Abstract
Background:
While some systemic infections are associated with Parkinson’s disease (PD), the relationship between herpes zoster (HZ) and PD is unclear.
Objective:
To investigate whether HZ is associated with incident PD risk in a matched cohort study using data from the US Department of Veterans Affairs.
Methods:
We compared the risk of PD between individuals with incident HZ matched to up to 5 individuals without a history of HZ using Cox proportional hazards regression. In sensitivity analyses, we excluded early outcomes.
Results:
Among 198,099 individuals with HZ and 976,660 matched individuals without HZ (median age 67.0 years (IQR 61.4–75.7); 94% male; median follow up 4.2 years (IQR 1.9–6.6)), HZ was not associated with an increased risk of incident PD overall (adjusted HR 0.95, 95% C.I. 0.90–1.01) or in any sensitivity analyses.
Conclusion:
We found no evidence that HZ was associated with increased risk of incident PD in this cohort.
Keywords: Herpes zoster, Parkinson’s disease, matched cohort study, electronic health records
Graphical Abstract
Introduction
The global burden of Parkinson’s disease (PD) is rising rapidly with population growth and ageing1. Neurodegeneration in PD, which is characterised by α-synuclein aggregates (Lewy bodies) leading to loss of midbrain dopaminergic neurones, may occur decades before clinical PD diagnosis2. Its complex aetiology remains poorly understood. Around 22% of PD risk is accounted for by genetic variation3; while associations with several environmental factors have been described, risks of reverse causation, residual confounding and other biases raise concerns about whether these associations are causal4.
Infections have been postulated as triggers of PD for decades5. The strongest epidemiological evidence for a relationship comes from large studies showing a long-term increase in the risk of incident PD with influenza6, influenza/pneumonia7, viral hepatitis7 or any hospitalised infection occurring at least 5 years earlier8. Studies of herpes zoster (HZ), caused by reactivation of the neurotropic varicella zoster virus which is nearly ubiquitous in adult populations, show conflicting results. While two matched cohort studies using the Taiwanese National Health Insurance Database found increases in PD risk after HZ (HR 1.80 (95% C.I. 1.43–2.28)9 and HR 1.17 (95% C.I. 1.10–1.25)10), a nested case-control study using US Medicare claims data showed an inverse association OR 0.88 (95% C.I. 0.85–0.91)11.
We therefore aimed to investigate the association between HZ and incident PD risk in the largest integrated healthcare system in the US, the Department of Veterans Affairs (VA), using a matched cohort study design.
Materials and methods
Data source
The VA provides comprehensive healthcare to ~9 million patients per year at over 1,200 sites of care nationwide, including hospitals, medical centres, and community outpatient clinics. All care within the VA is recorded in an electronic health record (EHR) with daily uploads into the VA Corporate Data Warehouse. Available data include demographics, outpatient and inpatient encounters, diagnoses, laboratory measures, pharmacy fill/refills, smoking and alcohol consumption, and death records.
Study design and population
A matched cohort design was used to compare a cohort of patients with incident HZ with a similar cohort of patients without HZ. Patients entered at the latest of: study start (1 January 2008), 40th birthday, or one year after first VA visit. Patients were excluded if they had a history of HZ, PD, or conditions strongly associated with PD (e.g., Lewy body dementia, secondary Parkinsonism). Eligible patients with incident HZ were matched to up to five eligible patients who had not been diagnosed with HZ on age (within 365 days), sex, race/ethnicity, site of care, and calendar time. Further information on study design and follow up is provided in supplementary information.
Exposure, outcome and covariates
The primary exposure was incident HZ defined as the presence of at least one inpatient or outpatient diagnosis of HZ or acute HZ complications using International Classification of Diseases - Ninth Edition/Tenth Edition (ICD-9/10) codes. We excluded codes indicating chronic complications such as post-herpetic neuralgia as the onset date for HZ episodes defined using only those codes would be unclear. The main outcome was incident PD defined as the presence of at least one inpatient or two outpatient diagnoses using ICD-9/10 codes (ICD-9: 332.0 and ICD-10: G20). Covariates included age, sex, race/ethnicity, body mass index, clinical comorbidities (alcohol use disorder, asthma, autoimmune disease, cardiovascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, diabetes, herpes simplex, hypertension, immunosuppression, liver disease, mood disorders, renal disease, traumatic brain injury), oral corticosteroid use, alcohol consumption, smoking status, and summary measures of comorbidity burden and physiologic frailty. Covariate definitions are provided in the supplementary information. All codelists are published online: https://datacompass.lshtm.ac.uk/id/eprint/2848/.
Statistical analysis
We described cohort characteristics by HZ status as well as characteristics of those with and without missing covariate data. We then computed crude rates of incident PD by HZ status. We employed Cox proportional hazards regression models to estimate associations between HZ and PD. All models used age as the underlying timescale and stratified on matched group thereby accounting for all matching factors. Fully adjusted models additionally included covariates specified above. In secondary analysis, we stratified the HZ group by receipt of antiviral therapy (AVT) (acyclovir, valacyclovir, famcyclovir, foscarnet, amantadine) within 7 days of HZ diagnosis. We additionally explored effect modification by age group and frailty.
Sensitivity analyses
First, we excluded outcomes that occurred within 6, 12, 24 months and 5 years of follow-up to mitigate the potential of reverse causality. Second, we used an expanded definition of PD for the outcome, which additionally included conditions strongly associated with PD (e.g., Lewy body dementia, secondary Parkinsonism). The analysis was conducted using Stata version 17. (StataCorp. 2021).
Results
Demographic and clinical characteristics are summarised in table 1. Among 198,099 patients with incident HZ and 976,660 patients without HZ, distributions of age, sex, and race/ethnicity were similar, although the HZ group had a higher prevalence of some comorbidities, including CVD, hypertension, immunosuppression, mood disorders and auto-immune disease. Patients with any missing data had similar median age and years of follow-up to those with no missing data, although their prevalence of comorbidities was lower (eTable 1).
Table 1.
Baseline characteristics by HZ status
| Characteristic | Individuals without HZ, N (%) | Individuals with HZ, N (%) | ||
|---|---|---|---|---|
| N= 976,660 (83.1) | N=198,099 (16.9) | |||
| Years of follow-up: | ||||
| Mean (SD) | 4.44 | (2.9) | 4.70 | (2.96) |
| Median (25th, 75th ptile) | 4.1 | (1.9,6.6) | 4.5 | (2.2, 6.9) |
| Baseline year: | ||||
| 2008/2009 | 182,593 | (18.7) | 36,664 | (18.5) |
| 2010/2011 | 184,104 | (18.9) | 37,184 | (18.8) |
| 2012/2013 | 225,731 | (23.1) | 46,299 | (23.4) |
| 2014/2015 | 187,214 | (19.2) | 38,346 | (19.4) |
| 2016/2017 | 131,854 | (13.5) | 26,505 | (13.4) |
| 2018 | 65,164 | (6.7) | 13,101 | (6.6) |
| Age at baseline (years): | ||||
| Mean (SD) | 68.14 | (11.0) | 68.17 | (11.0) |
| Median (25th, 75th ptile) | 67.33 | (61.4, 75.7) | 67.36 | (61.5, 75.8) |
| Grouped age: | ||||
| 40-<50 | 55,001 | (5.6) | 11,067 | (5.6) |
| 50-<60 | 146,565 | (15.0) | 29,202 | (14.7) |
| 60-<70 | 386,603 | (39.6) | 78,892 | (39.8) |
| 70-<80 | 231,014 | (23.7) | 46,913 | (23.6) |
| 80+ | 157,477 | (16.1) | 32,025 | (16.2) |
| Gender | ||||
| Men | 918,407 | (94.0) | 185,902 | (93.8) |
| BMI | ||||
| Mean (SD) | 29.60 | (5.9) | 29.46 | (5.9) |
| Median (25th, 75th ptile) | 28.87 | (25.7, 32.7) | 28.72 | (25.5, 32.6) |
| BMI category: | ||||
| Underweight | 8,195 | (0.8) | 2,136 | (1.1) |
| Normal Weight | 161,599 | (16.6) | 39,337 | (19.9) |
| Overweight | 311,580 | (31.9) | 72,003 | (36.4) |
| Obese 1 | 210,901 | (21.6) | 47,968 | (24.2) |
| Obese 2 | 85,733 | (8.8) | 19,116 | (9.7) |
| Obese 3 | 43,721 | (4.5) | 10,045 | (5.1) |
| Missing | 154,931 | (15.9) | 7,494 | (3.8) |
| Smoking status: | ||||
| Never | 292,347 | (29.9) | 61,011 | (30.8) |
| Former | 360,685 | (36.9) | 77,243 | (39.0) |
| Current | 285,915 | (29.3) | 57,500 | (29.0) |
| Missing | 37,713 | (3.9) | 2,345 | (1.2) |
| AUDIT-C category | ||||
| 0 | 436,358 | (44.7) | 105,884 | (53.5) |
| 1–3 | 290,078 | (29.7) | 63,452 | (32.0) |
| 4–7 | 95,270 | (9.8) | 18,972 | (9.6) |
| 8+ | 19,742 | (2.0) | 3,882 | (2.0) |
| Missing | 135,212 | (13.8) | 5,909 | (3.0) |
| Race/ethnicity | ||||
| White | 736,570 | (75.4) | 149,183 | (75.3) |
| Black | 119,376 | (12.2) | 24,091 | (12.2) |
| Hispanic | 49,693 | (5.1) | 10,177 | (5.1) |
| Asian | 5,173 | (0.5) | 1,143 | (0.6) |
| American Indian/Alaska Native | 5,374 | (0.6) | 1,148 | (0.6) |
| Native Hawaiian/Pacific Islander | 6,290 | (0.6) | 1,252 | (0.6) |
| Mixed | 5,727 | (0.6) | 1,275 | (0.6) |
| Unknown | 48,457 | (5.0) | 9,830 | (5.0) |
| Baseline comorbidity | ||||
| Alcohol use disorder | 50,628 | (5.2) | 12,364 | (6.2) |
| Asthma | 25,615 | (2.6) | 7,277 | (3.7) |
| Autoimmune disease | 38,462 | (3.9) | 13,292 | (6.7) |
| Cardiovascular disease | 138,528 | (14.2) | 38,991 | (19.7) |
| Cerebrovascular disease | 72,229 | (7.4) | 19,750 | (10.0) |
| COPD | 101,278 | (10.4) | 29,311 | (14.8) |
| Diabetes | 277,893 | (28.5) | 66,202 | (33.4) |
| HSV | 2,939 | (0.3) | 1,912 | (1.0) |
| Hypertension | 530,500 | (54.3) | 122,734 | (62.0) |
| Immunosuppression | 22,176 | (2.3) | 11,516 | (5.8) |
| Liver disease (MILDLD + MSLD) | 39,965 | (4.1) | 10,624 | (5.4) |
| Mood disorder | 223,234 | (22.9) | 58,467 | (29.5) |
| Renal disease | 76,884 | (7.9) | 22,473 | (11.3) |
| Traumatic brain injury | 2,977 | (0.3) | 923 | (0.5) |
| VACS Index scorea | ||||
| Mean (SD) | 71.1 | (12.2) | 72.0 | (13.2) |
| Median (25th, 75th ptile) | 69.5 | (62.0, 78.9) | 70.2 | (62.1, 80.2) |
| VACS Index score quartiles | ||||
| 1 | 172,844 | (17.7) | 41,517 | (21.0) |
| 2 | 174,142 | (17.8) | 40,161 | (20.3) |
| 3 | 174,492 | (17.9) | 40,976 | (20.7) |
| 4 | 168,979 | (17.3) | 45,973 | (23.2) |
| missing | 286,203 | (29.3) | 29,472 | (14.9) |
| Charlson Comorbidity Index | ||||
| Mean (SD) | 1.3 | (1.7) | 1.9 | (2.1) |
| Median (25th, 75th ptile) | 1 | (0, 2) | 1 | (0, 3) |
| Charlson Comorbidity Index category | ||||
| 0 | 424,814 | (43.5) | 62,579 | (31.6) |
| 1 | 215,922 | (22.1) | 44,801 | (22.6) |
| 2 | 150,594 | (15.4) | 34,408 | (17.4) |
| 3 | 83,019 | (8.5) | 21,110 | (10.7) |
| 4 | 46,158 | (4.7) | 13,271 | (6.7) |
| 5+ | 56,153 | (5.8) | 21,930 | (11.1) |
| Steroid use | ||||
| Used oral corticosteroids | 80,201 | (8.2) | 32,882 | (16.6) |
| Secondary exposure | ||||
| Unexposed | 976,660 | (100.0) | 0 | (0.0) |
| HZ | 0 | (0.0) | 111,457 | (56.3) |
| HZ + AVT | 0 | (0.0) | 86,642 | (43.7) |
During follow-up, 1,779 patients with HZ and 8,214 patients without HZ experienced incident PD. Crude rates per 1000 person-years were 1.91 (95%CI 1.83–2.00) in the HZ group and 1.90 (95%CI 1.86–1.94) among those without HZ. HZ was not associated with incident PD in the main analysis (adjusted HR 0.95 (95% CI 0.90–1.01). In secondary analysis, there was no evidence for a difference in the association with PD by receipt of AVT, HR 0.95, 95% CI 0.89–1.03 for no AVT and HR 0.95, 95% CI 0.87–1.03 for AVT. Findings were similar across sensitivity analyses (table 2). We found no evidence of effect modification by age-group or physiologic frailty (eTable2).
Table 2.
Associations between HZ and Parkinson’s disease
| Type of analysis | N (total) | N (outcome) | HR (95% CI) |
|---|---|---|---|
| Primary analysis | |||
| Adjusted for matching factors onlya | 1,174,759 | 9,993 | 1.01 (0.96–1.06) |
| Adjusted for matching factors onlya among complete cases | 798,338 | 7,032 | 1.00 (0.95–1.06) |
| Fully adjusted modelb among complete cases | 798,338 | 7,032 | 0.95 (0.90–1.01) |
| Secondary analysis | |||
| Fully adjusted modelb among complete cases | |||
| • Unexposed | 798,338 | 7,032 | 1.00 |
| • No AVT | 0.95 (0.89–1.03) | ||
| • AVT | 0.95 (0.87–1.03) | ||
| Sensitivity analysis | |||
| (i) Fully adjusted modelb, excluding outcomes | |||
| • < 6 months | 798,338 | 6,289 | 0.95 (0.90–1.01) |
| • < 12 months | 798,338 | 5,618 | 0.96 (0.90–1.02) |
| • < 24 months | 798,338 | 4,390 | 0.99 (0.92–1.06) |
| • < 5 years | 798,338 | 1,768 | 1.03 (0.92–1.15) |
| (ii) Expanded outcome (Fully adjusted modelb) | 798,058 | 8,487 | 0.94 (0.90–0.99) |
Adjusted for age, sex, race/ethnicity, site of care, and calendar time
Adjusted for all variables in (a) in addition to: Body Mass Index, clinical comorbidities (alcohol use disorder, asthma, autoimmune disease, cardiovascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, diabetes, herpes simplex, hypertension, immunosuppression (including HIV), liver disease, mood disorder, renal disease, traumatic brain injury), oral corticosteroid use, alcohol consumption, smoking status, Charlson Comorbidity Index, and VACS Index
Discussion
We showed no evidence of an increased risk of incident PD after HZ in a large, population-based matched cohort study using data from the US Veterans Health Administration. The null finding was replicated across various sensitivity analyses including introducing lag times of up to 5 years to reduce the risk of reverse causation and broadening the outcome definition to increase sensitivity.
This null finding may be unsurprising given the decades-long nature of neurodegeneration and long prodromal phase of PD12. It seems unlikely that HZ, which typically occurs in later life as cell-mediated immunity declines, would predate the onset of the neurodegenerative process. While HZ has been linked to acute inflammatory and vascular complications13,14, large EHR studies from Europe15–17 do not support an association with other long-term neurodegenerative conditions such as dementia. National studies from Korea on HZ and incident dementia risk show conflicting results18,19, while studies using the Taiwan NHIRD have suggested an association between HZ and both dementia20,21 and PD9,10. Differences in those studies’ findings may reflect differing methodological approaches. For example, the studies of PD risk from Taiwan identified unexposed matches from among those who did not develop HZ at any time during the study period rather than identifying unexposed matches at the diagnosis date of an exposed individual. This approach tends to select healthier individuals as unexposed matches, who may be less likely to develop a neurodegenerative condition. Further methodological research to understand reasons for the differences between our study and previous matched cohorts would be valuable.
Nevertheless, several studies with long-term follow up suggest associations between other clinically-diagnosed systemic infections (influenza6, influenza/pneumonia7, hepatitis7 or any hospital-treated infection8), and incident PD. While none of these studies investigated HZ specifically, they all used measures that could identify HZ (combined herpes simplex and zoster6, chickenpox7, hospital-treated skin infections8) and found no link with PD risk, consistent with our findings. Mechanisms linking systemic infections to incident PD risk may include systemic inflammation with high levels of cytokine production, in which transfer across the blood-brain-barrier leads to microglial activation, neuronal damage and cell death22. Other studies show that infections such as influenza can induce alpha synuclein aggregation in human mesencephalic dopaminergic cells23 and that norovirus infection may lead to alpha synuclein expression in the enteric nervous system24.
Strengths of our study include its large size, real world nature and the US-wide distribution of clinics enables generalizability to Veterans from around the US. While Veterans are majority male and are more likely to have some PD risk factors such as traumatic brain injury than non-Veterans, they represent an important and sizeable population for study. Requiring regular engagement with healthcare helped to optimise recording.
Our study nevertheless had some limitations. While we followed individuals for up to 11 years, the long prodromal phase of PD means that we cannot exclude reverse causation. Our lagged analysis, however, did not suggest any evidence for this. HZ recording in EHRs may be incomplete: although 91% of individuals with HZ typically access healthcare in the US25, those with milder symptoms, recurrent zoster and individuals from some ethnic groups may be less likely to seek medical attention. Any HZ episodes coded only with post-herpetic neuralgia codes would not be captured in our study. This would lead to a small amount of misclassification of HZ status, likely to be non-differential, which would tend to bias results towards the null. PD diagnoses may be misclassified using ICD-9/10 codes. However, a validation study showed that using ICD-9 332.0 assigned at least twice in any VA clinic had high sensitivity (89%) and PPV (79%) but lower specificity (28%) and NPV (46%)26. Our sensitivity analysis using a broader definition of PD was consistent with the main analysis.
We cannot exclude residual confounding by variables not routinely recorded in EHRs such as genetic susceptibility to PD and exposure to pesticides. Our approach may not have fully accounted for time-varying confounders such as BMI measured within 2 years prior to baseline. Other covariates were incompletely recorded, though results from minimally-adjusted models were similar in the full study population and in the subset with complete data available. In addition, lifestyle factors such as smoking and alcohol tend to be well-recorded in Veterans’ data, with AUDIT-C screening routinely integrated into the VA since 200427. Further studies are needed to generalize findings to non-Veteran populations and to women.
In conclusion, we found no evidence that HZ was associated with an increase in incident PD risk in US veterans overall or in any subsets of age-group or frailty, suggesting that HZ is unlikely to play a major role in PD development.
Supplementary Material
Acknowledgements
This work uses data provided by patients and collected by the VA as part of their care and support. The data were extracted and cleaned by the Veterans Aging Cohort Study (VACS; https://medicine.yale.edu/intmed/vacs/). The views and opinions expressed in this manuscript are those of the authors and do not necessarily represent those of the Department of Veterans Affairs or the United States government.
Funding
This work was supported by the National Institute on Alcohol Abuse and Alcoholism (P01-AA029545, U01-AA026224, U24-AA020794, U01-AA020790, U10-AA013566). CWG was supported by Wellcome Intermediate Clinical Fellowship (201440/Z/16/Z) and now holds a Wellcome Career Development Award (225868/Z/22/Z). RSW is supported by a Wellcome Clinical Research Career Development Award (205167/Z/16/Z). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.
Footnotes
Conflicts of interest
The authors declare no conflicts.
Data availability
Due to US Department of Veterans Affairs (VA) regulations and our ethics agreements, the analytic data sets used for this study are not permitted to leave the VA firewall without a data use agreement. This limitation is consistent with other studies based on VA data. However, VA data are made freely available to researchers with an approved VA study protocol. For more information, please visit https://www.virec.research.va.gov or contact the VA Information Resource Center at VIReC@va.gov.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Due to US Department of Veterans Affairs (VA) regulations and our ethics agreements, the analytic data sets used for this study are not permitted to leave the VA firewall without a data use agreement. This limitation is consistent with other studies based on VA data. However, VA data are made freely available to researchers with an approved VA study protocol. For more information, please visit https://www.virec.research.va.gov or contact the VA Information Resource Center at VIReC@va.gov.