Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-γ-producing lymphocytes and IL-6- and TNF-α-producing macrophages

Billiau, An; Roskams, Tania; Damme‐Lombaerts, Rita Van; Matthys, Patrick; Wouters, Carine

doi:10.1182/blood-2004-08-2997

Cited by 275 publications

(184 citation statements)

References 22 publications

(25 reference statements)

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“…In our patients, ferritin levels are excessively high in three cases (other two not done), indicating the impact of acute phase reactions in the disease process. Uncontrolled Thelper1 lymphocyte and monocyte-macrophage activation leading to excessive secretion of proinflammatory cytokines [7] Clinical criteria Fever Splenomegaly Laboratory criteria Cytopenia (affecting !2 of 3 lineages in the peripheral blood; hemoglobin < 90 g/L, platelets < 100 Â 10 9 /L, neutrophils < 1.0 Â 10 9 /L) Hypertriglyceridemia (!265 mg/dL) and/or hypofibrinogenemia ( 1.5 g/L) Histopathologic criteria Hemophagocytosis in bone marrow or spleen or lymph nodes such as IFNg, TNFa, IL-6, IL-1, and soluble IL-2 receptor, all these appear to be the crucial mechanisms involved in the pathogenesis of HPS [6,[8][9][10][11]. Recently, over-secretion of IL-18 by monocytes in patients with primary and secondary HPS has been described.…”

Section: Discussionmentioning

confidence: 99%

“…IL-18 is known to be a potent inducer of IFNg and TNFa production by T lymphocytes and NK cells as well as induction of Fas-L expression on lymphocytes, which can mediate cytotoxicity against Fas expressing cells such as hepatocytes [12][13][14][15][16]. As a result, clinical manifestation of HPS such as fever, hepatosplenomegaly, cytopenias, liver dysfunction, and coagulopathy are mostly attributable to hypercytokinemia [6,[8][9][10][11][13][14][15]. HPS can be primary due to underlying genetic defects such as a mutation of the perforin gene (PRF1), the MUNC13-4 mutation, and a mutation of syntaxin 11.…”

Section: Discussionmentioning

confidence: 99%

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Crimean‐Congo hemorrhagic fever: Five patients with hemophagocytic syndrome

Fışgın

Tanyel

et al. 2007

American J Hematol

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Three pediatric and two adult Turkish patients with Crimean Congo Hemorrhagic Fever (CCHF) induced hemophagocytic syndrome (HPS) were admitted to Ondokuz Mayis University Hospital, which is in the Middle Black Sea Region of Turkey. All of them had remarkable hemophagocytosis in the bone marrow with severe bleeding symptoms along with the other known clinical and laboratory findings of CCHF. We would like to present these patients and to discuss the pathophysiology and the effect of acquired HPS on the severity of the disease. Am. J. Hematol., 2008. © 2007 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Crimean‐Congo hemorrhagic fever: Five patients with hemophagocytic syndrome

Fışgın

Tanyel

et al. 2007

American J Hematol

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“…34,35,37 As a result of continuous stimulation with proinflammatory cytokines (most notably, interferon gamma (IFNg)), macrophages will become hemophagocytic. 33,38 Although familial cases of MAS in sJIA have not been reported, as in FHLH, sJIA/MAS patients may also have functional defects in the exosome degranulation pathway. 39 --41 Furthermore, these functional abnormalities are associated with SNPs in the FHLHassociated genes, including PRF1 40 and MUNC13-4.…”

Section: Genetic Factors For Mas In Sjiamentioning

confidence: 99%

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

et al. 2012

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Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30 --40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro-and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA.

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“…In patients with miliary tuberculosis, the pathological specimens show hemophagocytosis in the bone marrow. Previous reports have shown IFN-γ production to be accelerated in the hemophagocytic reaction (8)(9)(10). On the other hand, the baseline concentration of IFN-γ is high in patients with autoimmune diseases, such as systemic lupus erythematosus (11)(12)(13) and rheumatoid arthritis (13,14).…”

Section: Discussionmentioning

confidence: 98%

Miliary Tuberculosis with Indeterminate Interferon Gamma Release Assay Results

et al. 2013

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Recently, interferon gamma release assays (IGRAs) have become an important clinical tool for detecting latent tuberculosis. However, IGRA results may impede making a diagnosis. We herein present an interesting case of miliary tuberculosis with a nonspecific IGRA reaction due to hemophagocytosis. Case ReportA 64-year-old man with advanced chronic kidney disease due to nephrosclerosis and ischemic heart disease was admitted to our hospital with an intermittent high-grade fever lasting for one week. The plan was to initiate hemodialysis therapy, and the patient underwent surgery for internal shunt ostomy in the left upper arm two months prior to admission. He was given neither steroids nor other immunosuppressants. On admission, he was free from respiratory symptoms, such as a productive cough. His laboratory data and radiological findings were evaluated. The clinical laboratory data obtained on admission confirmed a high alkaline phosphatase level (above 2,000 IU/mL) and a decreased hemoglobin (Hgb) level (below 10.0 g/dL). The serum C-reactive protein and procalcitonin levels were elevated, indicating an inflammatory reaction. The soluble interleukin-2 receptor (sIL-2R) level was elevated to 18,986 U/mL. Both anti-HIV and anti-human T-cell leukemia virus (HTLV) antibodies were negative. He had no history of hematological diseases. Chest roentogenography performed on admission showed no abnormalities, except cardiomegaly ( Figure A).We initially suspected a bloodstream infection, such as infectious endocarditis, and thus performed blood cultures and serological surveillance. However, these microbiological inspections yielded no useful data. On the other hand, chest computed tomography revealed slight density changes in both lung fields ( Figure B); however, the patient had no respiratory symptoms. Although we recognized a slight density elevation in the pulmonary alveolar field, radiologists in our hospital did not mention these findings, and miliary tuberculosis was not suspected. The detection of a column appearance depends on the type of monitor used. We attempted to obtain respiratory samples to detect pulmonary infections, including tuberculosis. However, due to the lack of sputum production, we were unable to obtain respiratory samples. The interferon gamma release assay (IGRA, QuantiFERON-TB TM Gold In-tube (QFT-3G)) results showed values for both negative and positive controls as well as the patient's samples exceeding 8.01 IU/mL. According to previous guidelines for using IGRAs (1), our patient's results were invalid due to the nonspecific reaction of the negative control (a positive reaction in the negative control).Despite conducting further studies, a final diagnosis was not reached, and the patient's condition deteriorated. Hemo-

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Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-γ-producing lymphocytes and IL-6- and TNF-α-producing macrophages

Cited by 275 publications

References 22 publications

Crimean‐Congo hemorrhagic fever: Five patients with hemophagocytic syndrome

Crimean‐Congo hemorrhagic fever: Five patients with hemophagocytic syndrome

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Miliary Tuberculosis with Indeterminate Interferon Gamma Release Assay Results

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