Eirini Christaki

The beginning of personalized medicine in sepsis: small steps to a bright future.

There is a growing recognition that there is a need for a more personalized approach towards sepsis care. In most clinical trials investigating novel therapeutic interventions against sepsis, patients have been considered a rather homogeneous population. However, there is probably more individual variability between septic patients than previously considered. The pathophysiology of sepsis is a complex and dynamic process that originates from the host immune response to infection and varies according to the genetic predisposition, immune status and co‐morbid conditions of the host, the type of pathogen and the site and extent of infection. Until now, efforts to stratify septic patients according to their immune profile were hampered by the lack of specific biomarkers. Recent advances in molecular medicine have made it possible to develop tools that will facilitate a faster and more precise diagnosis of infection. Individual variability between each patients responses to infection can assist in tailoring therapeutic interventions to the individuals disease profile and monitoring treatment response. In this review, we describe those recent advances in genomics and theragnostics, which are slowly entering clinical practice and which will make possible a more personalized approach to each septic patient in the next decade.

A monoclonal antibody against RAGE alters gene expression and is protective in experimental models of sepsis and pneumococcal pneumonia.

The RAGE (receptor for advanced glycation end products) is believed to play a role in sepsis by perpetuating inflammation. The interaction of RAGE with a variety of host-derived ligands that accumulate during stress and inflammation further induces the expression of RAGE. It was previously shown that a rat anti-RAGE monoclonal antibody protected mice from lethality in a cecal ligation and puncture model. We studied the effects of a humanized anti-RAGE monoclonal antibody in the murine pneumococcal pneumonia model of sepsis. Moreover, a gene expression analysis was performed in lung tissue of animals that underwent cecal ligation and puncture and treated with the rat anti-RAGE monoclonal antibody, compared with controls. Administration of humanized anti-RAGE mAb 6 h after intratracheal infection with Streptococcus pneumoniae improved mortality in BALB/c mice whether a 7.5 mg/kg (P < 0.01) or a 15 mg/kg dose (P < 0.01) was administered in combination with antibiotics. Gene expression analysis showed that many of the genes modulated by treatment with the anti-RAGE antibody were those that play an important role in regulating inflammation. Anti-RAGE monoclonal antibody offered a survival advantage to septic mice. This protective role in treated animals is supported by the observed gene expression profile changes of genes involved in sepsis and inflammation.

Is the mortality rate for septic shock really decreasing

Purpose of reviewTo critically examine the mortality rates of septic shock over the last 25 years to determine if significant improvements have been accomplished. Recent findingsA gradual and progressive improvement in mortality rates associated with septic shock has been realized over the few decades. These improvements in outcome are quantitatively small but significant and they primarily represent improvements in supportive care, and the recognition that well meaning and seemingly logical treatments have been overused and probably contributed to excess mortality rates in the past. SummarySurvival rates for patients in septic shock have gradually improved in critical care units worldwide over the last 25 years. Further improvement will be predicated on the discovery of new therapies to disrupt the underlying pathophysiology of sepsis and the development of improved rapid, diagnostic testing and immune monitoring of individual patients.

Specific Antibody to Cryptococcus neoformans Glucurunoxylomannan Antagonizes Antifungal Drug Action against Cryptococcal Biofilms In Vitro

The fungus Cryptococcus neoformans possesses a polysaccharide capsule and can form biofilms on medical devices. We investigated the efficacy that the combination of a specific antibody to the capsular polysaccharide and antifungal therapy has against cryptococcal biofilms. The antibody enhanced the susceptibility of planktonic cells to antifungal agents, but an antagonistic effect was observed for combination therapy against C. neoformans biofilms. Our findings suggest that antibody therapies for infectious diseases that involve biofilms may antagonize certain antimicrobial therapies, and they also imply that products of the immune response may contribute to drug resistance of biofilms formed in vivo.

Estrogen Receptor β Agonism Increases Survival in Experimentally Induced Sepsis and Ameliorates the Genomic Sepsis Signature: A Pharmacogenomic Study

BACKGROUND Nonsteroidal agonists have been developed that selectively bind to and activate estrogen receptor beta (ERbeta) rather than estrogen receptor alpha (ERalpha). ERbeta is expressed equally in both male and female mammals in multiple extragonadal tissues. Work reported elsewhere has demonstrated that ERbeta agonists have beneficial effects in multiple (but not all) models of inflammatory diseases and also increase survival in experimentally induced sepsis. METHODS In these experiments, ERbeta agonists (ERB-041 or WAY-202196) were compared with vehicle control in the murine cecal ligation and puncture (CLP) model and in the pneumococcal pneumonia model of sepsis. The effect of WAY-202196 on the gene expression profile in the CLP model was further studied by transcriptome analysis of lung and small intestine tissue samples. RESULTS ERbeta agonists provided a significant survival benefit in both experimental models of bacterial sepsis. This survival advantage was accompanied by reduced histologic evidence of tissue damage, reduced transcription of multiple proinflammatory proteins by transcriptome analysis and was not associated with increased bacterial outgrowth. CONCLUSIONS ERbeta agonist administration provided a survival advantage in septic animals and appears to be a promising therapeutic modality in sepsis.

Receptor for advanced glycation end products in bacterial infection: is there a role for immune modulation of receptor for advanced glycation end products in the treatment of sepsis?

Purpose of review Sepsis is still associated with excess morbidity and mortality worldwide, despite significant advances in critical care medicine. A novel approach is needed in the treatment of sepsis, one that will aim to correct the specific immunologic imbalance that is detrimental to the septic host. Recent findings As receptor for advanced glycation end products (RAGE) is involved in diverse cellular mechanisms that to a lesser or greater extent participate in the septic process, modulating its function could favorably affect outcome. Altering RAGE may result in regulating the release of proinflammatory cytokines, controlling apoptosis or modifying endothelial architecture. In that regard, several strategies have been used to study RAGE deficiency in experimental models of sepsis including antibodies against RAGE, genetically deleted RAGE knockouts, siRNA to silence RAGE, soluble forms of RAGE, and antibodies and inhibitors directed toward RAGE ligands, such as HMGB1 and S100 proteins. Summary These studies thus far have yielded inconsistent results as to whether RAGE is beneficial or not to the host response during bacterial infection and sepsis.

The complex pathogenesis of bacteremia: From antimicrobial clearance mechanisms to the genetic background of the host

Bacteremia develops when bacteria manage to escape the host immune mechanisms or when the otherwise well-orchestrated immune response fails to control bacterial spread due to inherent or acquired immune defects that are associated with susceptibility to infection. The pathogenesis of bacteremia has some characteristic features that are influenced by the genetic signature of the host. In this review, the host defense mechanisms that help prevent bacteremia will be described and the populations who are at risk because of congenital or acquired deficiencies in such mechanisms will be defined. A special mention will be made to novel insights regarding host immune defense against the most commonly isolated organisms from patients with community-acquired bloodstream infections.

New technologies in predicting, preventing and controlling emerging infectious diseases

Surveillance of emerging infectious diseases is vital for the early identification of public health threats. Emergence of novel infections is linked to human factors such as population density, travel and trade and ecological factors like climate change and agricultural practices. A wealth of new technologies is becoming increasingly available for the rapid molecular identification of pathogens but also for the more accurate monitoring of infectious disease activity. Web-based surveillance tools and epidemic intelligence methods, used by all major public health institutions, are intended to facilitate risk assessment and timely outbreak detection. In this review, we present new methods for regional and global infectious disease surveillance and advances in epidemic modeling aimed to predict and prevent future infectious diseases threats.

NK and NKT Cell Depletion Alters the Outcome of Experimental Pneumococcal Pneumonia: Relationship with Regulation of Interferon-γ Production

Background. Natural killer (NK) and natural killer T (NKT) cells contribute to the innate host defense but their role in bacterial sepsis remains controversial. Methods. C57BL/6 mice were infected intratracheally with 5 × 105 cfu of Streptococcus pneumoniae. Animals were divided into sham group (Sham); pretreated with isotype control antibody (CON) group; pretreated with anti-asialo GM1 antibody (NKd) group; and pretreated with anti-CD1d monoclonal antibody (NKTd) group before bacterial challenge. Serum and tissue samples were analyzed for bacterial load, cytokine levels, splenocyte apoptosis rates, and cell characteristics by flow cytometry. Splenocyte miRNA expression was also analyzed and survival was assessed. Results. NK cell depletion prolonged survival. Upon inhibition of NKT cell activation, spleen NK (CD3−/NK1.1+) cells increased compared to all other groups. Inhibition of NKT cell activation led to higher bacterial loads and increased levels of serum and splenocyte IFN-γ. Splenocyte miRNA analysis showed that miR-200c and miR-29a were downregulated, while miR-125a-5p was upregulated, in anti-CD1d treated animals. These changes were moderate after NK cell depletion. Conclusions. NK cells appear to contribute to mortality in pneumococcal pneumonia. Inhibition of NKT cell activation resulted in an increase in spleen NK (CD3−/NK1.1+) cells and a higher IFN-γ production, while altering splenocyte miRNA expression.

The kinetics of T regulatory cells in shock: beyond sepsis

During the past decade, there have been an increasing number of studies investigating the precise role of T regulatory cells in human disease. First recognized for their ability to prevent autoimmunity, T regulatory cells control effector CD4+ and CD8+ T lymphocytes and innate immune cells by several different suppressive mechanisms, like cell to cell contact, secretion of inhibitory cytokines and cytolysis. This suppressive function of T regulatory cells could contribute in a similar way to the profound immune dysfunction seen in critical illness whether the latter is due to sepsis or severe injury.