Which infections in children can precipitate macrophage activation syndrome (MAS)?

Pediatric Infections That Can Precipitate Macrophage Activation Syndrome (MAS)

Viral infections, particularly Epstein-Barr virus (EBV), are the most common infectious triggers of MAS in children, though bacterial infections including Staphylococcus epidermidis and rickettsial infections like scrub typhus can also precipitate this life-threatening complication.

Primary Infectious Triggers

Viral Pathogens

The most frequently implicated infectious agents include:

• Epstein-Barr virus (EBV) - documented as a trigger in children with underlying systemic juvenile idiopathic arthritis (sJIA) 1
• Adenovirus - identified as precipitating MAS in pediatric rheumatic disease patients 1
• SARS-CoV-2 - associated with multisystem inflammatory syndrome in children (MIS-C), which can progress to MAS 2, 3

Bacterial Infections

• Staphylococcus epidermidis - reported to trigger MAS even in patients with underlying conditions like cystic fibrosis and familial Mediterranean fever 4

Rickettsial Infections

• Scrub typhus (Orientia tsutsugamushi) - documented to cause MAS with concomitant MIS-C presentation 2

Clinical Context and Risk Stratification

Infections act as triggers primarily in children with underlying inflammatory or immune dysregulation conditions, not typically in previously healthy children. The key at-risk populations include:

• Children with systemic juvenile idiopathic arthritis (sJIA) - where 10% develop fulminant MAS and 30-40% exhibit subclinical disease 5
• Patients with systemic lupus erythematosus 6, 5
• Children with Kawasaki disease 5
• Those with genetic autoinflammatory disorders (e.g., NLRC4 gain-of-function mutations) 5
• Patients with primary immunodeficiencies characterized by immune dysregulation 5

Pathophysiology of Infection-Triggered MAS

Infections precipitate MAS through excessive activation and proliferation of T lymphocytes and macrophages 4. In the recent literature, 22.4% of pediatric MAS patients carry HLH-related genetic variants affecting the perforin-mediated cytolytic pathway 7, 8. These variants, even in heterozygous states, partially reduce cytolytic activity leading to:

1. Prolonged survival of infected target cells
2. Increased production of proinflammatory cytokines (IL-1β, IL-6, IL-18, IFN-γ)
3. Overstimulation of macrophages
4. Resulting "cytokine storm" 8

Critical Diagnostic Considerations

Infection-triggered MAS has worse outcomes than sJIA-associated MAS. Key data from recent studies show:

• ICU admission rates: 68.2% for infection-triggered MAS vs. 25.0% for sJIA-associated MAS (p=0.02) 7
• Mortality rates: 36.4% for non-MIS-C infection-triggered MAS vs. 6.3% for sJIA-associated MAS (p=0.04) 7
• Recurrence: Less common in infection-triggered MAS (15.9%) compared to sJIA (28.1%) 7

Common Pitfalls

• Do not wait for bone marrow confirmation - hemophagocytosis was definitive in only 4 of 7 cases examined, yet all required treatment 1
• ESR paradoxically falls during MAS despite severe inflammation - mean ESR dropped from 115 to 28 mm/h in active cases 1
• Infection may coexist with MIS-C - making differentiation challenging but critical for appropriate antimicrobial therapy 2

Specific Infectious Scenarios

MIS-C with Concurrent Infection

The case of scrub typhus with MIS-C progressing to MAS 2 illustrates that:

• Tropical infections can mimic or coexist with MIS-C
• Both conditions require specific treatment (azithromycin for scrub typhus + immunosuppression for MIS-C/MAS)
• Identification of concurrent infection is essential in endemic areas to guide appropriate antimicrobial coverage

Opportunistic Infections

Pneumocystis jiroveci emerged as a complication during MAS treatment in immunosuppressed patients 6, highlighting the need for prophylaxis consideration in high-risk scenarios.

Practical Recognition Algorithm

When evaluating a febrile child with suspected infection for MAS development, assess for:

1. Falling platelet count (average drop from 346 to 99 × 10⁹/L) 1
2. Paradoxically falling ESR despite worsening clinical status 1
3. Hepatosplenomegaly (77% of cases) 6
4. Hyperferritinemia - ferritin >469 μg/L has 100% sensitivity for MAS in MIS-C 3
5. New cytopenias - particularly thrombocytopenia <114 × 10⁹/L 3
6. Coagulopathy with hypofibrinogenemia 6

The combination of ferritin >469 μg/L OR platelets <114 × 10⁹/L discriminates MAS with 100% sensitivity and 94.9% specificity in the MIS-C population 3, though these thresholds require validation in other infection-triggered MAS contexts.