Clinical features and correct diagnosis of macrophage activation syndrome

Abstract

Macrophage activation syndrome (MAS) is increasingly recognized among febrile hospitalized patients. Clinically, MAS resembles multiorgan dysfunction and shock. Laboratory features include hepatobiliary dysfunction, coagulopathy, pancytopenia, hyperferritinemia and markers of immune activation. Pathologically, hemophagocytosis is commonly seen but is only present in 60% of MAS patients. MAS, or secondary hemophagocytic lymphohistiocytosis (HLH), is triggered by infectious (e.g., herpes family viruses), rheumatologic (e.g., systemic lupus erythematosus [SLE]) and oncologic (e.g., T-cell leukemia) conditions. Formal HLH criteria, while specific, are frequently insensitive for MAS diagnosis. Thus, disease-specific (e.g., SLE) and generic MAS criteria have been published. Recently, novel criteria for MAS in children with systemic juvenile idiopathic arthritis (sJIA) were developed and are a key focus of this review.

Keywords:

• coagulopathy
• fever
• hemophagocytic lymphohistiocytois
• hemophagocytosis
• hyperferritinemia
• macrophage activation syndrome
• multi-organ dysfunction
• systemic juvenile idiopathic arthritis

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH) is being recognized as a more common condition in children and adults, and early recognition and treatment is crucial to improving survival.

• MAS results from a hyperinflammatory state and an overly exuberant immune response.

• A wide array of infectious, oncologic and rheumatic disorders is associated with the development of MAS.

• Many patients with MAS share mutations in fHLH associated cytolytic pathway genes.

• MAS likely results from a two-hit or multifactorial setting (e.g., genetic predisposition + infection and/or inflamed state from exacerbated autoinflammatory, autoimmune or malignant conditions) leading to the hyperinflammatory state.

• Despite a broad variety of MAS triggers, many clinical (e.g., fever, coagulopathy, CNS dysfunction and splenomegaly) and laboratory features (e.g., elevated serum ferritin, pancytopenia and liver enzyme elevation) are shared among patients with MAS and fHLH.

• Although HLH-2004 criteria are likely too restrictive for many occurrences of MAS, new criteria for diagnosing MAS broadly are being explored.

• Disease-specific MAS criteria are being studied for the more common rheumatic disease MAS associations (e.g., systemic juvenile idiopathic arthritis [sJIA] and systemic lupus erythematosus).

• Using large cohorts of sJIA and confusable control real patient data, combined with consensus expert opinion and sophisticated statistical analyses, a novel set of simple yet highly sensitive and specific classification criteria for MAS in the setting of sJIA have recently been developed.

• Suppression of the hyperinflammatory immune response is a key to controlling MAS, and the use of both broadly immunosuppressive medications and biologic therapies targeted to proinflammatory cytokines has been shown to be an effective therapeutic approach.

Notes

Adapted with permission from Ravelli et al. (2012) [2].