Sepsis is characterized by an injurious host response against various severe infections and is among the most serious medical conditions worldwide, leading to high mortality rates of patients in the intensive care unit (ICU) (Rudd et al., 2020; Cavaillon et al., 2020). Among the deaths from sepsis, approximately 15% are acute, occurring soon after sepsis onset, while 85% are late phase, usually due to ICU-acquired infections (Nedeva et al., 2020). Currently, the dominant view on the underlying causes of these deaths is that the patients with sepsis experience immunosuppression (Stortz et al., 2018). Immunosuppressed patients are highly susceptible to dangerous ICU-acquired opportunistic pathogens and can rapidly succumb to infection (Sundar and Sires, 2013; Koch et al., 2017). The ICU-acquired infections are significantly associated with increased in-hospital mortality, length of stay (LOS), and poor prognosis (Otto et al., 2011; van Vught et al., 2017). Therefore, it is necessary to identify the risk factors of ICU-acquired infections in patients with sepsis.

In patients with sepsis, this risk of developing ICU-acquired infection is influenced by multiple interrelated factors. For example, some studies from 10 years ago with small sample sizes or covering a short period of (Chen et al., 2022) time showed that advanced age, disease severity, deep venous catheterization, and invasive ventilation were associated with an increased risk of incident ICU-acquired infection in sepsis (Wolkewitz et al., 2014; van Vught et al., 2016; Chen et al., 2019). Despite associations of lower human leukocyte antigen expression and increased interleukin-10 (IL-10) levels with ICU-acquired infection (van Vught et al., 2017; Stortz et al., 2018), identifying which patients are at a higher risk of sepsis-associated ICU-acquired infection remains clinically challenging. Currentlly, many decisions surrounding the management of sepsis-associated ICU-acquired infection mainly rely on accurate estimates of a patient’s future likelihood of developing infection (van Vught et al., 2016). However, sepsis-associated ICU-acquired infections have yet to be fully characterized.

Here, we analyzed the data from the large public database Medical Information Mart for Intensive Care (MIMIC) IV and attempted to identify the differences in clinical characteristics between septic patients who did and did not experience ICU-acquired infection, identify the risk factors associated with septic ICU-acquired infection occurrence and its outcomes, and develop a novel risk prediction model that predicts ICU-acquired infections for patients with sepsis.

To the best of our knowledge, this is the first study using the large public database MIMIC IV to explore ICU-acquired infections in sepsis. Our study strictly followed the Sepsis-3 definition of suspected infection with organ dysfunction. Additionally, the database spanned a period of 10 years, far exceeding those of previous investigations, ensuring the practical significance in the context of an epidemic and showing feasibility in the real world.

We highlight that microbiological burden and mortality from ICU-acquired infection gradually increase over time in survivors of sepsis, despite higher mortality during the first 28 days in the non-ICU-acquired infection group. Severe infection triggers a cytokine storm, promoting widespread host responses, including microcirculation failure, organ dysfunction, shock, and death (Kaukonen et al., 2014). Early sepsis mortality has significantly decreased with the active implementation of the Surviving Sepsis Campaign (Coopersmith et al., 2018). Consequently, long-term outcomes after sepsis have attracted increasing attention. Two recent large studies had shown that ICU-acquired infection can greatly increase sepsis-related death, reporting rates of 44.2% and 49.2% by day 60 (van Vught et al., 2016; van Vught et al., 2017). While Goldenberg et al. (2014) reported that ICU-acquired infection only accounted for 14% of deaths in sepsis, with other potential contributors to sepsis mortality including mitochondrial dysfunction and microvascular leak. The incidence rate of ICU-acquired infections in sepsis was 17.1% in this study. Similar findings were reported in those two previous large observational studies, which were 14.4% and 13.5%, respectively, although we recorded a slightly higher cumulative incidence of ICU-acquired infections (van Vught et al., 2016; van Vught et al., 2017). Nevertheless, the higher observation was discovered in two retrospective studies, which were 31.0% and 38.9% (Zhao et al., 2016; Chen et al., 2019). This may have been due to the relatively limited sample size and the definition of sepsis 2.0.

For ICU patients, the SIRS, SOFA, OASIS, LODS, APS III, SAPS II, and CCI scores are fundamental individualized risk assessments for characterizing disease severity and degree of organ dysfunction (Minne et al., 2008; Chen et al., 2019; Li et al., 2020; Zhu et al., 2022). As is well known, severe sepsis may be related to immunosuppression. Immunosuppressed patients are highly susceptible to dangerous opportunistic pathogens and can rapidly succumb to infection (Sundar and Sires, 2013). Furthermore, the SAPS II, SIRS, and the degree of organ failure had been identified as poor early warning tools for the infection (Vincent et al., 2009; Herrod et al., 2018). Given the finding, we attempted to build regression models with these scoring systems and compare with our newly developed predictive model. The nomogram included the LODS providing the best discrimination capacity and a net benefit over any current common clinical scoring system models across all thresholds.

SOFA score was conceived as a tool to describe the occurrence of dysfunction in various organs and predict outcome, but several studies clarified that the prognostic values of the LODS or SAPS II were slightly better than those of SOFA scores in predicting sepsis mortality events (Li et al., 2020; Zhu et al., 2022). Consistent with this, the SOFA score in predicting the acquisition of infection, which increases the morbidity and mortality of patients with sepsis, shows a poorer prediction in the present study.

Being an adult accompanied by cerebrovascular insufficiency was an independent risk factor of ICU-acquired infection, especially traumatic brain injury, ischemic stroke, and intracerebral hemorrhage, which had not been reported in sepsis previously. The brain injury–induced immunosuppression syndrome initiated after acute brain injury and ischemia had been recognized from animal models, which was mediated by an intense activation of the hypothalamic-pituitary axis and the sympathetic nervous system (Dirnagl et al., 2007). Enhanced catecholamine levels and subsequent suppressed immune function are associated with the occurrence of infections after acute brain injury (Haeusler et al., 2008; Klehmet et al., 2009).

Almost 40% of patients undergoing craniotomy develop infection at least once, such as pneumonia independent of mechanical ventilation (15%), ventilator-associated pneumonia (VAP; 23%), or urinary tract infection (UTI; 9%), and postoperative surgical site infections (SSIs) occur in 9% (Kourbeti et al., 2015). Moreover, invasive procedures, including central venous catheter, urinary catheter, mechanical ventilation, and tracheostomy, are potential risk factors during the first 48 h in the ICU, predicting an ICU-acquired infection in our study due to the fact that these tubes provide an ideal opportunity for bacterial adhesion and biofilm formation (Sottile et al., 1986; Elsayed et al., 2022). The rapid colonization of microbiota contributes to the infection. Therefore, more research should focus on antimicrobial-coated catheter materials to prevent the occurrence of infection and progression.

Transfusion of RBCs had emerged as a potential risk factor for hospital-acquired infections in various clinical settings, including sepsis (Dupuis et al., 2017; Dupuis et al., 2017; Nederpelt et al., 2020). In addition, it is associated with an increased risk of venous thrombosis with allogeneic transfusion and transfusion-related infections (Jaffray et al., 2020; Miyamoto et al., 2021). Furthermore, stored RBCs and platelets can release intracellular cytokines and other components that induce an immunosuppressive phenotype in antigen-presenting cells and lymphocytes (Aslam et al., 2008; Torrance et al., 2015).

Notably, sepsis caused by Gram-negative bacillus infection enhances the risk of ICU-acquired infection. Among the 27,766 cases of central venous catheter-associated bloodstream infections reported to the National Healthcare Safety Network (NHSN) between 2009 and 2010, a large proportion of ICU-isolated drug-resistant bacteria are Gram-negative (Sader et al., 2014). Treatment resistance and non-susceptibility to antimicrobial agents lead to low treatment efficacy and complex therapeutic regimens. There is increasing awareness that elevated susceptibility to ICU-acquired infection can be pathogen-specific due to different patterns of immune barrier destruction, which can lead to opportunistic bacterial and fungal infections (Koch et al., 2017).

Although the use of a large dataset from a public database provides substantial support for our findings, our study has several limitations. First, our findings may have been influenced by confounding factors due to septic patients being admitted to the ICU with varying severities of illness, but the largest cohort study including patient data collected for almost 10 years should be clinically representative. Second, all of the variables included in our predictive model related mainly to patient demographic characteristics, underlying disease, pathogens, and supportive treatments, and our model lacked some meaningful laboratory metrics, leading to a low predictive efficiency of our model. However, all of the clinical information is available in lots of institutions, and a multivariable logistic risk model was used to evaluate the real clinical situations. Indeed, there were no significant differences in the levels of lymphocytes, neutrophils, partial thromboplastin time (PT), or activated partial thromboplastin time (APTT) in our cohort. Microcirculation disorders occur early, 12 h after the sepsis, and are associated with neutrophil–endothelium interactions, microthrombus formation, and vascular leakage (Wu et al., 2015). This may explain that the indicators of coagulation function did not differ between those with ICU-acquired infection and those without. Additionally, the occurrence of acquired infection is mainly related to immune cell function; the value of some biomarkers of immune cell function in predicting susceptibility to ICU-acquired infections warrants exploration (van Vught et al., 2016). Third, up to dozens of risk factors were included in our model, which may be related to the heterogeneity of the group with sepsis. To overcome this limitation, we strictly followed the latest diagnostic criteria for sepsis and comprehensively accounted for pathogens, antibiotics, and other relevant factors, which may have improved the prediction of secondary infection occurrence.

Septic survivors are burdened with an elevated risk of ICU-acquired infections, and the acquired infections resulted in an increase in long-term mortality. Patients with cerebrovascular insufficiency or Gram-negative bacteria, in the surgical ICU, undergoing management of the central venous catheter or urinary catheter, mechanical ventilation, tracheostomy, or RBC transfusion, and receiving anticoagulant medication within 48 h after ICU admission were much more likely to develop ICU-acquired infection. The findings may assist physicians in optimizing the management of sepsis-related ICU-acquired infection and improve the prognosis of sepsis.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The MIMIC-IV database was approved by the Massachusetts Institute of Technology (Cambridge, MA) and Beth Israel Deaconess Medical Center (Boston, MA).

YH extracted the data from the MIMIC-IV database. JX, YH, and YS contributed to literature search, and drafted the manuscript. YS and JX contributed to this work and designed the study. All authors contributed to the article and approved the submitted version.

This study was supported by National Natural Science Foundation of China (No. 82002026, 81971818, and 81772047), and the National Key Research and Development Project (2021YFC2500802). The funders had important role in the design of the study, in the collection, analysis, and interpretation of the data, or in the writing of the manuscript.

We would like to thank the Massachusetts Institute of Technology and the Beth Israel Deaconess Medical Center for the MIMIC project.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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