Forbes, HJ (2016) Understanding risk factors for herpes zoster and postherpetic neuralgia in UK ...

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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
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DOI: https://doi.org/10.17037/PUBS.03141180
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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
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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.
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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.

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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.

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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
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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

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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
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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

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