Abstract
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 of CD8-lymphocytes. sHLH is also known as macrophage activation syndrome (MAS). Macrophage activation syndrome (MAS) in adults is poorly studied. Main features are fever, hepatosplenomegaly, hepatobiliary dysfunction (HBD), coagulopathy, cytopenia of 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 (DIC) were classified as patients with macrophage activation-like syndrome (MALS). The frequency of MALS ranged between 3 and 4% and it was an independent entity associated with early mortality after 10 days. Ferritin was proposed as a diagnostic and surrogate biomarker. Concentrations >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 h 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 management. Only one of them is focusing in sepsis. The acronym of the trial is PROVIDE (ClinicalTrials.gov NCT03332225) and it is a double-blind 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.
Highlights
The need for adjunctive therapies in sepsis is coming from the failure of antimicrobial treatment and source control to restrain the high lethality
We aim to review and suggest specific biomarkers of the detection of patients who develop sepsisassociated organ dysfunction with dominant pro-inflammatory mechanism and to suggest therapies that act on this proinflammatory mechanism
We developed ferritin measurement of the first 24 h as a diagnostic biomarker of macrophage activation-like syndrome (MALS)
Summary
The need for adjunctive therapies in sepsis is coming from the failure of antimicrobial treatment and source control to restrain the high lethality. The majority of patients with fHLH carry mutations in PRF1, which encodes perforin, or in genes encoding proteins required for the docking and fusion of granules for excretory protein like UNC13D (encoding MUNC13–4), STX11 (encoding syntaxin 11), and STXBP2 (encoding syntaxin-binding protein 2) These mutations transform NK cells to become over-active and stimulate a fulminant cytokine storm leading to organ dysfunctions [1]. Children are classified into HLH if they meet at least five of the eight criteria of the International Histiocyte Society (2004-HLH criteria) published in 2007: (a) fever, (b) splenomegaly, (c) cytopenia of at least two lineages; (d) fasting triglycerides ≥265 mg/dl and fibrinogen ≤150 mg/dl; (e) hemophagocytosis in the bone marrow; (f) low or absent NK-cell activity; (g) ferritin ≥500 ng/ml; and soluble CD25 ≥2,400 units/ml [2] These patients are further classified into fHLH or sHLH if they have or if they do not have positive molecular assay for one of the mutations listed above. The majority of analyzed cases developed sHLH as a complication of hematologic malignancy (57% of cases), infection (25% of cases), or both malignancies and infection (4% of cases)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
