Impaired peripheral mononuclear cell metabolism in patients at risk of developing sepsis: A cohort study

Purpose Dysregulated immune response is a key driver of disease progression in sepsis and known to be associated with impaired cellular metabolism. This association has been studied mostly in the late stage sepsis patients. Here, we investigate whether such impairment in cellular metabolism is present in uncomplicated infection patients who do not develop sepsis. Methods Forty sepsis (fulfilled Sepsis-3 criteria) and 27 uncomplicated infection patients were recruited from the emergency department along with 20 healthy volunteers. Whole blood was collected for measurement of gene expression, cytokine levels and cellular metabolic functions (including mitochondrial respiration, oxidative stress and apoptosis). Results Our analysis revealed the impairment of mitochondrial respiration in uncomplicated infection and sepsis patients (p value <0.05), with greater degree of impairment noted in the established sepsis. The impairment was significantly correlated with increased mitochondrial oxidative stress level; the latter was increased in uncomplicated infection and more so in established sepsis patients. Further analysis revealed that the oxidative stress level correlated significantly with cytokine level (tumor necrosis factor-α) and gene expression levels (CYCS, TP53, SLC24A24 and TSPO). Conclusions These findings suggest that impaired immune cell metabolism is present in infection patients without presenting sepsis, thereby opening potential window for early diagnosis and intervention (e.g. antioxidant therapy) in such patients. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement No external funding was received. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by Human Research Ethics Committee at Westmead Hospital and at the Research Governance at the Westmead Institute for Medical Research (reference number HREC/18/WMEAD/67). Written informed consent was obtained from all subjects recruited. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data referred to in the manuscript will be available from the corresponding author upon reasonable request.