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Varicella linked to giant cell arteritis
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Varicella zoster virus may be linked to giant cell arteritis among the elderly, according data from the University of Colorado School of Medicine.
“The presence of [varicella zoster virus (VZV)] antigen in [giant cell arteritis (GCA)] lesions is not likely to be a bystander effect due to sublinical reactivation induced by inflammation,” the researchers wrote in Neurology. “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.”
The researchers analyzed 82 temporal artery biopsy specimens taken from patients aged older than 50 years with confirmed GCA and samples from 13 control temporal artery specimens taken from age-matched subjects. The specimens underwent immunohistochemical analysis to detect VZV antigen and sections adjacent to those that contained the antigen underwent histopathologic analysis for features of GCA. All samples containing VZV antigen underwent PCR amplification of VZV DNA.
VZV antigen was found in 61 of the samples with confirmed GCA, and in one of the control specimens (RR = 9.67; 95% CI, 1.46-63.629). In 49 of the GCA-positive samples that contained VZV, the virus was found in skip areas, most commonly in the adventitia (49%), followed by the media (32%) and intima (19%). Thirty-two of the GCA-positive samples containing VZV antigen also contained muscle, and VZV antigen was found in 12 of those adjacent skeletal muscles.
Only 45 of the GCA-positive samples with VZV antigen contained amplifiable cellular DNA; of those, 18 contained VZV DNA. VZV DNA also was identified in one control specimen. Of the skeletal muscles with VZV antigen, 10 had amplifiable cellular DNA, and six contained VZV DNA. Among GCA-positive specimens, 89% of sections adjacent to sections containing VZV antigen had GCA pathology. In the one control sample with VZV antigen, there were no areas of GCA pathology (P < .0001).
“The collective findings … directly affect future treatment considerations for patients with GCA,” the researchers wrote. “The dramatic favorable response to treatment with corticosteroids in many patients with GCA indicates that the disorder is the result of an inflammatory response to VZV.” – by Emily Shafer
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Leonard Calabrese, DO
There have been many infectious etiologic agents posited as possible etiologic agents for giant cell arteritis (GCA), including Chlamydia, parvovirus B19 and, most recently, Burkholderia. However, none have stood the rigor of proof. At the same time, it is incontrovertible that GCA, unlike other systemic vasculitides, is tied to age and by at least one association in the form of immunosenescence. Varicella is a ubiquitous virus that similarly to GCA is associated with advancing age and immunosenescence as well, yet attempts to link the two disorders in the past have been unconvincing.
In a recent high impact publication, the laboratory led by Donald H. Gilden, MD, and Maria A. Nagel, MD, at the University of Colorado School of Medicine have published remarkable data which reaffirms the association and this time the evidence is strong. These investigators are among the leaders in the field on varicella zoster virus (VZV) neurobiology and have an extraordinary track record of contributions to the field. Concerns are always lurking when a laboratory dedicated to a single pathogen finds that just that pathogen may have problems with contamination. However, I do not believe it is the case this time. In 74% of GCA biopsies from 82 patients with pathologically documented GCA, there is clear evidence of virus by both DNA amplification as well as impressive immunohistochemistry and ultra-structural examination. The virus favors the adventitia but can be seen throughout the vessel and in the nearby muscle. Varicella zoster virus also was found in one control without evidence of GCA.
Gilden and colleagues present a strong argument from the vantage point of have been working on the forefront of neurovirology for decades that VZV is not a bystander in most circumstances and is likely a driver.
If so, how does this occur? Why have glucocorticoids been so effective? Why does GCA end pathologically at the foramen magnum in the vast majority of cases where as VZV can and does cause intracranial arteritis?
A major limitation of the study is the lack of clinical information on their patients yet the data deserve careful attention. The authors suggest adjunctive antiviral therapy makes sense.
These data need to be confirmed with similar techniques in other laboratories using similar techniques. Second a dedicated search for VZV needs to be embarked upon on normal vasculature that is traditionally afflicted by GCA from normal, especially aging individuals, to help understand what role VZV plays in the vascular biology of health. If the association is confirmed, then a clinical trial of adjunctive antiviral therapy would be important as the drugs used for this pathogen are safe and relatively inexpensive compared to biologics presently undergoing active investigation. I am also particularly impressed by the data because of the numerous recent epidemiologic studies strongly supporting a link between VZV and stroke. Just why and how VZV may do all of this, if it is causal, remains to be seen.
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