Pract Res Clin Rheumatol, 2020) [MEDLINE]
- Hemophagocytic Lymphohistiocytosis (HLH) Complicates Up to 1% of All Malignancies in Adults (Lancet, 2014) [MEDLINE] (Cancer, 2017) [MEDLINE] (Immunol Rev, 2019) [MEDLINE] (Best Pract Res Clin Rheumatol, 2020) [MEDLINE] (Pathology, 2020) [MEDLINE]
- Hematological Malignancy (Particularly T, NK, and B-Cell Lymphoma) Account for Most of the Cases of Hemophagocytic Lymphohistiocytosis with Malignancy (M-HLH)
  - Hemophagocytic Lymphohistiocytosis with Malignancy (M-HLH) May Occur Before Cancer Treatment or During Therapy
  - Likely Due to Treatment-Related Immunosuppression and/or Associated Infections
Demographics
- Older Adults: most common
- Children: rare
Susceptibility
- Hematologic Malignancy
  - B-Cell Lymphoma (see Lymphoma)
  - T-Cell Lymphoma (see Lymphoma)
  - Hodgkin Lymphoma (see Hodgkin Lymphoma)
  - NK Cell Lymphoma (see Lymphoma)
  - Castleman Disease (Giant Lymph Node Hyperplasia) (see Castleman Disease)
  - Leukemia
- Solid Tumor
Triggers
- Hematologic Malignancy (Especially T or NK Lymphoma)
Diagnosis
- None
Unique Laboratory/Clinical Features
- Hemophagocytic Lymphohistiocytosis (HLH) May Occur Before Cancer Treatment or During Therapy
  - Likely Due to Immunosuppression and Associated Infections
- Smoldering or Chronic Hemophagocytic Lymphohistiocytosis-Like Disease
Prognosis
- Hemophagocytic Lymphohistiocytosis with Malignancy (M-HLH) Has the Worst Prognosis of All Hemophagocytic Lymphohistiocytosis (HLH) Types (Best Pract Res Clin Rheumatol, 2020) [MEDLINE]

Iatrogenic Hemophagocytic Lymphohistiocytosis (Rx-HLH)

Demographics
- Children/Adults Treated with Any of the Following
  - Chimeric Antigen Receptor T-Cell (CAR-T) Therapy
  - Immune Checkpoint Inhibitor (ICI) Therapy
  - Drugs Associated with Drug-Induced Hypersensitivity Syndrome (DIHS)
Susceptibility
- Specific HLA-A or HLA-B Alleles (Drug-Induced Hypersensitivity Syndrome Only)
Triggers
- Exposure to Drug/Therapy
Diagnosis
- None
Unique Laboratory/Clinical Features
- Drug-Induced Hypersensitivity Syndrome (DIHS)
  - Peripheral Eosinophilia (see Peripheral Eosinophilia)
  - Prominent Rash
- Chimeric Antigen Receptor T-Cell (CAR-T) Therapy
  - Hemophagocytic Lymphohistiocytosis (HLH) Occurs in the Setting of Cytokine-Release Syndrome

Physiology

Interferon-γ (IFN-γ), Interleukin (IL)-1β, and IL-18 Appear to Be the Main Soluble Mediators Involved in the Pathogenesis of Hemophagocytic Lymphohistiocytosis (HLH) (Best Pract Res Clin Rheumatol, 2020) [MEDLINE]

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Diagnosis

Bone Marrow Biopsy (see Bone Marrow Biopsy)

Findings

Low, Normal or High Bone Marrow Cellularity (Blood, 2011) [MEDLINE]
Bone Marrow Hemophagocytosis
- Bone Marrow Hemophagocytosis is Observed in Approximately 25-100% of Cases (Am J Med, 2014) [MEDLINE]
  - In a Large Review (n = 775 Adult Cases), Positive Bone Marrow Aspirate for Hemophagocytosis was Observed in 85% of Cases (Lancet, 2014) [MEDLINE]
  - In a Large Review (n = 775 Adult Cases), Positive Bone Marrow Biopsy fof Hemophagocytosis was Observed in 64% of Cases (Lancet, 2014) [MEDLINE]
- Presence of Bone Marrow Hemophagocytosis is Not Pathognomonic for Hemophagocytic Lymphohistiocytosis
  - In a Review of Bone Barrow Aspirates Which Demonstrated Hemophagocytosis, 51% were Attributable to Hemophagocytic Lymphohistiocytosis, While 49% were Attributable to an Alternate Diagnosis (Haematologica, 2018) [MEDLINE]
  - However, the Presence of Phagocytosis of Nucleated Cells or Multiple Nucleated Cells is Strongly Correlated with the Diagnosis of Hemophagocytic Lymphohistiocytosis
  - In One Review of Adult Bone Barrow Aspirates Which Demonstrated Hemophagocytosis, 64% were Attributable to Lymphoma (Especially T/NK and B Cell Lymphoma) (Ann Hematol, 2016) [MEDLINE]
    - Of 182 Patients with Sufficient Clinical Data to Judge HLH-2004 Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis, Only 29% Had 5 of 8 Criteria
    - Of Those Who Had a Malignancy, Median Survival was 9 Months, vs 71.8 Months for Those with Non-Malignant Disorders
- Interestingly, Some Patients May Demonstrate Hemophagocytosis Only Later in the Disease Course, as They are Clinically Improving (Blood, 2011) [MEDLINE]
Infiltration of Bone Marrow by Activated Macrophages
- The Macrophages in Hemophagocytic Lymphohistiocytosis DO Not Have the Cellular Atypia Associated with Malignant Histiocytes and They are Notably Different from the CD1a-Staining Langerhans Cells of Langerhans Cell Histiocytosis (see Langerhans Cell Histiocytosis)
- It is Helpful to Stain the Bone Marrow for the Hemoglobin-Haptoglobin Scavenger Receptor CD163 to Identify the Macrophages (Both Hemophagocytosing and Not)

Immunologic Testing

Soluble IL-2 Receptor Alpha (sCD25 or sIL-2R)

Of All of the Immunologic Studies, Elevated Soluble IL-2 Receptor Levels Appear to Correlate Most Closely with Disease Activity (Blood, 2011) [MEDLINE]
Ratio of Soluble IL-2 Receptor/Serum Ferritin May Be Useful in Patients with Lymphoma
- In a Review of Patients with Lymphoma-Associated Hemophagocytic Lymphohistiocytosis vs Non-Lymphoma-Associated Cases, the Former Group Had a Much Higher Ratio of Soluble IL-2 Receptor/Serum Ferritin than the Latter Group (Ratio 8.56 vs 0.66) (Ann Hematol, 2014) [MEDLINE]
Levels of the Soluble IL-2 Receptor are Generally Available within 1-2 Days, While the Other Immunologic Tests Take Longer to Result
- Therapy Should Not Be Delayed While Awaiting Results of Immunologic Testing
Single-Center Retrospective Study of sIL-2r Levels in the Diagnosis of Hemophagocytic Lymphohistiocytosis in Adults (Blood Adv, 2017) [MEDLINE]
- Adult Reference Range for sIL-2r (ELISA): 241-846 U/mL
- Receiver Operating Characteristic Curve for sIL-2r Indicates that it is a Good-Excellent Diagnostic Test for Adult Hemophagocytic Lymphohistiocytosis, with an Area Under the Curve (AUC) of 0.90 (95% Confidence Interval: 0.83-0.97)
  - AUC was 0.78 (95% CI: 0.67-0.88) for Ferritin
- Optimal Threshold for sIL-2r was 2,515 U/mL (Sensitivity: 100%; Specificity: 72.5%)
- While There was a Large Indeterminate Range for sIL-2r, the Following were Proposed Cutoff Levels
  - sIL-2r ≤2,400 U/mL was Helpful for Ruling Out Hemophagocytic Lymphohistiocytosis (Sensitivity: 100%)
  - sIL-2r >10,000 U/mL was Helpful for Ruling in Hemophagocytic Lymphohistiocytosis (Specificity: 93%)
- Mean sIL-2r Levels by Etiology (P < 0.05)
  - Malignancy-Associated Hemophagocytic Lymphohistiocytosis: 20,241 U/mL
  - Infection-Associated Hemophagocytic Lymphohistiocytosis: 9,720 U/mL
  - Macrophage Activation Syndrome: 5,008 U/mL
- sIL-2r >10,000 U/mL were Not Associated with a Worse Prognosis in Patients with Hemophagocytic Lymphohistiocytosis
- Serum sIL-2r is a Sensitive Test for the Diagnosis of Adult Hemophagocytic Lymphohistiocytosis, But is Not as Specific as Previously Reported in Children

Tests of NK Cell Function/Degranulation (by Flow Cytometry for Surface Expression of CD107alpha, Also Called LAMP-1 [Lysosomal-Associated Membrane Protein 1])

Decreased Function (or Decreased Expression of CD107alpha)
NK Cytotoxicity Assay is Not Widely Available, is Labor Intensive, and Has Limited Clinical Utility in Cases of Low Circulating NK Cells
Flow Cytometry for Decreased/Absent NK Cell Perforin and CD107alpha is More Sensitive and Has Equivalent Specificity in Screening Patients for Hemophagocytic Lymphohistiocytosis, and May Be an Acceptable Surrogate for NK Cell Function (Blood, 2017) [MEDLINE]

Flow Cytometry for Cell Surface Expression of Perforin

Decreased Perforin
Flow Cytometry for Decreased/Absent NK Cell Perforin and CD107alpha is More Sensitive and Has Equivalent Specificity in Screening Patients for Hemophagocytic Lymphohistiocytosis, and May Be an Acceptable Surrogate for NK Cell Function (Blood, 2017) [MEDLINE]

Flow Cytometry for Cell Surface Expression of Granzyme B Protein

Elevated Granzyme B Has Been Found and is Thought to Be Part of the Immune Signature of Lymphocyte Activation (Front Immunol, 2013) [MEDLINE]

Flow Cytometry for Cell Surface Expression of SAP and XIAP Proteins in Males

Decreased SAP or XIAP

Soluble Levels of the Hemoglobin-Haptoglobin Scavenger Receptor (sCD163)

Elevated sCD163

Immunoglobulin Levels (IgG, IgA, IgM)

Variable (J Pediatr Hematol Oncol, 1996) [MEDLINE]

Lymphocyte Subsets (Underlying Immune Deficiency Diseases are Sometimes Found)

Peripheral Blood Lymphocyte Subsets Generally Demonstrate Normal T-Cell Numbers and Helper/Suppressor Ratio, and May Demonstrate Decreased Numbers of B-Cells or NK Cells

Immunoassays for CXCL9 and CXCL10

Hemophagocytic Lymphohistiocytosis Associated with Lymphoma May Be Challenging to Differentiate from Sepsis
- In a Study in 15 Adults with Lymphoma-Associated Hemophagocytic Lymphohistiocytosis, Elevated CXCL9 and CXCL10 Levels Had a High Sensitivity and Specificity for Lymphoma-Associated Hemophagocytic Lymphohistiocytosis, as Compared to Sepsis (Ann Hematol, 2014) [MEDLINE]

Brain Magnetic Resonance Imaging (MRI) (see Brain Magnetic Resonance Imaging)

Technique

With and With Contrast

Findings

Parameningeal Infiltrations
Subdural Effusions
Necrosis

Lumbar Puncture (LP) (see Lumbar Puncture)

Findings

Cellular Pleocytosis
Elevated Protein
Hemophagocytosis: may occur rarely

Serum Ferritin (see Serum Ferritin)

Findings

Hyperferritinemia (see Hyperferritinemia)

Clinical Differentiation of Hemolytic Syndromes

Clinical Diagnostic Criteria

Clinical Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis (HLH) (HLH-2004) (Pediatr Blood Cancer, 2007) [MEDLINE] and (Biol Blood Marrow Transplant, 2010) [MEDLINE]

Either of the Following

Molecular Diagnosis Consistent with Hemophagocytic Lymphohistiocytosis
At Least 5 of the Following Criteria
- Fever (T >38.5 C) (see Fever)
- Splenomegaly (Tip Palpated >3 cm Below Left Inferior Costal Margin) (see Splenomegaly)
- Bicytopenia (Involving ≥2 Lines)
  - Absolute Neutrophil Count <1000/μL (see Leukopenia and Neutropenia)
  - Hemoglobin <9 g/dL (see Anemia)
  - Platelet Count <100k (see Thrombocytopenia)
- Hypertriglyceridemia or Hypofibrinogenemia (see Hypertriglyceridemia, [[Hypertriglyceridemia]] or Hypofibrinogenemia)
- Hemophagocytosis in Bone Marrow/Spleen/Lymph Nodes
  - Cerebrospinal Fluid (CSF): evidence of hemophagocytosis may rarely be seen in the CSF
  - Liver: evidence of hemophagocytosis many be seen in liver in some cases
- Low/Absent NK Cell Activity (By 51-Cr Release Assay)
  - Present in Approximately 50% of HLH Patients
- Hyperferritinemia with Ferritin >500 μg/L (see Hyperferritinemia)
  - Ferritin >500 μg/L: 84% sensitivity
  - Ferritin >10k μg/L: 90% sensitivity, 96% specificity
- Soluble CD25 (IL-2 Receptor) >2400 U/mL: >2 SD above the age-adjusted mean
  - CD25 is Expressed by T-Cells

Clinical-Diagnostic Criteria (HScore) (Arthritis Rheumatol, 2014) [MEDLINE]

Three Clinical Criteria
- Fever (see Fever)
- Organomegaly
  - Hepatomegaly (see Hepatomegaly)
  - Splenomegaly (see Splenomegaly)
- Underlying Immunosuppression
Five Biologic Criteria
- Cytopenia
  - Anemia (see Anemia): Hb <9 g/dL
  - Leukopenia/Neutropenia (see Leukopenia)
  - Thrombocytopenia (see Thrombocytopenia): platelets <100k
- Elevated Alanine Aminotransaminase (ALT) (see Elevated Liver Function Tests)
- Hyperferritinemia (see Hyperferritinemia)
- Hypertriglyceridemia (see Hypertriglyceridemia)
- Hypofibrinogenemia (see Hypofibrinogenemia)
One Cytologic Criterion
- Hemophagocytic Features on Bone Marrow Aspirate
Online Calculator: https://saintantoine.aphp.fr/score/
- HScore ≤90: confers a <1% probability of hemophagocytic lymphohistiocytosis
- HScore ≥250: confers a 99% probability of hemophagocytic lymphohistiocytosis

Clinical Manifestations

General Comments

Over 85% of Hemophagocytic Lymphohistiocytosis Cases Manifest Fever, Cytopenias, and Hyperferritinemia (Am J Hematol, 2015) [MEDLINE]

Cardiovascular Manifestations

Hypotension/Shock (see Hypotension)

Epidemiology
- Hypotension/Shock Has Been Reported (J Crit Care, 2024) [MEDLINE]
Clinical/Treatment
- Hypotension May Be Severe (Requiring Vasopressors)
Prognosis
- Mortality Rate May Be Higher in HLH Cases with Cardiac Involvement (J Crit Care, 2024) [MEDLINE]

Myocardial Dysfunction/Congestive Heart Failure (CHF) (see Congestive Heart Failure)

Epidemiology
- Myocardial Dysfunction/Congestive Heart Failure (CHF) Has Been Reported (J Crit Care, 2024) [MEDLINE]
Clinical/Treatment
- May Be Severe Enough to Require Inotropic Support
Prognosis
- Mortality Rate May Be Higher in HLH Cases with Cardiac Involvement (J Crit Care, 2024) [MEDLINE]

Pericardial Effusion (see xxxx)

Epidemiology
- Pericardial Effusion Has Been Reported (J Crit Care, 2024) [MEDLINE]
Clinical/Treatment
- Some Cases May Severe Enough Require Pericardial Drainage
Prognosis
- Mortality Rate May Be Higher in HLH Cases with Cardiac Involvement (J Crit Care, 2024) [MEDLINE]

Dermatologic Manifestations

Rash

Epidemiology
- Rash Occurs in Approximately 3-65% of Cases
  - In a Large Review (n = 775 Adult Cases), Skin Lesions were Observed in 25% of Cases (Lancet, 2014) [MEDLINE]
Clinical
- Erythroderma (see Erythroderma)
- Maculopapular (see xxxx)
  - Most Common Pattern
- Nodular (see xxxx)
  - Occasional Pattern
- Peripheral Edema (see Peripheral Edema)
- Petechiae (see Petechiae)
- Purpura (see Purpura)

Endocrinologic Manifestations

Hypertriglyceridemia (see Hypertriglyceridemia)

Epidemiology
- Hypertriglyceridemia Occurs in Approximately 59-100% of Cases
  - In a Large Review (n = 775 Adult Cases), Hypertriglyceridemia >1.7 mmol/L was Observed in 69% of Cases (Lancet, 2014) [MEDLINE]
  - In a Large Review (n = 775 Adult Cases), Hypertriglyceridemia >3.0 mmol/L was Observed in 42% of Cases (Lancet, 2014) [MEDLINE]
Physiology
- Due to Hepatic Involvement

Gastrointestinal/Hepatic Manifestations

General Comments

In a Large Review (n = 775 Adult Cases), Gastrointestinal Involvement was Observed in 18% of Cases (Lancet, 2014) [MEDLINE]

Acute Hepatic Failure (see Acute Hepatic Failure)

Epidemiology
- XXXXXX
Clinical
- XXXXXX

Hepatitis

Epidemiology
- Hepatitis Occurs in Nearly All Patients with Hemophagocytic Lymphohistiocytosis
Diagnosis
- Increased Alkaline Phosphatase (see Increased Liver Function Tests)
  - In a Large Review (n = 775 Adult Cases), Increased Alkaline Phosphatase >290 IU/L was Observed in 71% of Cases (Lancet, 2014) [MEDLINE]
- Increased GGT (see Increased Liver Function Tests)
- Increased Serum Lactate Dehydrogenase (LDH) (see Elevated Serum Lactate Dehydrogenase)
  - In a Large Review (n = 775 Adult Cases), Increased LDH >500 IU/L was Observed in 78% of Cases (Lancet, 2014) [MEDLINE]
  - In a Large Review (n = 775 Adult Cases), Increased LDH >1,000 IU/L was Observed in 53% of Cases (Lancet, 2014) [MEDLINE]
- Hyperbilirubinemia (see Hyperbilirubinemia)
- Increased AST and ALT (Transaminitis) (see Increased Liver Function Tests)
  - In a Large Review (n = 775 Adult Cases), Increased AST and ALT >40 IU/L was Observed in 57% of Cases (Lancet, 2014) [MEDLINE]
  - In a Large Review (n = 775 Adult Cases), Increased AST and ALT >100 IU/L was Observed in 42% of Cases (Lancet, 2014) [MEDLINE]
Clinical
- XXXX

Hepatomegaly (see Hepatomegaly)

Epidemiology
- Hepatomegaly Occurs in Approximately 39-97%% of Cases
  - In a Large Review (n = 775 Adult Cases), Hepatomegaly was Observed in 67% of Cases (Lancet, 2014) [MEDLINE]

Hyperbilirubinemia (with Jaundice) (see Hyperbilirubinemia)

Epidemiology
- Hyperbilirubinemia Occurs in 74% of Cases

Hematologic Manifestations

Coagulopathy (see Coagulopathy)

Epidemiology
- Coagulopathy Due to Impaired Hepatic Synthetic Function and/or Disseminated Intravascular Coagulation are Common
- In a Large Review (n = 775 Adult Cases), Coagulopathy was Observed in 59% of Cases (Lancet, 2014) [MEDLINE]
Physiology
- Hepatic Synthetic Defect

Cytopenias

Clinical
- Anemia (see Anemia)
  - Anemia Occurs in Approximately 89-100% of Cases
    - In a Large Review (n = 775 Adult Cases), Anemia with Hemoglobin <5.6 mmol/L was Observed in 67% of Cases (Lancet, 2014) [MEDLINE]
    - In a Large Review (n = 775 Adult Cases), Anemia with Hemoglobin <4.3 mmol/L was Observed in 22% of Cases (Lancet, 2014) [MEDLINE]
- Leukopenia (see Leukopenia)
  - In a Large Review (n = 775 Adult Cases), Leukopenia <4,000 Cells/mm3 was Observed in 69% of Cases (Lancet, 2014) [MEDLINE]
- Neutropenia (see Neutropenia)
  - Neutropenia Occurs in Approximately 58-87%% of Cases
    - In a Large Review (n = 775 Adult Cases), Neutropenia <1,000 Cells/mm3 was Observed in 42% of Cases (Lancet, 2014) [MEDLINE]
    - In a Large Review (n = 775 Adult Cases), Neutropenia <500 Cells/mm3 was Observed in 23% of Cases (Lancet, 2014) [MEDLINE]
- Thrombocytopenia (see Thrombocytopenia)
  - Thrombocytopenia Occurs in Approximately 82-100% of Cases
    - In a Large Review (n = 775 Adult Cases), Thrombocytopenia <100k Cells/mm3 was Observed in 78% of Cases (Lancet, 2014) [MEDLINE]
    - In a Large Review (n = 775 Adult Cases), Thrombocytopenia <10k Cells/mm3 was Observed in 6% of Cases (Lancet, 2014) [MEDLINE]

Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)

Epidemiology
- Disseminated Intravascular Coagulation (DIC) is Common
- In a Large Review (n = 775), Disseminated Intravascular Coagulation (DIC) was Observed in 40% of Cases (Lancet, 2014) [MEDLINE]
Diagnosis
- Thrombocytopenia (see Thrombocytopenia)
  - In a Large Review (n = 775 Adult Cases), Thrombocytopenia <100k Cell/mm3 was Observed in 78% of Cases (Lancet, 2014) [MEDLINE]
  - In a Large Review (n = 775 Adult Cases), Thrombocytopenia <10k Cell/mm3 was Observed in 6% of Cases (Lancet, 2014) [MEDLINE]
- Increased Fibrin Split Products (FSP’s) (see Increased Fibrin Split Products)
- Increased Prothrombin Time (PT)/International Normalized Ratio (INR) (see Coagulopathy)
Clinical
- XXXX

Increased Serum Lactate Dehydrogenase (LDH) (see Elevated Serum Lactate Dehydrogenase)

Epidemiology
- XXXX
Clinical
- XXXX

Hemophagocytosis

Clinical
- Bone Marrow
- Cerebrospinal Fluid (CSF) (see Lumbar Puncture)
  - Evidence of Hemophagocytosis May Rarely Be Observed in the Cerebrospinal Fluid (CSF)
- Liver
- Lymph Nodes
- Spleen

Increased Plasma D-Dimer (see Elevated Plasma D-Dimer])

Epidemiology
- Increased Plasma D-Dimer May Occur
  - In a Large Review (n = 775 Adult Cases), Increased Plasma D-Dimer >54.8 mmol/L was Observed in 49% of Cases (Lancet, 2014) [MEDLINE]
Physiology
- Due to Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)

Hemorrhage

Physiologic Mechanisms
- Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)
- Liver Failure
- Platelet Granule Processing Defect
- Thrombocytopenia (see Thrombocytopenia)

Hyperferritinemia (see Hyperferritinemia)

Epidemiology
- A Very High Serum Ferritin Level is Common in Hemophagocytic Lymphohistiocytosis (Especially in Children) and This Finding Has a High Sensitivity and Specificity
  - In a Large Review (n = 775 Adult Cases), Hyperferritinemia >1123.5 ρmol/L was Observed in 90% of Cases (Lancet, 2014) [MEDLINE]
  - In a Large Review (n = 775 Adult Cases), Hyperferritinemia >2247.0 ρmol/L was Observed in 71% of Cases (Lancet, 2014) [MEDLINE]
  - In a Large Review (n = 775 Adult Cases), Hyperferritinemia >22,470 ρmol/L was Observed in 24% of Cases (Lancet, 2014) [MEDLINE]
Diagnosis
- In the HLH-94 Study, the Median Ferritin Level was 2,950 ng/mL and the Following Ferritin Levels were Observed (Blood, 2011) [MEDLINE]
  - Ferritin >500ng/mL is Observed in 93% of Cases
  - Ferritin >5000 ng/mL is Observed in 42% of Cases
  - Ferritin >10,000 ng/mL is Observed in 25% of Cases

Hypofibrinogenemia (see Hypofibrinogenemia)

Epidemiology
- Hypofibrinogenemia Occurs in 19-85% of Cases
  - In a Large Review (n = 775 Adult Cases), Hypofibrinogenemia <4.4 μmol/L was Observed in 48% of Cases (Lancet, 2014) [MEDLINE]

Lymphadenopathy (see Lymphadenopathy)

Epidemiology
- Lymphadenopathy Occurs in 17-52%% of Cases
  - In a Large Review (n = 775 Adult Cases), Lymphadenopathy was Observed in 33% of Cases (Lancet, 2014) [MEDLINE]

Splenomegaly (see Splenomegaly)

Epidemiology
- Splenomegaly Occurs in Approximately 35-100% of Cases
  - In a Large Review (n = 775 Adult Cases), Splenomegaly was Observed in 69% of Cases (Lancet, 2014) [MEDLINE]

Neurologic Manifestations

General Comments

Neurologic Findings Occur in 7-47% of Hemophagocytic Lymphohistiocytosis (HLH) Cases

Abnormal Cerebrospinal Fluid (CSF) (see Lumbar Puncture)

Epidemiology
- 50% of Cases Have Cerebrospinal Fluid Abnormalities
Diagnosis
- Cellular Pleocytosis
- Elevated Protein
- Hemophagocytosis
  - May Occur Rarely in the Cerebrospinal Fluid (CSF)

Ataxia (see Ataxia)

Epidemiology
- XXXXXXX
Clinical
- XXXXX

Brain Magnetic Resonance Imaging (MRI) with Focal Areas of Inflammation (see Brain Magnetic Resonance Imaging)

Diagnosis
- Parameningeal Infiltrations
- Subdural Effusions
- Hypodense or Necrotic Areas
CNS involvement of virus-associated hemophagocytic syndrome: MR imaging appearance. AJNR Am J Neuroradiol. 2000 Aug;21(7):1248-50 [MEDLINE]
- The MR imaging appearance of a case of virus-associated hemophagocytic syndrome complicated by diffuse CNS infiltration is presented. Virus-associated hemophagocytic syndrome is a rare condition, precipitated by viral infection and characterized by proliferation of benign histiocytes with phagocytosis
- In severe cases, the CNS may be involved

Encephalopathy/Delirium (see Delirium)

Epidemiology
- In a Large Review (n = 775 Adult Cases), Encephalopathy was Observed in 9% of Cases (Lancet, 2014) [MEDLINE]

Meningismus (see Meningismus)

Epidemiology
- XXXX

Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome)

Epidemiology
- XXXX
Diagnosis
- Characteristic Features of Vasogenic Cerebral Edema Predominantly in the Posterior Cerebral Hemispheres are Seen on Brain Magnetic Resonance Imaging (MRI) (see Brain Magnetic Resonance Imaging)

Seizures (see Seizures)

Epidemiology
- XXXX

Pulmonary Manifestations

General Comments

In a Large Review (n = 775 Adult Cases), Pulmonary Involvement was Observed in 42% of Cases (Lancet, 2014) [MEDLINE]

Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)

Epidemiology
- May Occur
Clinical
- Hypoxemia/Acute Hypoxemic Respiratory Failure (see Hypoxemia and Respiratory Failure)

Renal Manifestations

General Comments

In a Large Review (n = 775 Adult Cases), Renal Involvement was Observed in 16% of Cases (Lancet, 2014) [MEDLINE]

Hyponatremia Due to SIADH (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)

Epidemiology
- In a Large Review (n = 775 Adult Cases), Hyponatremia <135 mEq/L was Observed in 78% of Cases (Lancet, 2014) [MEDLINE]
- In a Large Review (n = 775 Adult Cases), Hyponatremia <130 mEq/L was Observed in 59% of Cases (Lancet, 2014) [MEDLINE]
Physiology
- XXXXXXXX

Other Manifestations

Fever (see Fever)

Epidemiology
- Fever Occurs in Approximately 60-100% of Cases
  - In a Large Review (n = 775 Adult Cases), Fever was Observed in 96% of Cases (Lancet, 2014) [MEDLINE]

Treatment

Blood Product Support

Cryoprecipitate (see Cryoprecipitate)
- As Required
Packed Red Blood Cells (PRBC) (see Packed Red Blood Cells)
- As Required
Platelet Transfusion (see Platelet Transfusion)
- As Required

Clinically-Stable Hemophagocytic Lymphohistiocytosis

Treat Underlying Disease
- Treatment of Underlying Infection/Rheumatologic Disease in Clinically-Stable Patients May Be Effective without Other Therapy
Underlying Disease-Specific Regimens
- Active Epstein-Barr Virus (EBV) Infection (see Epstein-Barr Virus)
  - Rituximab (Rituxan) (see Rituximab)
  - Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin): less effective than rituximab
- Leishmaniasis (see Leishmaniasis)
  - Treat Underlying Leishmaniasis
- Rheumatologic Disease
  - Treat Underlying Rheumatologic Disease

Clinically-Unstable Hemophagocytic Lymphohistiocytosis

Criteria for “Clinically-Unstable” Hemophagocytic Lymphohistiocytosis
- Worsening Hyperferritinemia (see Hyperferritinemia)
- Increasing D-Dimer (see Elevated Plasma D-Dimer)
- Increasing Liver Function Tests (LFT’s) (see Elevated Liver Function Tests)
- Worsening Cytopenias (Leukopenia, Anemia, Thrombocytopenia) (see Leukopenia, Anemia, and Thrombocytopenia)
Hemophagocytic Lymphohistiocytosis-Specific Chemotherapy
- Indications
  - Incomplete Response or High-Risk Factors (Gene Mutations, Central Nervous System Disease, Hematologic Malignancy)
- Dexamethasone + Etoposide (VP-16) (see Dexamethasone and Etoposide)
  - Preferred Regimen
  - Dexamethasone is the Preferred Corticosteroid Since it Crosses the Blood-Brain Barrier
Intrathecal Chemotherapy
- Indications
  - Central Nervous System Disease
Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant)
- Indications
  - Incomplete Response to Hemophagocytic Lymphohistiocytosis (HLH)-Specific Chemotherapy

Anakinra (Kineret) (see Anakinra)

Rationale

Anakinra is an Interleukin-1 (IL-1) Antagonist
Review of Emerging Therapeutic Options for Hemophagocytic Lymphohistiocytosis (HLH) (Ann Pharmacother, 2023) [MEDLINE]
- Review Cites Use of Hematopoietic Stem Cell Transplantation, Emapalumab, Alemtuzumab, Anakinra, Ruxolitinib, and Tocilizumab

Clinical Efficacy

Small Trial of Anakinra in Secondary Hemophagocytic Lymphohistiocytosis (HLH) in Children (Pediatr Blood Cancer, 2020) [MEDLINE]: n = 6
- Initial Treatment with Anakinra (with or without Dexamethasone) is a Feasible Treatment Alternative for Patients with Secondary Hemophagocytic Lymphohistiocytosis (HLH) and May Allow for Avoidance of Etoposide
- Early Anakinra Initiation is Recommended
Retrospective Series of Anakinra in the Treatment of Secondary Hemophagocytic Lymphohistiocytosis (HLH) in Adults (Int J Hematol, 2022) [MEDLINE]: n = 16 (multi-hospital series)
- Provoking Factors of Secondary Hemophagocytic Lymphohistiocytosis (HLH)
  - Hematologic Malignancy (n = 7, 44%)
  - Bacterial Infection (n = 7, 44%)
  - Viral Infection (n = 5, 31%)
  - Rheumatologic Disorder (n = 4, 25%)
  - Unknown (n = 1, 6%)
- Outcomes
  - Five Patients Remained Alive at the Time of Last Follow-Up (Overall Survival = 31%)
  - Median Overall Survival was 1.7 mos from the Initiation of Anakinra (Range: 0.2-59)
  - Overall Survival Among Patients with Rheumatologic Etiologies of Secondary Hemophagocytic Lymphohistiocytosis (HLH) was 75%, Whereas Only 17% of Patients with Other Provoking Factors Survived (p = 0.0293)
- Adverse Effects
  - Anakinra was Well Tolerated, with Only 1 Patient Experiencing Associated Toxicity (Grade 3 Liver Injury)
- Conclusions
  - Anakinra May Be Useful in the Management of Secondary Hemophagocytic Lymphohistiocytosis (HLH) in Adults Provoked by Rheumatologic Conditions, Although its Benefit in Secondary Hemophagocytic Lymphohistiocytosis (HLH) in Adults Provoked by Other Factors May be Limited

Ruxolitinib (Jakafi) (see Ruxolitinib)

Rationale

Ruxolitinib is a Janus Kinase (JAK) Inhibitor
- Selective for Subtypes JAK1 and JAK2
Review of Emerging Therapeutic Options for Hemophagocytic Lymphohistiocytosis (HLH) (Ann Pharmacother, 2023) [MEDLINE]
- Review Cites Use of Hematopoietic Stem Cell Transplantation, Emapalumab, Alemtuzumab, Anakinra, Ruxolitinib, and Tocilizumab

Clinical Efficacy

Study of Ruxolitinib for the Treatment of Hemophagocytic Lymphohistiocytosis (HLH) in Children (Blood, 2022) [MEDLINE]: n = 52
- Overall Response Rate of Ruxolitinib Monotherapy (by Day 28) was 69.2% with 42.3% Achieving Sustained Complete Remission
- All Responders Achieved Their First Response to Ruxolitinib within 3 Days
- Response to Ruxolitinib was Significantly Associated with Underlying Etiology (P = .009)
  - Epstein-Barr Virus (EBV)-HLH Patients were the Most Sensitive to Ruxolitinib (Overall Response Rate 87.5%; 58.3% in Complete Remission)
- After Ruxolitinib, 57.2% of Patients Entered Intensive Therapy with Additional Chemotherapy
  - Median Interval to Additional Treatment Since the First Ruxolitinib Administration was 6 Days (Range: 3-25 Days)
- Ruxolitinib Had Low Toxicity and was Well-Tolerated, as Compared to Intensive Chemotherapy

Prognosis

Median Survival is 7.67 mos (Am J Hematol, 2015) [MEDLINE]

Survival was Markedly Worse in Malignancy-Associated Cases (1.13 Months), as Compared to Non-Malignancy Associated Cases (46.53 Months)
Ferritin >50,000 μg/L is Correlated with 30-Day Mortality

Mortality Rate in Cases Admitted to the Intensive Care Unit (ICU)

Retrospective Review of 71 Cases of Hemophagocytic Lymphohistiocytosis (HLH) Admitted to the Intensive Care Unit (ICU) (Medicine-Baltimore, 2015) [MEDLINE]
- 28-Day Mortality Rate (Starting at Intensive Care Unit-ICU Admission): 38%
- Hospital-Mortality Rate: 68%
- Risk Factors for High Mortality
  - Advanced Age
  - High Sequential Organ Failure Assessment (SOFA) Score at Intensive Care Unit (ICU) Admission
  - Presence of Lymphoma-Related or Idiopathic Hemophagocytic Lymphohistiocytosis (HLH)

References

General

Mumps virus-associated hemophagocytic syndrome. Emerg Infect Dis. 2005 Feb. Available from https://wwwnc.cdc.gov/eid/article/11/2/04-0993.htm
Virus associated hemophagocytic syndrome. Cancer. 1979;44:993-1002
Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol. 1997 Sep;29(3):157-66 [MEDLINE]
Hemophagocytic syndromes and infection. Emerg Infect Dis. 2000;6:601-8
Haemophagocytic syndromes in adults: current concepts and challenges ahead. Swiss Med Wkly. 2005 May 28;135(21-22):299-314 [MEDLINE]
Histiocytic disorders: recent insights into pathophysiology and practical guidelines. Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S82-9. doi: 10.1016/j.bbmt.2009.11.014. Epub 2009 Nov 22 [MEDLINE]
Etanercept-induced lupus accompanied by hemophagocytic syndrome. Intern Med. 2011;50(17):1843-8. Epub 2011 Sep 1 [MEDLINE]
The hyperferritinemic syndrome: macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med. 2013 Aug 22;11:185. doi: 10.1186/1741-7015-11-185 [MEDLINE]
Adult haemophagocytic syndrome. Lancet 2014;383(9927): 1503e16 [MEDLINE]
Hemophagocytic Lymphohistiocytosis in Intensive Care Unit: A 71-Case Strobe-Compliant Retrospective Study. Medicine (Baltimore). 2015 Dec;94(51):e2318. doi: 10.1097/MD.0000000000002318 [MEDLINE]
Hemophagocytic Syndrome and Critical Illness: New Insights into Diagnosis and Management. J Intensive Care Med. 2015 Oct;30(7):401-12. doi: 10.1177/0885066613517076. Epub 2014 Jan 8 [MEDLINE]
Hemophagocytic lymphohistiocytosis: An update on pathogenesis, diagnosis, and therapy. Best Pract Res Clin Rheumatol. 2020 Aug;34(4):101515. doi: 10.1016/j.berh.2020.101515 [MEDLINE]

Etiology

Adult haemophagocytic syndrome. Lancet 2014;383(9927): 1503e16 [MEDLINE]
A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer 2017;123(17):3229e40 [MEDLINE]
Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases. Immunol Rev 2019;291(1):174e89 [MEDLINE]
Epstein-Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach. Pathology 2020;52(1):111e27 [MEDLINE]
HLH Associated With Disseminated Tuberculosis. N Engl J Med. 2020 Apr 30;382(18):1749 [MEDLINE]

Diagnosis

Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 1996;18(4):340 [MEDLINE]
HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124-13 [MEDLINE]
How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041 [MEDLINE]
Elevated Granzyme B in Cytotoxic Lymphocytes is a Signature of Immune Activation in Hemophagocytic Lymphohistiocytosis. Front Immunol. 2013;4:72 [MEDLINE]
Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014 Sep;66(9):2613-20 [MEDLINE]
IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol. 2014 Mar;93(3):393-401 [MEDLINE]
Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503 [MEDLINE]
Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med. 2014;127(11):1118 [MEDLINE]
A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol. 2014 May;93(5):821-6 [MEDLINE]
Clinical significance of bone marrow hemophagocytosis in adult patients with malignancy and non-malignancy-induced hemophagocytic lymphohistiocytosis. Ann Hematol. 2016 Jan;95(2):325-35 [MEDLINE]
Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv. 2017 Dec 6;1(26):2529-2534. doi: 10.1182/bloodadvances.2017012310. eCollection 2017 Dec 12 [MEDLINE]
Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH. Blood. 2017;129(22):2993 [MEDLINE]
Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica. 2018;103(10):1635 [MEDLINE]

Clinical

Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577 [MEDLINE]
Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol. 2015 Mar;90(3):220-4. doi: 10.1002/ajh.23911. Epub 2015 Jan 16 [MEDLINE]
Heart involvement: A neglected manifestation of haemophagocytic syndrome associated with high mortality. J Crit Care. 2024 Apr:80:154498. doi: 10.1016/j.jcrc.2023.154498 [MEDLINE]

Treatment

The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2020 Nov;67(11):e28581. doi: 10.1002/pbc.28581 [MEDLINE]
A study of ruxolitinib response-based stratified treatment for pediatric hemophagocytic lymphohistiocytosis. Blood. 2022;139(24):3493-3504. doi:10.1182/blood.2021014860 [MEDLINE]
Anakinra for the treatment of adult secondary HLH: a retrospective experience. Int J Hematol. 2022 Dec;116(6):947-955. doi: 10.1007/s12185-022-03430-9 [MEDLINE]
A Review of Current and Emerging Therapeutic Options for Hemophagocytic Lymphohistiocytosis. Ann Pharmacother. 2023 Jul;57(7):867-879. doi: 10.1177/10600280221134719 [MEDLINE]