Making Sense of the Cytokine Storm: A Conceptual Framework for Understanding, Diagnosing, and Treating Hemophagocytic Syndromes

Abstract

SYNOPSIS Cytokine Storm Syndromes (CSS) are a group of disorders representing a variety of inflammatory etiologies with the final common result of overwhelming systemic inflammation, hemodynamic instability, multiple organ dysfunction, and potentially death. The hemophagocytic syndromes hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) represent two clinically similar CSS with an unknown degree of pathoetiologic overlap. The clinical presentations of all CSS can be strikingly similar, creating diagnostic uncertainty. However, clinicians should avoid the temptation to treat all CSS equally, as their inciting inflammatory insults vary widely. Failure to identify and address this underlying trigger will result in delayed, inoptimal, or potentially harmful consequences. This review endeavors to place the hemophagocytic syndromes HLH and MAS within a conceptual model of CSS, and thus provide a logical framework for diagnosis and treatment of CSS of suspected rheumatic origin.

Haemophagocytic lymphohistiocytosis: A fulminant syndrome associated with multiorgan failure and high mortality that frequently masquerades as sepsis and shock

“…In acquired HLH, the exact cause of depressed CTL and NK cell activity is less well understood, but it is strongly associated with specific viral infections, malignancies and autoimmune disorders. [3,5] It is postulated that patients who develop acquired HLH may in fact have an underlying (as yet unidentified) genetic predisposition. [6] Genetic HLH arises in childhood, usually before 1 year of age, but there are reports of adults presenting with primary HLH at advanced ages.…”

“…[1] Importantly, haemophagocytosis is not specific to HLH and can be demonstrated in various non-HLH conditions such as post-blood transfusion, haemolysis, myelodysplasia/bone marrow failure or sepsis. [4,5,13,15] Moreover, haemophagocytosis may not be seen in up to 20% of initial bone marrow biopsies [16] and therefore, despite the nomenclature, can neither be diagnosed nor excluded solely on the basis of presence or absence of haemophagocytosis. [1,15] We describe five cases of acquired HLH that were diagnosed over the course of 5 months (May -September 2013 ) in private hospitals in the greater Johannesburg area, South Africa (SA), with the aim of raising awareness and increasing the diagnostic pickup rate of acquired HLH in adult patients admitted to wards and ICUs with multiorgan dysfunction and/or presumed sepsis/SIRS.…”

“…Members of the herpesvirus family coincidentally are the most frequent triggers of viral-associated HLH. [5,6,20] These include Epstein-Barr virus (EBV), the reactivation of which has been implicated the most in viral-associated HLH, [21] CMV and human herpesvirus 8 (HHV-8). EBV was detected by in situ hybridisation of the trephine in case 2.…”

Hydrogen Medicine Therapy: An Effective and Promising Novel Treatment for Multiple Organ Dysfunction Syndrome (MODS) Induced by Influenza and Other Viral Infections Diseases?

“…Proinflammatory cytokines are secreted throughout the body; these cytokines also initiate activation of inflammation cells like neutrophils, eosinophils, basophils, lymphocytes, and monocytes to produce more proinflammatory cytokines [5,30]. Those cytokines and inflammation cells are reciprocal causation, developing into a cytokine storm(systemic inflammatory response syndrome) [30,31]. The term cytokine storm is used to accommodate the observation that multiple excessive inflammatory causes can induce excessive release of inflammation factors like interleukin-1, interleukin-6, interleukin-12, tumor necrosis factor-α, interferon-α, interferon-β, interferon-γ, Monocyte Chemoattractant Protein-1 and interleukin-8 thereby leading to a disease that appears similar to sepsis [30,31].…”

“…Those cytokines and inflammation cells are reciprocal causation, developing into a cytokine storm(systemic inflammatory response syndrome) [30,31]. The term cytokine storm is used to accommodate the observation that multiple excessive inflammatory causes can induce excessive release of inflammation factors like interleukin-1, interleukin-6, interleukin-12, tumor necrosis factor-α, interferon-α, interferon-β, interferon-γ, Monocyte Chemoattractant Protein-1 and interleukin-8 thereby leading to a disease that appears similar to sepsis [30,31]. Importantly, excessive inflammation reactions can also induce acute oxidative stress [2].…”