New Evidence of Varicella-Zoster in Giant Cell Arteritis

Pauline Anderson

February 20, 2015

Results of a new study fuel the theory that the varicella-zoster virus (VZV), a herpesvirus linked to chickenpox in children and shingles (herpes zoster) in adults, also causes giant cell arteritis (GCA) in older people.

The study, published online February 18 in Neurology, detected the VZV antigen in 74% of temporal arteries pathologically positive for GCA.

Varicella, a highly contagious disease that manifests as a blister-like rash, itching, tiredness, and fever, often targets children. The same virus can attack later in life in the form of shingles.

"Our analysis, which is the largest to-date, provides compelling evidence that the virus also reactivates in people over 60 in another way, triggering giant cell arteritis," said study author Don Gilden, MD, Department of Neurology and Microbiology, University of Colorado School of Medicine, Denver, and fellow of the American Academy of Neurology (AAN), in an AAN press release.

Affecting an estimated 29 of 100,000 people, GCA is the most common type of inflammation of blood vessels in the elderly. It's characterized by severe headache/head pain and scalp tenderness. Some patients sustain stroke or vision loss. The cause of this condition is uncertain.

The researchers obtained biopsy specimens from patients older than 50 years of age with confirmed GCA from 13 institutions. They also obtained control temporal arteries removed postmortem from age-matched persons. None of the controls exhibited skin evidence of recent herpes zoster or had any recent history of diabetes, cancer, alcohol or other substance abuse, or immunosuppression.

Researchers performed an immunohistochemical analysis of 4100 sections from 82 pathologically verified GCA-positive temporal arteries (50 slides per temporal artery). They detected VZV antigen in 61 (74%), compared with 1 in the 13 (8%) normal temporal artery controls (relative risk, 9.67; 95% confidence interval, 1.46 - 63.69; P < .0001).

The researchers also performed other tests to detect the virus, including polymerase chain reaction amplification of VZV DNA in temporal artery sections containing VZV antigen and transmission electron microscopy.

The analyses showed the presence of VZV in skip areas, paralleling a characteristic feature of GCA pathology. Other evidence was the close proximity of VZV antigen in temporal arteries with adjacent GCA pathology, and the presence of VZV antigen and VZV DNA in skeletal muscle adjacent to VZV antigen-positive temporal arteries, the authors report.

VZV antigen was found in cells in the adventitia, media and intima of temporal arteries, consistent with the well-documented ability of VZV to replicate in all organs during disseminated varicella and zoster as well as in all human non-neuronal cells in tissue culture, they write.

The presence of VZV antigen in GCA lesions is not likely a "bystander effect" due to subclinical reactivation induced by inflammation, say the authors. "After more than 3 decades of analysis of tissue sections for VZV from patients with inflammatory/infectious diseases, we found that while VZV causes inflammation, inflammation does not cause VZV to reactivate and infect the inflamed region."

Because multiple agents underlie other diseases (eg, pneumonia and meningitis), "it remains possible that agents in addition to VZV cause GCA," write the authors.

They note that previous studies have tried to find VZV in temporal arteries histopathologically positive or negative for GCA. Some of these studies detected it while many did not. The difference might be that the current study is larger and more exhaustive, including more sections (50) per artery.

The dramatic favorable response of patients with GCA to corticosteroid treatment suggests that the disorder is the result of an inflammatory response to VZV. According to the authors, "the apparent role of VZV in triggering the immunopathology of GCA warrants addition of antiviral treatment to corticosteroids."

Avindra Nath, MD, chief, Section of Infections of the Nervous System, and clinical director, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, thinks it's too early to take this step. He stressed that the authors have shown an association, not a causation.

"Based on this study, I don't think you can say that everybody who has GCA should get treated" with antivirals, he told Medscape Medical News.

Dr Nath also noted that the researchers found VZV in one normal specimen. "So we have to be a careful before we can say definitely that this is the cause of GCA."

However, he added, proving causation could be difficult. For one thing, there are no animal models; VZV is an exclusively human virus that doesn't produce disease in experimentally infected animals.

For another, while antiviral therapies such as acyclovir are now available, "there are a number of questions that remain unanswered," said Dr Nath.

"You don't know exactly which of those drugs would work or at what doses it would work, or for how long it should it be given."

According to Dr Nath, a placebo-controlled clinical trial of one of these antivirals in a group of patients with GCA might be the next logical study.

Although some experts think GCA is an autoimmune disease, Dr Nath isn't so sure. It's unusual for an autoimmune disease to develop in older age, he said.

VZV can lie dormant for many years. "So it's in your body someplace and then it gets reactivated," explained Dr Nath. "It's like getting shingles except instead of getting shingles on the skin, it's affecting the blood vessels and this is causing this arteritis."

But now that vaccinations are recommended to prevent shingles in older patients, the incidence of GCA should decrease, he said. The Centers for Disease Control and Prevention (CDC) recommends the one-time shingle vaccine (Zostavax, Merck) for people 60 years old and older. The older a person is, the more severe the effects of shingles typically are.

On its website, the CDC cites a clinical trial involving thousands of adults 60 years old or older that found the vaccine reduced the risk for shingles by 51% and the risk for postherpetic neuralgia by 67%. While it was most effective in people 60 to 69 years old, it also provided some protection for older groups. Research suggests that the shingles vaccine is effective for at least 6 years but may last longer.

The National Institutes of Health supported the study. The authors have disclosed no relevant financial relationships.

Neurology. Published online February 18, 2015. Abstract

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