Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis

Abstract

Purpose of Review Macrophage activation syndrome is the rheumatic disease-associated member of a group of hyperinflammatory syndromes characterized by uncontrolled cytokine storm. In this review, we highlight recent publications related to the pathoetiology of hyperinflammatory syndromes with an emphasis on how this new knowledge will guide our diagnosis, treatment, and future research efforts to better understand these deadly conditions. Recent findings The heterogeneity of clinical manifestations seen in patients with hyperinflammatory syndromes continues to grow as novel genetic and immunotherapeutic triggers of cytokine storm have been identified. Recent studies characterize unique cytokine and gene expression profiles from patients with different hyperinflammatory syndromes, while novel murine models begin to define networks of immune dysregulation thought to drive excessive inflammationin cytokine storm. Summary Emerging evidence suggests hypercytokinemia is the driving cause of pathology and morbidity/mortality in hyperinflammatory syndromes. Therefore, approaches to block cytokine function may be fruitful in treating hyperinflammatory syndromes with less toxicity than current therapies. However, not all hyperinflammatory syndromes result in the same pathogenic cytokine profile implying a personalized approach will be required for effective use of anti-cytokine therapies in the treatment of hyperinflammatory syndromes.

Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis

“…Whether primary or secondary, HLH is characterized by defective cytotoxic cell control of an initial immune response progressing to uncontrolled macrophage activity and hypercytokinemia [14,15]. This produces an exaggerated inflammatory response and hypersecretion of cytokines in what is known as a "cytokine storm" [16].…”

Clinical Utility of Extracorporeal Cytokine Hemoadsorption Therapy: A Literature Review

“…Many cytokine storm syndromes are triggered by infection, and sepsis remains the largest catch-all term used to categorize these conditions [16]. Noninfectious conditions that may trigger a cytokine storm include active rheumatic diseases (e.g., macrophage activation syndrome) and certain malignancies (e.g., malignancy-associated syndrome of hyper-inflammation) [16,17]. Clinical manifestations of a cytokine storm may include refractory fevers, cytopenias, coagulopathy, MODS, and death [17].…”

“…Noninfectious conditions that may trigger a cytokine storm include active rheumatic diseases (e.g., macrophage activation syndrome) and certain malignancies (e.g., malignancy-associated syndrome of hyper-inflammation) [16,17]. Clinical manifestations of a cytokine storm may include refractory fevers, cytopenias, coagulopathy, MODS, and death [17]. For the purposes of this review, we will focus on sepsis and septic shock, since the most available research into cytokine adsorption therapy has historically been performed in this setting.…”

2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative

“…The difficulties in making the diagnosis of MAS and its clinical heterogeneity, together with the recent advances in its treatment and in understanding of its pathophysiology and underlying genetic defects (11,(21)(22)(23), emphasize the need for accurate criteria to aid physicians in appropriately classifying patients as having MAS to facilitate enrollment into clinical studies. The recognition that the syndrome is clinically similar to hemophagocytic lymphohistiocytosis (HLH) has led some to recommend the use of the HLH-2004 diagnostic guidelines (24).…”