C. difficile infection (CDI) may be complicated by the development of nosocomial bloodstream infections (n-BSI). Nevertheless, whether CDI predisposes subjects to subsequent BSI is still controversial and neither the clinical link between CDI and n-BSI nor its exact pathogenesis have been demonstrated yet. Given that the observed n-BSIs following CDI were mostly caused by fungi and bacteria belonging to the enteric flora, a possible role of alteration of the normal gut integrity as the pathogenetic trigger for the development of n-BSI was hypothesized. Microbial translocation (MT), defined as the migration of bacteria or their products from the gut to the systemic circulation, might be promoted by the increased intestinal permeability and the intestinal damage (ID) present during CDI.
The hypotheses of the project are that a certain degree of inflammation, intestinal injury and microbial translocation occur during the course of CDI and that these alterations might play a role in the development of n-BSI after CDI.
Thus, primary endpoints are: i) to evaluate the dynamic changes of circulating levels of LPS-binding protein (LBP) and EndoCab IgM (markers of MT), IL-6 (marker of inflammation, IN) and Intestinal Fatty Acid Binding Protein (I-FABP, marker of ID) in patients with CDI and ii) to analyze whether these biomarkers are specifically modified in subjects developing n-BSI within 60 days after the onset of CDI compared with those not developing n-BSI.
This is a single-center, prospective study including subjects with documented CDI hospitalized at the Department of Public Health and Infectious Diseases, Sapienza University of Rome. For each subject, blood samples will be collected at T0 (i.e. before therapy or within 24h from the onset of CDI-specific therapy) and T1 (within 48h from the end of CDI-specific therapy), respectively. Circulating levels of LBP, EndoCab IgM, IL-6 and I-FABP will be analyzed by ELISA assays.
Clostridium difficile infection (CDI) is the most common cause of nosocomial infectious diarrhea in hospitalized patients, with up to 35% of patients having recurrent infections (Lassa, 2015). Recently, CDI was shown to be complicated by the development of nosocomial bloodstream infection (n-BSI), with causative pathogens represented by Candida spp and enteric bacteria and an overall mortality exceeding 50% (Russo, 2015). Furthermore, a large epidemiological study showed that among 2.026 candidemia cases, 189 (9%) had CDI co-infection, highlighting the concept that clinicians should be vigilant in looking for CDI in the context of candidemia, given that nearly 1 in 10 patients with candidemia had CDI coinfection (Tsay, 2018).
However, since a recent large retrospective study did not confirm this association, the possible link between CDI and n-BSI is still a matter of debate (Ulrich, 2017). In fact, from a clinical point of view, being aware of the possibility of n-BSI after CDI might drive physicians into an early recognition and treatment of n-BSI, especially during the first 4 weeks after CDI diagnosis, since this complication is associated with high mortality rates. On the other hand, from a pathogenetic standpoint, it appears essential to demonstrate whether or not there is a condition predisposing to the passage of bacteria or fungi from the gut into the systemic circulation, with the hypothesized mechanism residing mostly on the possible alteration of mucosal integrity occurring during CDI.
Thus, this project aims to investigate the pathogenetic basis of the observed clinical link between CDI and subsequent n-BSI, by demonstrating for the first time whether a certain degree of microbial translocation (MT), inflammation (IN) and intestinal damage (ID) is present during the course of CDI and, if it is present, whether the dynamic alteration of these biomarkers are responsible for the development of n-BSI.
Notably, the importance of the results of this project might have important clinical consequences, in terms of the awareness that the gut alteration during CDI possibly leads to a subsequent passage of microorganisms into the systemic circulation. If this clinical hypothesis is confirmed, the measurement of MT, IN and ID biomarkers might be implemented in the clinical practice in order to early identify those subjects at higher risk of developing n-BSI.
In conclusion, the innovation of this project resides on the fact that for the first time it may be explained the pathogenesis of the observed clinical link between CDI and n-BSI in human subjects. As for the advancement of the current medical knowledges, the importance of the present project is:
- clinicians are aware of the risk of n-BSI following CDI due to gut permeability alteration;
- the identification of subject at higher risk of developing n-BSI by the measurement of blood circulating MT, IN and ID biomarkers might prompt physicians to an early recognition and treatment of n-BSI;
- apart from CDI, all the conditions possibly associated with gut permeability alteration (i.e. prolonged extracorporeal circulation by the induction of low level of gut perfusion, inflammatory bowel diseases) might deserve further attention for the possibility of developing a subsequent BSI.