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Neurology Today:
doi: 10.1097/01.NT.0000444232.00461.e5
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Herpes Zoster Identified as Potential Risk Factor for Vascular Disease

Fitzgerald, Susan

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ARTICLE IN BRIEF

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Investigators reported — based on a retrospective study — that herpes zoster (HZ) is an independent risk factor for vascular disease, particularly for stroke, transient ischemic attack, and myocardial infarction in those who had HZ before the age of 40.

Herpes zoster (HZ) could one day be added to the list of risk factors for vascular disease — particularly for stroke, transient ischemic attack (TIA), and myocardial infarction (MI) in affected people younger than 40 — if the findings of a large retrospective, case-control study from the United Kingdom are confirmed by more research.

The study, published online Jan. 2 ahead of the Jan. 21 print issue of Neurology, was based on a retrospective review of medical records for hundreds of thousands of people who were followed for an average of 6.3 years and as long as 24 years after onset of herpes zoster.

“Herpes zoster is an independent risk factor for lifetime transient ischemic attack or myocardial infarction generally, and doubles the risk of stroke, TIA, and MI if it occurs [in people] under the age of 40 years,” said Judith Breuer, MD, the study's lead author and a medical virologist at University College London.

Dr. Breuer told Neurology Today that the study also found that “herpes zoster is increased in those with risk factors for vascular disease.”

The study raises the question of whether getting vaccinated against HZ, commonly known as shingles, could in turn lower a person's risk of vascular disease, but more research is needed to answer that question, the researchers said.

“In the meantime, the vaccine could now be offered to adults with risk factors for vascular disease, irrespective of age, to reduce the associated risk of HZ,” they wrote. “At the same time, screening for vascular risk factors in patients presenting with HZ, especially younger patients in whom intervention may have the most impact, should now be encouraged.”

While reactivation of the latent varicella zoster virus (VZV) typically causes a painful skin rash, neurologic complications can also occur.

“Both ischemic and hemorrhagic strokes have been described following HZ affecting the ophthalmic branch of the trigeminal nerves,” the researchers wrote in their introduction to the study. “In these patients, the virus spreads transaxonally to cerebral arteries via trigeminal and other ganglionic afferents,” they wrote, adding that autopsies have found VZV vasculopathy in patients who suffered a stroke or TIA.

“Similar pathology has also been found in strokes and TIA which follow HZ occurring at non-ophthalmic sites and even in the absence of rash,” the investigators wrote, “raising the possibility that VZV is more widely implicated in the pathogenesis of cerebrovascular disease.”

In a 2010 population-based study published in Neurology, investigators in Taiwan reported a 30-percent increased risk for stroke within a year of acute HZ, and a 4.5-fold increase following herpes zoster ophthalmicus.

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STUDY METHODOLOGY

For this latest study, the UK researchers used a database called THIN (The Health Improvement Network), a primary-care database that contains anonymous demographic, medical and prescription information covering more than three million active patients in the UK. They compared 106,601 HZ cases with 213,202 control cases that were matched for their age at index case, sex, and the general (primary care) practice. Patients and controls younger than 18 and those who had experienced a cardiovascular event (stroke, MI, or TIA) before the index case were excluded. Patients with recurrent HZ were also excluded because that is a rare form of the disease and is often confused with herpes simplex virus, the researchers said. The median age of HZ onset was 59.43 years.

In calculating the risk for vascular disease, the researchers adjusted the data for other vascular risk factors, including a body mass index greater than 30, smoking, elevated cholesterol, and diabetes. Their analysis found that people who had a history of HZ were 1.15 times more likely to have a TIA [95% CI: 1.09-1.21] and 1.10 times more likely to have a myocardial infarction [95% CI: 1.05-1.16]. They were not at heightened risk for stroke. People under the age of 40 who had HZ were 2.42 times more likely to have a stroke [95% CI: 1.34-4.36], 1.49 times more likely to have TIA [95% CI: 1.04-2.15], and 1.74 times more likely to have a MI [95% CI: 1.13-2.66] compared with the controls.

In addition, risk factors for vascular disease were significantly more common in those who had HZ compared with controls, though the researches said this could be due to the fact that there is a better recording of risk factors in people who present at the doctor with HZ. The study found, however, that “subjects under 40 years were significantly less likely to be asked about vascular risk.”

“Overall these data add to the growing body of evidence linking varicella zoster virus, a ubiquitous pathogen which establishes persistent infections in over 95 percent of individuals, to vascular disease,” the researchers wrote. Research has shown the VZV virus can be detected for months in blood and saliva after a person gets HZ, which suggests that even beyond the acute phase of the disease circulating virus could cause inflammation and damage to arteries, particularly in persons already at risk for vascular disease.

“Population studies are now needed to evaluate whether immunization to prevent HZ could also reduce the incidence of vascular events including stroke, TIA, and MI,” the researchers wrote. Also, “more research is needed to understand the pathogenesis of increased HZ in patients with risk factors for vascular disease and to determine the impact of treatment on risk.”

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EXPERTS COMMENT

Several researchers not connected with the study said the research raises interesting questions, but they stopped short of advocating for an expanded use of the shingles vaccine, which in the US is recommended for persons 60 or older.

“The study does not prove cause and effect,” said Barbara Yawn, MD, director of research at Olmsted Medical Center in Rochester, MN, and principal investigator for the Rochester Epidemiology Project.

For example, there could be a common underlying cause for shingles and other events, which might predispose people to an increased risk of stroke.

Dr. Yawn is in the process of launching a study using that database of older Rochester residents to likewise examine whether there is a connection between HZ and a heightened risk for vascular disease.

Don Gilden, MD, Louise Baum professor of neurology at University of Colorado School of Medicine, said the new finding on the association between herpes zoster and vascular disease “was interesting because it confirmed the findings of two previous studies,” including the one from Taiwan. “For the first time it revealed an increased risk for vascular disease — TIA, stroke, myocardial infarction — in persons under the age of 40.”

Dr. Gilden, who conducts research on VZV and HZ and was a reviewer for the UK study for Neurology, said the findings should prompt doctors to ask more about their patients' medical histories.

“If somebody comes in with transient ischemic attack, stroke or heart disease, physicians should ask about their recent history for shingles,” he said. Likewise, clinicians should consider that patients with HZ could be at heightened risk for vascular problems independent of other risk factors they might have, he said.

Maria Nagel, MD, assistant professor of neurology at the University of Colorado School of Medicine, said the findings of a possible longer-term consequence of HZ make sense given research that she and others have conducted. In a paper published in Neurology in 2011, for instance, she, Dr. Gilden, and others reported that VZV can persist in saliva for years, which means circulating virus could cause arterial damage over time. Another study that she published in 2008 found that one third of patients with VZV vasculopathy do not have a rash, one third have normal cerebrospinal fluid, and the average time from rash to neurological symptoms and signs is four months.

This latest study “will hopefully lead to more awareness of zoster as a risk factor,” Dr. Nagel said.

Dr. Yawn, the Minnesota researcher, told Neurology Today that she found the latest study on the connection between HZ and vascular disease problematic, in part, because the researchers included follow-up data for up to nearly 25 years after the HZ case.

“It's a very long time,” she said, making it difficult to say “that something that happened six years, 10 years, 25 years ago is a factor” in why a person developed vascular disease. She said it would be impossible to account for all the variables that could have come into play during that time. Her study using a cohort of older Minnesota residents will be limited to a five-year period.

“I think it is premature to say anything about the use of the [HZ] vaccine to prevent vascular disease,” Dr. Yawn said.

The federal Centers for Disease Control and Prevention estimates that one million people annually in the US get shingles. While the Advisory Committee on Immunization Practices recommends the vaccine for persons 60 or older, only about 10 percent, or slightly more, of them have been vaccinated.

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LINK UP FOR MORE INFORMATION:

•. Breuer J, Pacou M, Gautier A, et al. Herpes zoster as a risk factor for stroke and TIA: A retrospective cohort study in the UK. Neurology. 2014; E-pub 2014 Jan. 2.

•. Kang JH, Ho JD, Chen YH, et al. Increased risk of stroke after a herpes zoster attack: A population-based follow-up study. Stroke. 2009; 40:3553–3448.

•. Lin HC, Chien CW, Ho JD. Herpes zoster ophthalmicus and the risk of stroke: A population-based follow-up study. Neurology. 2010; 74:792–797.

•. Nagel MA, Traktinskiy I, Azarkh Y, et al. Varicella zoster virus vasculopathy: Analysis of virus-infected arteries. Neurology. 2011; 77:364–370.

•. Gilden D, Nagel MA, Cohrs RJ. Persistence of varicella zoster virus DNA in saliva after herpes zoster. J Infect Dis. 2012; 205:1178.

Wolters Kluwer Health | Lippincott Williams & Wilkins

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