Macrophagic activation syndrome is a severe and acute clinical event occurring with fever, hepatosplenomegaly, and pancytopenia due to uncontrolled phagocytosis of blood cells and precursors.

Hemophagocytic syndrome results from a inappropriate stimulation of macrophages in bone marrow and lymphoid organs, leading to phagocytosis of blood cells and production of high amounts of pro-inflammatory cytokines.

This life-threatening disease combines non-specific clinical signs (fever, cachexia, hepatomegaly, enlargement of spleen and lymph nodes) as well as typical laboratory findings (bi- or pancytopenia, abnormal hepatic tests, hypofibrinemia, elevation of serum LDH, ferritinemia and triglyceride levels). Diagnosis is confirmed by cytological or pathological examination of bone marrow or tissue specimens.

Microscopical synopsis

 erythrophagocytosis
 lymphocytophagocytosis
 hemophagocytosis

Etiologies

Primary - Constitutional Immune deficiency

 familial hemophagocytic lymphohistiocytosis

• HPLH2 mutations (10q22)
• perforine 1 mutations(MIM)

 Griscelli syndrome (MYO5 mutations)
 X-linked EBV associated lymphoproliferative disease (SH2D1A mutations) (XLP)
 Maladie de Chediak-Higashi (OMIM) (#2165746#)
 Maladie d'Ommen (MIM) - 11p13 RAG1 mutations (MIM) et RAG2 mutations (MIM)
 Abnormal response to EBV

Secondary (reactive hemophagocytic syndrome)

 infections (IAHS Infection Associated Hemophagocytic Syndrome)(#11076718#)

• viral infections (VAHS virus-associated hemophagocytic syndrome)
  • EBV infection (EBV-associated hemophagocytic syndrome) (#12481907#, #12467966#, #11456362#, #8389318#)
    • abnormal response to EBV infection (fatal infectious mononucleosis)(#8892735#, #8241498#)
    • chronic active Epstein-Barr virus infection (#1850588#)

• bacterial infections
  • severe sepsis
  • spirochetoses
    • leptospirosis (Leptospira sp.) (#9398130#)
    • Borreliose (Borrelia burgdorferi)
    • Syphilis (Treponema pallidum)
  • brucellosis (Brucella melitensis) (#8213671#)
  • typhoïd fever (Salmonella typhi)

• mycobactérioses (mycobacteremia)
  • tuberculosis with mycobacteremia (Mycobacterium tuberculosis) (#12374364#, #3779613#, #16271925#)
  • Mycobacterium avium intracellulare (#12729056#)

• Chromobacterium violaceum
• psitaccosis (Chlamydia psitacci)
• Coxiella burnetti
• erlichiosis (Ehrlichia canis) (#1951324#)
• Mycoplasma pneumoniae (#11483400#)
• rickettsioses, mediterranean spotted fever (Richettsia conorii)(#7824495#, #2592187#)
• Orientia tsutsugamushi
• scrub typhus (tsutsugamushi disease) (#10879646#)
• acute Q fever (#8645795#)

 parasitic infections
 fungal infections

• Apergillose
• Candidose
• Cryptococcose
• histoplasmosis (#11888034#)
• Penicillium marneffei
• Trichophyton beigelii

• protozooses
  • visceral leishmaniasis (Kala-azar) (Leishmania sp.) (#12240858#, #11764103#, #11205842#, #8241681#)
  • malaria(Plasmodium falciparum) (#12458577#, #8923789#)
  • babesiosis (Babesia microti) (#8781622#, #7668227#, #3946448#)
  • toxoplasmosis

• helminthiases
  • Strongyloidiase (Strongylides stercoralis)

 metabolic diseases

• lysinuric protein intolerance (#9931537#)
• lipid rich parenteral nutrition

 dysimmunity - autoimmunity (#11407091#)

• systemic erythematosus lupus (#11868605#, #9678692#)
• Still disease (#12737332#, #9263166#)
• allogeneic peripheral blood stem cell transplantation (#12040480#, #11372742#, #11039676#)
• visceral allograft (#9771844#)
• vasculitis
  • Kawasaki disease (#12886898#, #10845231#)
  • systemic erythematosus lupus (#11868605#, #9678692#)

 tumoral diseases (Tumors)

• Lymphomas (#11420457#)
  • T lymphoma (#10824495#, #8590855#, #8080885#), nasal T-cell lymphoma (#2423228#)
  • CD30+ anaplastic large-cell lymphoma (ALCL) (#11426532#, #9575683#)
  • subcutaneous panniculitic T-cell lymphoma (cytophagic histiocytic panniculitis) (#8621826#)
  • B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS)(#11579948#, #10965786#)
  • hepatosplenic B-cell lymphoma (#10642947#)
  • hepato-splenic gammadelta T-cell lymphoma (#9883807#)
  • intravascular B-cell lymphoma (intravascular lymphomatosis, angiotropic large B-cell lymphoma)(#10342574#, #7808970#)

• Leukemias
  • T-cell acute lymphoblastic leukemia (T-ALL) with t(11;14)(p15;q11) (#3024802#)
  • NK cell leukemia (#8854571#, #1746541#)

• Langerhans cell histiocytosis (#11910507#, #7626381#)

Miscellaneous

 deletion of 22q11 (#10588839#)
 fulminant ulcerative colitis (#9772064#)

 Web. CDC.

References

 Gaffey MJ, Frierson HF Jr, Medeiros LJ, Weiss LM. The relationship of Epstein-Barr virus to infection-related (sporadic) and familial hemophagocytic syndrome and secondary (lymphoma-related) hemophagocytosis: an in situ hybridization study. Hum Pathol. 1993 Jun;24(6):657-67. PMID: #8389318#

 Favara BE. Hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. Semin Diagn Pathol. 1992 9:63-74. PMID: 1561489; UI: #92221172#

 Arya S, Hong R, Gilbert EF. Reactive hemophagocytic syndrome. Pediatr Pathol. 1985;3(2-4):129-41. PMID: #4095022#;