Macrophage Activation Syndrome Diagnostic Criteria

HLH-2004 Diagnostic Criteria

The diagnosis of Macrophage Activation Syndrome (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, as recommended by the American Society of Hematology 1
The HLH-2004 criteria include cytopenias affecting ≥2 of 3 lineages, with parameters such as hemoglobin, platelets, and neutrophils, and hypertriglyceridemia and/or hypofibrinogenemia, with parameters such as fasting triglycerides and fibrinogen, as outlined by the American Society of Hematology 1
Low or absent NK cell activity is a diagnostic parameter, according to local laboratory reference, as specified by the American Society of Hematology 1
Ferritin ≥ 500 μg/L is a diagnostic parameter, though levels >10,000 μg/L are highly specific for MAS, as noted by the American Society of Hematology 1
Soluble CD25 (soluble IL-2 receptor) ≥ 2,400 U/mL is a diagnostic parameter, as recommended by the American Society of Hematology 1

Ferritin levels should always prompt inclusion of MAS in the differential diagnosis, with levels >7,000-10,000 μg/L being >90% sensitive and specific for HLH in children, as stated by the American Academy of Pediatrics 1
Soluble IL-2 receptor has demonstrated excellent diagnostic performance, with an area under the curve of 0.90, making it a superior low-cost diagnostic test, as reported by the American Society of Hematology 1
Emerging biomarkers, such as IL-18, C-X-C motif ligand 9, adenosine deaminase 2 activity, and S100 proteins, show promise for MAS diagnosis, as noted by the European League Against Rheumatism 2, 3

MAS is frequently underdiagnosed because its features overlap substantially with severe cytokine release syndrome (CRS), sepsis, disease flares, or drug adverse effects, as warned by the National Comprehensive Cancer Network 4
Serial assessment of hemophagocytic activity may be necessary, as the absence of hemophagocytosis does not exclude MAS, as emphasized by the American Society of Hematology 1

For Still's disease (sJIA/AOSD), the same HLH-2004 criteria apply, as these represent a continuum of the same disease entity, as stated by the European League Against Rheumatism 5, 2, 3

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, as described by the Mayo Clinic Proceedings 6, 7
Activated macrophages phagocytose blood cells in the bone marrow, leading to cytopenias and multi-organ dysfunction, according to the Mayo Clinic Proceedings 6, 7

Progressive cytopenias (anemia, thrombocytopenia, leukopenia) are a characteristic feature of MAS, as reported by the Mayo Clinic Proceedings 6, 7

MAS can occur in juvenile dermatomyositis (JDM), as noted by the Mayo Clinic Proceedings 6, 7

Laboratory findings include markedly elevated ferritin (>10,000 ng/mL), as indicated by Arthritis and Rheumatology 8 and Nature Reviews Clinical Oncology 9
Bone marrow examination showing hemophagocytosis (macrophages engulfing blood cells) is a diagnostic feature of MAS, according to the Mayo Clinic Proceedings 6, 7

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, as recommended by the Mayo Clinic Proceedings 6, 7
First-line therapy options include high-dose intravenous glucocorticoids (methylprednisolone), cyclosporine A (CsA), and anakinra (IL-1 receptor antagonist), as suggested by the Mayo Clinic Proceedings 6, 7 and Annals of the Rheumatic Diseases 10
For refractory cases, intravenous immunoglobulin (IVIG) at 2 gm/kg may be considered, as noted by Praxis Medical Insights 11
Etoposide (VP-16) may be considered in severe cases, according to Annals of the Rheumatic Diseases 10

Serial laboratory testing to monitor response to therapy, including ferritin levels, complete blood count, coagulation parameters, and liver function tests, is essential for managing MAS, as recommended by Praxis Medical Insights 11