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.