Macrophage activation syndrome D76.1

Scott and Robb-Smith, 1939

Clinically, the disease is characterized by sudden onset of high fever (status febrilis), hepatosplenomegaly, clouding of consciousness, and exanthema; less commonly, lymphadenopathy, purpura, ascites, or pleural effusion; furthermore, pulmonary (interstitial infiltrates that may develop into acute pulmonary edema; and intestinal symptoms (abdominal pain, diarrhea).

A distinction is made:

• primary forms from secondary, reactive forms, which can be triggered by viral - or bacterial infections, hemato-oncological diseases and certain autoimmune diseases.
• Primary (genetic) macrophage activation syndrome: occurs mainly in the pediatric population.
• Secondary (reactive) macrophage activation syndrome: can be found in any age group.

The disease is rare, but its prevalence is probably underestimated. For Japan, the annual incidence is 1: 800,000 population. For secondary MAS occurring as a complication of infection, the incidence is 0.9 cases per 1. 000. 000 adults. There is no known sex predilection.

The cause is an infection-related activation of macrophages.

A larger proportion of secondary MAS is due to viral infections: herpes viruses (EBV, CMV, HSV, VZV); hepatitis viruses (A, B, C), parvovirus B19, adenoviruses, influenza A virus, enteroviruses, flaviviruses, HIV, COVID-19 (McGonagle D et al. 2020).

In bacterial infections, numerous pathogens play a role e.g.. Salmonella typhi, Staphylococcus aureus, Streptococcus, Haemophilus influenzae, Pseudomonas, Legionella, Fusobacterium, Enterobacteria, Rickettsia, Brucella, Borrelia burgdorferi, Leptospires, Coxiella burnetii, Mycoplasma, Chlamydia, Bartonella, Mycobacterium tuberculosis and other mycobacteria.

Furthermore: parasites like Leishmania, Toxoplasma, fungi (Candida, Cryptococcus, Pneumocystis jiroveci, Aspergillus fumigatus).

MAS may be complicating in neoplasms (T-, B- or NK-cell lymphomas, Hodgkin's lymphomas, acute leukemias), autoimmune diseases - most commonly systemic lupus erythematosus, Still's syndrome, or after drug ingestion.

Lab:

• thrombocytopenia
• Increased: GOT (AST) (>59 U/ml)
• Leukopenia (>4x109 )
• hypofibrinogenemia (<2.5g/l

Clinical criteria

• Dysfunctions of the central nervous system (excitability, disorientation, lethargy, headaches, seizures, coma)
• Haemorrhages (purpura, poor wound healing, bleeding of the mucous membranes)
• Hepatosplenomegaly (>3cm below the costal arch)
• Histopathological criteria: Macrophage haemophagocytosis in bone marrow puncture.

Note: the diagnosis of MAS requires the presence of 2 or >2 laboratory criteria or 2 of 3 or >3 clinical and/or laboratory criteria. Bone marrow puncture for the detection of haemophagocytosis is only necessary in doubtful cases.

Other laboratory criteria: Hyperferritinaemia (Note: Ferritin is released by macrophages and hepatocytes and during blood cell phagocytosis. A ferritinaemia of > 10 000 µg/l indicates MAS in the paediatric population with 90% sensitivity and 96% specificity).

Treatment consists of the immediate parenteral administration of prednisolone with simultaneous discontinuation of all applied drugs.