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Hormone and Cytokine Responses to Repeated Endotoxin Exposures—No Evidence of Endotoxin Tolerance After 5 Weeks in Humans


Rittig, Nikolaj; Thomsen, Henrik Holm; Bach, Ermina; Jørgensen, Jens Otto Lunde; Møller, Niels

doi: 10.1097/SHK.0000000000000433
Letters to the Editor

Department of Internal Medicine and Endocrinology, and Medical Research Laboratories, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark

Reply: We thank Zwaag et al. for their interest and points raised with regard to our recent article entitled “Hormone and Cytokine Responses to Repeated Endotoxin Exposures—No Evidence of Endotoxin Tolerance After 5 Weeks in Humans” (1). In general, we agree with the comments, in particular, the statement that knowledge about the nature of endotoxin tolerance is of major importance when designing and interpreting experimental clinical studies using repeated exposures to endotoxin.

We acknowledge that our data were obtained from two separate randomized crossover trials with various nutritional supplements during human endotoxemia and that these trials were not originally designed to investigate human endotoxin tolerance. In consequence, there is a theoretical possibility, which cannot be ruled out statistically, that these various modes of intervention may have affected inflammatory responses differentially, albeit we find no detectable evidence of any such phenomenon. We chose to present data as a comparison between the area under the curve for the two endotoxin exposures for the sake of clarity and simplicity (difference in percentages). Notice that the areas under the curve represent a dependent variable across the time course of a trial day and therefore a good measure of the total exposure to this variable. We did not find any difference between the two endotoxin exposures with regard to the kinetic profiles.

As referred to in our article, we also agree that our data could reflect a minute degree of endotoxin tolerance because proinflammatory cytokines tended to be lower and interleukin-10 to be higher during the second endotoxin exposure, with values of P ranging between 0.12 and 0.78. These findings were by all statistical conventions not significant and should therefore be viewed as being caused by coincidence. Even if our results should represent a type 2 error, the degree of tolerance seems to be of a minor and, in most cases, clinically negligible magnitude (<10%).

Finally, we entirely agree that our study “does not provide definitive evidence (few studies do so) that endotoxin tolerance is absent 5 weeks after endotoxin administration.” We maintain that our data do not show evidence of any significant in vivo tolerance to repeated endotoxin exposure after at least 5 weeks, which in our opinion is an important and novel experimental observation. Nonetheless, as with all clinical crossover studies, it evidently remains crucial, whenever possible, to conduct future investigations in this field in a randomized fashion to bypass any minute endotoxin tolerance as well as other time-dependent phenomena.

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1. Rittig NF, Thomsen HH, Bach E, Jorgensen JO, Moller N. Hormone and cytokine responses to repeated endotoxin exposures—no evidence of endotoxin tolerance after 5 weeks in humans. Shock 2015; 44 1:32–35.
© 2015 by the Shock Society