Macrophage Activation Syndrome Clinical Presentation

Updated: Nov 21, 2018
  • Author: Angelo Ravelli, MD; Chief Editor: Lawrence K Jung, MD  more...
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Presentation

History

The clinical presentation of macrophage activation syndrome (MAS) is generally acute and occasionally dramatic. Typically, patients become acutely ill with the sudden onset of nonremitting high fever, profound depression in all 3 blood cell lines (ie, leukopenia, anemia, and thrombocytopenia), hepatosplenomegaly, lymphadenopathy, and elevated serum liver enzyme levels. High levels of triglycerides and lactic dehydrogenase and low sodium levels are consistently observed.

The coagulation profile is often abnormal, with prolongation of prothrombin time (PT) and partial thromboplastin time (aPTT), hypofibrinogenemia, and detectable fibrin degradation products. In children with systemic juvenile idiopathic arthritis, the clinical picture may mimic sepsis or an exacerbation of the underlying disease. However, the pattern of nonremitting fever is different from the remitting high-spiking fever seen in systemic juvenile idiopathic arthritis. Moreover, patients may show a paradoxical improvement in the underlying inflammatory disease at the onset of macrophage activation syndrome, with disappearance of signs and symptoms of arthritis and a precipitous fall in the erythrocyte sedimentation rate. The latter phenomenon probably reflects the degree of hypofibrinogenemia secondary to fibrinogen consumption and liver dysfunction. [20]

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Physical

Physical findings include the following:

  • Mucocutaneous findings

    • Purpura

    • Easy bruising

    • Mucosal bleeding

  • Hepatomegaly

  • Splenomegaly

  • Lymphadenopathy

  • CNS dysfunction

    • Lethargy

    • Irritability

    • Disorientation

    • Headache

    • Seizures

    • Coma

  • Other findings: Renal, pulmonary, and cardiac involvement have been reported in some patients.

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Causes

Macrophage activation syndrome affects most commonly children with systemic juvenile idiopathic arthritis (SJIA) but has been observed in other rheumatic diseases, such as juvenile systemic lupus erythematosus (SLE) [21, 22] and Kawasaki disease [23] and, occasionally, polyarticular juvenile idiopathic arthritis. [17]

Although an identifiable precipitating factor is often not identified, macrophage activation syndrome has been related to numerous triggers, including a flare of the underlying disease, toxicity of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), viral infections, a second injection of gold salts, and sulfasalazine therapy. [5] One report described a young girl with SJIA who developed macrophage activation syndrome shortly after the first methotrexate (MTX) administration without any other apparent inciting factor; this suggests that macrophage activation syndrome could have been a direct consequence of MTX toxicity. [24]

The shortness of the time interval between MTX dosing and onset of macrophage activation syndrome (24 h) and the characteristics of clinical symptoms, particularly the intense and generalized itching, suggested hypersensitivity or an idiosyncratic reaction, a mechanism similar to that hypothesized in the pathogenesis of macrophage activation syndrome secondary to gold salt injections.

Recently, instances of macrophage activation syndrome in patients with SJIA during treatment with biologic medications, including tumor necrosis factor (TNF)-α inhibitors and interleukin (IL)-1 receptor antagonists, have been described. However, whether these drugs are responsible for the induction of macrophage activation syndrome is controversial.

Serious episodes of macrophage activation syndrome have been observed in patients who underwent autologous bone marrow transplantation for SJIA refractory to conventional therapy. [25, 26, 27, 28] In most of these cases, an infectious trigger for macrophage activation syndrome was identified; however, the complication was believed to be favored by stringent T-cell depletion, with resultant inadequate control of macrophage activation. [27, 29] After an adaptation of a protocol consisting of less profound T-cell depletion, better control of systemic disease before transplantation, and slow tapering of corticosteroids after the procedure, no further cases of macrophage activation syndrome have occurred. [27] The development of hemophagocytosis in 3 patients with SJIA who received fludarabine as part of the conditioning regimen has been reported. [26]

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