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Front. Immunol. | doi: 10.3389/fimmu.2019.00055

Macrophage Activation-Like Syndrome: A Distinct Entity Leading To Early Death In Sepsis

  • 14th Department of Internal Medicine, National and Kapodistrian University of Athens, Greece

Hemophagocytic lymphohistocytosis (HLH) is characterized by fulminant cytokine storm leading to multiple organ dysfunction and high mortality. HLH is classified into familial (fHLH) and into secondary (sHLH). fHLH is rare and it is due to mutations of genes encoding for perforin or excretory granules of natural killer (NK) cells. sHLH is also known as macrophage activation syndrome (MAS). MAS in adults is poorly studied. Main features are fever, hepatosplenomegaly, hepatobiliary dysfunction (HBD), coagulopathy, cytopenia or two to three cell lineages, increased triglycerides and hemophagocytosis in the bone marrow. sHLH/MAS complicates hematologic malignancies, autoimmune disorders and infections mainly of viral origin. Pathogenesis is poorly understood and it is associated with increased activation of macrophages and NK cells. An autocrine loop of interleukin (IL)-1β over-secretion leads to cytokine storm of IL-6, IL-18, ferritin and interferon-gamma; soluble CD163 is highly increased from macrophages. The true incidence of sHLH/MAS among patients with sepsis has only been studied in the cohort of the Hellenic Sepsis Study Group. Patients meeting the Sepsis-3 criteria and who had positive HSscore or co-presence of HBD and disseminated intravascular coagulation were classified as patients with macrophage activation-like syndrome (MALS). The frequency of MALS ranged between 3% to 4% and it was an independent entity associated with early mortality after 10 days. Ferritin was proposed as a diagnostic and surrogate biomarker. Concentrations greater than 4,420 ng/ml were associated with diagnosis of MALS with 97.1% specificity and 98% negative predictive value. Increased ferritin was also associated with increased IL-6, IL-18, IFNγ and sCD163 and by decreased IL-10/TNFα ratio. A drop of ferritin by 15% the first 48 hours was a surrogate finding of favorable outcome. There are 10 on-going trials in adults with sHLH; two for the development of biomarkers and eight for the management. Only one of them is focusing in sepsis. The acronym of the trial is PROVIDE (ClinicalTrials.gov NCT03332225) and it is a double-dummy randomized clinical trial aiming to deliver to patients with septic shock treatment targeting their precise immune state. Patients diagnosed with MALS are receiving randomized treatment with placebo or the IL-1β blocker anakinra.

Keywords: Macrophage Activation Syndrome, Sepsis, Hemophagocytic lymphohistocytosis, ferritin, Interleukins, Interferon-gamma

Received: 15 Oct 2018; Accepted: 10 Jan 2019.

Edited by:

Thierry Roger, Lausanne University Hospital (CHUV), Switzerland

Reviewed by:

Randy Q. Cron, University of Alabama at Birmingham, United States
Scott Weiss, University of Pennsylvania, United States  

Copyright: © 2019 Giamarellos-Bourboulis and Karakike. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Evangelos Giamarellos-Bourboulis, National and Kapodistrian University of Athens, 4th Department of Internal Medicine, Athens, 12462, Greece, egiamarel@med.uoa.gr