The Role of Exogenous Reinfection in Patients with Recurrent TB Disease in the United States Pubblico

Abstract

Purpose. Traditionally, recurrent tuberculosis (TB) has been assumed to result from endogenous reactivation. Genotyping now allows us to determine how much of recurrence is actually due to exogenous reinfection. To determine the extent of and to better understand factors leading to reinfection rather than reactivation, we analyzed patients in the United States with two episodes of TB disease during 1993 to 2011.
Methods. The study population was drawn from all TB cases in the 50 states, Puerto Rico, and the District of Columbia, as reported of June 25, 2012. We identified recurrent cases by matching on date of birth, sex, race, country of origin, state, and year of first episode. Genotyping was used to distinguish between reinfection and reactivation. Selection required time from treatment completion in first episode be ≥12 months before the start of second episode. To statistically evaluate the effects of predictors on reinfection, a logistic regression model was fit.
Results. Among patients with recurrent TB who completed treatment during their first episode, 136 patients were identified, involving 116 reactivations and 20 reinfections. Reinfection occurred in 15% of the population with recurrent TB. Three factors were statistically significant for reinfection after adjustment, including being black or Hispanic (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.1-17.2), living ≤12 years in the United States (OR 3.5, 95% CI 1.0-11.9), and having received treatment exclusively by directly observed therapy (DOT) during first episode (OR 4.8, 95% CI 1.2-19.8).
Conclusions. In persons who experience two episodes of TB, genotyping evidence suggests that the majority of second episodes are reactivation of the first episode. However, minorities, those more recently immigrated to the United States, and those with more rigorous treatment regimens during first episodes have a greater risk for exogenous reinfection. This suggests that these populations are being successfully treated for TB, but other risk factors for recent transmission increase their risk of reinfection. Public health interventions should continue to focus on these populations and their areas of residence, work, and recreation for evidence of recent TB transmission to prevent further and future spread of TB.

Table of Contents

Chapter I: Literature Review....................................................................................... 1 Section 1: Overall Epidemiology of Tuberculosis.............................................................. 1 1. What is Tuberculosis............................................................................................. 1 2. Signs and Symptoms............................................................................................. 1 3. Transmission....................................................................................................... 2 4. TB Infection and Disease....................................................................................... 2 5. Detection of TB................................................................................................... 3 6. Treatment.......................................................................................................... 5 7. Global TB Prevalence............................................................................................ 6 Section 2: Tuberculosis in the United States................................................................ 7 1. Incidence and Decline.......................................................................................... 7 2. High-Risk Populations........................................................................................... 8 3. CDC and TB Reporting......................................................................................... 10 Section 3: Second Episodes of Tuberculosis Disease..................................................... 11 1. What is Recurrence?........................................................................................... 11 2. Risk Factors for Recurrence.................................................................................. 13 3. High-Incidence Characteristics.............................................................................. 15 4. Low-Incidence Characteristics.............................................................................. 16 5. Immigration....................................................................................................... 17 Section 4: Genotyping............................................................................................ 18 1. Definition and Uses............................................................................................. 18 2. Typing Methods................................................................................................. 19 3. Strain Discrimination........................................................................................... 21 4. National Tuberculosis Genotyping and Surveillance Network........................................ 22 Section 5: Immunology........................................................................................... 23 1. Why reinfection is Possible................................................................................... 23 2. Protective and Partial Immunity............................................................................ 24 3. The Effects of First Infection Strain Type on Second Infection Strain Type.................. 26 4. Strain Virulence and Prevalence........................................................................... 26 5. Mixed Infections................................................................................................ 28 Section 6: Treatment Implications............................................................................ 29 1. Development of Drug Resistance........................................................................... 29 2. Treatment Choices............................................................................................. 29 3. Vaccine Development......................................................................................... 31 Chapter II: Manuscript........................................................................................... 33 A. Title, Authors, Abstract...................................................................................... 33 B. Introduction...................................................................................................... 34 C. Methods........................................................................................................... 36 Data Source and Study Population............................................................................ 36 Genotyping........................................................................................................... 37 Analysis............................................................................................................... 38 Ethical Approval.................................................................................................... 40

D. Results............................................................................................................ 40

Participants......................................................................................................... 40 Reinfection versus Reactivation............................................................................... 41 Multivariable Analysis............................................................................................. 42 Unrestricted Recurrent Population Comparison............................................................ 42 E. Discussion....................................................................................................... 43 Limitations.......................................................................................................... 46 Conclusions......................................................................................................... 47 References.......................................................................................................... 48 Tables................................................................................................................ 57 Table 1a. Demographic characteristics of patients with two episodes of TB, among those completing treatment during first episode, in the United States, 1993-2011..................... 57 Table 1b. Clinical and treatment characteristics of patients with two episodes of TB, among those completing treatment during first episode, in the United States, 1993-2011... 59 Table 2a. Demographic characteristics of patients with two episodes of tuberculosis in the United States, 1993-2011...................................................................................... 61 Table 2b. Clinical and treatment characteristics of patients with two episodes of tuberculosis in the United States, 1993-2011............................................................. 63 Table 3. Predictors of tuberculosis recurrence among 136 patients completing treatment during the first episode. Bivariate and multivariate analysis. United States, 1993-2011....... 65 Figures................................................................................................................ 66 Figure 1. Description of the study cohort................................................................... 66 Figure 2. Distribution of years living in the United States at second episode among patients with recurrent TB completing treatment in first episode, 1993-2011.................... 67 Chapter III: Public Health Implications and Future Directions.......................................... 68 Appendices.......................................................................................................... 70 Appendix A: IRB Approval........................................................................................ 70 Appendix B: Individual Variable Tables....................................................................... 71 Appendix C: Models............................................................................................... 91 Appendix D: SAS code.......................................................................................... 100 Matching Algorithm............................................................................................... 100 Data Cleaning and New Variable Creation.................................................................. 103 Data Analysis...................................................................................................... 118

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School	Rollins School of Public Health
Department	Epidemiology
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Parola chiave	Genotyping Tuberculosis Reactivation Reinfection Recurrence
Committee Chair / Thesis Advisor	Gandhi, Neel R, Emory University
Committee Members	Haddad, Maryam B, Emory University
Partnering Agencies	CDC

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