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Abstract
BackgroundFulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality. This study aimed to investigate the effect of targeting two key molecules of innate immunity, complement component C5, and co-receptor CD14 in the Toll-like receptor system, on the inflammatory response in meningococcal sepsis.MethodsMeningococcal sepsis was simulated by continuous intravenous infusion of an escalating dose of heat-inactivated Neisseria meningitidis administered over 3 h. The piglets were randomized, blinded to the investigators, to a positive control group (n = 12) receiving saline and to an interventional group (n = 12) receiving a recombinant anti-CD14 monoclonal antibody together with the C5 inhibitor coversin.ResultsA substantial increase in plasma complement activation in the untreated group was completely abolished in the treatment group (p = 0.006). The following inflammatory mediators were substantially reduced in plasma in the treatment group: Interferon-γ by 75% (p = 0.0001), tumor necrosis factor by 50% (p = 0.01), Interleukin (IL)-8 by 50% (p = 0.03), IL-10 by 40% (p = 0.04), IL-12p40 by 50% (p = 0.03), and granulocyte CD11b (CR3) expression by 20% (p = 0.01).ConclusionInhibition of C5 and CD14 may be beneficial in attenuating the detrimental effects of complement activation and modulating the cytokine storm in patients with fulminant meningococcal sepsis.
Highlights
Fulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality
Fulminant meningococcal sepsis is a rapid and devastating infection caused by Neisseria meningitidis, characterized by whole-body inflammation and severe disturbances in homeostasis leading to high mortality despite optimal antimicrobial and intensive care treatment [1,2,3]
In the positive control group, terminal C5b-9 complex (TCC) increased from mean 273 (±87; 95% CI) complement arbitrary units (CAU)/L at T0 to mean 1233 (±871) CAU/L at T180 (p = 0.01) (Fig. 1, upper panel), confirming systemic activation of complement
Summary
Fulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality. Different clinical trials aiming to reduce the inflammatory response caused by LPS have failed to Hellerud et al Journal of Intensive Care (2017) 5:21 improve the outcome in patients with severe sepsis. This includes studies attempting to neutralize LPS or attenuate the response to LPS by blocking different steps of the inflammatory mechanisms, including binding of LPS to TLR4-MD2 or blocking the effect of individual inflammatory mediators like IL-1β and tumor necrosis factor (TNF) [6,7,8,9]
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