Haemophagocytic Lymphohistiocytosis

Life-threatening hyperimmune state characterised by excessive macrophage and T-cell activation secondary to ↑ cytokine production, which may be either:

The name comes from the blood film findings which demonstrate macrophages ingesting other blood cells.

The division between congenital and acquired forms are becoming blurred; as there is ↑ recognition of the interplay of genetic, disease, and environmental factors that may lead to different clinical disease expression. That aside, for practical purposes the information here refers to adult expressions HLH.

Epidemiology and Risk Factors

Pathophysiology

Two complementary mechanisms:

  1. Loss of inflammatory negative feedback mechanisms
    Genetic mutation in genes that prevent positive feedback loops occurring in inflammation.
    • Primary determinant in paediatric presentations
    • Less important in adult HLH
  2. Inflammatory trigger
    • Infection
    • Malignancy

Aetiology

Causes include:

  • Infection
  • Malignancy
    • Haematological malignancy
      • Lymphomas
  • Transplantation
    • Solid organ
    • Bone marrow transplant
  • Immunotherapy
    • CAR T-cell therapy
Infectious Causes of Haemophagocytic Lymphohistiocytosis
Viral Bacterial Fungal Parasitic
  • EBV
  • CMV
  • HSV
  • HHV-6
  • VZV
  • Adenoviruses
  • Enteroviruses
  • Hepatitis viruses
  • HIV
  • Parvovirus B19
  • Dengue/Ebola viruses
  • Influenza A
    Particularly H5N1 and H1N1.
  • Mycobacteria spp.
  • Rickettsia spp.
  • Legionella spp.
  • Staphylococcus spp.
  • E. coli
  • Histoplasma
  • Pneumocystis jiroveci
  • Candida spp.
  • Aspergillus spp.
  • Leishmania spp.
  • Plasmodium spp.
  • Toxoplasma spp.

EBV may be a direct trigger, or cause HLH via an associated malignancy.

Clinical Features

  • CNS
    25-50% of cases, may rarely occur without systemic features:
    • Delirium → obtundation → coma
    • Focal deficits
    • Headaches
    • Meningism
    • PRES
  • Haematological
    • Splenomegaly
    • Hepatomegaly
    • Petechiae → generalised purpura
  • Inflammatory
    • Fever
      Classically persistent, non-remitting, and non-responsive to antibiotics.
    • Capillary leak
    • Rashes
    • Lymphadenopathy
    • Myocarditis
    • ARDS
    • AKI

Assessment

History:

Exam:

Investigations

Bedside:

Laboratory:

  • Blood
    • Diagnosis
      • FBE
        Cytopenias.
      • Iron studies
      • Soluble CD25
        Indicates T-cell activation.
      • Blood film
    • Complications
      • LFTs
        Hepatitic picture.
      • ↑ Triglycerides
      • Coagulation abnormality
        Hyperfibrinolysis from macrophage activation.
    • Precipitant
      • HIV
      • ANA
      • Viral PCR
      • (1→3)-β-D-glucan
Haemophagocytosis

Imaging:

  • CT
    For malignancy or occult infection.

Other:

  • Bone marrow biopsy
    • Repeat biopsy may be required
      Insensitive in early disease.
  • Lumbar puncture
    • Primary indication is exclusion of alternative diagnoses
    • Must be balanced against any risk with coagulopathy
    • May demonstrate haemophagocytosis

Diagnostic Approach and DDx

Congenital HLH is diagnosed on genetic testing. Acquired HLH requires five of:

Genes which may accrue mutations consistent with HLH include: PRF1,UNC13D, Munc18-2, Rab27a, STX11, SH2D1A, or BIRC4.

  • Fever
  • Splenomegaly
  • Poly-cytopenia
    ⩾2 cell lines.
  • Histological evidence of haemophagocytosis
  • Ferritin >500μg/mL
    May be substantially higher:
    • >3000μg/mL is concerning
    • >10,000μg/mL is 96% specific and 90% sensitive in children
  • Low or absent NK activity
  • Soluble IL-2 receptor CD25 >2400U/mL
    The utility of this is questionable in practice given the long turna round time.

There is a substantial overlap in features with sepsis (see Sepsis); consider HLH as a differential diagnosis in septic patients without a source.

Implementing these criteria disease is hard in practice:

  • Haemophagocytosis is insensitive early in disease
  • NK-cell activity and CD25 have a long latency before they return
  • Critically ill patients are critically ill, and require immediate management

Management

  • Treat underlying disease
  • Immunosuppression
    • Corticosteroids
    • Anakinra

Resuscitation:

Specific therapy:

  • Pharmacological
    • Corticosteroids
      • Daily steroid
        • Dexamethasone 15-20mg IV daily
          Preferred in neurological disease due to CNS penetration.
      • Pulsed steroids
        Typically preferred for rheumatological disease:
        • Methylprednisolone 1g IV daily for 3 days, then 2-3mg/kg/day
    • Anakinra 1-2mg/kg SC Q12H
      Preferable to steroids inf the diagnosis is unclear.
    • IVIG 2g/kg
    • Later-line therapies
      Discuss with a haematologist:
      • Cyclosporin
      • Etoposide
  • Procedural
    • Bone marrow transplant
      Considered in selected cases.
  • Physical

Anakinra is a recombinant IL-1 receptor antagonist that ↓ the cytokine storm.

Supportive care:

Disposition:

Preventative:

Marginal and Ineffective Therapies

  • Plasma exchange

Anaesthetic Considerations

Complications

  • Death
    40%; ↑ risk with:
    • Neurological symptoms
    • Ferritin >5,000μg/mL
  • H
    • DIC

Prognosis

Key Studies

References

Procedure

Indications

Contraindications

Anatomy

Equipment

Technique

Complications

References

  1. Bauchmuller K, Manson JJ, Tattersall R, et al. Haemophagocytic lymphohistiocytosis in adult critical care. Journal of the Intensive Care Society. 2020;21(3):256-268. doi:10.1177/1751143719893865