Hemophagocytic Lymphohistiocytosis (HLH, Hemophagocytic Syndrome)

Classification of Histiocytic Disorders

Benign Disorders with Variable Biologic Behavior

Dendritic Cell-Related Disorders

Macrophage-Related Disorders


Malignant Disorders



Association with Other Diseases





Bone Marrow Biopsy (see Bone Marrow Biopsy)


  • 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)


  • With and With Contrast


  • Parameningeal Infiltrations
  • Subdural Effusions
  • Necrosis

Lumbar Puncture (LP) (see Lumbar Puncture)


  • Cellular Pleocytosis
  • Elevated Protein
  • Hemophagocytosis: may occur rarely

Serum Ferritin (see Serum Ferritin)


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)
    • 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
  • Five Biologic Criteria
  • 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

Cardiovascular Manifestations

Hypotension (see Hypotension)

Dermatologic Manifestations


Endocrinologic Manifestations

Hypertriglyceridemia (see Hypertriglyceridemia)

Gastrointestinal/Hepatic Manifestations

Acute Hepatic Failure (see Acute Hepatic Failure)


Hepatomegaly (see Hepatomegaly)

Hyperbilirubinemia (with Jaundice) (see Hyperbilirubinemia)

Hematologic Manifestations

Coagulopathy (see Coagulopathy)


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

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


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


Hyperferritinemia (see Hyperferritinemia)

Hypofibrinogenemia (see Hypofibrinogenemia)

Lymphadenopathy (see Lymphadenopathy)

Splenomegaly (see Splenomegaly)

Neurologic Manifestations

General Comments

Abnormal Cerebrospinal Fluid (CSF) (see Lumbar Puncture)

Ataxia (see Ataxia)

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

Encephalopathy/Delirium (see Delirium)

Meningismus (see Meningismus)

Seizures (see Seizures)

Pulmonary Manifestations

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

Renal Manifestations

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

Other Manifestations

Fever (see Fever)


Blood Product Support

Clinically-Stable Hemophagocytic Lymphohistiocytosis

Clinically-Unstable Hemophagocytic Lymphohistiocytosis