The Impact of Positive Fluid Balance on Sepsis Subtypes: A Causal Inference Study.

Introduction: Sepsis, the leading cause of death in hospitalized patients globally, was investigated in this study, examining the varying effects of positive fluid balance on sepsis subtypes through causal inference. Methods: In this study, data from the eICU database were utilized, extracting 35 features from sepsis patients. Fluid balance during ICU stay was the treatment, and ICU mortality was the primary outcome. Data preprocessing ensured linear assumptions for logistic regression. Binarized positive fluid balance with mortality was examined using DoWhy's logistic regression, while continuous data were analyzed with random forest T-learner. ATE served as the primary metric. Results: Results revealed that septic patients with higher fluid balance had worse mortality outcomes, with an ATE of 0.042 (95% CI: (0.034, 0.047)) using logistic regression and an ATE of 0.0340 (95% CI: (0.028-0.040)) using T-learner. In the pulmonary sepsis subtype, higher mortality was associated with increased fluid balance, showing an ATE of 0.047 (95% CI: (0.037, 0.055)) using logistic regression and an ATE of 0.28 (95% CI: (0.22, 0.34)) with T-learner. Conversely, urinary sepsis patients had improved mortality with higher fluid balance, presenting an ATE of -0.135 (95% CI: (-0.024, -0.0035)) using logistic regression and an ATE of -0.28 (95% CI: (-0.34, -0.22)) with T-learner. Conclusion: Our research implies that fluid balance impact on ICU mortality differs among sepsis subtypes. Positive fluid balance raises mortality in sepsis and pulmonary sepsis but may protect against urinary sepsis. Further trials are needed to confirm these findings.

Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.

Interleukin-2 (IL2) was among the earliest reagents used for cancer immunotherapy due to its ability to support the survival and function of tumor-reactive T cells. However, treatment with IL2 is accompanied by off-target toxicity and low response rates in patients. In mouse models, these issues are largely overcome when IL2 is administered as a cytokine/antibody complex (IL2c). The complex has a longer serum half-life and can be designed for preferential cytokine delivery to specific cells of interest. Early studies showed IL2c could boost antitumor immunity in mice by activating tumor-reactive CD8+ T cells. But such functional T cells are often limited in the tumor microenvironment, where instead unresponsive tolerant T cells are eventually eliminated by apoptosis, representing a major obstacle to the success of cancer immunotherapy. We found that IL2c treatment rescued tumor-specific CD8+ T cells from a state of established tolerance, providing effective immunotherapy in tumor-bearing mice. Expression of the transcription factor T-bet was necessary to drive intratumoral IFNγ production and effector activity by T cells rescued with IL2c. Furthermore, IL2c promoted T-bet expression in human CD4+ and CD8+ T cells in humanized tumor-bearing mice, but also increased the frequency of Foxp3+ regulatory T cells. Our study reveals a novel role for IL2c as a powerful immunotherapeutic reagent capable of reversing tolerance in tumor-reactive T cells, and provides the first evidence that IL2c influences human T cells in vivo, highlighting the translational potential to modulate human antitumor immune responses. Cancer Immunol Res; 4(12); 1016-26. ©2016 AACR.