Hemophagocytic lymphohistiocytosis

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Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome caused by the abnormal activation of macrophages and cytotoxic T cells. The disease is broadly classified into primary and secondary HLH. Primary HLH typically manifests in infants due to genetic defects impairing lymphocyte cytotoxicity or immune regulation. Secondary HLH is more common in older children and adults and is often caused by an underlying infection, malignancy, or autoimmune disorder. Clinical manifestations typically resemble sepsis and include fever, hepatosplenomegaly, and bleeding diathesis. Laboratory findings such as marked cytopenias, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia are common. Management involves treatment of the underlying condition and suppression of the excessive inflammatory response using agents such as glucocorticoids and interleukin-1 inhibitors. Even with prompt intervention, mortality remains high.

HLH is a rare, life-threatening hyperinflammatory syndrome caused by the abnormal activation of macrophages and cytotoxic T cells. ^[2]

• Primary HLH: caused by genetic mutations; typically manifests in infancy and early childhood
• Secondary HLH: arises from an underlying acquired condition; more common in older children and adults

• Incidence: rare but significantly underdiagnosed ^[2]
• Age
  • Primary HLH: onset at median age of 3–6 months ^[2]
  • Secondary HLH: bimodal distribution, with peaks between 16 and 30 years of age and 56 and 70 years of age ^[3]

Epidemiological data refers to the US, unless otherwise specified.

Primary HLH ^[2]

• Caused by pathogenic genetic variants that impair cytotoxic T-cell and natural killer cell function and immune downregulation.
• Most often inherited in an autosomal recessive pattern

Secondary HLH ^[2]

Secondary HLH typically has an identifiable trigger, e.g.:

• Infection
  • Viral; (e.g., EBV, CMV, HIV, influenza)
  • Bacterial, parasitic, or fungal
• Malignancy
  • Hematologic (e.g., non-Hodgkin lymphoma, adult T-cell leukemia)
  • Solid organ cancers
• Macrophage activation syndrome: HLH secondary to autoimmune and inflammatory disorders
  • Systemic lupus erythematosus
  • Systemic-onset juvenile idiopathic arthritis
• Other
  • Solid organ or bone marrow transplantation
  • Medications: immune checkpoint inhibitors (e.g., pembrolizumab) ^[4]

HLH secondary to autoimmune and inflammatory disorders is often referred to as macrophage activation syndrome. ^[2]

Primary HLH and secondary HLH manifest with a similar sepsis-like syndrome and are difficult to distinguish based on clinical features alone. ^[2][4][5]

• Characteristic clinical triad
  • Persistent fever that does not respond to antibiotics
  • Splenomegaly and/or hepatomegaly
  • Clinical features of cytopenias (e.g., symptomatic anemia, signs of thrombocytopenia)
• Additional features of hyperinflammation and organ dysfunction
  • Lymphadenopathy
  • Rash
  • Jaundice
  • Dyspnea
  • Neurological: altered mental status, seizures, ataxia
• Features of the underlying condition: in secondary HLH (e.g., clinical features of infectious mononucleosis)

Approach ^[2][6][7]

Consider HLH in patients with clinical features of sepsis that rapidly worsen or fail to respond to appropriate treatment (e.g., antibiotics).

• Obtain initial laboratory studies, including CBC, ferritin, fibrinogen, AST, and triglyceride levels.
• Consult specialists (e.g., hematology) early.
• Obtain additional studies in consultation with a specialist (e.g., soluble CD25, bone marrow biopsy, genetic testing).
• Consider using an assessment tool to facilitate diagnosis (e.g., diagnostic criteria for HLH or HScore).
• Evaluate for an underlying cause of secondary HLH (e.g., screen for viral infections).

Diagnosis of HLH is challenging. Clinical features are nonspecific, there are no definitive diagnostic studies for secondary HLH, and studies for primary HLH take time. ^[2]

Initial studies ^[2][6]

For full assessment of fever with organ dysfunction, see "Diagnosis of sepsis."

• CBC with differential: ≥ 2 cytopenias, typically thrombocytopenia and anemia
• Ferritin: markedly elevated
• Coagulation panel: reduced fibrinogen, elevated serum D-dimer levels
• Triglycerides: elevated
• CRP: elevated
• CMP: elevated liver chemistries (e.g., aspartate aminotransferase, bilirubin)
• LDH: elevated

Hyperferritinemia is less specific in adults than in children, as multiple conditions (e.g., malignancy, infections) cause ferritin elevations in adults; values > 10,000 ng/mL are common in secondary HLH. ^[6]

Additional studies ^[2][6]

Additional studies are obtained in consultation with a specialist and may include:

• Bone marrow aspiration and biopsy: phagocytosis of hematopoietic cells
• Specialized biomarkers of inflammation (e.g., soluble CD25)
• Tests for central nervous system (CNS) involvement, if suspected: ^[2]
  • Lumbar puncture: elevated lymphocytes and protein ^[8]
  • MRI brain: Findings include multifocal white-matter signal abnormalities and/or leptomeningeal enhancement. ^[9]
• Lymphocyte cytotoxicity assays (e.g., natural killer cell activity)
• Genetic testing for primary HLH

Investigations for the underlying cause ^[4][6]

Consider workup for an underlying cause of secondary HLH based on clinical suspicion, e.g.:

• Infection: blood cultures, viral PCR (e.g., EBV, CMV)
• Autoimmune conditions: antinuclear antibody
• Malignancy: cross-sectional imaging (e.g., PET-CT scan), tissue biopsy (e.g., lymph node biopsy)

Diagnostic criteria for HLH ^[2][10]

Any one of the following: ^[2][6][7]

• Genetic testing consistent with primary HLH in a patient with a suggestive clinical presentation
• Lymphocyte cytotoxicity testing consistent with HLH in a patient with a suggestive clinical presentation
• Presence of at least 5 of the following 7 clinical diagnostic findings:
  • Fever ≥ 101.3°F
  • Splenomegaly ≥ 2 cm below costal margin
  • Cytopenias with ≥ 2 cell lines affected, i.e.:
    • Hemoglobin < 9 g/dL
    • Platelets < 100,000/mm³
    • Neutrophils < 1,000/mm³
  • Fibrinogen ≤ 150 mg/dL or triglycerides ≥ 265 mg/dL
  • Ferritin ≥ 500 ng/mL
  • Hemophagocytosis in bone marrow or other tissues
  • Soluble CD25 (soluble interleukin-2 receptor) ≥ 2,400 U/mL

Multiple conditions may mimic HLH, coexist with HLH, or trigger secondary HLH: ^[4][8]

• Severe infection or critical illness (e.g., sepsis, septic shock, multiple organ dysfunction syndrome)
• Autoimmune or inflammatory disorders (e.g., systemic-onset juvenile idiopathic arthritis, adult-onset Still disease, catastrophic antiphospholipid syndrome, Evans syndrome)
• Malignancy (e.g., leukemia, lymphoma)
• Liver disease (e.g., acute liver failure)
• Drug reaction (e.g., drug reaction with eosinophilia and systemic symptoms)
• Bone marrow suppression or failure (e.g., chemotherapy-related cytopenias)

The differential diagnoses listed here are not exhaustive.

Care is multidisciplinary (e.g., hematology, critical care, infectious diseases).

Approach ^[4][6][7]

• Provide supportive care of the critically ill patient, including broad-spectrum antibiotics for sepsis.
• Consult specialists (e.g., hematology) early for suspected HLH.
• Identify and treat any potential underlying causes of secondary HLH.
• Manage hyperinflammation with immunosuppressive therapy (may be indicated while diagnostic testing is ongoing).
• Monitor clinical and laboratory response to treatment (e.g., daily ferritin levels).

Allogenic hematopoietic cell transplantation may be considered for definitive treatment of primary HLH and in selected patients with refractory or recurrent secondary HLH. ^[2][4]

Pharmacological therapy ^[4][6]

Immunosuppressive therapy is led by the specialist team. The approach is based on the underlying condition and disease severity; agents may include:

• Glucocorticoids
• Intravenous immunoglobulin
• Etoposide
• Cyclosporine A
• Interleukin-1 inhibitors (e.g., anakinra)
• Intrathecal therapy for CNS involvement

Initiate immunosuppressive therapy promptly in most patients; do not await full diagnostic workup if clinical deterioration is evident. ^[4][6]

• In-hospital mortality: approx. 18% ^[3]
• One-year survival: 50% ^[11]
• Factors associated with poor prognosis include: ^[6]
  • Associated malignancy: 2-year survival 20–30% ^[10]
  • CNS involvement
  • Acute liver failure
  • Multiple organ dysfunction syndrome