• persistent or intermittent fever
• elevated or rising ferritin or other inflammatory markers (CRP, LDH)
• splenomegaly (eventually hepatosplenomegaly)
• inappropriately low or falling haemoglobin, platelets or white cells (neutrophils and lymphocytes) -evolving into severe pancytopenia
• coagulation abnormalities (in particular, hypofibrinogenemia, increased D-dimers, even DIC)
• hepatic dysfunction including high triglycerides
• CNS dysfunction (including seizures and encephalopathy, with raised CSF protein)

The underlying problem is the inability to kill infected target cells. The frustrated NK-l and cytotoxic T-cell activity leads to a massive inflammatory cascade, resulting in macrophage activation, dissemination, and organ infiltration. The haemophagocytosis of the name refers to characteristic macrophage/histiocyte consumption of erythrocytes, most evident in the marrow but sometimes seen in the peripheral blood film.  Not always dramatic, not always evident at presentation so serial bone marrow examinations may be required (spleen aspirate?).

There are four categories:

• a familial syndrome (perforin deficiency)
• associated with infection (Epstein-Barr virus, cytomegalovirus, parvovirus B19, bacteria, fungi, mycobacteria, and parasites)
• associated with juvenile idiopathic arthritis (where it is usually called macrophage activation syndrome)
• associated with immunodeficiency 
  • DiGeorge syndrome should be excluded by FISH
  • Lysinuric protein intolerance – hyperammonemia is characteristic
  • the accelerated phases of Chediak-Higashi and Griscelli syndromes (both characterized by albinism,  mutations in LYST or RAB27A genes respectively)
• In male infants, consider X-linked lymphoproliferative disease where natural killer cells are unable to kill Epstein-Barr virus.

So do ferritin (spectacularly high,eg >1000)! And repeat if initially normal! Other bloods as above. ESR surprisingly low, due to low fibrinogen cf underlying JIA. All inflammatory markers can be low if very ill due to consumption.

Specialist markers include CD25, CD163, IL-18, CXCL9.

Diagnostic criteria perform well in specific settings but none perfect – get an expert! And go looking for underlying causes if not already known to have. Genetic testing in particular can dramatically impact on diagnosis and management.

MRI Brain and lumbar puncture for infants, known genetic disorder, or clinical indications – do cytopathology.

Treatment

For probable cases with worsening organ dysfunction, consider immunomodulatory treatment while diagnostic resting still ongoing. Empirical treatment can be high dose steroids, Anakinra or IVIG, plus treatment of underlying infection/malignancy. [EULAR/ACR 2022 diagnostic criteria]