Macrophage Activation Syndrome Diagnostic Criteria
The diagnosis of MAS should be based on the HLH-2004 criteria, requiring 5 of 8 diagnostic parameters to be fulfilled, though clinical judgment may warrant initiating treatment even when fewer criteria are met. 1
HLH-2004 Diagnostic Criteria (5 of 8 Required)
The following eight parameters constitute the standard diagnostic framework 1:
Fever - Present in 95% of cases 2
Splenomegaly - Though only present in 38% of cases at early diagnosis 2
Cytopenias affecting ≥2 of 3 lineages:
- Hemoglobin < 90 g/L (< 100 g/L in infants < 4 weeks)
- Platelets < 100 × 10⁹/L
- Neutrophils < 1.0 × 10⁹/L 1
Hypertriglyceridemia and/or hypofibrinogenemia:
- Fasting triglycerides ≥ 3.0 mmol/L (≥ 265 mg/dL)
- Fibrinogen ≤ 1.5 g/L 1
Hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy - Present in only 63% at early diagnosis 2
Low or absent NK cell activity according to local laboratory reference 1
Ferritin ≥ 500 μg/L - Though levels >10,000 μg/L are highly specific for MAS 1, 3, 4
Soluble CD25 (soluble IL-2 receptor) ≥ 2,400 U/mL 1
Critical Diagnostic Considerations
Hyperferritinemia as a Key Marker
Ferritin levels should always prompt inclusion of MAS in the differential diagnosis. 1 Levels >7,000-10,000 μg/L are >90% sensitive and specific for HLH in children, though less specific in adults. 1 Ferritin >3,000 ng/mL is suspicious, while >10,000 ng/mL is highly indicative of MAS. 4
Soluble CD25 Performance
Soluble IL-2 receptor has demonstrated excellent diagnostic performance with an area under the curve of 0.90 (95% CI: 0.83-0.97) compared to ferritin's 0.78 (95% CI: 0.67-0.88), making it a superior low-cost diagnostic test. 1
Novel Biomarkers
Emerging biomarkers showing promise for MAS diagnosis include 1:
- IL-18 - Elevated in both systemic and MAS presentations
- C-X-C motif ligand 9 - Interferon-γ-related marker
- Adenosine deaminase 2 activity - Interferon-γ-related marker
- Activated T cells - Flow cytometry assessment
- S100 proteins (S100A8/A9 and A12) - Calcium-binding proteins
Common Diagnostic Pitfalls
Overlap with Underlying Disease
MAS is frequently underdiagnosed because its features overlap substantially with severe cytokine release syndrome (CRS), sepsis, disease flares, or drug adverse effects. 1, 5 In CAR T-cell therapy patients, most with moderate-to-severe CRS meet classic HLH criteria, yet MAS symptoms often resolve with CRS management alone. 1
Serial Assessment Required
If hemophagocytic activity is not proven initially, serial bone marrow aspirates over time may be necessary, or material from other organs should be obtained. 1 The absence of hemophagocytosis does not exclude MAS, as it is present in only 60% of cases. 6
Context-Specific Interpretation
The best approach for early recognition requires assessing relative changes in parameters from baseline rather than absolute values alone, combined with continuous thorough physical examination. 7 For patients with rheumatic disease presenting with persistent fever, hepatic dysfunction, coagulation disorders, multiple organ impairment, significantly increased IL-10 and IFN-γ, and persistently rising ferritin, MAS development should be strongly suspected. 2
Supportive Laboratory Findings
Additional abnormalities that strengthen the diagnosis include 1:
- Cerebrospinal fluid pleocytosis (mononuclear cells) and/or elevated protein
- Liver biopsy resembling chronic persistent hepatitis
- Elevated liver enzymes (present in 86% of cases) 2
- Hypoproteinemia
- Hyponatremia
- Elevated VLDL/low HDL
- Elevated D-dimer
- Decreased ESR despite high inflammation 5
Disease-Specific Considerations
For Still's disease (sJIA/AOSD), the same HLH-2004 criteria apply, as these represent a continuum of the same disease entity. 1 MAS occurs as a life-threatening complication in both pediatric and adult presentations with similar prevalence and clinical features. 1