Use of Procalcitonin as a Biomarker of Bacterial Infection in Acute Liver Failure and Acute Liver Injury

161 Pages·2017·1.89 MB·English

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VVCCUU SScchhoollaarrss CCoommppaassss
Theses and Dissertations Graduate School
2012
UUssee ooff PPrrooccaallcciittoonniinn aass aa BBiioommaarrkkeerr ooff BBaacctteerriiaall IInnffeeccttiioonn iinn AAccuuttee
LLiivveerr FFaaiilluurree aanndd AAccuuttee LLiivveerr IInnjjuurryy
Jody Balko
Virginia Commonwealth University
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Use of Procalcitonin as a Biomarker of Bacterial Infection in Acute Liver Failure and
Acute Liver Injury

A dissertation submitted in partial fulfillment of the requirements for the degree of
Doctor of Philosophy at Virginia Commonwealth University

by

Jody Anne Balko
Bachelor of Science in Medical Technology, Georgia Southern College, 1979
Master of Medical Science in Clinical Chemistry, Emory University, 1992

Advisor: William J. Korzun, Ph.D.,
Associate Professor
Department of Clinical Laboratory Sciences

Virginia Commonwealth University
Richmond, Virginia
March 27, 2012
ii

ACKNOWLEDGEMENTS

There are many people who have in one way or another guided me to this point.
First, I would like to thank my committee members Dr. William Korzun, Dr. Teresa
Nadder, Dr. Diane Dodd-McCue, Dr. Linda Hynan, and most especially Dr. William Lee.
Thank you, Dr. Lee for giving me the opportunity to work with you on this project and
many others over the years. I would also like to give a special thank you to Dr. Frank H.
Wians, Jr. for giving me the opportunity explore my limits and helping me believe that I
could accomplish this journey.
I especially want to remember my grandparents Ollie Mae and Owen Davis. They
were not here to see this journey but without their love and support, it might never have
begun. They never understood my love of science but encouraged me to keep going as far
as I could. I dedicate this to their memory. Also my father, Bernie Crouse, he started this
journey with me, but missed the end by such a short time.
This adventure would not have been nearly as much “fun” without Cohort 2008 to
share it with. Emily, Kevin, Maribeth, Kate, Jason, Scott, Kristie, Laurie, Ferell, and
Andi – we have shared many of life’s ups and downs together, as well as classes and
comps. There couldn’t have been a better group to travel with.
iii

My thanks for the support of my co-workers – Corron, Nahid, Rehana, Theresa,
Stacey, Sycil, and Paola. Thanks for covering, for putting up with the worry over missed
timelines, and for all of the help you gave me to see this project completed.
I would also like to thank Jim Freeman and the others at Siemens Healthcare in
Tarrytown, NY. Their help and support made the completion of this project much easier
and meant that it was accomplished in as short a time period as possible.
Finally, Wayne Rule, your support through the good times and the bad, made it
possible to finish this journey. I will never be able to thank you enough. Thank You!
iv

TABLE OF CONTENTS

LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vii
LIST OF FIGURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
GLOSSARY OF ABBREVIATIONS AND DEFINITIONS OF TERMS. . . . . . . . . . . . x
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
CHAPTER 1: INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .1
Purpose of This Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Specific Aims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
CHAPTER 2: LITERATURE REVIEW. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Liver Structure and Physiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . 6
Acute Liver Failure and Acute Liver Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Bacterial Infection and Sepsis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
SIRS, Sepsis, Severe Sepsis, and Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . .15
Methods to Identify Bacterial Organisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20
Procalcitonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Procalcitonin Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
PCT as a Biomarker of Bacterial Infection or Sepsis. . . . . . . . . . . . . . . . . . . . .. .28
PCT Use to Guide Antibiotic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36
Procalcitonin and Liver Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
Significance of This Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46
CHAPTER 3: METHODS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47
Research Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47
Specific Aims, Hypotheses, and Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .48
v

Databases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50
Acute Liver Failure Database. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51
Acute Liver Injury Database. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52
Liver Disease Database. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 53
Nucleic Acid, Serum, and Tissue Repository for the Study of Liver
Diseases Database. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 55
Sampling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Specific Aim One. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55
Specific Aim Two. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61
Specific Aim Three. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 62
Testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63
Specimen Procurement and Retrieval. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63
ADVIA Centaur Immunoassay Analyzer Testing. . . . . . . . . . . . . . . . . . . . . . . . .63
Statistical Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .67
CHAPTER FOUR: RESULTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Assay Statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .70
Specific Aim One. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71
Sample Selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .72
Demographic Information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .74
Statistical Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 76
Specific Aim Two. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86
Sample Selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86
Demographic Information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86
Statistical Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 87
Specific Aim Three. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95
Sample Selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95
Demographic Information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .97
Statistical Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
CHAPTER FIVE: DISCUSSION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Overview of the Problem. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Discussion of the Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .105
Specific Aim One. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .106
Specific Aim Two. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112
Specific Aim Three . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .118
vi

Limitations of the Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1 19
Recommendations for Future Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
APPENDIX A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
VITA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
vii

LIST OF TABLES

Table 1: KRYPTOR vs. ADVIA Centaur Assays for SPCTC . . . . . . . . . . . . . . . . . . 29
Table 2: Published Studies of PCT Guided Antibiotic Therapy vs. SOC. . . . . . . . . . . 39
Table 3: Comparison of SPCTC Values in Appropriate and Inappropriate
Antibiotic Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .40
Table 4: SPCTC and Child-Pugh Scores in Patients with Cirrhosis, With and
Without Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . .43
Table 5: SPCTC in Patients with Liver Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44
Table 6: Databases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51
Table 7: Severe Sepsis Signs and Symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 58
Table 8: Categories and Numbers of Subjects Desired for Specific Aim One . . . . . . .61
Table 9: PCT Assay Imprecision. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71
Table 10: Category and Sample Availability of ALF and ALI Subjects. . . . . . . . . . . . .72
Table 11: Number of Subjects Tested for PCT Based Upon Severity Category
and ALF Etiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Table 12: Demographic Information for Patients Based Upon Severity of Illness
Classifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . 75
Table 13: Biodata and Laboratory Values for Patients Based Upon Severity of
Illness Classifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .76
Table 14: Comparison of tSPCTC in Non-Infected Patients to the Published
Reference Value (<0.1 ng/mL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .79
viii

Table 15: Results for post hoc Pairwise Testing Using the Dunn Method . . . . . . . .. . . .79
Table 16: Demographic and Biodata Results Based Upon the Calculated Infection
Cut-off Value of 1.62 ng/mL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . .83
Table 17: Comparison of Median SPCTC Results of Subjects in Specific Aim
One Sorted by Category and Etiologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Table 18: Demographic Information for 34 Patients Analyzed for SPCTC to
Detect Bacterial Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88

Table 19: Demographic Data for All Subjects and Each of the Three Subgroups
on the Day of Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Table 20: Friedman Test for PCT Results for All Samples and Subsets A, B,
and C. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Table 21: Number of Samples Tested by Days and Outcomes. . . . . . . . . . . . . . . . . . . .96
Table 22: Demographic Information Based on Outcomes for Patients with a
Documented Infection on Day of Admission to the ALF or ALI Studies. . . .98

Table 23: Laboratory Values for Patients with a Documented Infection on the
Day of Admission to the ALF or ALI Studies . . . . . . . . . . . . . . . . . . . . . . . .99
Table 24: Change in Medians of SPCTC From Day 1 in TFS and DoT Subjects. . . . .101
Table 25: Summary of Study Hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Table 26: Comparison of SIRS Category SPCTC Results by SIRS Category
Between This Study and Previously Published Results. . . . . . . . . . . . . . . .. . 112