What are the diagnosis and management of macrophage activation syndrome (MAS)?

Macrophage Activation Syndrome: Diagnosis and Management

Diagnosis of MAS

MAS should be suspected in any patient with persistent fever, splenomegaly, elevated or rising serum ferritin, inappropriately low cell counts, abnormal liver function tests, intravascular coagulation activation, and elevated or rising triglycerides. 1

Key Clinical Features to Identify

• Fever: Persistent high-grade fever unresponsive to antipyretics is present in virtually 100% of cases 1, 2
• Hepatosplenomegaly: Present in approximately 77% of patients, often with lymphadenopathy (38%) 2, 3
• Cytopenias: Look for thrombocytopenia (77%), anemia (46%), and leukopenia (54%) that are disproportionate to the underlying disease activity 2, 3
• Coagulopathy: Hypofibrinogenemia (40%) and elevated D-dimer (50%) suggest intravascular coagulation 2, 3
• Neurological involvement: Occurs in approximately 31% of cases and indicates severe disease 3

Critical Laboratory Markers

• Ferritin: Hyperferritinemia is present in 88% of cases; levels >5000 ng/mL should raise high suspicion 4, 2, 3
• Paradoxical ESR: Decreased erythrocyte sedimentation rate (67% of cases) despite active inflammation is a distinctive feature 2, 3
• Liver enzymes: Elevated transaminases occur in 77% of patients 2, 3
• Triglycerides: Hypertriglyceridemia is present in 91% of cases 2, 3
• Lactate dehydrogenase: Elevated in 100% of cases 3
• Bone marrow: Hemophagocytosis is found in 83% of cases but is NOT required for diagnosis 2, 3

Diagnostic Approach

Screen using HLH-2004 criteria, but do not wait for all criteria to be met before initiating treatment, as early intervention is crucial to prevent irreversible organ damage. 1, 4

• Multi-system involvement: Symptoms must affect at least 2 organ systems concurrently (cardiovascular, respiratory, dermatologic, gastrointestinal) 1
• Relative changes matter most: The best diagnostic approach is based on relative changes in parameters from baseline, not absolute values 5
• Continuous reassessment: Perform thorough physical examination and laboratory monitoring at least every 12 hours 1, 4

Diagnostic Pitfalls

• Do not confuse with sepsis: MAS presents with a sepsis-like syndrome but shows disproportionate inflammatory response to antimicrobial therapy 1, 5
• Do not wait for hemophagocytosis: Bone marrow findings may be absent early or require multiple aspirates 2, 5
• Recognize masked fever: Antipyretics, continuous renal replacement therapy, and extracorporeal life support can mask fever 1

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Management of MAS

MAS treatment must include high-dose glucocorticoids, and in severe cases or inadequate response, cyclosporine A and/or anakinra should be added within 24-48 hours. 1, 4

First-Line Treatment: High-Dose Glucocorticoids

• Dosing: Intravenous methylprednisolone 15-30 mg/kg/day (maximum 1g/infusion) for 3-5 consecutive days 1, 4
• Evidence: 97.7% of MAS patients receive glucocorticoids as cornerstone therapy 4
• Timing: Initiate immediately upon diagnosis without delay 1, 4

Second-Line Treatment: Cyclosporine A

Add cyclosporine A within 24-48 hours if there is inadequate initial response or if the patient presents with severe disease. 4

• Dosing: 2-7 mg/kg/day, administered orally or intravenously 1, 4
• Rationale: High-dose glucocorticoids alone cannot control hyperinflammation in a significant proportion of patients 4

Biologic Therapies for Refractory or Severe Cases

Anakinra (IL-1 blockade) shows complete response rates of 50-100% in published studies and should be considered early in severe cases. 4

• Anakinra dosing: 2-10 mg/kg/day subcutaneously in divided doses 1, 4
• Tocilizumab (IL-6 blockade): Increasing evidence supports its use, particularly in Still's disease-related MAS 1, 4
• Emapalumab (anti-IFN-γ): The only biologic with controlled trial data showing >90% complete response rates; reserved for patients who fail high-dose glucocorticoids 4
• JAK inhibitors: Ruxolitinib and baricitinib show efficacy in chronic-relapsing MAS not responsive to other therapies 4

Treatment Algorithm by Severity

For mild-moderate MAS:

• Initiate high-dose IV methylprednisolone (15-30 mg/kg/day, max 1g) 4
• Monitor response every 12 hours 4
• Add cyclosporine A if inadequate response within 24-48 hours 4

For severe MAS or rapid deterioration:

• Use combination therapy from the start: high-dose methylprednisolone PLUS cyclosporine A 4
• Consider adding anakinra early 4
• Transfer to ICU immediately if grade 3 or higher neurotoxicity, shock, severe organ dysfunction, platelet count <30 g/L, or grade ≥2 cytokine release syndrome with concurrent neurotoxicity 4
• Reassess at least every 12 hours 4

Context-Specific Considerations

For Still's disease-related MAS (sJIA/AOSD):

• IL-1 and IL-6 inhibitors should be prioritized due to high evidence of efficacy 1
• Patients with sJIA respond well to corticosteroids and cyclosporine 3

For infection-triggered MAS:

• Initiate appropriate antimicrobial therapy alongside immunosuppressive treatment without delay 1, 4
• Inadequate antimicrobial therapy is a common and deadly mistake 4
• Specific pathogens (Leishmania, Rickettsia, tuberculosis) may require targeted therapy 1

For malignancy-associated MAS:

• Treat both the MAS and underlying malignancy simultaneously 4
• Consider etoposide as last resort for refractory cases, though it carries significant toxicity 4

Monitoring Response to Therapy

Indicators of treatment response include:

• Decreasing ferritin levels 4
• Improving cytopenias 4
• Resolving coagulopathy 4
• Defervescence 4

Continue monitoring at least every 12 hours:

• Inflammatory markers 4
• Complete blood counts 4
• Coagulation parameters 4
• Organ function tests 4

Critical Management Pitfalls

• Do not delay treatment: Delayed diagnosis and treatment significantly increases mortality 4, 5, 6
• Do not use glucocorticoids alone in severe cases: Add cyclosporine A early 4
• Do not wait for all HLH-2004 criteria: Early empirical treatment is crucial 4
• Maintain high suspicion: In patients with persistent fever, cytopenias, and ferritin >5000 ng/mL 4

Supportive Care in Critical Illness

• Mechanical ventilation as needed 4
• Vasopressor support 4
• Renal replacement therapy 4
• Transfusion support 4
• Antifungal prophylaxis 4