Characterization of differences in immune responses during bolus and continuous infusion endotoxin challenges using mathematical modelling

Abstract Endotoxin administration is commonly used to study the inflammatory response, and though traditionally given as a bolus injection, it can be administered as a continuous infusion over multiple hours. Several studies hypothesize that the latter better represents the prolonged and pronounced inflammation observed in conditions like sepsis. Yet very few experimental studies have administered endotoxin using both strategies, leaving significant gaps in determining the underlying mechanisms responsible for their differing immune responses. We used mathematical modelling to analyse cytokine data from two studies administering a 2 ng kg−1 dose of endotoxin, one as a bolus and the other as a continuous infusion over 4 h. Using our model, we simulated the dynamics of mean and subject‐specific cytokine responses as well as the response to long‐term endotoxin administration. Cytokine measurements revealed that the bolus injection led to significantly higher peaks for interleukin (IL)‐8, while IL‐10 reaches higher peaks during continuous administration. Moreover, the peak timing of all measured cytokines occurred later with continuous infusion. We identified three model parameters that significantly differed between the two administration methods. Monocyte activation of IL‐10 was greater during the continuous infusion, while tumour necrosis factor α and IL‐8 recovery rates were faster for the bolus injection. This suggests that a continuous infusion elicits a stronger, longer‐lasting systemic reaction through increased stimulation of monocyte anti‐inflammatory mediator production and decreased recovery of pro‐inflammatory catalysts. Furthermore, the continuous infusion model exhibited prolonged inflammation with recurrent peaks resolving within 2 days during long‐term (20–32 h) endotoxin administration

Personalized mathematical model of endotoxin-induced inflammatory responses in young men and associated changes in heart rate variability

The objective of this study was to develop a personalized inflammatory model and estimate subject-specific parameters that could be related to changes in heart rate variability (HRV), a measure that can be obtained non-invasively in real time. An inflammatory model was developed and calibrated to measurements of interleukin-6 (IL-6), tumor necrosis factor (TNF-alpha), interleukin-8 (IL-8) and interleukin-10 (IL-10) over 8 hours in 20 subjects administered a low dose of lipopolysaccharide. For this model, we estimated 11 subject-specific parameters for all 20 subjects. Estimated parameters were correlated with changes in HRV, computed from ECG measurements using a built-in HRV module available in Labchart. Results revealed that patients could be separated into two groups expressing normal and abnormal responses to endotoxin. Abnormal responders exhibited increased HRV, most likely as a result of increased vagal firing. The observed correlation between the inflammatory response and HRV brings us a step further towards understanding if HRV predictions can be used as a marker for inflammation. Analyzing HRV parameters provides an easy, non-invasively obtained measure that can be used to assess the state of the subject, potentially translating to identifying a non-invasive marker that can be used to detect the onset of sepsis

A HaemSTAR-led, UK-wide ‘flash-mob’ audit of ­intravenous immunoglobulin use in immune ­thrombocytopenia

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