Introduction

Approximately 15 million people worldwide suffer from a stroke every year leading to five million deaths and an additional 5 million individuals left disabled. Common risk factors for stroke include smoking, atrial fibrillation, hypertension and other cardiovascular factors. Although improved management of modifiable risk factors has reduced the burden of stroke, the total number continues to increase due to an aging population. [1].

In recent years, varicella zoster virus (VZV) has also been identified as a risk factor for stroke. Primary infection with VZV usually manifests as chickenpox during childhood. After primary infection, the virus becomes latent and can reactivate years later as herpes zoster; the risk of herpes zoster increases with age and immunosuppression.[2]–[4] Only two epidemiologic studies have investigated the incidence of stroke in adults after herpes zoster. These studies showed a 31% and 450% increased risk of stroke the first year after herpes zoster and herpes zoster ophthalmicus, respectively. [5], [6] Few studies have focused on the time lag between herpes zoster and the onset of stroke. Most reports have described the onset of neurological symptoms occurring days to months after varicella or herpes zoster, while one review of 30 cases found neurologic symptoms to occur up to 2.5 years after the rash.[7]–[11].

We conducted a nationwide population-based cohort study using the Danish national registers to investigate the risk of stroke/transient ischemic attack (TIA) after receiving systemic antiviral medication for herpes zoster, andto assess the delay between herpes zoster and development of stroke/TIA.

Methods

Results

The cohort consisted of 4,620,980 individuals; 2,278,782 men and 2,342,198 women. We identified 117,926 exposed individuals, of whom 4876 developed a stroke during the follow-up period. A total of 230,341 persons were diagnosed with stroke during 52,862,971 person-years of follow-up.

Figure 1 shows the IRR of stroke amongst exposed compared with non-exposed individuals, by time since exposure in the exposed group. The IRR was particularly high within the first two weeks and remained slightly elevated throughout the first year, after which it decreased. The IRR of developing stroke within the first year of exposure was 1.21 (95% CI 1.14–1.29).

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Figure 1. Incidence rate ratio (IRR) of stroke with 95% confidence intervals in individuals receiving antiviral treatment for herpes zoster by time since treatment compared with individuals with no antiviral treatment in Danish adults 1995–2008.

The 12 dots represent point estimates for days 0 and 1–6; weeks 1 and 2–3; months (m) 1, 2, 3, 4, and 5; and the intervals 6 months to just below 1 year (y), 1 to 4 years, and 5 years or more.

https://doi.org/10.1371/journal.pone.0069156.g001

Table 1 presents the IRRs of stroke by history of antiviral treatment for herpes zoster by sex, age at the time of exposure, and time since exposure. Individuals that had received treatment for herpes zoster had a 2.27 (95% CI 1.83–2.82) fold higher risk of stroke during the first two weeks following treatment when compared to individuals that had no history of herpes zoster treatment. Between two weeks and one year after herpes zoster, the overall risk remained slightly elevated (IRR 1.17, 95% CI 1.09–1.24) but after one year, the overall risk did not appear to be much higher amongst exposed persons when compared with unexposed persons (IRR 1.05, 95% CI 1.02–1.09).

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Table 1. Incidence rate ratio (IRR) of stroke in individuals receiving antiviral treatment for herpes zoster by time since treatment compared with individuals with no history of antiviral treatment in Danish adults 1995–2008.

https://doi.org/10.1371/journal.pone.0069156.t001

Men and women had a similar increased risk within the first two weeks of treatment, (IRR 2.38 vs. 2.19, p = 0.71), between two weeks and one year after treatment (IRR 1.18 vs. 1.15, p = 0.72) and after one year (IRR 1.04 vs. 1.06, p = 0.49). We found an overall increased risk of stroke regardless of age at treatment, but the risk decreased with increasing age, both within the first two weeks of exposure as well as after one year. However, the difference in risks between age groups within the first two weeks was not significant (p = 0.84) whereas the difference between two weeks and one year (p = 0.0002), and after one year were significant (p = 0.002). To further evaluate the multiplicative interaction with age we also estimated the mean rate in the three age groups: <40 years: 2.0 per 10,000 person-years, 40–59 years: 11.8 per 10,000 person-years, and ≥60 years: 30.2 per 10,000 person-years.

We adjusted the overall effect within the first two weeks for the following potential confounders but found no important changes in risk estimates: atrial flutter/fibrillation (IRR 2.23, 95% CI 1.80–2.76), acute myocardial infarction (IRR 2.25, 95% CI 1.81–2.79), treatment with drugs used for atrial flutter/fibrillation (IRR 2.19, CI 1.77–2.72), treatment with antihypertensives (IRR 2.20, 95% CI 1.77–2.73), treatment with drugs used for dyslipidaemia (IRR 2.26, 95% CI 1.82–2.80), cancer (RR 2.26, 95% CI 1.82–2.80), and treatment with immunosuppressive drugs (IRR 2.27, 95% CI 1.83–2.81). The estimates were also adjusted for highest obtained educational level, with no effect on the results. Similarly, adjusting for these potential confounders had no effect on the estimates for the time periods between two weeks and one year, and for more than one year.

To investigate the potential influence of health care-seeking behaviour, parallel analyses were conducted using forearm, femur, and lower leg fractures as outcomes. No markedly increased risk was seen among patients receiving treatment for herpes zoster within the first two weeks after treatment (IRR 1.03, 95% CI 0.79–1.35), between two weeks and one year (IRR 1.08, 1.02–1.14), and after one year (IRR 1.03, 95% CI 1.00–1.05) after having herpes zoster when compared to unexposed persons. These results were not modified by age, sex, or time since having herpes zoster. We investigated the IRRs for the first two weeks, between two weeks and one year, and more than one year after having herpes zoster in herpes zoster patients compared with others in three different age-groups. For individuals under the age of 40, the three IRRs were 0.29 (95% CI 0.04–2.05), 0.83 (95% CI 0.64–1.07) and 0.89 (95% CI 0.79–1.00), for individuals between the age of 40 and 59 they were 0.61 (95% CI 0.25–1.47), 1.12 (95% CI 0.97–1.28) and 1.11 (95% CI 1.04–1.18), and for individuals aged 60 or above they were 1.19 (95% CI 0.89–1.58), 1.10 (95% CI 1.03–1.17) and 1.02 (95% CI 0.98–1.05).

Discussion

This nationwide cohort study found an increased risk of stroke after herpes zoster. This association was particularly pronounced during the first 14 days following herpes zoster and continued to be strong for more than three months. To our knowledge, this study is the largest study to date that examines the association between herpes zoster and stroke, and the first epidemiologic study to examine the time lag between herpes zoster episode and development of stroke in a large cohort.

Our findings are in line with two studies from Taiwan that reported a 31% increased risk of stroke the first year after herpes zoster and a 450% increased risk the first year after herpes zoster ophthalmicus. [5], [6] This study also confirms the short-term effect described in previous case reports and reviews. [7], [8], [11] It expands on previous reports by providing a detailed analysis with respect to time since herpes zoster infection, including an analysis of the long-term risk following infection. The risk was increased by 127% during the first two weeks, 17% between two weeks and one year after herpes zoster, and 5% after one year. The association was observed in both young and old age groups, with the highest increased risk observed in young patients.

The short-term effect may be explained by a productive viral infection that damages and weakens the walls of cerebral arteries, resulting in thrombosis, occlusions, infarctions, aneurysms or haemorrhage; significant changes have been identified on brain imaging and angiograms in patients with stroke occurring after herpes zoster.[3], [6], [9], [14]–[19] The observed association may also be the result of a transient prothrombotic condition caused by the viral infection. [8], [19].

Whilst the observed short term risk was high and may support a causal association, the long-term risk was less evident, with an overall increased risk of 5% after one year. The small increase is close to what was observed for the risk of selected fractures. We did however observe an increased long-term risk of stroke in patients younger than 60 years at the time of diagnosis of herpes zoster, which was not observed for selected fractures. Thus, a long-term effect, if any, is likely primarily to be expected in the younger age-groups. The long term-effect may be explained by a gradual atherosclerotic process induced by inflammation of the vessels caused by infection with herpes zoster. [5] Alternatively, the long-term effect in younger patients may simply be due to their lower age-specific incidence of stroke. We observed that the mean rate difference in younger patients was similar to that of older patients. This suggests that the additional increase in risk is the same regardless of age, but that this increase represents a higher relative increase in the younger age group.

We performed a similar analysis with fractures as an outcome, thereby investigating whether an increased risk of stroke was the result of a particular type of health care-seeking behavior amongst exposed persons. Had all persons receiving acyclovir had an increased tendency for subsequent hospital contact, we would have observed a similar increased risk of fractures. However, this was not the case, as neither the overall short-term risk nor the age-specific estimates for fractures after herpes zoster were as high as those for stroke after herpes zoster.

Our study was subject to several limitations. The use of acyclovir treatment as a proxy for herpes zoster may have resulted in false positive exposures as some people may have received it for herpes simplex. However, a misclassification of this nature would most likely lead to a bias towards the null. We minimized this potential bias by restricting the exposure to individuals that had only received one prescription of the recommended treatment regimen for herpes zoster (a 7-day course of 800mg tablets). By censoring persons who received a second acyclovir prescription, we may have censored persons with prolonged herpes zoster and a possibly greater risk of stroke. However, despite this, our results remained significant. Individuals who experienced VZV reactivation without the presence of the rash (zoster sine herpete), untreated herpes zoster, or a history of herpes zoster before the NRMPS was established would be defined as unexposed in our study; while this would bias estimates towards the null, individuals misclassified for these reasons consitute only a small fraction of the unexposed group. Therefore, this bias would be negligible. We investigated stroke risk in patients treated for herpes zoster; because antiviral treatment might reduce stroke risk conferred by the infection, our results may not apply to untreated herpes zoster. However, a previous study did not find a significant difference in stroke development between patients that had received antiviral treatment and those that had not. [6] We adjusted for a number of important potential confounders, but were unable to account for untreated cardiovascular risk factors, obesity, smoking and family history. In the event of differential prevalence of one or several of these factors in the exposed and unexposed groups, confounding could have been introduced; this could potentially bias results in either direction. However, adjustment for e.g. myocardial infarction, antihypertensive medication use, and use of lipid-lowering drugs had no impact on the main estimate. This argues against cardiovascular risk factors being strong confounders of the association between herpes zoster and stroke. Finally, the date of filling the prescription may not be the precise date of onset of herpes zoster, a misclassification that would underestimate the short-term effect. However, antiviral therapy is recommended within 3 days of disease onset, [20] and the date of filling the prescription is therefore likely close to the date of onset of herpes zoster.

Our study took advantage of the person-identifiable and mandatory registration of demographic and healthcare information in Denmark. It was based on a large cohort consisting of all adults in Denmark during a 14-year period, making selection bias unlikely, and we avoided loss to follow-up by using up-to-date vital status information from the Danish Civil Registration System. As the study was based on three different nationwide registers, it allowed for independent ascertainment of demographic information, exposure (prescription) information and stroke diagnosis, so a significant influence by differential misclassification of the exposure and outcome and by recall bias was avoided.

In conclusion, we found an increased risk of stroke following herpes zoster, that was most pronounced in the first 3 months following the exposure. A long term effect, if any, was only observed for persons who developed herpes zoster at a younger age.