More evidence links herpes zoster (HZ) with vascular disease events.

A new study shows HZ to be an independent risk factor for transient ischemic attack (TIA) and myocardial infarction (MI) in all adults up to 24 years after an acute episode, and for stroke as well, although only among people whose HZ occurred when they were under 40 years of age.

"The messages from this study are that people who are found to have risk factors for vascular disease should be vaccinated to prevent herpes zoster, which in itself is a severe disease, and that people who have herpes zoster may be at increased risk for stroke," said lead study author Judith Breuer, MD, professor, virology, University College, London, United Kingdom (UK).

It's not clear yet whether the vaccine will prevent stroke, "although we think that it might," said Dr. Breuer.

The study is published online January 2 in Neurology. The research was supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre, and Sanofi Pasteur MSD, the European maker of the herpes zoster vaccine.

No Stroke Signal

Researchers used The Health Improvement Network (THIN) primary care database, which includes information on more than 3 million patients and is representative of the UK population. The analysis included 106,601 cases of HZ as well as 213,202 controls (2 for every case) who did not have a record of HZ and were matched for age, sex, and general practice.

To reduce miscoding, the study excluded recurrent HZ, which can be confused with herpes simplex.

After adjustment for sex, age, obesity, smoking status, history of elevated cholesterol, hypertension, diabetes, ischemic heart disease, atrial fibrillation, intermittent arterial claudication, carotid stenosis, and valvular heart disease, the study showed a 15% increased risk for TIA and a 10% increased risk for MI associated with HZ.

TIA itself was a risk factor for stroke, increasing the incidence 7-fold compared with age-matched controls (14.32% vs 2.07%).

However, the analysis showed no significant difference in stroke risk for cases compared with controls.

"We found an association for MI and for TIA, which is a form of stroke, but we didn't find a signal for stroke; it was slightly more common in people who had herpes zoster, but not significantly so," said Dr. Breuer.

Table 1. Risk for Vascular Events With Herpes Zoster, Adjusted for Vascular Risk Factors

Endpoint Adjusted Hazard Ratio (95% Confidence Interval) P Value TIA 1.15 (1.09 - 1.21) <.05 MI 1.10 (1.05 - 1.16) <.05 Stroke 1.02 (0.98 - 1.07) NS NS = not significant.

This lack of statistical association may have been due to the fact that the study looked at events occurring more than a year after the acute HZ episode. Dr. Breuer pointed to another study from Denmark published this past summer on July 17 that looked at the "immediate aftermath" and did find that herpes zoster was a short-term risk factor for stroke, although it looked at stroke and TIA together.

However, stroke, as well as TIA and MI, was significantly increased in those whose HZ occurred when they were younger adults, between ages 18 and 40 years.

Table 2. Risk for Vascular Events With Herpes Zoster Occurring at Ages 18 to 40 Years

Endpoint Adjusted Hazard Ratio (95% Confidence Interval) P Value TIA 2.42 (1.34 - 4.36) <.05 MI 1.49 (1.04 - 2.15) <.05 Stroke 1.74 (1.13 - 2.66) <.05

Predisposing Conditions

Irrespective of age, conditions that predispose to vascular disease, including smoking and obesity, were significantly more common in patients with HZ, although some of this could be due to better recording of risk factors in patients who present with HZ, said the authors.

General practitioners aren't required to specify the location of the HZ for the THIN database. According to the authors, this could explain the 10-fold lower-than-expected percentage of HZ ophthalmicus cases in this study (1.6%) compared with previous UK studies.

Another potential study limitation was that GP recordings of transient neurologic symptoms mimicking TIA may have led to overestimates of the incidence of TIA after HZ occurrence. However, records of TIA in the THIN database mostly reflected typical disease, said the authors.

The prevalence of stroke in this study (2.5%) is higher than in other recent studies in the UK population. The incidence of stroke has decreased by more than 30% in the past 10 years in the UK, partly because of screening initiatives for vascular risk factors in persons older than 45 years. The incidence of stroke has remained unchanged, though, among those aged 45 years or younger, in whom such policies have not been implemented.

The authors offer several potential explanations of how HZ may increase the risk for cerebrovascular disease. It's possible, they write, that the circulating virus is able to infect arterial tissue, particularly when damaged by preexisting risk factors, which could contribute to prolonged inflammation with increased vascular insult.

"We think that the virus reactivates repeatedly and occasionally causes zoster," said Dr. Breuer. "Our hypothesis is that some people are more likely to have reactivation than others, that there's potentially a genetic predisposition or an underlying disease like diabetes, or immunosuppression that may cause reactivation."

Dr. Breuer called the virus–vascular disease link a "vicious cycle." "Having risk factors for vascular disease predisposes you to herpes zoster, and herpes zoster, in turn, adds to your risk of actually having a stroke or a vascular event," she said.

A vaccine that is licensed in the UK for people over age 70 years (and over age 60 in the United States) prevents about 50% of herpes zoster, which in itself "is a bad disease," said Dr. Breuer. "It may be worth considering vaccinating people who are found to have risk factors for stroke or vascular disease — high cholesterol, high blood pressure, diabetes, et cetera — to prevent herpes zoster."

This applies to some younger adults because they, too, can have risk factors for vascular events, she said. Patients presenting with HZ, especially younger patients, should be screened for vascular risk factors, she added.

Be "Mindful"

Reached for a comment, Glenn Graham, MD, PhD, deputy national director for neurology, Department of Veterans Affairs, said the study's most significant finding was the association between herpes zoster and stroke, as well as MI and TIA, in people who had HZ under age 40 years, although this could just be because strokes are so uncommon in this age group.

Dr. Graham found it curious that all but 1 vascular risk factor was significantly more common in patients who had herpes zoster. "I know the authors tried to correct for this, but I find it a little puzzling that every single one of them — hypertension, diabetes, heart disease, cholesterol, smoking, obesity, et cetera — was more common in cases than in controls, and statistically significantly so, with the exception of carotid stenosis."

It's important to be "mindful" that the study is case-controlled, noted Dr. Graham. "It shows a correlation, but doesn't show why this is true, and it can't necessarily definitely prove cause and effect. Of course, you can't go and give people shingles prospectively and see if they go on and have stroke."

Dr. Graham speculated that the cause of the association between herpes zoster and vascular events goes beyond inflammation. "I'm not a virologist, but my guess is that it's more than just a general inflammatory reaction because then you'd see it equivalently in people of different ages. It points to me that it has something to do with the involvement in the vessel itself."

That the zoster vaccine might reduce the risk for vascular events "seems to be a logical and actionable conclusion" of the study, said Dr. Graham. Herpes zoster itself is unpleasant and painful, and it affects quality of life. Reducing vascular risk in terms of TIA and MI "might be an additional reason to be immunized," he said.

However, he added that it will take further research to prove that the vaccine actually does decrease vascular events. "I don't know that we can just assume that, but it's something to think about."

The research was supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre, and Sanofi Pasteur MSD, the European maker of the shingles vaccine. Dr. Breuer has received funding from SPMSD for the VZV Identification Programme, which undertakes genotyping of varicella-zoster virus (VZV) from vaccine adverse events. She also heads the VZV reference laboratory, which has genotyped VZV for Glaxo/SmithKline.

Neurology. Published online January 2, 2014. Abstract