What is macrophage activation syndrome?

Macrophage Activation Syndrome (MAS)

Macrophage activation syndrome is a severe, life-threatening, systemic inflammatory condition characterized by the presence of activated macrophages that phagocytose erythroid precursors in the bone marrow, leading to progressive cytopenias, fever, hepatosplenomegaly, and coagulopathy. 1

Definition and Pathophysiology

• MAS is a form of hemophagocytic lymphohistiocytosis (HLH) that occurs in patients with inflammatory rheumatologic conditions, characterized by inappropriate activation of macrophages and T-lymphocytes 2
• The condition involves a cytokine storm with secretion of tumor necrosis factor, interleukins (particularly IL-1β, IL-6, IL-18), and interferon-gamma 2, 3
• Activated macrophages phagocytose blood cells in the bone marrow, leading to cytopenias and multi-organ dysfunction 1

Clinical Presentation

• Persistent high-grade fever unresponsive to antipyretics 2, 4
• Hepatosplenomegaly and lymphadenopathy 4
• Progressive cytopenias (anemia, thrombocytopenia, leukopenia) 1
• Coagulopathy with hypofibrinogenemia and elevated D-dimer 4
• Neurological involvement (altered mental status, seizures) 3
• Sepsis-like presentation with hemodynamic instability 4
• Liver dysfunction with elevated transaminases 3, 4

Associated Conditions

• Most commonly associated with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) 3, 5
• Can occur in juvenile dermatomyositis (JDM) 1
• Other associated conditions include systemic lupus erythematosus (SLE), Kawasaki disease, rheumatoid arthritis, and Sjögren's syndrome 3
• May be triggered by viral infections (including SARS-CoV-2, EBV, herpes viruses, influenza) 6
• Rarely can occur in previously healthy individuals before manifestation of autoimmune disease 2

Diagnostic Approach

• Laboratory findings include:
  • Markedly elevated ferritin (>10,000 ng/mL) 1
  • Cytopenias affecting at least two cell lines 4
  • Elevated liver enzymes and bilirubin 3
  • Elevated triglycerides 4
  • Decreased fibrinogen 4
  • Elevated inflammatory markers (CRP, ESR) 2
• Bone marrow examination showing hemophagocytosis (macrophages engulfing blood cells) 1
• Specific diagnostic criteria exist for HLH, MAS-associated sJIA, and MAS-associated SLE 4

Treatment

• Affected patients should be managed in a critical care setting, and treatment involves high-dose corticosteroids, cyclosporine, and anakinra, a recombinant IL-1 receptor antagonist. 1
• First-line therapy options include:
  • High-dose intravenous glucocorticoids (methylprednisolone) 1
  • Cyclosporine A (CsA) 1
  • Anakinra (IL-1 receptor antagonist) 1
• For refractory cases:
  • Intravenous immunoglobulin (IVIG) at 2 gm/kg 7
  • Etoposide (VP-16) may be considered in severe cases 1
  • Other biologics targeting IL-6 (tocilizumab) or JAK inhibitors (ruxolitinib) 1
• Supportive care:
  • Correction of coagulopathy 7
  • Management of organ dysfunction 7
  • Surveillance for and treatment of infections 7

Monitoring and Prognosis

• Serial laboratory testing to monitor response to therapy:
  • Ferritin levels 7
  • Complete blood count 7
  • Coagulation parameters 7
  • Liver function tests 7
• MAS has a high mortality rate (estimated at 40% in children) if not recognized and treated promptly 5
• Early diagnosis and treatment are crucial to prevent progressive tissue damage leading to organ failure and death 2, 4

Clinical Pearls and Pitfalls

• MAS can be difficult to distinguish from sepsis or disease flare-up of the underlying rheumatologic condition 4
• Relative changes in laboratory parameters from baseline are more important than absolute values 4
• Delay in diagnosis is common and associated with poor outcomes 4
• MAS can develop rapidly and progress to multi-organ failure within days 2
• Consider MAS in any patient with persistent fever, cytopenias, and markedly elevated ferritin, especially in the context of autoimmune disease 2, 4
• MAS in the context of COVID-19 may present with features localized to the lungs 6