Macrophage activation syndrome

Background

• Macrophage activation syndrome (MAS) is a severe, potentially fatal hyperinflammatory syndrome caused by uncontrolled activation and proliferation of T lymphocytes and macrophages, leading to a massive cytokine storm and widespread hemophagocytosis
• MAS is a form of secondary hemophagocytic lymphohistiocytosis (HLH) occurring in the context of rheumatic disease
  • "MAS" is used when triggered by rheumatic disease; "secondary HLH" is used when triggered by infection or malignancy — the pathophysiology and management are similar
• Mortality: 20-40% even with treatment; higher if diagnosis is delayed
• Underdiagnosed — frequently confused with sepsis, disease flare of the underlying rheumatic condition, or drug side effects

Triggers and Associations

• Most commonly associated with systemic juvenile idiopathic arthritis (sJIA) — ~10% overt MAS, up to 30-40% subclinical
• Other rheumatic diseases:
  • Adult-onset Still's disease (AOSD)
  • Systemic lupus erythematosus (SLE)
  • Kawasaki disease
  • Juvenile dermatomyositis
  • Polyarteritis nodosa
• Infectious triggers (may precipitate MAS in patients with underlying rheumatic disease or de novo):
  • Viral: EBV (most common), CMV, influenza, COVID-19, HSV, parvovirus B19
  • Bacterial: sepsis, endocarditis
• Malignancy-associated (especially T-cell lymphoma)
• Medication changes (including initiation or alteration of biologic agents)
• Disease flares of underlying rheumatic condition

Pathophysiology

• Defective NK cell and cytotoxic T cell function → failure to eliminate antigen-presenting cells → persistent immune activation
• Massive release of pro-inflammatory cytokines (IL-1, IL-6, IL-18, IFN-γ, TNF-α)
• Uncontrolled macrophage activation → phagocytosis of blood cells (hemophagocytosis) in bone marrow, liver, spleen, and lymph nodes
• Results in consumptive cytopenias, coagulopathy, and multi-organ dysfunction

Clinical Features

MAS can develop explosively — a child or adult with known rheumatic disease can deteriorate from stable to critically ill within hours to days

Systemic

• Unremitting high fever — in sJIA patients, evolution from quotidian spiking fever to continuous fever is a red flag
• Profound malaise, rapid clinical deterioration
• Paradoxical improvement of arthritis may occur as MAS develops (due to immune exhaustion)

Organ Involvement

• Hepatic: hepatomegaly, transaminitis, jaundice, liver failure
• Hematologic: petechiae, purpura, mucosal bleeding, easy bruising (from consumptive coagulopathy and thrombocytopenia)
• Neurologic: altered mental status, lethargy, irritability, seizures, encephalopathy (present in 30-35% of cases)
• Spleen: splenomegaly (often rapidly enlarging)
• Lymphadenopathy (generalized)
• Cardiac: myocarditis, pericardial effusion
• Pulmonary: ARDS, pleural effusion
• Renal: acute kidney injury
• DIC: clinical or subclinical disseminated intravascular coagulation

ED Pearls

• In a child with known sJIA, any of the following should prompt evaluation for MAS:
  • Fever pattern change from intermittent to continuous
  • Falling platelet count (even if still within "normal" range)
  • Falling ESR (paradoxical — due to fibrinogen consumption)
  • Rising ferritin disproportionate to other acute phase reactants
  • New hepatomegaly or transaminitis
  • New bleeding or bruising
• MAS can be the presenting feature of undiagnosed sJIA in 22-53% of cases
• MAS mimics sepsis — and the two can coexist (infection is a common MAS trigger)

Differential Diagnosis

• Sepsis/septic shock — most important mimicker; MAS and sepsis can coexist
• Primary hemophagocytic lymphohistiocytosis (familial/genetic HLH) — typically presents in infancy
• Malignancy-associated HLH (T-cell lymphoma, leukemia)
• Disease flare of underlying rheumatic condition (sJIA, SLE, AOSD) without MAS
• DIC from other causes
• Thrombotic thrombocytopenic purpura (TTP)
• Drug reaction (e.g. to biologic agents, NSAIDs)
• Liver failure from other causes
• Toxic shock syndrome
• Severe viral illness (EBV, CMV, COVID-19)

Evaluation

Workup

Order the following in any patient with suspected MAS:

Hematology

• CBC with differential: pancytopenia (or falling counts from previously elevated baseline — especially falling platelets and falling WBC)
• Peripheral blood smear: evaluate for hemophagocytosis, blasts (leukemia)
• Reticulocyte count

Inflammatory Markers

• Ferritin: the single most important lab — markedly elevated, often >10,000 ng/mL; may exceed 100,000 ng/mL in fulminant MAS
• ESR: may be paradoxically low or falling (due to fibrinogen consumption) even as CRP rises — this discordance is highly suggestive of MAS
• CRP: elevated
• Ferritin:ESR ratio >21.5 is suggestive of MAS in sJIA patients

Coagulation

• Fibrinogen: low or falling (consumed in DIC-like process) — often <150 mg/dL
• PT/PTT: prolonged
• D-dimer: elevated
• FDP: elevated

Hepatic

• AST/ALT: elevated (AST >48 U/L is part of the 2016 classification criteria)
• LDH: markedly elevated
• Bilirubin: may be elevated
• Albumin: low

Other

• Triglycerides: elevated (>156 mg/dL per HLH-2004 criteria)
• Lactate: if concern for tissue hypoperfusion
• sIL-2R (soluble CD25): markedly elevated if available (may take days to result)
• sCD163: elevated (marker of macrophage activation; not widely available)
• Blood cultures: mandatory to evaluate for concurrent infection
• Viral studies: EBV, CMV, influenza, COVID-19, HSV (infection is a common MAS trigger)
• CXR, echocardiography: assess for pleural effusion, pericardial effusion, ARDS
• Bone marrow biopsy: may show hemophagocytosis; however, absence of hemophagocytosis does not rule out MAS (present in only ~60% of cases, and may not be seen early)

Diagnosis

There is no single gold-standard diagnostic test. MAS is a clinical diagnosis supported by laboratory and sometimes histopathologic findings.

2016 EULAR/ACR/PRINTO Classification Criteria for MAS Complicating sJIA

A febrile patient with known or suspected sJIA is classified as having MAS if:

• Ferritin >684 ng/mL PLUS any 2 or more of:
  • Platelet count ≤181 × 10⁹/L
  • AST >48 U/L
  • Triglycerides >156 mg/dL
  • Fibrinogen ≤360 mg/dL

Note: These criteria were validated for sJIA. For MAS in other settings, the HLH-2004 criteria or HScore may be more appropriate.

HLH-2004 Diagnostic Criteria

Diagnosis requires 5 of 8 criteria:

1. Fever ≥38.5°C
2. Splenomegaly
3. Cytopenias in ≥2 lineages (Hgb <9 g/dL; platelets <100 × 10⁹/L; neutrophils <1.0 × 10⁹/L)
4. Hypertriglyceridemia (fasting ≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
5. Hemophagocytosis in bone marrow, spleen, or lymph nodes
6. Low or absent NK cell activity
7. Ferritin ≥500 ng/mL
8. Elevated sIL-2R (soluble CD25) ≥2400 U/mL

Note: HLH-2004 criteria may underdiagnose MAS in sJIA because baseline inflammatory markers are already elevated in active sJIA

HScore

• A validated scoring system that calculates the probability of reactive HLH/MAS based on clinical and laboratory variables
• Variables: temperature, organomegaly, number of cytopenias, ferritin, triglycerides, fibrinogen, AST, hemophagocytosis on aspirate, known immunosuppression
• HScore >169 has 93% sensitivity and 86% specificity for HLH
• Available at: MDCalc - HScore

Key Laboratory Trends (Most Useful in the ED)

• Ferritin rising rapidly (doubling or tripling over hours to days)
• Platelet count falling (even if still "normal" — a trend from 400 → 200 × 10⁹/L in a patient with sJIA is ominous)
• ESR falling while CRP rises (paradoxical ESR drop reflects fibrinogen consumption)
• Fibrinogen falling
• AST/ALT rising
• LDH rising

Management

MAS is a medical emergency. Early aggressive treatment reduces mortality. Initiate treatment based on clinical suspicion — do not wait for bone marrow results.

Resuscitation and Stabilization

• ABCs: Airway, breathing, circulation — patients may present in or rapidly progress to shock
• IVF resuscitation for hypotension
• Vasopressors if refractory to fluids (see Sepsis (Main))
• Blood products as indicated:
  • Platelets for active bleeding or platelets <10,000/mm³
  • FFP or cryoprecipitate for severe coagulopathy (DIC) with bleeding
  • pRBCs for symptomatic anemia
• Empiric broad-spectrum antibiotics — MAS and sepsis can coexist and are clinically indistinguishable; treat for sepsis until infection is excluded
• Correct DIC if present (see DIC)

Immunosuppressive Therapy

Definitive treatment targets the underlying hyperinflammatory process. Initiate in consultation with rheumatology and/or hematology.

First-line

• High-dose IV methylprednisolone: 30 mg/kg/dose IV (max 1g), typically daily for 3 consecutive days, then taper
  • May be given as pulse therapy for fulminant MAS
• Cyclosporine A: 2-7 mg/kg/day divided BID (oral or IV); monitor levels and renal function
  • Used in combination with IV steroids, especially in sJIA-associated MAS
• Anakinra (IL-1 receptor antagonist): increasingly used as first-line combination therapy with IV steroids, especially in the United States
  • Typical dose: 2-10 mg/kg/day SC or IV (doses higher than standard RA dosing may be needed)
  • Advantages: rapid onset, short half-life (allows quick titration), effective even in MAS refractory to steroids
  • May be started in the ED or inpatient setting by rheumatology

Refractory MAS

• Etoposide: cytotoxic chemotherapy agent used in HLH-2004 protocol; reserved for refractory cases given risk of myelosuppression
• IVIG: 2 g/kg over 2-5 days; may be helpful particularly in infection-triggered MAS
• Emapalumab (anti-IFN-γ): FDA-approved for primary HLH; used off-label in refractory MAS
• Ruxolitinib (JAK inhibitor): emerging evidence for refractory HLH/MAS
• Tocilizumab (anti-IL-6): may be used when anakinra is unavailable, though evidence is more limited
• Rituximab: for EBV-triggered HLH/MAS

Treat the Underlying Trigger

• Infection: aggressive antimicrobial therapy; specific antiviral therapy if EBV, CMV, HSV identified
• Malignancy: urgent hematology/oncology consultation for chemotherapy
• Rheumatic disease flare: optimize control of underlying sJIA, SLE, or AOSD

Monitoring

• Frequent (q6-12h initially) monitoring of:
  • Ferritin (most important for tracking response)
  • CBC with differential (platelet trend)
  • Fibrinogen
  • AST/ALT, LDH
  • Coagulation studies
• Improving trends = response to therapy; worsening trends = consider escalation or alternative diagnosis

Consultations

• Pediatric rheumatology (or adult rheumatology for AOSD/SLE): all patients
• Hematology/oncology: to rule out malignancy-associated HLH and for consideration of etoposide or bone marrow biopsy
• Critical care/ICU: most patients with overt MAS require ICU-level monitoring
• Infectious disease: if infection trigger suspected

Disposition

• ICU admission for nearly all patients with overt MAS:
  • Multi-organ dysfunction is common and can progress rapidly
  • Continuous hemodynamic monitoring required
  • May need ventilatory support (ARDS), vasopressors, blood product transfusion
• Ward admission may be appropriate for:
  • Subclinical/early MAS identified on labs with stable clinical exam
  • Close monitoring with q6-12h lab trending and ability to rapidly escalate to ICU
• Do not discharge patients with suspected MAS
• Mortality remains 20-40% even with treatment; delay in diagnosis and treatment is the primary driver of mortality

See Also

• Systemic JIA
• Hemophagocytic lymphohistiocytosis
• Sepsis (Main)
• DIC
• Kawasaki disease
• Adult-onset Still's disease
• Pericardial effusion and tamponade

External Links

• MDCalc - HScore for Reactive Hemophagocytic Syndrome
• Medscape - Macrophage Activation Syndrome
• PMC - MAS and Secondary HLH in Childhood Inflammatory Disorders (2020)