Varicella Zoster Virus and Giant Cell Arteritis

When an effective vaccine is deployed in a population, the infectious agent ought to disappear or almost disappear, unless the vaccine is a live agent, which can become latent and subsequently reactivate. The live attenuated varicella zoster virus (VZV) vaccine, for example, has greatly reduced the prevalence of varicella; however, vOka, the vaccine virus, establishes latency and can reactivate to give rise to zoster [1]. The varicella vaccine was licensed in the United States in 1995. This event and the consequent near-universal administration of the vaccine caused the incidence of varicella to decline by >90% [2]; nevertheless, the incidence of zoster has not declined significantly over the same period [1]. Both wild-type (WT) VZV and vOka are now causes of zoster [3]. Fortunately, however, the reduction in both circulating VZV and the prevalence of varicella have not also caused a massive increase in the incidence of zoster that was feared on the basis of models that assumed that continuous contact with circulating VZV was necessary to maintain immunity [4]. In fact, the incidence of zoster had already been increasing as a result of the introduction of immunosuppressive therapeutic modalities in the 1950s, which preceded varicella vaccination, and the adoption of universal varicella vaccination did not alter the trajectory of this rise. It, thus, does not appear to be necessary to subject children continually to varicella to protect adults from zoster [5, 6]. The incidence of zoster is probably increasing as a function of many factors of modern life, including the aging of the population, and improved ascertainment, as well as a greater use of immunosuppressive therapy to treat individuals with cancer or autoimmune illnesses and recipients of organ transplants [5]. Although a live attenuated zoster vaccine that also uses vOka is available for healthy individuals aged >60 years, it is not widely used and is at best only 50%–60% effective in preventing zoster. Its protective efficacy, moreover, lasts only about 8 years [7]. The zoster vaccine shares the ability of the varicella vaccines to cause zoster, although the vaccine virus does so less frequently than WT VZV [3, 8, 9]. Despite the availability of effective vaccines against it, VZV continues to be, paradoxically, a serious pathogen with expensive outcomes, owing to the considerable morbidity and even some mortality it causes. Recent discoveries have made it clear that VZV is a dangerous virus that does not deserve its reputation is a generally nonthreatening virus. Gilden, Nagel, and their colleagues have demonstrated that the reactivation of VZV can cause significant damage to the vascular system [10–13]. VZV famously establishes latency in dorsal root ganglia and cranial nerve ganglia and then, when it reactivates, transmits infection to the epidermis to give rise to the infectious rash of zoster [14]. Zoster occurs in a dermatomal distribution because the neurons within which it reactivates project to these regions of the skin. VZV, however, also establishes latency in ganglia that do not project to the skin, including neurons of the sympathetic, parasympathetic [15], and enteric nervous systems [16, 17]. When VZV reactivates in these neurons, a secondary infection (a form of zoster) will occur in sites to which these neurons project. Presence at those sites leads to occult infections, which are difficult to diagnose because they are not associated with the rash that is almost universally but erroneously expected to accompany zoster [18]. The arteries that sympathetic neurons innervate, and the gastrointestinal wall, which enteric neurons innervate, are, thus, targets for reactivating VZV to infect. The development of polymerase chain reaction analysis made diagnosis of VZV without rash possible because VZV DNA can be detected in cerebrospinal fluid, arterial walls, gut, and other infected tissues and fluids [16, 18]. About 20 years ago, Don Gilden and his colleagues became intrigued by the presence of giant cells in granulomatous arteritis, which suggested that the disorder might be due to a viral infection [19]. They studied cerebral arteries in a patient who had died from vasculitis and found both VZV DNA and VZV antigens in the tissue. There was no evidence of cytomegalovirus or herpes simplex virus infection in this patient. The Gilden group went on to find evidence of productive VZV infection, including identification of viral particles, in intracerebral vasculopathy, which can lead to strokes [10, 20].The age of people inwhom granulomatous arteritis syndromes (temporal arteritis, intracranial vasculopathy, giant cell arteritis, and Takayasu aortitis) occur is often >50 years, which is consistent with the idea that these syndromes Received and accepted 15 March 2016. Correspondence: A. A. Gershon, Department of Pediatrics, Columbia University P&S, 622 W 168th St, New York, NY 10032 (aag1@columbia.edu). The Journal of Infectious Diseases © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com. DOI: 10.1093/infdis/jiw110