Macrophage Activation Syndrome in Sepsis: Does It Exist and How to Recognize It?

Abstract

Within the group of patients with sepsis, a subset will rapidly deteriorate and die early. These patients meet many of the features of the macrophage activation syndrome, characterized by fever, cytopenias of two or more lineages, hypertriglyceridemia or hypofibrinogenemia, hepatobiliary dysfunction, coagulopathy, encephalopathy, and bone marrow phagocytosis. Using the hemophagocytic lymphohistiocytosis (HLH)-2004 classification criteria or the HScore classification system, it is estimated that almost 3.5–5% of critically ill patients with sepsis suffer from macrophage activation syndrome. The hallmark of macrophage activation syndrome pathogenesis is a cytokine storm elicited by tissue macrophages, natural killer cells, and CD8 lymphocytes, with excess production of interleukin (IL)-1β and of interferon-gamma playing a major role. Since bone marrow aspirates cannot routinely be performed, diagnosis relies on biomarkers. Serum ferritin >4420 ng/ml provides 97.9% specificity and 97.1% negative predictive value for diagnosis and is associated with almost 67% mortality after 10 days. Retrospective analysis of a former trial in severe sepsis revealed that anakinra treatment that blocks IL-1β offered 30% reduction in 28-day mortality in patients with features of macrophage activation syndrome. The ongoing PROVIDE study (Clinicaltrials.gov Identifier: NCT0333225) that aims to prospectively assess the impact of anakinra in sepsis patients with macrophage activation syndrome is anticipated to enrich our knowledge on the prevalence of this condition among patients with septic shock and the therapeutic potential of anakinra.