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Original Investigation |

Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis

Maria A. Nagel, MD1; Teresa White, BS1; Nelly Khmeleva, BS1; April Rempel, BS1; Philip J. Boyer, MD, PhD2; Jeffrey L. Bennett, MD, PhD1,3; Andrea Haller, MD4; Kelly Lear-Kaul, MD5; Balasurbramaniyam Kandasmy, MD2; Malena Amato, MD6; Edward Wood, MD6,7; Vikram Durairaj, MD6; Franz Fogt, MD8; Madhura A. Tamhankar, MD9; Hans E. Grossniklaus, MD10; Robert J. Poppiti, MD11; Brian Bockelman, MD11; Kathy Keyvani, MD12; Lea Pollak, MD13; Sonia Mendlovic, MD14; Mary Fowkes, MD, PhD15; Charles G. Eberhart, MD, PhD16; Mathias Buttmann, MD17; Klaus V. Toyka, MD17; Tobias Meyer-ter-Vehn, MD18; Vigdis Petursdottir, MD19; Don Gilden, MD1,20
[+] Author Affiliations
1Department of Neurology, University of Colorado School of Medicine, Aurora
2Department of Pathology, University of Colorado School of Medicine, Aurora
3Department of Ophthalmology, University of Colorado School of Medicine, Aurora
4Fort Wayne Neurological Center, Fort Wayne, Indiana
5Arapahoe County Coroner’s Office, Centennial, Colorado
6Texas Oculoplastic Consultants, Austin
7University of Texas Southwestern–Austin Transitional Year Program, Austin
8Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia
9Scheie Eye Institute, University of Pennsylvania, Philadelphia
10Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia
11A. M. Rywlin Department of Pathology, Mount Sinai Medical Center and Florida International University, Miami
12Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany
13Department of Neurology, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
14Pathological Institute, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
15Department of Pathology, Icahn School of Medicine, Mount Sinai Health System, New York, New York
16Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
17Department of Neurology, University of Würzburg, Würzburg, Germany
18Department of Ophthalmology, University of Würzburg, Würzburg, Germany
19Landspitali University Hospital, Reykjavik, Iceland
20Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora
JAMA Neurol. 2015;72(11):1281-1287. doi:10.1001/jamaneurol.2015.2101.
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Importance  Giant cell arteritis (GCA) is the most common systemic vasculitis in elderly individuals. Diagnosis is confirmed by temporal artery (TA) biopsy, although biopsy results are often negative. Despite the use of corticosteroids, disease may progress. Identification of causal agents will improve outcomes. Biopsy-positive GCA is associated with TA infection by varicella-zoster virus (VZV).

Objective  To analyze VZV infection in TAs of patients with clinically suspected GCA whose TAs were histopathologically negative and in normal TAs removed post mortem from age-matched individuals.

Design, Setting, and Participants  A cross-sectional study for VZV antigen was performed from January 2013 to March 2015 using archived, deidentified, formalin-fixed, paraffin-embedded GCA-negative, GCA-positive, and normal TAs (50 sections/TA) collected during the past 30 years. Regions adjacent to those containing VZV were examined by hematoxylin-eosin staining. Immunohistochemistry identified inflammatory cells and cell types around nerve bundles containing VZV. A combination of 17 tertiary referral centers and private practices worldwide contributed archived TAs from individuals older than 50 years.

Main Outcomes and Measures  Presence and distribution of VZV antigen in TAs and histopathological changes in sections adjacent to those containing VZV were confirmed by 2 independent readers.

Results  Varicella-zoster virus antigen was found in 45 of 70 GCA-negative TAs (64%), compared with 11 of 49 normal TAs (22%) (relative risk [RR] = 2.86; 95% CI, 1.75-5.31; P < .001). Extension of our earlier study revealed VZV antigen in 68 of 93 GCA-positive TAs (73%), compared with 11 of 49 normal TAs (22%) (RR = 3.26; 95% CI, 2.03-5.98; P < .001). Compared with normal TAs, VZV antigen was more likely to be present in the adventitia of both GCA-negative TAs (RR = 2.43; 95% CI, 1.82-3.41; P < .001) and GCA-positive TAs (RR = 2.03; 95% CI, 1.52-2.86; P < .001). Varicella-zoster virus antigen was frequently found in perineurial cells expressing claudin-1 around nerve bundles. Of 45 GCA-negative participants whose TAs contained VZV antigen, 1 had histopathological features characteristic of GCA, and 16 (36%) showed adventitial inflammation adjacent to viral antigen; no inflammation was seen in normal TAs.

Conclusions and Relevance  In patients with clinically suspected GCA, prevalence of VZV in their TAs is similar independent of whether biopsy results are negative or positive pathologically. Antiviral treatment may confer additional benefit to patients with biopsy-negative GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

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Figure 1.
Identification of Giant Cell Arteritis Pathology in the Temporal Artery Adjacent to a Section Containing Varicella-Zoster Virus (VZV) Antigen in a Temporal Artery Signed Out as Pathologically Negative for Giant Cell Arteritis

A-C, Immunohistochemical analysis using mouse anti-VZV gE IgG1 antibody revealed VZV antigen at the border of the adventitia and media of a temporal artery that was originally signed out as negative for giant cell arteritis (A and B, pink), but not when mouse isotype IgG1 antibody was substituted for mouse anti-VZV gE IgG1 antibody (C) on adjacent sections (original magnification ×100 [A] and ×600 [B and C]). D, Hematoxylin-eosin staining of a temporal artery section adjacent to that containing VZV antigen in A and B revealed giant cell arteritis pathology, with extensive inflammation in the adventitia (yellow arrowhead) and lesser inflammation in the media (blue arrowhead) and intima (black arrowhead) (original magnification ×100). Inset, Medial damage as well as numerous epithelioid cells were seen throughout the artery (hematoxylin-eosin, original magnification ×600).

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Figure 2.
Identification of Inflammatory Cells in a Section of the Temporal Artery Adjacent to Varicella-Zoster Virus (VZV) Antigen

A, Immunohistochemical analysis using mouse anti-VZV gE IgG1 antibody revealed VZV antigen in the adventitia of a giant cell arteritis–negative temporal artery (bright pink) (original magnification ×600). B-D, Hematoxylin-eosin staining of a temporal artery section adjacent to that containing VZV antigen in A revealed inflammatory cells (B) expressing CD45 antigen with rabbit anti-CD45 antibody (C, pink) not detected when normal rabbit serum was substituted for rabbit anti-CD45 antibody (D) (original magnification ×600).

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Figure 3.
Colocalization of Varicella-Zoster Virus (VZV) Antigen and Claudin-1 in Cells in the Perineurium of Nerve Bundles in Temporal Arteries Pathologically Negative for Giant Cell Arteritis

A, B, E, and F, Immunohistochemical analysis using mouse anti-VZV gE IgG1 antibody revealed VZV antigen predominantly in association with the perineurium of nerves in 2 representative temporal arteries (A and B, pink), but not in adjacent sections in which mouse isotype IgG1 antibody was substituted for mouse anti-VZV gE IgG1 antibody (E and F) (original magnification ×600). C, D, G, and H, Immunohistochemical analysis of sections adjacent to those containing VZV antigen with rabbit anti–claudin-1 antibody confirmed that the VZV antigen was located in association with perineurial cells expressing claudin-1 (C and D, pink), but not when normal rabbit serum was substituted for rabbit anti–claudin-1 antibody (G and H) (original magnification ×600).

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