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

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

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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]
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 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

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

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

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
Intrathecal Chemotherapy
- Indications
  - Central Nervous System Disease
Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant)
- Indications
  - Incomplete Response to Hemophagocytic Lymphohistiocytosis-Specific Chemotherapy

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

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]