Reply to Leijte et al.: Fever in Sepsis: Still a Hot Topic

From the Authors:

We thank Dr. Leijte, Dr. Kox, and Dr. Pickkers for their comments on our recent article on using temperature trajectories to identify sepsis subphenotypes (1). Using group-based trajectory modeling, we identified four subphenotypes with different demographics, physiological characteristics, and levels of inflammatory markers, and we hypothesized an immunological basis for these subphenotypes. Supporting our hypothesis of a connection between temperature and immunological markers, Leijte and colleagues present a human endotoxemia model revealing correlation between temperature slopes and levels of endogenous pyrogens (IL-6 and TNFα [tumor necrosis factor α]) in healthy volunteers after administration of Escherichia coli endotoxin (2). This data provide evidence for the relationship between body temperature and cytokine responses. In addition, the data use dynamic temperature measurement (i.e., temperature slopes) to study associations with cytokine levels. This finding aligns with our work indicating that dynamic measures of temperature (i.e., temperature trajectory, variability, and slopes) may have more significance than static measures.

Although the cytokine responses in this study provide an immunological basis for our hypothesis, the systemic inflammatory response is intentionally self-limited in these healthy volunteers. We believe that measurement of cytokine levels in naturally occurring sepsis would add further information to the relationship between the thermoregulatory and immunological systems. Sepsis is defined as a dysregulated immunological response to infection. After the initial endotoxin-driven cytokine storm in sepsis, there is a protracted dysregulated immunological process that follows. We propose that temperature trajectories may elucidate not only the initial cytokine response but also the sustained immunological process in patients with sepsis. For instance, hyperthermic, slow resolvers may have sustained high levels of proinflammatory cytokines, whereas hyperthermic, fast resolvers may have the same initial proinflammatory cytokine storm followed by a defervescence process. We look forward to studies such as those of Dr. Leijte, Dr. Kox, and Dr. Pickkers to illuminate the relationship between temperature and the immunological system.