LSHTM Research Online Forbes, HJ; (2016) Understanding risk factors for herpes zoster and postherpetic neuralgia in UK primary care: investigations to inform vaccine policy. PhD thesis, London School of Hygiene & Tropical Medicine. DOI: https://doi.org/10.17037/PUBS.03141180 Downloaded from: https://researchonline.lshtm.ac.uk/id/eprint/3141180/ DOI: https://doi.org/10.17037/PUBS.03141180 Usage Guidelines: Please refer to usage guidelines at https://researchonline.lshtm.ac.uk/policies.html or alternatively contact [email protected]. Available under license. To note, 3rd party material is not necessarily covered under this li- cense: Copyright the author(s) honline.lshtm.ac.ukhttps://researc Understanding risk factors for herpes zoster and postherpetic neuralgia in UK primary care: investigations to inform vaccine policy Harriet Forbes Thesis submitted in accordance with the requirements for the degree of Doctor of Philosophy May 2016 Department of Non-Communicable Disease Epidemiology Faculty of Epidemiology and Population Health London School of Hygiene & Tropical Medicine University of London Research group affiliation: Electronic Health Records Group Funded by the National Institute of Health Research 1 Thesis abstract Background: Herpes zoster affects millions of people worldwide each year and many go on to suffer long-term pain, called postherpetic neuralgia (PHN). As zoster is common and PHN is difficult to treat, preventing zoster through vaccination is important. This thesis aims to better understand risk factors for zoster and PHN, in order to inform vaccination policy. Methods: Three large observational studies were carried out using primary care data from the UK Clinical Practice Research Datalink and linked secondary care data from the Hospital Episodes Statistics. First, a matched case-control study quantified the effects of possible risk factors for zoster and explored whether their effects differed by age group. Second, a descriptive study looked at antiviral prescription patterns and patient characteristics associated with antiviral receipt after zoster diagnosis. Third, a cohort study assessed risk factors for PHN and investigated whether their effects were modified by antiviral use. Results: The case-control study of zoster risk factors included 144,959 zoster patients and 549,336 controls and found an increased risk of zoster among patients with rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma, chronic kidney disease, depression and type 1 diabetes; odds ratios ranged from 1.14 to 1.72. In general, the relative effects of these risk factors on zoster decreased with increasing age. In the descriptive study of antiviral use, of 142,216 zoster cases, only 58.1% received an antiviral prescription at zoster diagnosis. Antivirals were even under-prescribed among the immunosuppressed and older individuals, for whom guidelines recommend routine treatment. The cohort study of PHN risk factors identified 119,413 zoster patients, 5.8% of whom developed PHN. An increased risk of PHN was found among patients with rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma, depression, type 2 diabetes, lower socioeconomic status, smoking and under- or overweight; odds ratios ranged from 1.13-1.82. Antiviral use was not associated with PHN risk overall. The zoster case-control and PHN cohort study showed that patients with severely immunosuppressive conditions were at greatest risk of both zoster and PHN. Conclusions: A number of patient characteristics and comorbidities were associated with increased zoster and PHN risks. Patients at highest risk of zoster and PHN are those of older age and those with immunosuppression; currently, patients with immunosuppression are not eligible for vaccination, highlighting a need for alternative risk reduction strategies in this group. Low antiviral use at zoster diagnosis suggests treatment guidelines be revised to encourage greater use, especially among the immunosuppressed and older individuals who are recommended, but not routinely given, antivirals. Research on the cost-effectiveness of vaccinating patients with specific risk factors is needed. 3 Acknowledgements Thank you to my supervisors, Sinéad Langan and Krishnan Bhaskaran, for their guidance and encouragement throughout. Thanks also to Sara Thomas, Liam Smeeth and Tim Clayton, for being part of my advisory committee. I would also like to thank Caroline Minassian, Helen McDonald, Jenni Quint and CALIBER for providing previously developed code lists, from which I was able to work from. 4 Role of the candidate, ethics and funding The candidate was employed under an NIHR Clinician Scientist fellowship awarded to Sinéad Langan entitled, “The natural history and management of herpes zoster: the role of moderate immunosuppression from common diseases”. The research aims and objectives of this thesis grew from this fellowship, and from discussion between the candidate and supervisors. The candidate conceptualised the research and designed the studies, with input from supervisors. The candidate was responsible for all data management and analysis. Regarding the research papers included in the thesis, the candidate did all the analysis and wrote the initial draft for all papers, and incorporated comments from co-authors in an iterative process. This project was approved by the London School of Hygiene and Tropical Medicine Ethics Committee. The scientific protocol (included in full in appendix I) was by approved the Independent Scientific Advisory Committee for MHRA Database Research in April 2011, and further amendments were approved in May 2012 and April 2014. This project was funded by the National Institute of Health Research, specifically an NIHR Clinician Scientist Fellowship (to Doctor Langan, grant number: NIHR/CS/010/014).The work was carried out independently of the funding bodies. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the UK Department of Health. 5 Table of contents Candidate declaration ......................................................................................................... 1 Thesis abstract ................................................................................................................. 3 Acknowledgements ............................................................................................................. 4 Role of the candidate, ethics and funding ............................................................................ 5 List of tables ................................................................................................................. 8 List of figures ............................................................................................................... 10 Abbreviations ............................................................................................................... 11 Chapter 1: Introduction ............................................................................................ 12 1.1. Introducing herpes zoster and postherpetic neuralgia .............................................. 12 1.2. Aim, rationale and research questions ....................................................................... 16 1.3. Outline of thesis .......................................................................................................... 17 1.4. Chapter summary........................................................................................................ 19 Chapter 2: Epidemiology and prevention of herpes zoster: literature review ............. 20 2.1. Introduction ................................................................................................................ 20 2.2. Published paper .......................................................................................................... 21 2.3. Risk factors for zoster: 2016 literature review update ............................................... 33 2.4. Chapter summary........................................................................................................ 38 Chapter 3: Data sources and variable definitions ....................................................... 39 3.1. Data sources ................................................................................................................ 39 3.2. Creating code lists ....................................................................................................... 44 3.3. Outcome definitions ................................................................................................... 45 3.4. Potential explanatory variables .................................................................................. 55 3.5. Chapter summary........................................................................................................ 68 Chapter 4: Quantification of risk factors for zoster: population based case-control study …………………… ...................................................................................................... 69 4.1. Introduction ................................................................................................................ 69 4.2. Published paper .......................................................................................................... 70 4.3. Published appendices ................................................................................................. 85 4.4. Additional methods: selecting controls ...................................................................... 93 4.5. Additional results: body mass index, smoking and alcohol status ............................. 96 4.6. Additional biological evidence indicating impaired cell-mediated immunity associated with the exposures of interest ............................................................................................... 98 4.7. Chapter summary...................................................................................................... 101 Chapter 5: Prescription of antiviral therapy after herpes zoster: who receives therapy? …………………… .................................................................................................... 102 5.1. Introduction .............................................................................................................. 102 5.2. Published paper ........................................................................................................ 103 5.3. Chapter summary...................................................................................................... 113 Chapter 6: Systematic review and meta-analysis of risk factors for postherpetic neuralgia …………………… ........................................................................................ 115 6.1. Introduction .............................................................................................................. 115 6.2. Published paper ........................................................................................................ 116 6.3. Published appendices ............................................................................................... 144 6.4. Review of studies assessing risk factors for postherpetic neuralgia within general population samples .............................................................................................................. 163 6.5. Chapter summary...................................................................................................... 172 6 Chapter 7: Quantification of risk factors for postherpetic neuralgia in a cohort of herpes zoster patients ..................................................................................................... 173 7.1. Introduction .............................................................................................................. 173 7.2. Accepted paper ......................................................................................................... 174 7.3. Accepted appendices ................................................................................................ 191 7.4. Chapter summary...................................................................................................... 212 Chapter 8: Summary and conclusions ..................................................................... 213 8.1. Overview of key findings ........................................................................................... 213 8.2. Strengths and weaknesses of using electronic health records for research into zoster and PHN ............................................................................................................................... 219 8.3. Implications for clinical practice ............................................................................... 229 8.4. Implications for further research .............................................................................. 230 8.5. Overall conclusions ................................................................................................... 232 Bibliography …………………… ........................................................................................ 233 Appendix I: Scientific protocol ......................................................................................... 244 Appendix II: Permissions to reprint published articles ...................................................... 259 Appendix III: Section A of published appendices from BMJ zoster case control study ........ 263 Appendix IV: Section e-I of published appendices from Neurology PHN cohort study ........ 270 Appendix V: Code lists ..................................................................................................... 274 7 List of tables Chapter 2, Table 1: Epidemiology and prevention of herpes zoster: unanswered questions ... 25 Chapter 2, Table 2: Overview of how literature published between 2011-2016 on zoster risk factors either corroborates, challenges or extends conclusions from the 2011 review ............ 35 Chapter 3, Table 1: Description and contents of files types available and utilised in this thesis40 Chapter 3, Table 2: Some examples of PHN definitions in previous studies using EHR data .... 48 Chapter 3, Table 3. Medications used to treat PHN ................................................................... 52 Chapter 3, Table 4: Proportion of patients within the zoster cohort, and a similar non-zoster population, receiving a “new” PHN medication 90-180 days following zoster diagnosis .......... 53 Chapter 3, Table 5: PHN definition used in this thesis ............................................................... 55 Chapter 4, Table 1: Vaccine recommendations in United Kingdom, United States, Canada, Australia, and Sweden ................................................................................................................ 79 Chapter 4, Table 2: Description of cases and controls ............................................................... 80 Chapter 4, Table 3: Relative risk of zoster in patients with key risk factors of interest and other covariates .................................................................................................................................... 81 Chapter 4, Table 4: Numbers of cases and controls with various risk factors, stratified by age 82 Chapter 4, Table 5: Association of various risk factors with herpes zoster, stratified by age ... 83 Chapter 4, Table 6: Estimated rate of zoster in patients with various risk factors, by age group .................................................................................................................................................... 84 Chapter 4, Table 7: Relative risk of zoster by BMI category, smoking status and alcohol use .. 96 Chapter 5, Table 1: Proportion of patients prescribed antiviral medication, by patient characteristics ........................................................................................................................... 108 Chapter 5, Table 2: Proportion of patients prescribed antiviral medication, by comorbidities .................................................................................................................................................. 110 Chapter 6, Table 1: Studies assessing vaccine-targetable risk factors for postherpetic neuralgia nested within a population of patients with zoster: study characteristics............................... 123 Chapter 6, Table 2: Association between PHN and various risk factors (defined as either vaccine-targetable or clinical features of the acute zoster episode): risk factors, adjusted effect measure and 95% confidence interval (CI) by study................................................................. 131 Chapter 6, Table 3: Assessment of bias for individual studies ................................................. 140 Chapter 6, Table A1: Table of 97 studies excluded after full-text review ................................ 147 Chapter 6, Table A2: Sub group meta-analyses to identify causes of heterogeneity for effect of age and gender on PHN ............................................................................................................ 154 Chapter 6, Table A3: Association between PHN and various risk factors: risk factors, adjusted effect measure and 95% confidence interval by study ............................................................. 155 Chapter 6, Table A4: Assessment of bias: detailed notes ........................................................ 158 Chapter 6, Table 4: Studies assessing risk factors for PHN within a general population sample: study characteristics ................................................................................................................. 169 Chapter 6, Table 5: Association between PHN and various risk factors within a general population sample: risk factors, adjusted effect measure and 95% confidence interval by study. .................................................................................................................................................. 170 Chapter 6, Table 6: Assessment of bias in individual studies set within the general population .................................................................................................................................................. 171 Chapter 7, Table 1: Postherpetic neuralgia classifications ...................................................... 187 Chapter 7, Table 2: Baseline characteristics of 119413 eligible zoster cases and the proportion developing PHN ......................................................................................................................... 188 Chapter 7, Table 3: Unadjusted and adjusted associations between postherpetic neuralgia and demographic risk factors, comorbidities and health behaviours ............................................. 189 Chapter 7, Table e-1: Relative risk of PHN in patients with risk factors of interest stratified by age of diagnosis, about 70 years ............................................................................................... 201 Chapter 7, Table e-2: Relative risk of PHN in patients with risk factors of interest stratified by age of diagnosis, about 60 years ............................................................................................... 203 8 Chapter 7, Table e-3: Sensitivity analysis using alternative definitions of PHN ....................... 205 Chapter 7, Table e-4: Relative risk of diagnosed, probable or possible PHN by gender .......... 207 Chapter 7, Table e-5: Association between female gender and PHN, according to different PHN outcome definitions .................................................................................................................. 207 Chapter 7, Table e-6: Estimated mean number of consultations for patients aged 59.4 years (mean age of the cohort) with each risk factor, in the year prior to zoster diagnosis ............. 208 Chapter 7, Table e-7: Relative risk of PHN in patients with various risk factors, using a multiply imputed dataset ........................................................................................................................ 209 Chapter 7, Table e-8: Associations between postherpetic neuralgia and demographic risk factors, comorbidities and health behaviours, stratified by whether a patient received antivirals during acute zoster .................................................................................................... 210 9