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New Evidence that Varicella Zoster Virus Triggers Giant Cell Arteritis

ARTICLE IN BRIEF

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IMMUNOHISTOCHEMICAL analysis using mouse anti–varicella-zoster virus (VZV) glycoprotein E (gE) IgG1 antibody revealed VZV antigen in giant cell arteritis (GCA)-positive temporal arteries (TAs) in all arterial regions. VZV antigen (pink color) was seen in the adventitia and media (A), exclusively in the media (B), and in the media and intima (C) of 3 different GCA-positive TAs, as well as in the adventitia (D) of a positive control VZV-infected cadaveric cerebral artery 14 days after infection in vitro. The presence of VZV antigen was confirmed by immunostaining the same TA shown in panel A (E) and the same positive control VZV-infected cadaveric cerebral artery shown in panel D (F) with rabbit anti-VZV IE63 antibody. No staining was seen in sections adjacent to those containing VZV antigen when mouse isotype IgG1 antibody was substituted for mouse anti-VZV gE IgG1 antibody (G–J) or when normal rabbit serum was substituted for rabbit anti-VZV antibody (K, L). Discontinuous skip areas containing VZV antigen in a TA that was pathologically positive for GCA were shown by immunohistochemical staining with mouse anti-VZV gE IgG1 antibody. VZV antigen was seen at positions 125-130 mm (M), 215-220 mm (O), and 255-260 mm (Q), but not at intervening regions at positions 131-214 mm (N) and 221-254 mm (P). Sections adjacent to those shown in panels M–Q were negative after immunostaining with mouse isotype IgG1 antibody (S–W). VZV antigen was often seen in skeletal muscle adjacent to a VZV-infected TA immunostained with mouse anti-VZV gE IgG1 antibody (R) that was not seen with mouse IgG1 antibody (X). 6003 magnification.

A new study supports the hypothesis that varicella zoster virus triggers giant cell arteritis (GCA) immunopathology and that antiviral treatment may confer additional benefit to patients with GCA treated with corticosteroids.

The varicella zoster virus (VZV) has been identified as a culprit in an inflammatory cascade that triggers giant cell arteritis (GCA), a condition that occurs in the elderly and can lead to blindness, according to a study first published in the Feb. 18 online edition of Neurology.

The results could lead to a change in the way the disease is treated. Clinicians who spoke with Neurology Today called the findings “revolutionary,” and two neurologists hailed the paper as a “landmark study” in an accompanying editorial.

Lead author Donald H. Gilden, MD, FAAN, the Louise Baum endowed chair and professor of neurology at the University of Colorado School of Medicine in Aurora, has been studying VZV since the late 1970s. In 1983, he and his colleagues discovered that the virus, once it has entered the body, becomes latent in ganglia throughout the body and remains there for life. Dr. Gilden and his team have gone on to show that the virus can also be involved in stroke and eye diseases.

The role of VZV in neurologic and eye diseases got Dr. Gilden thinking about GCA, a not uncommon condition (occurring in about 29 per 100,000 people) that is characterized by severe pain, usually on one side of the head; people with GCA often have a history of jaw claudication and aching muscles without weakness (polymyalgia rheumatica). GCA often comes on quickly and its cause is puzzling, since these patients have no history of headaches. On exam, the temporal artery over the scalp may be hard, nodular, and tender. Laboratory tests often reveal a high sedimentation rate and high C-reactive protein. One-third of patients can become blind if the condition is not identified and treated quickly.

Usually, if GCA is suspected, the clinician will order a temporal artery biopsy and start immediate treatment with steroids. The biopsy can show vessel wall damage and inflammation with multinucleated giant cells and/or epithelioid macrophages, said Dr. Gilden. Medication is usually taken for months or even years. Some patients go on to develop stroke in other arteries, even after they have recovered from GCA.

STUDY METHODOLOGY

Dr. Gilden knew that there were only a few viruses that produced multinucleated giant cells, and VZV was one of them. Last year he began contacting pathologists around the world, looking for temporal artery specimens that had been positive for GCA. The samples, some decades old and all fixed in formalin, began arriving from 13 major medical centers around the globe. He and his colleagues have now catalogued more than 600 temporal arteries, all culled from patients who were over 50 years old at the time of the biopsy.

They looked at 82 temporal arteries, slicing at least 100 sections from each one and using immunochemistry to look for VZV in 50 sections and saving the other 50 for virus controls and pathology. They also collected 13 temporal arteries from age-matched people without GCA and used the same tools to look for the virus. When tissue was positive for VZV antigen, the investigators used polymerase chain reaction (PCR) to look for VZV DNA.

Other labs have looked for VZV in GCA, but the results were spotty. The problem, as Dr. Gilden sees it, is that they only sampled a handful of sections, which is why he and his colleagues spanned out across the artery to sample more than 50 areas.

Dr. Gilden and Maria A. Nagel, MD, both neurovirologists, placed each sample under light microscopy and looked for evidence of the virus. Their immunochemical analysis included an antibody directed at VZV that is found only in infected cells, Dr. Gilden said. They were blinded to where the tissue came from (biopsy from GCA patients or controls). A sample was marked as positive only when they both agreed. If there was any doubt about whether the tissue was positive, it was removed from the analysis.

They also stained regions adjacent to a positive sample to look for associated pathological changes. Philip J. Boyer, MD, PhD, a neuropathologist, and Drs. Gilden and Nagel again used light microscopy to look for evidence of medial damage, inflammation, and the presence of giant or epithelioid cells. Then, they used PCR to amplify VZV DNA in the temporal artery sections that contained the antigen. Overall, they analyzed 4,100 sections.

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DR. DONALD H. GILDEN: “Now we know that GCA is caused by the bodys immune response against the virus. It means we can add an antiviral agent to the treatment and we might be able to reduce the time that we treat with steroids. We believe that this finding will and should change the practice of medicine.”

Dr. Gilden and his team found VZV antigen in 61 of 82 arteries (74 percent). By comparison, only one of the 13 arteries (8 percent) from the control group turned up positive for the virus (p<0.0001). There were areas of the arteries where virus was present, then nothing, then more VZV virus (so-called “skip areas”). Dr. Gilden suspects that the rate would have been even higher had they tested 200 samples from each artery.

They also found VZV DNA in GCA-positive temporal arteries. It was not easy detecting VZV DNA because of the 61 GCA-positive temporal arteries that contained VZV antigen, only 45 contained enough cellular DNA to amplify. Dr. Gilden explained that the reason for the problem was that the samples were fixed in formalin. In one GCA-positive temporal artery examined by electron microscopy, they found VZV particles. The virus was also identified in skeletal muscle adjacent to the temporal artery in 39 of the 82 arteries studied.

“Now we know that GCA is caused by the body's immune response against the virus,” Dr. Gilden said. “It means we can add an antiviral agent to the treatment and we might be able to reduce the time that we treat with steroids. We believe that this finding will and should change the practice of medicine.”

The studies, primarily identifying VZV in specific areas of the temporal artery, revealed that once the virus reactivates, it travels from ganglia along axons into the arteries. Spending three decades studying VZV led Dr. Gilden and his colleagues to the understanding that while “VZV causes inflammation, inflammation does not cause VZV to reactivate and infect the inflamed region.”

The group also reported that they were able to link GCA with intracerebral VZV vasculopathy. Two patients in their biopsy series went on to suffer strokes a few months after their initial diagnosis of GCA. “Together, the collective clinical, pathological, and virologic findings indicate that GCA is essentially a VZV vasculopathy primarily affecting the temporal artery,” the researchers concluded in the paper.

Dr. Gilden has already begun to add antivirals — both oral and intravenous acyclovir — to the treatment plan for patients with GCA, and others who know of his team's work are doing the same. “It's likely to be a more effective therapy and may shorten the time of treatment with corticosteroids,” he said. But, he added, it is not clear yet whether oral antiviral therapy will be enough, or what doses or length of treatment would be needed to eradicate the infection.

EXPERTS COMMENT

Other experts who were not involved with the study agreed that the findings were very important, but they also welcomed the opportunity for another clinical trial to answer some outstanding questions.

In an editorial published in the Feb. 27 online edition of Neurology, Peter G. E. Kennedy, MD, PhD, the Burton chair of neurology at the University of Glasgow in Scotland, and Howard L. Lipton, MD, a professor in the departments of neurology and microbiology and immunology at the University of Illinois in Chicago, called the paper a “landmark study.”

“The critical question asked was how frequently VZV can be detected in proven GCA-positive cases,” they wrote. “The critical comparison was with age-matched autopsy cases to controls. Their findings were remarkable and provide strong evidence for the association of VZV with GCA.”

However, the neurologists raised practical concerns about the findings. Most hospital laboratories only examine a few sections of the temporal artery. If they should be studying more, they said, how should this be implemented on a national level? And if GCA is indeed a VZV vasculopathy, what are the implications for treatment?

“Both proven and highly suspected GCA cases are now treated urgently with corticosteroids,” they said. But “despite the important findings described in this seminal article, the combined administration of acyclovir and corticosteroids in patients with GCA may be premature.”

They noted that the situation would likely change if a future clinical trial can prove that combined antiviral and corticosteroid therapy in GCA produces substantial benefit compared to corticosteroids alone.

Adarsh Bhimraj, MD, head of the section of neurologic infectious diseases at the Cleveland Clinic, said he believes that “looking for the possibility that an infection is playing a role in a disease process is important. The Colorado group found a lot of virus in the tissue from GCA patients. This is a very promising study. The data are very convincing. If you find that much virus, I presume it is the cause of their condition.”

Dr. Bhimraj added that he thinks a clinical study would be necessary to prove that antivirals work. “Instead of taking steroids for months or years, you may be able to take a short course of antivirals. It could be revolutionary.”

Karen Roos, MD, the John and Nancy Nelson professor of neurology at Indiana University School of Medicine in Indianapolis, said that “this is an important discovery and worth paying attention to.” She added that she sees “no downside in treating patients with this combined approach. We know how to use acyclovir safely.”

Neurologists should ask pathologists to look for VZV antigen and VZV DNA following a temporal artery biopsy, which is currently not done, Dr. Roos said.

Catherine Amlie-LeFond, MD, an associate professor of neurology at University of Washington School of Medicine in Seattle who specializes in pediatrics, said that while chicken pox can cause severe problems, “the real morbidity of VZV is not in childhood but decades down the road. If we can prevent wild-type varicella virus from reactivating, we could decrease morbidity, and that would be an enormous contribution to medicine.”

John Kriesel, MD, research associate professor of infectious disease at the University of Utah in Salt Lake City, agreed. “If you are the patient, I would want to try a course of antivirals. Why not?”

Dr. Kriesel said that the researchers “outworked everyone and they figured it out. I congratulate them.”

EXPERTS: ON THE ROLE OF VARICELLA ZOSTER VIRUS IN GIANT CELL ARTERITIS

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DR. ADARSH BHIMRAJ said that “looking for the possibility that an infection is playing a role in a disease process is important. The Colorado group found a lot of virus in the tissue from GCA patients. This is a very promising study. The data are very convincing. If you find that much virus, I presume it is the cause of their condition.” He added that a clinical study would be necessary to prove that antivirals work.

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DR. KAREN ROOS said she “sees no downside in treating patients with this combined approach. We know how to use acyclovir safely.” She added that neurologists should ask pathologists to look for VZV antigen and VZV DNA following a temporal artery biopsy, which is currently not done.

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DR. CATHERINE AMLIE-LEFOND said “the real morbidity of VZV is not in childhood but decades down the road. If we can prevent wild-type varicella virus from reactivating, we could decrease morbidity, and that would be an enormous contribution to medicine.”

LINK UP FOR MORE INFORMATION:

•. Gilden G, White T, Khemeleva N, et al. Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis http://www.neurology.org/content/early/2015/02/18/WNL.0000000000001409.long. Neurology 2015: Epub 2015 Feb. 18.
    •. Kennedy PGE, Lipton HL. Varicella-zoster virus claims yet another painful scalp—Giant cell arteritis http://www.neurology.org/content/early/2015/02/27/WNL.0000000000001459.short. Neurology 2015; Epub 2015 Feb. 27.