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

• FHL1 (unknown gene at 9q21-q22) (MIM.267700)
• FHL2 (PRF1 mutations at 10q22) (MIM.603553)
• FHL3 (UNC13D mutations at 17q25) (MIM.608898)
• FHL4 (STX11 mutations at 6q24) (MIM.603552)

 Griscelli syndrome (Grsicelli disease)

• GS1 (MYO5A mutations at 15q21) (MIM.214450)
• GS2 (RAB27A mutations at 15q21) (MIM.607624)
• GS3 ( (MLPH mutations at 2q37) (MIM.609227)

 X-linked EBV associated lymphoproliferative disease

• XLP1 (SH2D1A or BIRC3 mutations at Xq25) (MIM.308240)
• XLP2 (XIAP mutations at Xq25) (MIM.300635)

 Chediak-Higashi disease (LYST mutations at 1q42) (MIM.214500) (2165746)

 Ommen disease (MIM.603554)

• RAG1 mutations at 11p13 (MIM.179615)
• RAG2 mutations at 11p13 (MIM.179616)
• DCLRE1C (Artemis) at 10p (MIM.605988)

 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)

• • Cytomegalovirus CMV (11868605)
  • Parvovirus B19 (8741323)
  • HIV (14704039)
  • Human Herpesvirus-6 (HHV6) (8607365)
  • Human Herpesvirus-8 (HHV8)
  • adenovirus (2291998)
  • Dengue
  • hepatitis A, B and C (10367794, 7771394)
  • Herpes simplex
  • Influenza A (H1N1), Parainfluenza type III
  • measles (7787329)
  • rubela (11475151)
  • varicella (11475151)
  • Hantaan virus hemorrhagic fever (11897077)
    
• 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)

 fungal infections

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

 parasitic infections

• 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)

 histiocytoses

• Langerhans cell histiocytosis (LCH) (11910507, 7626381, 7626381)
• systemic juvenile janthogranuloma (systemic XLG) (16047346, 15022067, 9025843)
• Erdheim-Chester disease (ECD) (15679446)

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;