It is notable that when GM-CSF was administered in patients with immune dysfunction (i.e., low mHLA-DR expression), its use was associated with prompt restoring of immune functioning and to reduced mechanical ventilation time and hospital length of stay [40]. definition [1]. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) revised the definitions emphasizing the role of the host response and the related pathophysiological mechanisms inducing organ dysfunction [2]. AMZ30 The change of perspective from invading pathogens to the host response has radically transformed the vision of sepsis pathobiology in the last decades. The current concepts indicate that sepsis progress on a double track sustained by products of infecting microorganisms and by endogenous mediators derived from complement activation and by specific cell-surface receptors expressed on immune, epithelial, and endothelial cells. A complex system of intracellular signals is created by the binding of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that lead to the expression of several common gene classes involved in inflammation, adaptive immunity, and cellular metabolism [3]. Specifically, the recognition of PAMPs and DAMPs produces AMZ30 the recruitment of proinflammatory intermediates that initiate the expression of early activation genes [4]. == 2. Sepsis Related Immune-Paralysis == Recent data on septic patients clarified that host response may be hyper- or hyporeactive with an overwhelming inflammation associated with a boost of proinflammatory cytokines in the former and an immune-paralysis with the prevalence of anti-inflammatory cytokines and cellular apoptosis in the latter. Although proinflammatory and anti-inflammatory responses occur simultaneously, early phases of sepsis are usually characterized by hyperinflammatory processes associated with classical clinical signs ranging from slight to severe impairment of organ function, including shock appearance [5]. On the other hand, immune-suppressive state becomes predominant in later stages of sepsis producing the so-called persistent inflammation/immunosuppression and catabolism syndrome (PICS) [6]. The hypothesis for explaining PICS developing are mainly two: (i) a persistent and dysregulated activity of PAMPs, DAMPs, inflammasomes, and tissue alarmins and (ii) the role of opportunistic infections (e.g., viral reactivation, infectionAcinetobacterspp), changes in the host microbiota, and invasive procedures performed in critically ill patients [4]. Sepsis related immunosuppression causes profound changes in both the innate and adaptive immunity [7,8] with persistent lymphopenia and high level of immature forms of myeloid cells. The sepsis induced immune dysfunction makes critically ill patient highly susceptible to colonization and secondary infections, including Rabbit Polyclonal to Ik3-2 breakthrough infections, by opportunistic nosocomial multidrug resistant (MDR) bacteria. Therefore, patients carrying MDR bacteria might be considered AMZ30 a special population requiring specific strategies directed to supported immune system beyond the appropriate antibiotic therapy and standard supportive treatments. == 3. Patients with MDR Bacteria: Why Are They a Special Population? == Sepsis and septic shock related to MDR bacteria are progressively increasing in the last decades with gram negative pathogens responsible for the majority of cases [9]. International guidelines define MDR bacteria as microorganisms nonsusceptible in vitro to at least three different antimicrobial categories (previously excluding intrinsic resistance), XDR as nonsusceptible to at least one agent in all but two or fewer antimicrobial categories, and PDR as resistant to any agents in all antimicrobial classes tested [10]. The burden of infections sustained by MDR bacteria is variable in different areas: world data show a lower incidence in northwest of Europe, USA, and Canada and a higher incidence in southeast of Europe, Latin America, and Asia Pacific [11]. According to recent studies, around one-third of the intensive care unit (ICU) acquired infections are sustained by MDR bacteria most of whom areAcinetobacterspp.,Klebsiella pneumoniae, andPseudomonasspp. isolates [12]. The capability of these bacteria to survive for prolonged time in the hospital environment, the high risk of AMZ30 transfer among patients and healthcare staff, and the antibiotic resistance are responsible for their increasing widespread. Note that MDR strains are progressively increasing also in community acquired infections and the acquisition of these pathogens through travels in different world regions is becoming frequent. MDR infections influences patients’ outcome with higher mortality rates in metallo–lactamasesEnterobacteriaceaeandPseudomonas aeruginosaand in carbapenem-resistantKlebsiella pneumoniae, likely due to the delay in the appropriate antimicrobial therapy [13]. The Centre for control of Diseases calculates that gram negative MDR infections are responsible for AMZ30 approximately 40,000 cases and more than 2,800 deaths in the United States (CDC 2013 Threat report). It is well known that the administration of an appropriate antimicrobial therapy within the first hour of diagnosis is strongly recommended in the management of patients septic shock and that an initial noneffective therapy is related to increased.
It is notable that when GM-CSF was administered in patients with immune dysfunction (i