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The toxicity caused by different organisms in septic shock is substantially complex and characterized by an intricate pathogenicity that involves several systems and pathways. Immune cells’ pattern recognition receptors initiate the host response to pathogens after the recognition of pathogen-associated molecular patterns. In essence, the subsequent activation of downstream pathways may progress to infection resolution or to a dysregulated host response that represents the hallmark of organ injury in septic shock. Likewise, the management of organism toxicity in septic shock is complicated and comprises a multiplicity of suitable targets. In this review, the classic immune responses to pathogens are discussed as well as other factors that are relevant in the pathogenicity of septic shock, including sepsis-induced immune suppression, inflammasome activation, intestinal permeability, and the role of lipids and proprotein convertase subtilisin/kexin type 9. Current therapies aiming to eliminate the organisms causing septic shock, recent and ongoing trials in septic shock treatment, and potential new therapeutic strategies are also explored.

Background: The IL10 family of genes includes crucial immune regulators. We tested the hypothesis that single nucleotide polymorphisms (SNPs) in IL10, IL19, IL20, and IL24 of the IL10 family gene cluster alter the clinical outcome of septic shock. Methods: Patients with septic shock (n = 1,193) were genotyped for 13 tag SNPs of IL10, IL19, IL20, and IL24. IL20 gene expression was measured in genotyped lymphoblastoid cells in vitro. Cardiac surgical ICU patients (n = 981) were genotyped for IL20 rs2981573 A/G. The primary outcome variable was 28-day mortality. Results: Patients with the G allele of IL20 rs2981573 had a significantly increased hazard of death over the 28-day period compared to patients with the A allele in the septic shock cohort (adjusted hazard ratio 1.27; 95% confidence interval 1.10-1.47; p = 8.0 × 10-4). Patients with the GG genotype had more organ dysfunction (p < 0.05). The GG genotype was associated with increased IL20 gene expression in stimulated lymphoblastoid cells in vitro (p < 0.05). The cardiac surgical ICU patients with the GG genotype had an increased length of ICU stay (p = 0.032). Conclusions: The GG genotype of IL20 rs2981573 SNP was associated with increased IL20 gene expression and increased adverse outcomes in patients with septic shock and following cardiac surgery.

Background and Hypothesis: The inflammatory response was targeted by unsuccessful therapies but ignored pathogen. We hypothesized that the inflammatory response differs according to organism in human septic shock. Materials and Methods: We measured 39 cytokines at baseline and 24 h in patients (n = 363) in the Vasopressin and Septic Shock Trial (VASST). We compared cytokine profiles (cytokine functional class) at baseline and at 24 h by organism and used hierarchical clustering to classify cytokines according to 28-day outcomes. Results: In 363 patients, 88 and 176 patients had at least 1 species isolated from blood and other sites, respectively. Cytokine levels differed significantly according to organism: Neisseria meningitidis and Streptococcus pneumoniae had the highest (baseline and at 24 h), while Enterococcus faecalis (blood) had the lowest mean cytokine levels. N. meningitidis and Klebsiella pneumoniae had significantly higher cytokine levels at baseline versus 24 h (p = 0.01 and 0.02, respectively); E. faecalis had significantly higher cytokine levels at 24 h versus baseline. Hierarchical clustering heat maps showed that pathogens elicited similar cytokine responses not related to the functional cytokine class. Conclusion: The organism type induces different cytokine profiles in septic shock. Specific gram-positive and gram-negative pathogens stimulated similar plasma cytokine-level patterns.

During septic shock, tumor necrosis factor alpha (TNFa) is an early response gene and induces a plethora of genes and signaling pathways. To identify robust signals in genes reliably upregulated by TNFa, we first measured microarray gene expression in vitro and searched methodologically comparable, publicly available data sets to identify concordant signals. Using tag single-nucleotide polymorphisms in the genes common to all data sets, we identified a genetic variant of the TNFAIP2 gene, rs8126, associated with decreased 28-day survival and increased organ dysfunction in an adult cohort in the Vasopressin and Septic Shock Trial. Similar to this cohort, we found that an association with rs8126 and increased organ dysfunction is replicated in a second cohort of septic shock patients in the St. Paul's Hospital Intensive Care Unit. We found that TNFAIP2 inhibits NF-κB activity, impacting the downstream cytokine interleukin (IL)-8. The minor G allele of TNFAIP2 rs8126 resulted in greater TNFAIP2 expression, decreased IL-8 production and was associated with decreased survival in patients experiencing septic shock. These data suggest that TNFAIP2 is a novel inhibitor of NF-κB that acts as an autoinhibitor of the TNFa response during septic shock.

Background: Genetic variations contribute to septic shock mortality. To discover a novel locus, we performed in vitro genome-wide association studies (GWAS) and further tested the result in a cohort of septic shock patients. Methods: Two in vitro GWAS using a quantitative trait locus analysis of stimulated IL-6 production in lymphoblastoid cells from 60 individuals of European ancestry were performed. VPS13D rs6685273 was genotyped in European ancestry patients (n = 498). The VPS13D gene was silenced in vitro. Results: Two GWAS using lymphoblastoid cells identified the locus of VPS13D rs6685273 that was significant in the same direction in both GWAS. The VPS13D rs6685273 C allele was associated with increased IL-6 production. Patients with septic shock who had the VPS13D rs6685273 CC genotype had an increased 28-day mortality (p = 0.023) and more organ failure (p < 0.05) compared to the CT/TT genotypes. VPS13D in vitro gene silencing in the HeLa cell line increased IL-6 production. Furthermore, the rs6685273 genotype was associated with differential VPS13D splice variant expression. Conclusions: The VPS13D rs6685273 C allele was associated with increased IL-6 production in vitro. The patients with the VPS13D rs6685273 CC genotype had increased 28-day mortality and increased organ failure. VPS13D appears to regulate IL-6 production.

The IL10 family of genes includes crucial immune regulators. We tested the hypothesis that single nucleotide polymorphisms (SNPs) in IL10, IL19, IL20, and IL24 of the IL10 family gene cluster alter the clinical outcome of septic shock.Patients with septic shock (n = 1,193) were genotyped for 13 tag SNPs of IL10, IL19, IL20, and IL24. IL20 gene expression was measured in genotyped lymphoblastoid cells in vitro. Cardiac surgical ICU patients (n = 981) were genotyped for IL20 rs2981573 A/G. The primary outcome variable was 28-day mortality.Patients with the G allele of IL20 rs2981573 had a significantly increased hazard of death over the 28-day period compared to patients with the A allele in the septic shock cohort (adjusted hazard ratio 1.27; 95% confidence interval 1.10-1.47; p = 8.0 × 10-4). Patients with the GG genotype had more organ dysfunction (p0.05). The GG genotype was associated with increased IL20 gene expression in stimulated lymphoblastoid cells in vitro (p0.05). The cardiac surgical ICU patients with the GG genotype had an increased length of ICU stay (p = 0.032).The GG genotype of IL20 rs2981573 SNP was associated with increased IL20 gene expression and increased adverse outcomes in patients with septic shock and following cardiac surgery.

Purpose: We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. Methods: Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce Escherichia coli endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. Results: We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced E. coli endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). Conclusions: Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock.

During septic shock, tumor necrosis factor alpha (TNFα) is an early response gene and induces a plethora of genes and signaling pathways. To identify robust signals in genes reliably upregulated by TNFα, we first measured microarray gene expression in vitro and searched methodologically comparable, publicly available data sets to identify concordant signals. Using tag single-nucleotide polymorphisms in the genes common to all data sets, we identified a genetic variant of the TNFAIP2 gene, rs8126, associated with decreased 28-day survival and increased organ dysfunction in an adult cohort in the Vasopressin and Septic Shock Trial. Similar to this cohort, we found that an association with rs8126 and increased organ dysfunction is replicated in a second cohort of septic shock patients in the St. Paul's Hospital Intensive Care Unit. We found that TNFAIP2 inhibits NF-x03BA;B activity, impacting the downstream cytokine interleukin (IL)-8. The minor G allele of TNFAIP2 rs8126 resulted in greater TNFAIP2 expression, decreased IL-8 production and was associated with decreased survival in patients experiencing septic shock. These data suggest that TNFAIP2 is a novel inhibitor of NF-x03BA;B that acts as an autoinhibitor of the TNFα response during septic shock.

Vasopressin is a stress hormone. However, vasopressin levels are inappropriately low in septic shock. Vasopressin stimulates AVPR1a, AVPR1b, AVPR2 and purinergic receptors. Vasopressin increases blood pressure by occupying AVPR1a receptors on vascular smooth muscle. An increase in ventricular afterload due to vasopressor administration limits ventricular systolic ejection, an effect that becomes increasingly important as systolic contractility is decreased. Stimulation of AVPR1a receptors may also decrease edemagenesis. Stimulation of AVPR1b by vasopressin releases ACTH and cortisol. AVPR2 stimulation increases retention of water by increasing cyclic AMP. Yet, vasopressin infusion may increase urine output, creatinine clearance and improve renal function in septic shock. Vasopressin has many effects on immune function such as altering cytokines, neuroimmunity, prostaglandins, humoral immunity and immune cells. For example, vasopressin decreases sepsis-induced pulmonary inflammation, could have renal anti-inflammatory effects and may decrease prostaglandin levels in a dose-dependent manner. Vasopressin may also modulate responses to stress by expression and release from immune cells. Interestingly, there are vasopressin receptors on immune cells. Many small clinical studies of vasopressin infusion in septic shock have shown that vasopressin infusion increases blood pressure, decreases requirements for norepinephrine and improves renal function. However, vasopressin could decrease coronary, cerebral and mesenteric perfusion. A multicenter trial of vasopressin versus norepinephrine in septic shock found no overall difference in mortality. Vasopressin may decrease mortality in patients with less severe septic shock. Vasopressin plus corticosteroid treatment may decrease mortality compared to corticosteroids plus norepinephrine. Potential mechanisms are that vasopressin plus corticosteroids beneficially alter immunity in septic shock.