Divergent mortality risks associated with lower body temperature and interleukin-6 levels in elderly and non-elderly patients with sepsis

Identifying prognostic indicators in sepsis is crucial for improving clinical practice. Aging is associated with attenuated physiological and immune responses, potentially altering these indicators' dynamics and prognostic values. Our previous study demonstrated that lower body temperature (BT) as well as higher blood interleukin-6 (IL-6) levels were significantly associated with higher mortality in non-elderly patients with sepsis, but not in the elderly.^{1, 2}

IL-6 plays a central role in inflammation and fever regulation.³ In severe inflammatory states, host response failure can manifest as hypothermia, which is associated with poor prognosis.⁴ Given the close relationship between IL-6 and BT, combining these indicators may enhance prognostic accuracy in sepsis.

To examine age-related differences in the associations between IL-6 and BT abnormalities at intensive care unit admission with mortality, we analyzed a published sepsis cohort in which patients were classified as non-elderly (<70 years) or elderly (≥70 years) with similar severity scores and mortality.² Blood IL-6 levels were categorized as low or high using a Youden index-derived cutoff of 1974 pg/mL.² BT was stratified into tertiles: low (<36.8°C), middle (36.8–37.9°C), and high (>37.9°C). An IL-6 cutoff of 1000 pg/mL⁵ and age cutoffs of 65 and 75 years were tested in sensitivity analyses. Interactions between age and IL-6 levels as well as age and BT for mortality were assessed. Continuous variables are presented as medians (interquartile ranges) and were analyzed using the Wilcoxon test. BT trends and mortality were analyzed using the Cochran–Armitage test for trend. A two-tailed P-value <0.05 was considered significant.

Elderly patients had significantly higher IL-6 levels than non-elderly patients (1021 [244–11,404] vs. 1767 [318–14,312] pg/mL, p = 0.029), whereas BT levels were similar (37.4 [36.5–38.3] vs. 37.3 [36.5–38.3]°C, p = 0.51). Consistent with prior findings,¹ lower BT was associated with higher mortality in non-elderly patients but not in elderly with high IL-6 (Figure 1). A novel finding was that lower BT was significantly associated with increased mortality in elderly patients with low IL-6 (p = 0.030, Figure 1). Analysis using a 1000 pg/mL IL-6 cutoff yielded similar results (Figure S1). Analyses with 65- and 75-year age cutoffs showed similar trends in the elderly low IL-6 groups (Figures S2 and S3). Interaction between age and IL-6 was significant (p = 0.0010), with a trend toward for age and BT (p = 0.16).

Elderly patients often have multiple comorbidities, resulting in complex prognostic factors beyond inflammation. Their host response is not as straightforward as that of non-elderly. Lower BT in sepsis may suggest host response dysregulation.⁴ While sepsis severity is typically associated with inflammation, poor prognosis in cases with lower inflammation despite dysregulated host responses suggests an alternative mechanism. Although hypothesis-generating, our findings raise the possibility that BT and IL-6 may serve as critical indicators in the elderly patients. While further studies are needed to determine whether IL-6 alone adequately reflect inflammatory phenotypes or host responses, our results prompt reconsideration of the prognostic significance of IL-6 and BT in sepsis, underscore the heterogeneity of sepsis pathophysiology across age groups, and emphasize the need for age-specific prognostic models.

This study was supported by JSPS KAKENHI (grant number: 21K09040). The funder had no role in the study design, data analysis, or manuscript preparation.

TS received a grant from JSPS KAKENHI (grant number 21K09040). TN is the CEO of Smart119, Inc. and owns stock. Smart119, Inc. played no role in this study. The other authors declare that they have no conflicts of interest.

Approval of the research protocol: This study was approved by the Chiba University Hospital Certified Clinical Research Review Board (approval number: HK202402-01).

Informed consent: The review board waived the requirement to obtain written consent from patients because of the retrospective study design.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.