Acute Respiratory Infection Among Hospitalized Individuals: Prediction and Prevention of Severe Influenza by Hannah Segaloff A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Epidemiological Science) in the University of Michigan 2019 Doctoral Committee: Assistant Professor Emily T. Martin, Chair Associate Professor Adam S. Lauring Professor Carl F. Marrs Professor Arnold S. Monto Assistant Professor Jon Zelner Hannah E. Segaloff [email protected] ORCID iD: 0000-0003-4716-7468 © Hannah E. Segaloff, 2019 Dedication To my family and my friends, and most of all, to my husband. I couldn’t have done this without all of you. ii Acknowledgements There are so many individuals who have made completion of this dissertation possible and to whom I owe many thanks. First, I would like to thank the chair of my committee, Dr. Emily Martin. From even before I began the doctoral program you provided me with guidance, knowledge and confidence, which was and is invaluable to me. I have experienced so much growth as an epidemiologist and as a person in the past four years, and much of that is due to your mentorship, for which I am grateful. Thank you also to the rest of my dissertation committee, Dr. Arnold Monto, Dr. Jon Zelner, Dr. Adam Lauring, and Dr. Carl Marrs. You all not only provided important advice and guidance, but also had my best interests in mind throughout the process. Thank you, Carl, for being a mentor over the past eight years, it is safe to say that I would not be where I am now without your guidance and direction. I am also grateful for the mentorship of Dr. Mark Katz, who not only has provided direct guidance on the content of this dissertation, but also has helped me grow as an epidemiologist. Thank you to my mentors/colleagues/pseudo-bosses, EJ McSpadden, Dr. Ryan Malosh, and Dr. Josh Petrie. You made me feel like part of the team and you taught me how to ‘lean in’, which was much needed. So much of my confidence now comes from you all pushing me to take a more active and leading role in my research. Thank you to the rest of my colleagues, past and present, of the Martin/Monto research group of whom there are too many to list individually. All of you have made this process possible and enjoyable. Special thanks to Rachel Truscon, Emileigh Johnson, and Bonnie Cheng who did much of the laboratory work included in this dissertation. I am also grateful to my friends and family who have supported me for the past four years. Thank you to my fellow students who have provided advice and commiserated throughout this entire process. I would not have made it through this process without all of the friendly faces and conversations. I am especially thankful to my husband who has stood by my side through this entire process, even when it meant long periods of time apart. I appreciate so much the sacrifices that you have made for me. iii Table of Contents Dedication ............................................................................................................................... ii Acknowledgements ................................................................................................................ iii List of Tables ......................................................................................................................... vii List of Figures ......................................................................................................................... ix List of Abbreviations ................................................................................................................ x Abstract ................................................................................................................................ xii Chapter 1 Introduction ....................................................................................................... 1 1.1 Specific Aims and Hypothesis .................................................................................................. 1 1.2 Background and Significance ................................................................................................... 2 Chapter 2 Influenza Vaccine Effectiveness Against Hospitalization in Fully and Partially Vaccinated Children in Israel; 2015-16, 2016-17, and 2017-18 ................................................ 17 2.1 Author Summary ................................................................................................................... 17 2.2 Abstract ................................................................................................................................ 17 2.3 Introduction .......................................................................................................................... 18 2.4 Methods ............................................................................................................................... 19 2.5 Results .................................................................................................................................. 23 iv 2.6 Discussion ............................................................................................................................. 25 Chapter 3 Influenza Vaccine Effectiveness in the Inpatient Setting; Evaluation of Potential Bias in the Test Negative Design by Use of Alternate Control Groups ..................................... 42 3.1 Author Summary ................................................................................................................... 42 3.2 Abstract ................................................................................................................................ 42 3.3 Introduction .......................................................................................................................... 43 3.4 Methods ............................................................................................................................... 45 3.5 Results .................................................................................................................................. 48 3.6 Discussion ............................................................................................................................. 51 Chapter 4 The Impact of Obesity and Timely Antiviral Administration on Severe Influenza Outcomes Among Hospitalized Adults ................................................................................... 65 4.1 Author Summary ................................................................................................................... 65 4.2 Abstract ................................................................................................................................ 65 4.3 Introduction .......................................................................................................................... 66 4.4 Methods ............................................................................................................................... 68 4.5 Results .................................................................................................................................. 71 4.6 Discussion ............................................................................................................................. 73 Chapter 5 Severe Morbidity Among Hospitalized Adults with Acute Influenza and Other Respiratory Infections; 2014-15 and 2015-16 ......................................................................... 80 5.1 Author Summary ................................................................................................................... 80 5.2 Abstract ................................................................................................................................ 80 5.3 Introduction .......................................................................................................................... 81 5.4 Methods ............................................................................................................................... 83 v 5.5 Results .................................................................................................................................. 86 5.6 Discussion ............................................................................................................................. 88 Chapter 6 Summary and Conclusions ................................................................................ 97 6.1 Summary of Findings ............................................................................................................. 97 6.2 Strength and Limitations ..................................................................................................... 104 6.3 Future Work ........................................................................................................................ 109 6.4 Conclusions ......................................................................................................................... 112 Bibliography ........................................................................................................................ 116 vi List of Tables Table 2.1 ICD9 Codes Used to Define Comorbidity Categories .................................................. 30 Table 2.2 Descriptive Characteristics of Hospitalizations of Children Aged Six Months Through Eight Years Tested for Influenza by RT-PCR, by Influenza Status ...................................... 34 Table 2.3