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Note: IL denotes interleukin. TNF denotes tumor necrosis factor. IL1ra denotes IL-1 receptor antagonist. MHC denotes major histocompatability complex. T cells are T lymphocytes that were derived from the thymus. B cells are B lymphocytes that were derives from bone marrow. TH1 denotes a class of T helper cells.

of Toll-like receptors (TLRs)83 or by impairment of neutrophil function.84 Toll-like receptors are a family of proteins that act as pattern recognition receptors and enable cells to recognize pathogen-associated molecular patterns. TLRs allows the innate immune system to immediately recognize highly conserved bacterial, viral, and fungal components.83,85 An evolutionary mechanism that evolved to protect the host from the harm of an overly responsive immune system, such as exaggerated IL-6 levels, is the inhibition of Toll-like receptor signaling by IL-1 receptor associated kinase-M.86 High IL-6 levels have also been reported in a small study (n = 21) of patients with HAIs who had impairment of neutrophil function resulting in impaired phagocytosis and bacterial killing.84 If the relationship of exaggerated or high IL-6 levels and development of HAIs is confirmed in this study, the underlying mechanism will require investigation.

There have been no clinical studies to determine how cytokines influence bacterial growth in sepsis. However, in 1997, Headley et al. studied the effect of infections and the inflammatory response in ICU patients (n = 34) with Acute Respiratory Distress Syndrome (ARDS). They found that the outcome in ARDS was not related to the development of HAIs but that it was attributed to the magnitude and duration of the inflammatory response. It is unclear if they specifically tested the association of baseline level of inflammation and development of subsequent HAI. One important finding was that when a new HAI developed, it was not accompanied by an increase in levels of inflammatory proinflammatory cytokines.87 The same authors have reported in the past that persistent elevation of inflammatory cytokines was a poor predictor of outcome. The authors provided evidence that non-survivors have high levels of inflammatory cytokines at baseline which persisted for at least the first 10 days, whereas, survivors had a lower baseline level which decreased over the first 10 days.88 It is unknown how long this relationship persists since data were not shown beyond 10 days. A similar persistent elevation of the pro-inflammatory cytokine, IL-6, was recently reported in non-survivors with severe sepsis.89 The first week to 10 days may describe a more homogenous population of early infections; however, infections may also be described as early, middle, and late infections.90 The relationship of persistent systemic inflammatory, when defined clinically as systemic inflammatory response syndrome (SIRS) and not based on cytokine levels, has been shown to significantly increase the risk for developing HAI in a trauma population.90,91 The relationship of severity of illness and health care associated infections has been described.10 McCluster et al. similarly report that patients who developed HAI had higher APACHE III scores than those who did not develop HAI but the relationship was not statistically significant.9 Kinasewitz et al. analyzed multiple biomarkers from the PROWESS data set (n = 1,690), a randomized controlled trial of recombinant human activated protein C in severe patients with sepsis. They found significant correlations in biomarkers relative to increasing levels of APACHE II. Of interest, median and interquartile ranges of IL-6 (pg/ml) were increased for all participants with an increase for each quartile of APACHE II (1st quartile: 289 (245 - 369), 2nd quartile: 384 (322 rd quartile: 623 (494 - 829), 4th quartile: 1043 (809 - 1613), p 0.001). Their data

for IL-10 (pg/ml) was inconclusive as 59% were below the detection limit: (1st quartile:

≤ 10 (10 - 10), 2nd quartile: ≤ 10 (10 - 10), 3rd quartile: ≤ 10 (10 - 30), 4th quartile: ≤ 10 (10 - 27), p = 0.001).12 The APACHE II ranges for each quartile were: 1st quartile (3

- 19), 2nd quartile (20 - 24), 3rd quartile (25 - 29), and 4th quartile (30 - 59). Criteria for the original study included severe sepsis with at least three signs of systemic inflammation and at least one organ failure.92 It is assumed that patients with sepsis who present with a high degree of baseline systemic inflammation will have persistent inflammation which may contribute to the development of HAI. The role of pro- versus anti-inflammatory cytokines in the development of sepsis is an area of debate. Assessment of the cytokine profile may be more predictive than assessing individual cytokines in isolation.93 Although other more common mechanisms for the development of HAI exist, such as poor aseptic techniques, the relationship of systemic inflammation and development of HAI in patients with sepsis presents a novel approach which is explored in this dissertation.

Rationale for Selecting IL-6 and IL-10

When planning this dissertation study, it was to be limited it to one proinflammatory cytokine, one anti-inflammatory cytokine, and one ratio. Before this project began, there was concerned about the use of IL-1β and IL-1ra due to reports of low detection limits in the literature. In addition to measuring IL-1β and IL-1ra, we also measured TNF-α, IL-6, and IL-10. IL-6 and IL-10 were included as an alternative pro- to anti- inflammatory ratio since they were less likely to be below detection limits and because there were other reports examining these ratios.94 A large number of cytokine values were below the detection limit for IL1B (66 or 84%) and IL1ra (50 or 64%) which indeed limited comparison of their ratios. These low detection limits also limited our ability to detect a difference in cytokine levels for the associated SNP. It is probable that these very low concentrations (below the 3.2 pg/ml threshold used in this study) are biologically important, despite the fact that they cannot be precisely measured. A total of 5 (6.4%) IL-6 levels and 29 (37.2%) IL-10 levels were below the detection limit.

Numerous articles throughout the literature include IL-1β, TNF-α, and IL-6 as pro-inflammatory cytokines; however, it should be noted that IL-6 also has many other functions. IL-6 not only induces the acute phase response causing the liver to release CRP and other acute phase reactants, it is also involved in immunoglobulin switching necessary for acquired immunity.95,96 IL-6 may have a protective effect against development of septic shock;96 whereas, minute amounts of TNF- α and IL-1β are potent initiators of septic shock.81 IL-6 has been shown to consistently correlate with clinical severity of inflammation, autoimmune, and infectious disease; whereas, this relationship is not always clear with IL-1 and TNF.97 IL-6 levels have been used to predict fatal outcome in septic shock whereas this has not been shown with TNF levels. Dinarello concludes that among patients with septic shock, IL-6 levels seems to “represent the net effect of biologically active IL-1 and TNF”.97

Sepsis Polymorphisms

Sepsis is a complex disease involving a large number of genes. Genes are composed of deoxyribonucleic acid (DNA) which is a polynucleotide chain made from sugar (2-deoxyribose) linked to phosphate backbone with protruding nucleotide bases.

These bases are either purines (Adenine and Guanine) or pyrimidines (Cytosine and Thymine). A polymorphism is a common variation (greater than one percent) in the DNA sequence among individuals; whereas, a mutation has a frequency of less than one percent. A single nucleotide polymorphism is the substitution of one of the four nucleotide bases with another nucleotide base and may confer a survival advantage.98 Another type of polymorphism is a tandem repeat or microsatellite polymorphism, in which a number of nucleotides are repeated once or several times. The normal or usual genotype is referred to as the wild type, although wild type can refer to the genotype or phenotype.99 Only about 10 percent of the DNA sequence in the human genome codes for genes, and SNPs occur approximately every 1,000 base pairs with most not resulting in a protein or secretion change.98 SNPs occurring in the promoter regions of genes have potential to influence the level of gene expression and are likely to be important. Several polymorphisms have been well characterized in sepsis.13-19 Knowledge is accumulating regarding the genetic susceptibility to infectious disease; however, gene-gene, geneenvironment, and host-pathogen interactions should also be considered.20-22 Identification of promoter polymorphisms is important when examining an exaggerated inflammatory response. There are a number of important candidate polymorphisms that may be involved in the development of HAIs. Table 2-2 includes a brief review of selected polymorphism. Although evidence supports the importance of these polymorphisms in sepsis, a study of young, healthy white males with no smoking or co-morbidity history, found a trend but no clear association between common polymorphisms and cytokine levels in a sepsis model of endotoxin exposure.100 There is research indicating that epigenetic factors may down regulation genes as early as 3-5 hours after an infectious insult which could be the reason the investigators did not find an association.101 It is reasonable to conclude that patients who have already shown susceptibility to sepsis by presentation to the ICU with sepsis have a different risk profile than these healthy young men. Additionally, polymorphisms in one cytokine gene may enhance expression levels of other cytokine genes.102

Cytokine Gene SNPs for IL-6 and IL-10

The gene for IL-6 is located on chromosome seven on the p arm. The gene for ILconsists of 4,856 nucleotides and begins at location 22,766,766. The promoter region lies upstream from the gene. It generally starts approximately 25 bp upstream from the gene starting point but transcription factors have a large “footprint” and their binding to the promoter is necessary prior to the binding of RNA polymerase II and ultimate transcription of IL-6 into mRNA.103 There are several SNPs located within the promoter Table 2-2. Selected Cytokine Polymorphism Investigated in Sepsis.

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Note: IL denotes Interleukin. TNF denotes tumor necrosis factor. IL1ra denotes IL-1 receptor antagonist.

region of IL-6. RS1800795, previously known as -174G/C, is located at 22,766,645 and has been well described in the literature. It has been associated with both higher and lower levels of IL-6 when position RS1800795 is encoded by G.16,18,108 The gene for IL-10 is located on chromosome one on the q arm. The gene for ILconsists of 4891 nucleotides and extends from location 206,945,839 to 206,940,948.

The promoter for IL-10 lies upstream from the gene and SNP RS1800896, previously known as -1082 G/A, is located upstream within the promoter region at 206,946,897. It has been shown that the presence of a G at this position is associated with shock, more severe sepsis, and more severe pneumonia.16,19,107 Figure 2-1 shows the location of these SNP upstream from the gene using the National Center for Biotechnology Information’s (NCBI) new Sequence Viewer v.2.12.

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The International HapMap Project began in 2002 with the goal of providing patterns of human DNA sequence variation to enable scientists to investigate genes affecting health, disease, and response to drugs and environmental factors. The HapMap Project is currently in its third phase, HapMap 3, which includes 1,301 samples from eleven human populations, and 270 of those samples originating from prior phases.109 HapMap 3 included samples from African ancestry in Southwest USA (ASW) and Utah residents with Northern and Western European ancestry (CEU) were included. Tables 2-3 and 2-4 show the distribution. Note the difference between ASW and Africans from Sub-Sahara. Courtesy: National Human Genome Research Institute.

Selection of Exclusion Criteria

This study was designed to examine systemic inflammation and its influence on the development of HAI. Patients with a disease process know to decrease immune function and those receiving certain immunosuppressants could confound findings on HAI. This includes patients with cancer and human immunodeficiency syndrome. It also includes patients on high dose corticosteroids or chemotherapy. Acute phase proteins are secreted by the liver in response to inflammation; thus, patients with a liver failure (Child Pugh Score of C or worse) were also excluded. While the elderly may be more susceptible to infections due to a functional decline in cell-mediated immunity,110 we opted not to exclude patients based on age so that this relationship could be examined if it existed in this population.

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Until recently, there had been no clinical studies examining the relationship of excessive baseline inflammation with the development of subsequent health care A.


Figure 2-1. Promoter SNP Locations.

Note: The red down facing arrow in each image denotes the SNP location. Image A shows the IL-6 gene and the location of rs1800795. Image B shows the IL-10 gene and the location of rs1800896. Images obtained from NCBI’s new Sequence Viewer v.2.12.

Available from: http://www.ncbi.nlm.nih.gov/SNP/.

Table 2-3. HapMap 3 RS1800795 Genotype and Allele Frequencies.

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Note: The ancestral allele is G. CEU represents Utah residents with Northern and Western European ancestry. ASW represents African ancestry from Southwest USA.

YRI represents Africans from Sub-Sahara. Courtesy: National Human Genome Research Institute.

Table 2-4. HapMap 3 RS1900896 Genotype and Allele Frequencies.

–  –  –

Note: The ancestral allele is A. CEU represents Utah residents with Northern and Western European ancestry. ASW represents African ancestry from Southwest USA.

YRI represents Africans from Sub-Sahara. Courtesy: National Human Genome Research Institute.

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