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Association Between Diabetes and Infection by © Waseem Abu-Ashour Association Between Diabetes And Infection by © Waseem Abu-Ashour A Thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Masters In Science Of Pharmacy School Of Pharmacy Memorial University of Newfoundland May, 2016 St. John’s Newfoundland and Labrador ABSTRACT Background: The objective of the study was to assess the association between diabetes and infection. Methods: A systematic review and meta-analysis was conducted to summarize and quantify the association between diabetes and the risk of infections in the existing literature. Second, a cohort study was done to estimate the association between diabetes and infections occurring in primary care. Results: The systematic review and meta-analysis demonstrated that diabetes is associated with an increased risk of infection. Results were generally consistent across types of infections. Findings from the cohort study suggest that patients with diabetes have a small increased risk of developing certain infections compared to patients without diabetes in primary care. Conclusion: Diabetes is associated with an increased risk of infections. The relationship varies according to type of infection present. However, more research is needed to determine the implications of patient characteristics such as BMI and glycemic control on the risk of infections. ii ACKNOWLEDGEMENTS I would first like to thank my supervisor Dr. John-Michael Gamble of the School of Pharmacy here at Memorial University of Newfoundland. The door to Dr. Gamble’s office was always open whenever I ran into a trouble or had a question about my research or writing. He consistently allowed this paper to be my own work, but steered me in the right the direction whenever he thought I needed it. I would also like to thank my supervisory committee who were involved in my research project: Dr. Laurie Twells of School of Pharmacy/Faculty of Medicine, and Dr. James Valcour of Faculty of Medicine here at Memorial University of Newfoundland. Without their guidance and input, this project could not have been successfully conducted. Finally, I must express my very profound gratitude to my parents Dr. Mohammed Abu- Ashour and Mrs. Heyam Abu-Ashour for providing me with unfailing support and continuous encouragement throughout my years of study and through the process of researching and writing this thesis. I would also like to mention my sisters for their continuing support; Wesam, Raneem, Salam, Leen and Rand. This accomplishment would not have been possible without all of them. Thank you. Waseem Abu-Ashour. iii Table of Contents Abstract.…………………………………………………………………………………...ii Acknowledgements.………………………………………………………………………iii Table of Contents…………………………………………………………………………iv List of Tables……………………………………………………………………………...vi List of Figures…………………………………………………………………………...viii List of Symbols, Nomenclatures and Abbreviations……………………………………...ix List of Appendices………………………………………………………………………..xi Chapter 1: Introduction……………………………………………………………………1 1.1 Background……………………………………………………………………1 1.2 Objectives…………………………………………………………………….11 References………………………………………………………………………..14 Chapter 2: Diabetes and the Association of Infection: A Systematic Review and Meta- Analysis of Observational Studies……………………………………………………….26 2.1 Introduction…………………………………………………………………..26 2.2 Methods………………………………………………………………………28 2.3 Results………………………………………………………………………..32 2.4 Discussion……………………………………………………………………37 2.5 Conclusion……………………………………………………………………41 References………………………………………………………………………..42 Chapter 3: Diabetes and the Occurrence of Infection in Primary Care: A Matched Cohort Study………………………...............................................................................................70 iv 3.1 Introduction…………………………………………………………………..70 3.2 Methods………………………………………………………………………72 3.3 Results………………………………………………………………………..76 3.4 Discussion……………………………………………………………………79 3.5 Conclusion……………………………………………………………………84 References………………………………………………………………………..85 Chapter 4: Summary …………………………………………………………………...104 4.1 Bradford Hill Considerations……………………………………………….105 4.2 Research and Clinical Implications…………………………………………110 4.3 Conclusion…………………………………………………………………..112 References………………………………………………………………………113 v List of Tables Table 2.1: Study Characteristics of Observational Studies Evaluating the Association Between Diabetes and Infection………………………………………………………….51 Table 2.2: Reported Infections in Included Studies ……………………………………..55 Table 2.3: Skin and Soft Tissue Infections……………………………………………….62 Table 2.4: Respiratory Tract Infections…………………………………………………..64 Table 2.5: Genitourinary Infections……………………………………………………...65 Table 2.6: Blood Infections………………………………………………………………66 Table 2.7: Viral Infections………………………………………………………………..67 Table 2.8: Head and Neck Infections…………………………………………………….67 Table 2.9: Gastrointestinal Infections……………………………………………………68 Table 2.10: Unspecified Infections………………………………………………………68 Table 3.1: Baseline Characteristics for 12,845 Patients With and Without Diabetes Over 4-year Period……………………………………………………………………………..96 Table 3.2: Proportion of New Infections in Patients with and without Diabetes Over 2 Follow-up Periods ……………………………………………………………………….98 Table 3.3: New Infections Per 100 Person-Years in Patients With and Without Diabetes Over 2 Follow-up Periods ……………………………………………………………...100 Table 3.4: Odds Ratio (OR) Between Diabetes and Infection: Crude and Covariate- Adjusted Results ……………………………………………………………………….101 Table 3.5: Odds Ratio (OR) Between Diabetes and Infection Over 1-Year Period: Crude and Covariate-Adjusted Results ……..…………………………………………………102 vi Table 3.6: Odds Ratio (OR) Between Diabetes and Any Infection Recurrence: Crude and Covariate-Adjusted Results …………………….............................................................103 vii List of Figures Figure 2.1: Study Selection Process……………………………………………………...50 Figure 2.2 (A): Cohort Studies Crude Results Odds Ratio (OR) by Infection Type…….58 Figure 2.2 (B): Cohort Studies Adjusted Results Odds Ratio (OR) by Infection Type….59 Figure 2.2 (C): Case-Control Studies Crude Results Odds Ratio (OR) by Infection Type………………………………………………………………………………………60 Figure 2.2 (D): Case-Control Studies Adjusted Results Odds Ratio (OR) by Infection Type………………………………………………………………………………………61 viii List of Symbols, Nomenclature or Abbreviations aOR: Adjusted Odds Ratio CCS: Case-Control Study CI: Confidence Interval cOR: Crude Odds Ratio CPCSSN: Canadian Primary Care Sentinel Surveillance Network CS: Cohort study EMR: Electronic Medical Record GI: Gastrointestinal GU: Genitourinary H&N: Head and Neck HIV: Human Immunodeficiency Virus I2: I-squared ICD-9: International Classification Disease IPA: International Pharmaceutical abstracts IRR: Incidence Rate Ratio MeSH: Medical Subject Heading MOOSE: Meta-analysis in Observational Studies in Epidemiology NL-CPCSSN: Newfoundland and Labrador Canadian Primary Care Sentinel Surveillance Network NOS: Newcastle-Ottawa Scale PRISMA : Preferred Reporting Items for Systematic Reviews and Meta-analysis. ix PY: Person-Year RTI: Respiratory Tract Infection SD: Standard Deviation SSTI: Skin and Soft Tissue Infection x List of Appendices Appendix 2.A: Search Strategy ………………………………………………………...124 Appendix 2.B: Individual Study Characteristics ……………………………………….131 Appendix 2.C: Publication Bias Funnel Plots (1-8).……………………………………139 Appendix 3.A: Exposure and Outcome Case Definitions………………………………147 Appendix 3.B: Diagnostic Codes for Exclusions……………………………………….150 Appendix 3.C: Timeline for Subject Recruitment and Follow-up ……………………..151 Appendix 3.D: Case Definitions for Potential Confounders and Effect Modifiers …….152 Appendix 3.E: Odds Ratio (OR) of All Covariates for All Types of Infection………...155 Appendix 3.F: Odds Ratio (OR) of All Covariates for All Types of Infection 1-Year Period……………………………………………………………………………………171 xi Chapter 1 Introduction 1.1 Background: 1.1.1 Burden of Diabetes Mellitus: Diabetes mellitus is a serious chronic condition with potentially devastating complications that affects all age groups worldwide. In the year 2015 more than 415 million people were diagnosed with diabetes mellitus globally. According to the International Diabetes Federation (IDF) this number is expected to rise to more than 640 million people by the year 2040 (1). Canada is one of the countries that will be significantly affected by this change. As of 2014, the estimated prevalence of diabetes in Canada was 6.7% of the population reflecting over 2 million Canadians living with diabetes (2). Diabetes and its complications increase costs and service pressures on the healthcare system. Among adults aged 20 to 49 years, those who had diabetes were 2 to 3 times more likely to see a family physician or a specialist (2). Also, people with diabetes were 3 1 times more likely to require hospital admission in the preceding year with longer lengths of stay compared to those without diabetes (2). People with diabetes are over 3 times more likely to be hospitalized with cardiovascular disease, 12 times more likely to be hospitalized with end stage renal disease(ESRD) and over 20 times more likely to be hospitalized for a nontraumatic lower limb amputation compared to the general population (2). Obesity, hypertension, and dyslipidemia are the most commonly distinctive comorbidities associated with diabetes. However, there are other conditions found at higher rates in people with diabetes; depression, obstructive sleep apnea, fatty liver disease, cancer, fractures, cognitive impairment,
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