Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis

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.

Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases

“…A hyperinflammatory syndrome known as secondary hemophagocytic lymphohistiocytosis (sHLH) or macrophage activation syndrome (MAS) can also result from fulminant and fatal hypercytokinemia [22]. Pulmonary involvement in patients with HLH/MAS revealed that dyspnea and cough were the most common symptoms at the onset of the disease, and radiographs revealed interstitial infiltrates with centrilobular nodules, ill-defined consolidation, or localized ground-glass opacities [23]. Similar radiological abnormalities are seen in patients who recovered from COVID-19 pneumonia, where initial lung findings on chest CT revealed small subpleural ground glass opacities (GGO) that grew larger with crazy-paving pattern and consolidation up to two weeks after disease onset, eventually being absorbed resulting in extensive GGO and subpleural parenchymal bands [24].…”

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“…Today the world is facing a global pandemic which has never been seen in the era of transplantation and immunotherapy. As of April 7, coronavirus disease 2019 (COVID- 19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been confirmed in .1.25 million people worldwide with a mortality rate of 5.7%. The presence of comorbid conditions is associated with higher risk of death, which is concerning because significant comorbidity is common in recipients of transplants.…”

“…17,18 Although the SARS-CoV-2 CRS appears distinct from both, there is certainly overlap between the predominant cytokines involved in HLH pathogenesis-such as IL-1b, IL-6, IL-18, and IFN-g-and that seen in patients with COVID-19. 19 As such, clinical interventional trials of tocilizumab (a mAb against IL-6) in patients who are infected is already underway. 16 This may have important consequences for patients who have received a transplant, because hyperinflammatory syndromes require immunotherapy rather than immunosuppression withdrawal, with treatment options including anakinra (an IL-1 receptor antagonist), tocilizumab, intravenous Ig, and steroids.…”

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“…In a xenomodel of macrophage activation syndrome, GO resolved the symptoms completely, and led to complete recovery of experimental animals [13]. Pathogenetic mechanisms of sepsis and macrophage activation syndrome are close [14]. The rapid efficacy of GO in our patients possibly arises from its ability to decrease the level of pro-inflammatory cytokines through CD33 positive cells elimination, such as CD33 positive blast cells, neutrophils, and monocytes, thereby, ameliorating the clinical and laboratory signs of tissue damage.…”