Should Antiviral/Anti-Varicella Zoster Virus Treatment Be Used in Patients With Giant Cell Arteritis?

Recent reports show that the varicella zoster virus (VZV) antigen is found in temporal artery (TA) biopsies in patients with giant cell arteritis (GCA). Two experts debate whether antiviral therapy should be used routinely in patients with GCA.

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Should Antiviral/Anti-Varicella Zoster Virus Treatment Be Used in Patients With Giant Cell Arteritis? Yaping Joyce Liao, MD, PhD, Sachin Kedar Recent reports show that the varicella zoster virus (VZV) antigen is found in temporal artery (TA) biopsies in patients with giant cell arteritis (GCA). Two experts debate whether antiviral therapy should be used routinely in patients with GCA. Pro: Y. Joyce Liao, MD, PhD GCA is the most prevalent vasculitis with a predisposition for cranial arteries in the elderly and has an incidence of 19.8 per 100,000 annually (1). It is associated with large and medium vessel granulomatous inflammation, which leads to thrombosis and ischemia (2,3). The most feared and most common neurologic consequence of GCA is irreversible vision loss due to arteritic anterior ischemic optic neuropathy (A-AION) (2,3). Diagnosis of GCA is based on clinical suspicion, elevated systemic inflammatory markers, and most importantly, temporal artery biopsy (TAB) to look for the presence of transmural inflammation, medial smooth muscle cell damage, and multinucleated giant cells. The mainstay of GCA treatment is chronic, high-dose corticosteroid treatment (4,5), which is limited because it has many short- and long-term side effects, and some patients continue to exhibit symptoms despite treatment. On the cellular level, corticosteroid therapy is limited because it reduces only CD4+ T helper (TH) 17- but not TH1-mediated tissuedestructive immune responses (3). The cause of GCA remains unknown, and many infectious organisms have been postulated but none has been proven. From 2002 to 2005, VZV was found in the extracranial superficial temporal arteries of patients with clinical manifestations of A-AION associated with temporal headache, jaw claudication, and herpes zoster (HZ) ophthalmicus, leading to the suspicion that VZV infection may contribute to GCA-like clinical manifestations (6). VZV is a neurotropic alphaherpesvirus that causes chickenpox (varicella) and shingles (HZ). VZV is the only human virus that has been shown to replicate in arteries and cause disease, and VZV infection in cerebral Departments of Ophthalmology and Neurology (YJL), Stanford University Byers Eye Institute, Palo Alto, California; and Neurology and Ophthalmology (SK), University of Nebraska Medical Center, Omaha, Nebraska. The authors report no relevant conflict of interest. Address correspondence to Y. Joyce Liao, MD, PhD, Departments of Ophthalmology and Neurology, Stanford University Byers Eye Institute, 2452 Watson Court, Palo Alto, CA 94303; E-mail: [e-mail] 134 arteries leads to cerebral VZV vasculopathy (7). Historically, the association between VZV and GCA (and other vasculitides) has been difficult to show because of the challenge of finding evidence of VZV in formalin-fixed tissues. VZV exhibits a tropism for cerebral blood vessels, and VZV infection leading to VZV vasculitis is well known to be an important cause of vasculitis, ischemic stroke, and development of cerebral aneurysms. The identification of VZV in TABs in patients with suspect GCA leads to the speculation that VZV is involved in the pathogenesis of GCA (6,7). VZV reactivation due to reduced cell-mediated immunity or viral-induced effects on the local vascular milieu may contribute to GCA pathogenesis. The high prevalence of VZV in biopsy-negative patients means that the presence of VZV alone is not sufficient to cause GCA pathology, although the presence of VZV raises the possibility of antiviral therapy in those with suspect GCA to prevent or reduce future recurrences (8). VZV vasculitis is an especially important consideration in severe cases of GCA that are refractory to treatment or have cerebral involvement (8). There are several compelling reasons that the diagnosis of overlapping VZV infection or VZV-triggered immunemediated effects should be considered when approaching patients with possible GCA and acute vision loss: 1) overlapping neuro-ophthalmic and systemic manifestations, 2) prevalence of VZV in superficial TABs, and 3) histologic overlap and immune activation in the tunica adventitia. Overlapping neuro-ophthalmic and systemic manifestations Patients with vision loss and symptoms of GCA can be indistinguishable from those with VZV infection because both present with neurological symptoms and systemic manifestations, both manifest with symptoms that are highly variable and can wax and wane, and both have Liao and Kedar: J Neuro-Ophthalmol 2019; 39: 134-141 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point a protracted course that may last for months to more than 1 year (9). These overlapping clinical manifestations can be diagnostic dilemmas and lead to a delay in initiation of appropriate treatment. Although VZV does not typically present as A-AION, this has been reported (10) and can occur with or without acute retinal necrosis or HZ ophthalmicus and may not be associated with rash (zoster sine herpete) (9). In 1 study of 9 surgically removed eyes using both DNA in situ hybridization for VZV DNA and immunohistochemistry using anti-VZV antibody for the presence of VZV antigen, 44% (4/9) of eyes exhibited optic neuritis; 89% (8/9), perineuritis; and 89% (8/9), perivasculitis of the posterior ciliary arteries (11), the same blood vessels that are predominantly involved in A-AION (12). Although the authors did not specify which layer of the vessel is involved, they noted the frequent association of viral DNA with vascular rather than with neuronal structures. This vascular association likely explains the manifestations of VZV including transient ischemic attack, stroke, aneurysm, and venous sinus thrombosis (13,14). Although strokes are more commonly associated with VZV infection, stroke also has been reported in GCA and can occur before or after the diagnosis of GCA is established (15-18). In a retrospective multicenter study of 40 patients with GCA and 200 controls, 73% of GCA-related strokes occurred in the vertebrobasilar territory, and patients with GCA had significantly greater association with ischemic ophthalmic symptoms compared with those without GCA (63% in GCA and 25% in controls) (18). In addition, like GCA, VZV vasculopathy can present as granulomatous aortitis or nonspecific vasculitis (13,14). England et al (19) used 2 independent health care provider data sets (Medicare, MarketScan) and determined that previous zoster infection is associated with a significantly increased hazard ratio of developing GCA (19). Although previous VZV vaccination has not been shown to decrease the incidence of GCA (20), this may be due to various factors including waning immunity with aging, limited size of study, and heterogenous populations. Prevalence of varicella zoster virus in the superficial temporal artery biopsies The localization of VZV antigens and DNA in TABs, especially in patients with suspect GCA, has been extensively studied since its initial observation in a small number of patients. Recent reports identifying VZV DNA by polymerase chain reaction (PCR) or presence of the VZV antigen by immunostaining with multiple anti-VZV antibodies have shown that VZV is found in a significantly higher percentage of TABs in both GCA-positive and GCAnegative individuals (21,22). In 1 large study, the VZV antigen was found in 68/93 (73%) GCA-positive TABs and in 45/70 (64%) GCA-negative TABs. This is higher than what was found in an earlier report of 11/49 (22%) Liao and Kedar: J Neuro-Ophthalmol 2019; 39: 134-141 negative TABs (22). A masked study of 10 TAB in 9 patients using both PCR of formalin-fixed and fresh frozen TABs and immunostaining using anti-VZV antibody found that the VZV antigen could be detected in 78% of GCApositive and GCA-negative TABs (21). These findings are consistent with the well-known tissue tropism of VZV for the trigeminal ganglia and transaxonal spread of infection along the superficial temporal branches to the extracranial vessels such as the superficial TA and that VZV alone is not sufficient to produce GCA (23). Although the presence of VZV in the aorta has not been well studied in patients with GCA, 1 report using 3 different anti-VZV antibodies identified the VZV antigen in 100% (11/11) of aortas with pathologically confirmed granulomatous aortitis and in 28% (5/18) of control aortas at autopsy (24). Again, this colocalization does not indicate a causal relationship but provides further evidence of the tissue tropism of VZV and presence of VZV in the vessels most commonly affected in GCA. Histologic overlap and immune activation in the tunica adventitia Histologically, VZV vasculopathy and GCA have virtually identical pathological findings in the blood vessels. In both conditions, there is granulomatous arteritis, in which inflammation, often transmural, is seen, along with necrosis in the arterial media; multinucleated giant cells, epithelioid macrophages, or both are also present (13). In the adventitia, both VZV infection and GCA lead to local, prominent inflammation. Such proinflammatory environment bathing the anterior optic nerve in the posterior ciliary artery territory can cause a breakdown of blood-optic nerve-barrier and vasculitis leading to A-AION. The tunica adventitia is particularly important in the early phase of the development of GCA and much more is known about the cell-mediated vasculitis in GCA at this location than in VZV vasculopathy. In GCA, T cells interact with endothelial cells in the adventitia in a tightly controlled and antigen-specific manner that shape the evolution of vasculitis through activation of (TH) 1 and (TH) 17 cells, which stimulate chemokine and cytokine production, including interferon g (IFNg), tumor necrosis factor a (TNFa), and interleukins (IL-6 and IL-17) (3,25). In patients with GCA, this process involves upregulation of Jagged1 in adventitial endothelial cells, which synergizes with activation of the Notch receptor and biasing the CD4+ T-cell repertoire toward TH1 and TH17 fate, leading to excessive inflammatory activity, production of cytokines, destructive granulomas, and vessel thrombosis (26). Strikingly, the greatest amount of VZV antigen in TABs from patients with GCA was localized in the tunica adventitia (14). In 58 patients with suspect GCA but biopsy negative, adventitial inflammation and CD45+ cells were seen adjacent to VZV immunoreactivity in 26 (52%), 135 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point which provided the first evidence of VZV pathology in GCA-negative TABs (27). The presence of VZV in the adventitia may contribute to a milieu of vasculitis, which is a critical part of vasculitis development. In 1 study, 1 TAB specimen that was obtained 3 days after the onset of vision loss from A-AION revealed an early, prominent colocalization of the VZV antigen and inflammatory cells, including T cells, activated macrophages, and rare B cells in the adventitia and intima (28). In VZV vasculopathy, the VZV antigen is also found in the adventitia during the early stage of disease from transaxonal spread and later in the media and intima through transmural spread of the virus within the vessel wall (9). This colocalization of the VZV antigen and avid vasculitis in 1 patient with acute A-AION and GCA does not indicate a causal relationship, but it does highlight the important role of the adventitia in the development of vasculitis in both VZV-associated vasculitis and GCA vasculitis. Although the immune milieu that leads to VZV vasculitis is not as well characterized as GCA, in VZV vasculitis, the CSF has significantly elevated proinflammatory cytokines IL-8 and IL-6 along with elevated MMP-2 (29). VZV-infected adventitial cells downregulate the expression of programmed death ligand 1 (PD-L1) in a posttranslational fashion and contribute to persistent vascular inflammation (30). It will be interesting to see whether these molecular and cellular changes can be dampened by antiviral therapy. Con: Sachin Kedar, MD An association between VZV and GCA was demonstrated by a group of investigators studying formalin-fixed paraffinembedded (FFPE) sections of TABs (27). Based on these results, the investigators proposed to empirically treat GCA, with a combination of steroids and oral antiviral medications for 4-12 weeks depending on the initial response. They also proposed treating GCA recurrence during steroid taper by adding antiviral medications to the steroids rather than increasing the steroid dosage. The authors acknowledged that in the absence of randomized or nonrandomized clinical trials, their recommendations were based on "level 5 class of evidence: expert opinion without critical appraisal, or based on physiology, bench research" (13). I will argue that it is premature to consider the empiric use of antiviral medications in GCA. GCA is a chronic, systemic vasculitis of the elderly, affecting medium and large arteries, especially branches of the internal and external carotid artery. Disease manifestation depends on the vascular territory involved and results in end-organ complications such as ischemic optic neuropathy, myocardial infarction, stroke, mesenteric ischemia, and aortitis and aortic aneurysms (31). Long-term corticosteroid therapy remains the mainstay of treatment for GCA but results in considerable treatment-related morbidity and mortality (32-34). Numerous steroid-sparing agents have proven ineffective in GCA (34). Recently, tocilizumab, an IL-6 receptor alpha inhibitor, has shown promise but the rates of systemic infection are high and comparable to those associated with chronic steroid usage (35). There clearly is a need for safer treatment options for GCA. Risk factors for GCA include advanced age, white race, female sex, and geographic distribution. Genetic susceptibility is suggested by an association with genetic polymorphisms of the human leukocyte antigen loci HLA-DRB1*04 and non-HLA loci such as PTPN 22 136 (36). Activation of dendritic cells results in an immunological cascade leading to recruitment of T cells and macrophages within the arterial wall. This leads to granulomatous inflammation within the arterial wall, disruption of internal elastic lamina, necrosis of arterial media, intimal hyperplasia, and luminal obstruction (37). The inciting event for dendritic cell activation has remained elusive; however, an infectious cause has long been suspected based on the cyclical and seasonal fluctuation seen in GCA (38). After sifting through a number of potential agents such as Epstein-Barr virus, parvovirus B19, and Chlamydia pneumonia, VZV has recently emerged as the primary suspect (39). VZV is an exclusive human neurotropic alphaherpesvirus, which produces chickenpox. Greater than 95% of human population demonstrates serological evidence of VZV infection before adolescence. Primary infection results in a lifelong period of latency in the cranial, dorsal root, autonomic, and enteric ganglia. VZV reactivation due to waning of cell-mediated immunity with advancing age or immunocompromised condition, results in replication of the virus in the ganglia and transaxonal spread to the mucocutaneous surfaces where it produces zoster (shingles) in the corresponding dermatome (40). On rare occasions, reactivation produces VZV vasculopathy through direct infection of the arteries and may cause a number of cerebrovascular diseases (13). A group of investigators has proposed that VZV may play a substantial role in causing GCA based on studies performed on FFPE sections of temporal arteries in biopsypositive GCA, biopsy-negative GCA, and postmortem specimens from normal controls (14,22,27). The VZV antigen was detected in the arterial vessel wall using immunohistochemistry in 70% biopsy-positive GCA, 58% biopsy-negative GCA, and 18% normal controls. The VZV antigen was 3.89 times more likely to be present in Liao and Kedar: J Neuro-Ophthalmol 2019; 39: 134-141 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point the vessel wall of biopsy-positive GCA and 3.22 times more likely in biopsy-negative GCA compared with controls. The VZV antigen was found in the perineural cells expressing claudin-1 around nerve bundles adjacent to areas of adventitial inflammation in a majority of GCA-positive biopsy specimens. Based on these observations, the investigators hypothesized that GCA results from transaxonal transport of the reactivated VZV from ganglia to the wall of the temporal artery, resulting in activation of dendritic cells followed by an inflammatory cascade. These results are impressive but do not provide evidence for a causal role of VZV in GCA for the following reasons: Lack of reproducibility Multiple groups of investigators have explored the role of VZV in GCA and only 2 other groups have found evidence of VZV in TAB specimens. VZV DNA was not detected in 13 biopsy-positive and 17 biopsy-negative TAB specimens by Helweg-Larsen et al (39), 15 biopsy-positive and 7 control TAB specimens by Kennedy et al (41), and 50 GCApositive and 97 biopsy-negative TAB specimens by Rodriguez-Pla et al (42). Procop et al (43) also failed to detect VZV DNA using 2 different validated PCR methods in 31 thoracic aorta specimens, including 8 with GCA, and 11 TAB specimens, including 5 with GCA obtained and processed in a surgically sterile manner. Mitchell et al (44) demonstrated VZV DNA in 9/35 (26%) biopsy-positive GCA compared with 0/29 control specimens and proposed an association. Alvarez-Lafuente et al (45) found VZV DNA in 18/57 GCA and 18/56 control TAB specimens and proposed a lack of association between VZV and GCA. Using both immunohistochemistry and PCR methods, Nordborg et al (46) failed to show evidence for VZV DNA or antigen in 10 biopsy-positive TAB specimens, whereas Muratore et al (47) found the VZV antigen in one and VZV DNA in none of the 79 TAB specimens, which included 34 biopsy-positive TAB. Some investigators have questioned the specificity of the antibodies used in the immunohistochemistry studies after finding significant cross-reactivity of VZV antibodies with various muscle tissues due to shared epitopes between VZV protein and muscular elements in the vessel wall (48). Lack of temporal relationship There is no convincing evidence that GCA is preceded by antecedent HZ (49). In a retrospective study of approximately 17 million subjects from 2 large administrative data sets from the United States, only 4% (236/5,942) GCA was preceded by zoster. Although antecedent HZ increased the risk of GCA, there was a variable and significant time lag (months to years) between the 2 events (19). I was unable to find literature that showed an increase in serological markers for VZV in patients with GCA. This not only weakens the hypothesis that VZV causes GCA but also raises serious questions about the rationale and timing for empiric treatment of GCA with antiviral medications. Lack of consistency with epidemiological studies Approximately 1 million new episodes of HZ are estimated to occur annually in the United States with a lifetime risk of 30%. The incidence of HZ across different populations is approximately 4-4.5 per 1,000 person-years and seems to be increasing (50). A causal relationship between VZV and GCA should be reflected by an increasing incidence of GCA. However, the annual incidence of GCA is considerably less (w18 per 100,000 in Olmsted County, Minnesota), varies significantly across different population groups, and does not seem to be increasing (51). Conversely, interventions to decrease VZV reactivation have not led to a decrease in the incidence of GCA. Vaccination using attenuated VZV has been demonstrated to be effective in decreasing the incidence of zoster by at least 50% (52). Studies using large administrative data sets of subjects aged .50 years have not shown a corresponding decrease in the incidence of GCA in the vaccinated versus nonvaccinated populations (19,20). In summary, there seems to be an association between VZV and GCA. The evidence, however, is weak and does not support a causal role for VZV. Using antiviral medications in the management of GCA makes sense only if there is concurrent VZV infection. At present, there is no evidence for a consistent temporal relationship between VZV reactivation and GCA, which makes recommendation for empiric use of antiviral agents for treatment of GCA premature and without sound rationale. Rebuttal: Dr. Liao According to Koch's postulates (53), there is no evidence linking VZV as the causative agent of GCA. The postulates dictate that: 1) the microorganism or other pathogens must be present in all cases of the disease, 2) the pathogen can be isolated from the diseased host and grown in pure culture, 3) the pathogen from the pure culture must cause the disease when inoculated into a healthy, susceptible laboratory animal, and 4) the pathogen must be reisolated from the Liao and Kedar: J Neuro-Ophthalmol 2019; 39: 134-141 new host and shown to be the same as the originally inoculated pathogen, In this case, there is no evidence that any of the 4 postulates are fulfilled. This lack of evidence does not mean that we should deny our patients the benefit of effective, potentially life-saving antiviral therapies. Because of the high prevalence of the VZV antigen in TABs in those with suspect GCA, some have advocated that antivirals should be considered in all 137 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point patients with suspect GCA (8). Even if there is currently insufficient data to support such a position, diagnostic testing for VZV infection or other causes of vasculitis and treatment with antiviral therapy should be considered in all atypical GCA cases. Atypical GCA cases that should prompt consideration of antiviral treatment include those with cerebral involvement or symptoms suggestive of VZV infection. VZV reactivation or infection can present with vascular syndrome as discussed earlier (13) and may also present with meningitis, encephalitis, trigeminal dermatomal zoster, Ramsay Hunt syndrome, retinal necrosis, or transverse myelitis (54). High clinical suspicion of VZV involvement should immediately prompt consideration of antiviral treatment, potentially before diagnostic testing results are available. When prescribed in the right setting, there is a relatively low risk of antiviral therapy in patients who are refractory to traditional treatment. Another reason for supporting the consideration of antiviral therapy in atypical GCA cases is the limited efficacy of current treatment choices for GCA. Although corticosteroid treatment is the mainstay of treatment for GCA, it effectively dampens TH17-mediated responses but not TH1-mediated immune responses (55), and some patients with repeat TAB after long-term corticosteroid treatment still show active disease. As Dr. Kedar pointed out, newer therapies such as tocilizumab are associated with significant side effects, including increased risk of infections (35,56), and there is no evidence that it actually helps save vision. With advancing age and decline in VZV-specific cellmediated immunity, there is a rise in the incidence of HZ (50). The estimated incidence of HZ is 3.4-4.82 per 1,000 person-years in the general population, which increases to more than 11 per 1,000 person-years in those aged above 80 years. In a prospective study of 11 patients with treated GCA compared with 26 age- and sex-matched healthy controls, patients with treated GCA exhibit significantly reduced VZV-specific T-cell-mediated immunity, but no difference in the total number of CD3+ T cells, the frequencies of IFNg-, TNFa, and IL-2-producing CD4+ T cells, the frequency of cytokine-producing CD4+ or CD8+ T cells after stimulation with VZV, or humoral immunity as measured using serum VZV-IgG levels (57). These results mean that in addition to GCA, these patients are at greater risk of VZV infection than agematched healthy controls so VZV vaccination is particularly important in this population. Until the role of VZV in the pathogenesis of GCA is ascertained, the most prudent approach is to be aware of the clinical overlap and to consider the possibility of VZV reactivation and antiviral therapy in those with compelling clinical presentation or in those who are refractive to 138 traditional immunomodulatory therapies. Antiviral treatment with acyclovir or valacyclovir is easy to administer and typically well tolerated. If VZV is contributory to GCA pathogenesis or persistence of granulomatous vasculitis in even a fraction of patients, antiviral therapy has the potential to reduce cell-mediated immunity at the vessels, which may be more effective than corticosteroid treatment, especially because corticosteroids therapy does not appropriately address all of the immune derangements in patients with suspect GCA (3). Another consideration in the treatment of patients with GCA is VZV vaccination, which may increase tolerance and reduce antigen-specific inflammation and vasculitis, although the data are mixed regarding the ability of VZV vaccination to reduce the frequency of GCA (19,20,52,57). The traditional VZV vaccine (Zostavax) contains live attenuated virus, which is not typically recommended for those undergoing immunosuppressive therapy because of concerns of infection and possible reduction in efficacy. The new, non-live attenuated vaccine (Shingrix) is now available, can reduce the risk of infection, and has been shown to be more effective than the live attenuated vaccine. Because of the importance of vaccination in this group of patients and concerns of the impact of immunosuppressive medication, some have even proposed vaccination at the time of GCA diagnosis, before the high-dose corticosteroid becomes effective (57), although this is rarely done. In the United States and many other countries, VZV vaccination is recommended for all adults aged 60 years or above because there is known age-related waning of VZV immunity and because of the increased prevalence of VZV reactivation such as shingles even in immunocompetent individuals. The traditional VZV vaccine (Zostavax) is a live attenuated virus that is the same strain as the varicella vaccine (Viravax) that is recommended for children but is 14 times more potent. Because vaccination with live attenuated virus is not recommended for those undergoing immunomodulatory therapy, vaccination is not recommended in the acute phase of GCA. However, once patients are out of the acute phase of disease and no longer undergoing highdose corticosteroid treatment, vaccination can be considered. Alternatively, the new adjuvanted recombinant subunit HZ vaccine is associated with a lower risk of infection than the live attenuated virus and is believed to be more effective (52,58,59). Because patients with GCA have reduced cell-mediated immunity to VZV, as measured by interferon g (IFNg) enzyme-linked immunospot and intracellular cytokine flow cytometry measurements, VZV vaccination in the nonacute setting may help reduce relapse in patients with GCA (57). Liao and Kedar: J Neuro-Ophthalmol 2019; 39: 134-141 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Rebuttal: Dr. Kedar Dr. Liao and I agree that recent literature supports a clinical and histological overlap between VZV and GCA. Let us consider these 3 possibilities regarding the association between VZV and GCA: 1. Innocent bystander: Nearly all humans harbor the VZV virus lifelong, in a latent state within ganglia, along the entire neuraxis after primary infection. A significant number will have VZV reactivation during their lifetime, but a much smaller number develop GCA. Because both VZV reactivation and GCA are diseases of the elderly, it is possible that VZV was "in the wrong place at the wrong time." In this scenario, treatment of GCA with antivirals would not be justified. 2. Indirect causation: The clinical, immunological, and histopathological overlap between VZV and GCA suggests that the role of VZV may be more than an "innocent bystander." Whether VZV triggers the immunopathology of GCA or vice versa is not clear. A recent study found that GCA might cause decreased immunity to VZV (57). Assuming VZV triggers immunopathology of GCA, the time to clinical presentation remains unknown. Patients with GCA do not have elevated serological markers for a recent VZV infection. In this scenario, concurrent use of antiviral treatment in all GCA cannot be justified. 3. Direct causation: Except a few case reports, which show VZV vasculopathy causing cerebrovascular events including ischemic optic neuropathy, there is no evidence that VZV is immediately responsible for GCA. Unless there is serological or biopsy evidence for recent and/or concurrent VZV reactivation, there is no rationale for treating primary, recurrent, or intractable GCA with antiviral medications. Finally, let us not forget that we have been down this road before. A number of microorganisms such as Chlamydia pneumonia, parvovirus B19, human papillomavirus, and Burkholderia-like bacterium have all been assigned blame for triggering GCA pathogenesis (60). None of these agents currently have a proven role in the pathogenesis (or management) of GCA. The current antiviral medications such as acyclovir and valacyclovir are safe to administer, but this should not be a justification for empiric treatment in GCA. As discussed, none of the 3 scenarios described above would support the use of antiviral treatment for GCA at present. Rather, all of these scenarios support VZV vaccination in the elderly. Conclusions: Drs. Lee and Van Stavern The overlap in histopathology and clinical manifestations between VZV vasculopathy and GCA are suggestive of an association but not necessarily a causal association. 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