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«INFLAMMATORY PROTEINS, GENETIC VARIATION, AND ENVIRONMENTAL INFLUENCES ON HEALTH CARE ASSOCIATED INFECTION DEVELOPMENT IN SEPSIS A Dissertation ...»

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INFLAMMATORY PROTEINS, GENETIC VARIATION, AND

ENVIRONMENTAL INFLUENCES ON HEALTH CARE ASSOCIATED

INFECTION DEVELOPMENT IN SEPSIS

A Dissertation

Presented for

The Graduate Studies Council

The University of Tennessee

Health Science Center

In Partial Fulfullment

Of the Requirements for the Degree

Doctor of Philosophy

From The University of Tennessee

By

Reba Antionette Umberger May 2011 Copyright © 2011 by Reba Antionette Umberger.

All rights reserved.

ii DEDICATION This dissertation is dedicated in memory of my loving grandmother, Nell Acree (1923-2010).

iii

ACKNOWLEDGEMENTS

I would like to first express gratitude to my family and friends for their patience, love, and support throughout this endeavor. They gave me strength and encouragement when I need it. I appreciate their understanding of my time constraints while pursuing this degree and working full time. I am humbled and grateful for the Lord’s guidance through the various challenges I have experienced.

I would like express my sincere appreciation to my dissertation chair, mentor, and advisor, Dr. Carol L. Thompson, whose guidance was invaluable. She has been an excellent role model in leadership, and helped me to stay focused while providing feedback and support throughout this process. I would also like to thank my committee members: Dr. Ann Cashion, Dr. David Kuhl, Dr. Jim Wan, and Dr. Ryan Yates. Each contributed significantly to this dissertation project and their guidance and support have been indispensable.

Many have contributed to my development as a nurse researcher and scientist. In addition to my committee, there are several College of Nursing faculty members who have contributed to my education and broadened my perspective. They include Dr. Mona Wicks, Dr. Carolyn Graff, and Dr. Patricia Cowan, who all have served as Program Chairs during my studies. I would like to acknowledge Dr.Veronica Engle, for designing seminar projects that contributed to early stages of this dissertation. I would also like to acknowledge the Office of Research and Grant Support (Dr. Mona Wicks, Ms. Gail Spake, and Ms. Deborah Talley) for review and assistance with grants submitted, as well as assistance with research posters. I am grateful to Ms. Spake for her initial review of this dissertation. Finally, Dr. Thompson and Dr. Cashion encouraged me to attend NIH’s Summer Genetics Institute in 2008, which significantly influenced this dissertation.

I would also like to thank my clinical co-investigators at the VAMC, Dr. G.

Umberto Meduri and Dr. Muthiah P. Muthiah, who allowed me access to patients in the MICU and provided their medical expertise as needed. My first experience in research, as a research nurse, was given to me by Dr. Meduri and he inspired me to further my education as a researcher and pursue doctoral education. Work from his laboratory by Dr.

Siva Kanagat generated ideas for this dissertation project. I would like to thank Dr. Andy Bell for his assistance in identifying potential subjects and in reviewing de-identified data with me for appropriate antibiotic usage. I also appreciate the MICU nurses who notified me of new patients and witnessed informed consents. I am grateful to Mr. Peter St.

Arnold, Mrs. Fredrika Curry, and Mr. Leighton Legos for their regulatory guidance at the VAMC IRB. I would also like to thank Mr. Barry Powell for providing me a place to work in the VAMC library and access to a photocopier for de-identified records.

Several individuals have contributed to laboratory components of this study. Dr.

Ted Strom allowed my use of the VAMC Core Laboratory for specimen processing and temporarily storage, and the Core Laboratory staff were helpful in providing access. I would like to express gratitude to Dr. Ryan Yates for allowing me to use space in his iv laboratory to complete cytokine analysis and DNA isolation, and for providing guidance.

His doctoral student, now Dr. Karin Emmons, was an essential resource by provided me with training and support in the use of Luminex for cytokine measurement. Additionally, his laboratory technician, Mrs. Wenbo Ge, provided assistance with equipment as needed. I am also grateful to the Molecular Resource Center faculty and staff, Dr.

William Taylor and Mrs. Felecia Waller, for their training and assistance with genotyping.

This project was funded by University of Tennessee Health Science Center’s College of Nursing (cytokine kits) and Millipore (additional cytokine kits). A grant from the International Society of Nurses in Genetics provided funding for genetic analysis, and the College of Nursing provided additional funding for expenses not covered by this grant. The College of Graduate Health Sciences provided travel awards for presentation of various aspects of this dissertation.

v ABSTRACT

The purpose of this study was to determine the impact of baseline systemic inflammation (pro-inflammatory cytokine, anti-inflammatory cytokine, and their ratio), genetic variability, and environment on the development of health care associated infections (HAI) among sepsis patients during their ICU stay (up to 28 days).





Methods: A prospective observation study was conducted at the Veterans Affairs Medical Center in the Medical Intensive Care Unit over an 18 month period. A total of 78 patients were enrolled within 72 hours of presenting to the ICU with sepsis. Patient were excluded if they were receiving immunosuppressants (chemotherapy or greater than one mg/kg of prednisone or equivalent dose), immunosuppressed (AIDS, cancer), or had liver failure (Child Pugh category C or higher). Baseline plasma and buccal swabs were collected. Patients were followed prospectively through their ICU stay (or for a maximum of 28 days) for the development of HAI as defined by CDC guidelines.

Primary variables included baseline IL-6 and IL-10 levels, IL-6 SNP rs1800795, IL-10 SNP rs1800896, APACHE II, invasive devices, and development of HAI.

Results: A total of 17 HAI were identified with 64% caused by Candida. There were no significant differences in levels of pro-inflammatory cytokine, anti-inflammatory cytokine, or their ratio among subjects who did and did not develop at least one HAI during their ICU stay. There were also no significant differences in rs1800795 or rs1800896 genotypes for those who did and did not develop HAI; however, racial differences were detected in genotypes among white and black patients with sepsis who did and did not develop HAI. There was a significant difference in rs1800795 genotype among black patients with sepsis who did not develop HAI compared to whites patients with sepsis who did not develop HAI (p = 0.006). Specifically, black patients had a lower CG (17.4% vs. 42.1%) and higher GG (82.6% vs. 42.1%) than white patients. There were no racial differences when comparing white and black sepsis patients who developed HAI (p = 1.0). In a series of Cox regression analyses investigating timing to first HAI among those who did and did not develop HAI during ICU stay, the final model included only APACHE II, cumulative invasive device score, and IL-6 rs1800795.

Conclusion: This study provides evidence of a genetic risk for development of HAI. Despite best evidenced based practices some patients will develop HAI. Strict aseptic technique is essential to preventing infection. In addition to eliminating invasive devices as quickly as possible, patients with a high severity of illness may need to be isolated to lower their risk. Early administration of antibiotics not only provides prompt treatment for the initial infection but also lowers risk for subsequent infections.

–  –  –

CHAPTER 1. INTRODUCTION

Overview

Specific Aims

Significance

Conceptual Model

Definition of Terms

Elements of Sepsis

Elements of Severity of Illness

Elements of Predisposing Factors

Elements of Inflammatory Response

Health Care Associated Infections

Assumptions

Potential Limitations

CHAPTER 2. BACKGROUND

Background and Significance

HAI Incidence and Infection Patterns

Antimicrobial Resistance

Risk Factors for Developing HAI

Role of the ICU Environment and HAI

Severity of Illness

Invasive Devices

Systemic Inflammatory Response Syndrome

Cytokines

HAI Risk Posed by the Inflammatory Response

Rationale for Selecting IL-6 and IL-10

Sepsis Polymorphisms

Cytokine Gene SNPs for IL-6 and IL-10

HapMap Data for Genotypes

Selection of Exclusion Criteria

Preliminary Studies

CHAPTER 3. METHODS

Research Design

Study Population

Inclusion Criteria

Exclusion Criteria

Procedures

Summary of Procedures

Screening

Informed Consent

vii Data Collection

Reliability and Validity of Common ICU Measures

Data Entry

Measurements

Health Care Associated Infections

Invasive Devices

Specimen Processing and Analysis

Plasma Processing

Cytokine Analysis

Reliability and Validity of Cytokine Measures

Buccal Swab Collection for DNA

DNA Extraction

DNA Analysis

Statistical Analysis

Aim 1

Aim 2

Aim 3

CHAPTER 4. RESULTS

Recruitment

Demographics and Baseline Infections

Description of First Health Care Associated Infection

Differences in Variables among Those Who Did and Did Not Develop HAI...... 45 Differences in Variables by Pro- and Anti-inflammatory Cytokine Quartiles among Those Who Did and Did Not Develop HAI

Cytokine and Genotype Measurements

Genotype Allele Frequencies

Genotype Comparisons to HapMap 3 Reference Population

Baseline Cytokine Levels by Genotype and Haplotypes

Aim 1

Aim 2

Aim 3

CHAPTER 5. DISCUSSION

Major Findings

Baseline Infections

First Health Care Associate Infection

Aim 1

Aim 2

Genotye and Cytokine Level

Genotype and Development of HAI

Aim 3

Strengths

Limitations

Implications

–  –  –

LIST OF REFERENCES

APPENDIX A. VETERAN’S ADMINISTRATION MEDICAL CENTER

INSTITUTIONAL REVIEW BOARD INITIAL

APPROVAL

APPENDIX B. VETERAN’S ADMINISTRATION RESEARCH AND

DEVELOPMENT COMMITTEE ANNUAL REVIEW

APPENDIX C. THE UNIVERSITY OF TENNESSEE HEALTH SCIENCE

CENTER INSTITUTIONAL REVIEW BOARD INITIAL

APPROVAL

APPENDIX D. VETERAN’S ADMINISTRATION RESEARCH

CONSENT FORM

APPENDIX E. DATA COLLECTION FORMS

VITA

–  –  –

Table 2-1. Summary of Cytokine Function.

Table 2-2. Selected Cytokine Polymorphism Investigated in Sepsis.

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

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

Table 3-1. Study Procedures.

Table 3-2. SNP Primer and Reporter Details for Genotyping.

Table 4-1. Demographic and Clinical Characteristics

Table 4-2. Baseline Infection Findings at ICU Admission.

Table 4-3. Most Common Baseline Micro-organisms.

Table 4-4. Description of First Health Care Associated Infection.

Table 4-5. First HAI Micro-organisms (Ranked).

Table 4-6. Differences in Variables among Those Who Did and Did Not Develop Health Care Associated Infections.

Table 4-7. Differences in Variables Pro- and Anti-inflammatory Cytokine Quartiles.

Table 4-8. RS1800795 Genotype and Allele Frequencies.

Table 4-9. RS1900896 Genotype and Allele Frequencies.

Table 4-10. Genotype Comparisons of IL-6 and IL-10 SNPs among Sepsis and HapMap Reference Population.

Table 4-11. Range of Plasma IL6 and IL10 Levels.

Table 4-12. Median and Inter-quartile Range of Pro- and Anti-Inflammatory Cytokine Levels by Genotypes.

Table 4-13. Comparison of Cytokine Levels among Subjects Developing HAI..........63

–  –  –

Table 4-15. Cytokine levels by Genotype.

Table 4-16. Univariate Cox Regression Hazard Ratios for Development of HAI.

Table 4-17. Final Multivariate Cox Regression Model.

–  –  –

Figure 1-1. Development of Health Care Associated Infections in Sepsis.

Figure 2-1. Promoter SNP Locations.

Figure 4-1. Subject Recruitment.

Figure 4-2. Monthly Subject Recruitment.

Figure 4-3. Box Plot of Plasma IL-6 levels by IL-6 Genotypes Pre and Post Log Transformation.

Figure 4-4. Box Plot of Plasma IL-10 levels by IL-10 Genotypes Pre and Post Log Transformation.

Figure 4-5. Box Plot of Plasma IL-6:IL10 ratios by IL-16 Genotypes Pre and Post Log Transformation.

Figure 4-6. Box Plot of Plasma IL-6:IL10 ratios by IL-10 Genotypes Pre and Post Log Transformation.

Figure 4-7. Log Plasma Cytokine Levels by Genotype.

–  –  –

A

APACHE

BAL

BMI

C

CAP

CRP

DNA

G

HAI

HCAP

IDSA

IL-1β

IL-1ra

IL-10

IL-6

LAR

MIF

MODS

MRC

NCBI

NNIS

–  –  –

PIRO

SIRS

SNP

SOFA

T

TLR

TNF-α

UTI

VAP

WBC

–  –  –



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