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)
- Infection: infection (especially viral infection) is a common precipitant of hemophagocytic syndrome
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
- Leukemias
- Dendritic Cell-Related Histiocytic Sarcoma: localized or disseminated
- Macrophage-Related Histiocytic Sarcoma: localized or disseminated
Epidemiology
History
- HLH was first described in 1939
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]
- Sex
- Male Sex: 56.2% of cases
Physiology
XXXXX
- xxxx
Diagnosis
Bone Marrow Biopsy (see Bone Marrow Biopsy)
Findings
- Bone Marrow Cellularity: low, normal, or high (Blood, 2011) [MEDLINE]
- Hemophagocytosis: observed in 25-100% of cases (Am J Med, 2014) [MEDLINE]
- Presence of 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]
- Presence of Hemophagocytosis is Not Pathognomonic for Hemophagocytic Lymphohistiocytosis
- 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
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)
- Cytopenia
- 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 Cases Manifest Fever, Cytopenias, and Hyperferritinemia (Am J Hematol, 2015) [MEDLINE]
Cardiovascular Manifestations
Hypotension (see Hypotension)
- Clinical
- Hypotension May Be Severe (Requiring Vasopressors)
Dermatologic Manifestations
Rash
- Epidemiology
- Rash Occurs in 3-65% of Cases
- 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 59-100% of Cases
- Physiology
- Due to Hepatic Involvement
Gastrointestinal/Hepatic Manifestations
Acute Hepatic Failure (see Acute Hepatic Failure)
- Epidemiology
- XXX
- Clinical
- XXX
Hepatitis
- Epidemiology
- Hepatitis Occurs in Nearly All Patients with Hemophagocytic Lymphohistiocytosis
- Diagnosis
- Elevated GGT – * (see Elevated Liver Function Tests)
- Elevated Serum Lactate Dehydrogenase (LDH) – * (see Elevated Serum Lactate Dehydrogenase)
- Hyperbilirubinemia (see Hyperbilirubinemia)
- Transaminitis (Elevated AST and ALT) (see Elevated Liver Function Tests)
- Clinical
- XXXX
Hepatomegaly (see Hepatomegaly)
- Epidemiology
- Hepatomegaly Occurs in 39-97%% of Cases
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
- Physiology
- Hepatic Synthetic Defect
Cytopenias
- Clinical
- Anemia (see Anemia)
- Occurs in 89-100% of Cases
- Neutropenia (see Neutropenia)
- Occurs in 58-87%% of Cases
- Thrombocytopenia (see Thrombocytopenia)
- Occurs in 82-100% of Cases
- Anemia (see Anemia)
Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)
- Epidemiology
- Common
Elevated Serum Lactate Dehydrogenase (LDH) (see Elevated Serum Lactate Dehydrogenase)
- Epidemiology
- XXXX
Hemophagocytosis
- Clinical
- Bone Marrow
- Cerebrospinal Fluid (CSF): evidence of hemophagocytosis may rarely be seen in the CSF
- Liver
- Lymph Nodes
- Spleen
Elevated Plasma D-Dimer (see Elevated Plasma D-Dimer])
- Epidemiology
- Elevated Plasma D-Dimer May Occur
- 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 Has a High Sensitivity and Specificity
- Diagnosis
- In the HLH-94 Study, Median Ferritin Level was 2950 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
- In the HLH-94 Study, Median Ferritin Level was 2950 ng/mL and the Following Ferritin Levels were Observed (Blood, 2011) [MEDLINE]
Hypofibrinogenemia (see Hypofibrinogenemia)
- Epidemiology
- Hypofibrinogenemia Occurs in 19-85% of Cases
Lymphadenopathy (see Lymphadenopathy)
- Epidemiology
- Lymphadenopathy Occurs in 17-52%% of Cases
Splenomegaly (see Splenomegaly)
- Epidemiology
- Splenomegaly Occurs in 35-100% of Cases
Neurologic Manifestations
General Comments
- Neurologic Findings Occur in 7-47% of Cases
Abnormal Cerebrospinal Fluid (CSF) (see Lumbar Puncture)
- Epidemiology
- 50% of Cases Have CSF Abnormalities
- Diagnosis
- Cellular Pleocytosis
- Elevated Protein
- Hemophagocytosis: may occur rarely
Ataxia (see Ataxia)
- Epidemiology
- XXXX
Brain Magnetic Resonance Imaging (MRI) with Focal Areas of Inflammation (see Brain Magnetic Resonance Imaging)
- Diagnosis
- Hypodense or Necrotic Areas
Encephalopathy/Delirium (see Delirium)
- Epidemiology
- XXXX
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 MRI (see Brain Magnetic Resonance Imaging)
Seizures (see Seizures)
- Epidemiology
- XXXX
Pulmonary Manifestations
Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)
- Epidemiology
- Pulmonary Involvement Has Been Reported in 42% of Adult Cases of Hemophagocytic Lymphohistiocytosis (Lancet, 2014) [MEDLINE]
Renal Manifestations
Hyponatremia Due to SIADH (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)
- Epidemiology
- XXXX
Other Manifestations
Fever (see Fever)
- Epidemiology
- Fever Occurs in 60-100% of Cases
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
- Active Epstein-Barr Virus (EBV) Infection (see Epstein-Barr Virus)
Clinically-Unstable Hemophagocytic Lymphohistiocytosis
- Criteria for “Clinically-Unstable” HLH
- 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
- Indications
- Intrathecal Chemotherapy
- Indications
- Central Nervous System Disease
- Indications
- Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant)
- Indications
- Incomplete Response to Hemophagocytic Lymphohistiocytosis-Specific Chemotherapy
- Indications
Prognosis
- Median Survival: 7.67 (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 was Correlated with 30-Day Mortality
- Mortality Rate in Cases Admitted to the Intensive Care Unit
- Retrospective Review of 71 Cases of HLH Admitted to the ICU (Medicine-Baltimore, 2015) [MEDLINE]
- 28-Day Mortality Rate (Starting at ICU Admission): 38%
- Hospital-Mortality Rate: 68%
- Risk Factors for High Mortality
- Advanced Age
- High Sequential Organ Failure Assessment (SOFA) Score at ICU Admission
- Presence of Lymphoma-Related or Idiopathic HLH
- Retrospective Review of 71 Cases of HLH Admitted to the ICU (Medicine-Baltimore, 2015) [MEDLINE]
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]
- 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]
Etiology
- HLH Associated With Disseminated Tuberculosis. N Engl J Med. 2020 Apr 30;382(18):1749 [MEDLINE]
Diagnosis
- HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124-13 [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]
- Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503 [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]
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]