The role of dendritic cell alterations in susceptibility to hospital-acquired infections during critical-illness related immunosuppression
Introduction
Patients suffering from critical diseases such as sepsis, severe trauma or brain-injuries are hospitalized in intensive care units (ICUs) because of their high risk of death. Improvements in the standard of care of these patients has progressed enormously, resulting in significant reductions in morbidity and mortality rates (Kaukonen et al., 2014). However, ICU patients remain at high risk of death from hospital-acquired complications, secondary to the initial cause of hospitalization. Nosocomial (airways) infections are a particular cause of morbidity and mortality, and their management in ICUs exacts high costs on the health system. Since bacterial colonization precedes the establishment of infection, numerous preventive strategies aimed at reducing the exposure of ICU patients to bacteria have been tested. However, a recent meta-analysis has shown that the only preventive strategy that has demonstrated effectiveness at reducing mortality consists of digestive decontamination accompanied with systemic antimicrobial therapy (Roquilly et al., 2015). As clinicians are facing a reduction in the efficiency of antimicrobial therapy due to the emergence of bacterial resistance, this strategy is becoming increasingly difficult to apply successfully. Furthermore, this meta-analysis suggests that bacterial colonization might be a first symptom and not the cause of nosocomial infections (Roquilly et al., 2015). Interest has thus been redirected to characterize the mechanisms that prevent ICU patients from responding adequately to secondary infections. Recent studies have revealed profound, long-term alterations in both the innate and adaptive arms of the immune system which increase the susceptibility of ICU patients to infections and that together are responsible for critical-illness related immunosuppression (CIRI). For example, patients who died following sepsis showed clear alterations in number and function of T cells and antigen presenting cells in lymphoid organs (Boomer et al., 2011). As dendritic cells (DCs) combine the capacity to detect environmental changes with the ability to communicate with T cells and innate lymphocytes, they might play a key role in CIRI. In this review we summarize recent studies describing profound alterations to the life cycle and functional properties of DC that likely contribute to CIRI, increasing the susceptibility to infection in critically ill patients.
Section snippets
Systemic inflammatory response syndrome is a common characteristic of critical illness
Systemic inflammatory response syndrome (SIRS) is a clinical condition commonly associated with critical diseases such as severe infection (sepsis) or trauma. SIRS has an internationally recognized definition consisting of the concomitant presence of two signs among abnormal temperature, increased heart rate, increased respiratory rate, and abnormal white-cell count (ACCP/SCCM, 1992). Mechanistically, SIRS is the clinical expression of a systemic inflammatory response to pathogen- or tissue
DC life cycle, antigen presentation function and response to SIRS
DCs are the chief antigen presenting cells for the initiation and regulation of T cell-dependent immune responses. DC precursors constantly leave the bone marrow and seed peripheral tissues and secondary lymphoid organs, where they develop into immature DCs (Merad et al., 2013). The term steady-state DCs refers to the DCs present in the periphery and lymphoid organs in the absence of inflammation. Steady-state DCs express low levels of two types of molecules required for activation of naive T
Protracted impairment of antigen presentation in DCs of ICU patients
Signs of CIRI are present for weeks after the onset of SIRS in critically ill patients, but it is useful to distinguish two periods: an early stage during which inflammation is evident, and a late one lasting several weeks after resolution of SIRS characterized by an apparent return to basal conditions (Fig. 1). The mechanisms of DC impairment appear distinct at these two periods, an important consideration when devising strategies for therapeutic restoration of immunocompetence.
Biological monitoring
An ability to predict which ICU patients have a high risk of developing complications associated with CIRI would be highly beneficial. Monitoring antigen presenting cell function as a test has attracted considerable attention over the past decade. Performing functional assays of antigen presentation is not practical in the clinic, so surface expression of MHC-II on circulating PBMCs has been used as a surrogate marker. As compared to healthy controls, patients with CIRI show low MHC II
Conclusion
In summary, over the past decade there has been considerable progress in our understanding of the susceptibility to infection in critically ill patients. Reduced antigen presentation function by DC is probably an important mechanism. Protracted formation of immunosuppressive cytokines may induce prolonged formation of paralyzed DC after SIRS. We anticipate important developments in coming years that may lead to treatments to prevent DC paralysis and hence to reduce the susceptibility of
Acknowledgments
Antoine Roquilly received grants from the Société Française d'Anesthésie Réanimation and the Fondation des “Gueules Casséées”. Jose Villadangos receives funding from the National Health and Medical Research Council of Australia.
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2018, Clinical Microbiology and InfectionCitation Excerpt :This metabolic adaptation, which is also seen in tumour cells (Warburg effect), appears to fail in circulating white blood cells at the onset of secondary infections possibly as a consequence of epigenetic reprogramming that occurs during critical illness [19,20]. Due to the various derangements in—or resetting of—homeostatic mechanisms, critically ill patients are at great risk of contracting nosocomial infections, which not only cause accrued morbidity and mortality, but also generate extra costs to the health system [21]. Ventilator-associated pneumonia is the most common infection in selected groups of critically ill patients (68%), followed by abdominal infections (22%), bloodstream infections (20%) and urinary tract infections (14%), and carries a risk of death [22–24].
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