Hemophagocytic lymphohistiocytosis (HLH), also known as macrophage activation syndrome when occurring in the setting of a rheumatologic disorder, is a non-malignant but often-fatal disorder of immune dysregulation affecting multiple organs.
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.
The secondary form may occur with several types of conditions, particularly in adults 5,12:
- viral (most common), including EBV 2,3, HIV, HHV8, CMV
- rheumatologic (known as macrophage activation syndrome, MAS-HLH)
- immune suppression
- immune activation
Systemic symptoms can be non-specific but the diagnosis can be made with the fulfillment of 5 of 8 criteria from the HLH-2004 trial 13:
- fever (≥38.5°C)
- cytopenias (at least 2 of 3: hemoglobin <9 g/dL, platelets <100,000/μL, absolute neutrophil count <1000/μL)
- hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenaemia (fibrinogen <150 mg/dL)
- hyperferritinemia (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 hematologic 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).
The condition is characterized 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.
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 activate macrophages. These disorders include the following 12:
- familial hemophagocytic 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)
Findings suggesting pulmonary edema 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.
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 by in 1952 by Farquhar and Claireaux who at that time called the disease familial hemophagocytic reticulosis 11.
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