Haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) is a non-malignant but often fatal disorder of immune dysregulation affecting multiple organs. It is also known as macrophage activation syndrome when occurring in the setting of a rheumatologic disorder.

Epidemiology

It typically affects infants and young children but can be seen at all ages ⁵.

The condition is considered primary (due to Mendelian inherited conditions) in a quarter of cases, while the remainder is considered secondary (associated with apparently non-Mendelian conditions) or of unknown origin ¹².

Associations

The secondary form may occur with several types of conditions, particularly in adults ^5,12:

• infection
  • viral (most common), including EBV ^2,3, HIV, HHV8, CMV, COVID-19
  • bacterial
  • fungal
  • parasitic
• malignancy
  • lymphoid (lymphomas and leukaemias; most common)
  • myeloid
  • solid ^10,11
• rheumatologic (known as macrophage activation syndrome, MAS-HLH)
  • systemic juvenile idiopathic arthritis (formerly Still disease; most common)
  • adult-onset Still disease
  • systemic lupus erythematosus
  • vasculitis
• iatrogenic
  • transplantation
  • immune suppression
  • immune activation

Clinical presentation

Systemic symptoms can be non-specific but the diagnosis can be made with the fulfilment of 5 of 8 criteria from the HLH-2004 trial ¹³:

• fever (≥38.5°C)
• splenomegaly
• cytopenias (at least 2 of 3: haemoglobin <9 g/dL, platelets <100,000/μL, absolute neutrophil count <1000/μL)
• hypertriglyceridaemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenaemia (fibrinogen <150 mg/dL)
• hyperferritinaemia (ferritin >500 ng/mL, although it is usually >3000 ng/mL)
• elevated soluble CD25 (IL-2 receptor alpha, two standard deviations above age-adjusted norms)
• low or absent natural killer cell activity (cytotoxicity assay)
• haemophagocytosis in bone marrow, spleen, lymph node, or liver

Multi-organ involvement is the rule. In addition to the haematologic system, systems commonly involved include liver (hepatitis, coagulopathy), neurologic (seizures, altered mental status), and respiratory (acute respiratory distress syndrome ¹⁴, pulmonary hypertension ⁸).

Alternatively, molecular identification of a known gene mutation can lead to the diagnosis. (e.g. pathologic mutations of PRF1, UNC13D, or STX11).

Pathology

Aetiology

The condition is characterised by impaired downregulation of activated macrophages, which accumulate in tissues and overproduce cytokines, resulting in organ damage. Acute episodes often have a trigger such as infection.

Subtypes

Some described sub-types include

• familial haemophagocytic lymphohistiocytosis (FHL)
• familial erythrophagocytic lymphohistiocytosis
• primary haemophagocytic lymphohistiocytosis
• secondary haemophagocytic lymphohistiocytosis
• macrophage activation syndrome

Genetics

The primary (genetic) form of the disorder is due to autosomal recessive mutations in which the cytolytic mechanisms of NK and cytotoxic T lymphocytes is impaired, resulting in an inability to eliminate activated macrophages. These disorders include the following ¹²:

• familial haemophagocytic lymphohistiocytosis (FHL)
  • FHL1 (unknown genetic basis)
  • FHL2 (PRF1, which encodes perforin)
  • FHL3 (UNC13D)
  • FHL4 (STX11)
  • FHL5 (STXBP2)
• other immunodeficiency syndromes
  • X-linked lymphoproliferative disease type 1 (SH2D1A) and type 2 (BIRC4)
  • Griscelli syndrome type 2 (RAB27A)
  • Chediak-Higashi syndrome (LYST)
  • lysinuric protein intolerance (SLC7A7)

Radiographic features

Chest

Findings suggesting pulmonary oedema or infection are seen in up to one-half of patients. Chest radiographs may show bilateral alveolar-interstitial opacities with pleural effusions ¹⁵. Chest CT may show centrilobular nodules, consolidation, and ground-glass opacities, with mediastinal lymphadenopathy ¹⁵.

Abdomen

Findings consistent with liver disease are common, including hepatosplenomegaly, gallbladder wall thickening, and ascites ⁵.

Brain

Non-specific periventricular white-matter abnormalities, brain-volume loss, and enlargement of extra-axial fluid spaces may be seen. Orbital myopathy has also been described.

History and etymology

It is thought to have been first reported in 1952 by Farquhar and Claireaux who at that time called the disease familial haemophagocytic reticulosis ¹¹.

See also

• 2016 Histiocyte Society classification of histiocytoses