Alexander Choe

Varicella zoster virus vasculopathy: analysis of virus-infected arteries.

Objective: Varicella zoster virus (VZV) is an under-recognized yet treatable cause of stroke. No animal model exists for stroke caused by VZV infection of cerebral arteries. Thus, we analyzed cerebral and temporal arteries from 3 patients with VZV vasculopathy to identify features that will help in diagnosis and lead to a better understanding of VZV-induced vascular remodeling. Methods: Normal and VZV-infected cerebral and temporal arteries were examined histologically and by immunohistochemistry using antibodies directed against VZV, endothelium, and smooth muscle actin and myosin. Results: All VZV-infected arteries contained 1) a disrupted internal elastic lamina; 2) a hyperplastic intima composed of cells expressing α-smooth muscle actin (α-SMA) and smooth muscle myosin heavy chain (SM-myosin) but not endothelial cells expressing CD31; and 3) decreased medial smooth muscle cells. The location of VZV antigen, degree of neointimal thickening, and disruption of the media were related to the duration of disease. Conclusions: The presence of VZV primarily in the adventitia early in infection and in the media and intima later supports the notion that after reactivation from ganglia, VZV spreads transaxonally to the arterial adventitia followed by transmural spread of virus. Disruption of the internal elastic lamina, progressive intimal thickening with cells expressing α-SMA and SM-MHC, and decreased smooth muscle cells in the media are characteristic features of VZV vasculopathy. Stroke in VZV vasculopathy may result from changes in arterial caliber and contractility produced in part by abnormal accumulation of smooth muscle cells and myofibroblasts in thickened neointima and disruption of the media.

Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis

Objective: Varicella-zoster virus (VZV) infection may trigger the inflammatory cascade that characterizes giant cell arteritis (GCA). Methods: Formalin-fixed, paraffin-embedded GCA-positive temporal artery (TA) biopsies (50 sections/TA) including adjacent skeletal muscle and normal TAs obtained postmortem from subjects >50 years of age were examined by immunohistochemistry for presence and distribution of VZV antigen and by ultrastructural examination for virions. Adjacent regions were examined by hematoxylin & eosin staining. VZV antigen–positive slides were analyzed by PCR for VZV DNA. Results: VZV antigen was found in 61/82 (74%) GCA-positive TAs compared with 1/13 (8%) normal TAs (p < 0.0001, relative risk 9.67, 95% confidence interval 1.46, 63.69). Most GCA-positive TAs contained viral antigen in skip areas. VZV antigen was present mostly in adventitia, followed by media and intima. VZV antigen was found in 12/32 (38%) skeletal muscles adjacent to VZV antigen–positive TAs. Despite formalin fixation, VZV DNA was detected in 18/45 (40%) GCA-positive VZV antigen–positive TAs, in 6/10 (60%) VZV antigen–positive skeletal muscles, and in one VZV antigen–positive normal TA. Varicella-zoster virions were found in a GCA-positive TA. In sections adjacent to those containing VZV, GCA pathology was seen in 89% of GCA-positive TAs but in none of 18 adjacent sections from normal TAs. Conclusions: Most GCA-positive TAs contained VZV in skip areas that correlated with adjacent GCA pathology, supporting the hypothesis that VZV triggers GCA immunopathology. Antiviral treatment may confer additional benefit to patients with GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

Varicella-Zoster Virus Transcriptome in Latently Infected Human Ganglia

ABSTRACT We recently developed a novel multiplex reverse transcription (RT)-PCR assay that allows rapid and sensitive detection of transcripts corresponding to all 68 unique varicella-zoster virus (VZV) open reading frames (ORFs) in only five amplification reactions (M. A. Nagel, D. Gilden, T. Shade, B. Gao, and R. J. Cohrs, J. Virol. Methods 157:62-68, 2009). Herein, we applied multiplex RT-PCR analysis to mRNA extracted from 26 trigeminal ganglia latently infected with VZV and one control trigeminal ganglion negative for VZV DNA that were removed from 14 men and women, 16 to 84 years of age, within 24 h after death. Analysis identified VZV transcripts mapping to VZV ORFs 29, 62, and 63, previously detected and sequence verified; VZV ORFs 4 and 40, previously detected by in situ hybridization; and VZV ORFs 11, 41, 43, 57, and 68, not previously detected. VZV ORF 63 transcripts were the most prevalent. Comparison of the 10 VZV ORFs transcribed during latency to their herpes simplex virus type 1 homologues reveals that the latently transcribed VZV genes encode immediate-early, early, and late transcripts.

Multifocal VZV vasculopathy with temporal artery infection mimics giant cell arteritis

Objective: To address the incidence of varicella-zoster virus (VZV) infection in patients with biopsy-negative giant cell arteritis (GCA), we examined archived biopsy-negative temporal arteries from subjects with clinically suspected GCA for the presence of VZV antigen. Methods: Formalin-fixed, paraffin-embedded temporal arteries that were pathologically negative for GCA and normal temporal arteries were analyzed immunohistochemically for VZV and herpes simplex virus-1 (HSV-1) antigen. Results: Five (21%) of 24 temporal arteries from patients who were clinically suspect but biopsy negative for GCA revealed VZV but not HSV-1 by immunohistochemical analysis. Thirteen normal temporal arteries did not contain VZV or HSV-1 antigen. All 5 subjects whose temporal arteries contained VZV antigen presented with clinical and laboratory features of GCA and early visual disturbances. Conclusion: Multifocal VZV vasculopathy can present with the full spectrum of clinical features and laboratory abnormalities characteristically seen in GCA.

Varicella-zoster virus vasculopathy Immune characteristics of virus-infected arteries

ABSTRACT Objective: Pathologic changes in varicella-zoster virus (VZV)–infected arteries include inflammation, thickened intima, and paucity of smooth muscle cells. Since no criteria have been established for early vs late VZV vasculopathy, we examined inflammatory cells and their distribution in 6 normal arteries, and 2 VZV-infected arteries 3 days after onset of disease (early) and 10 months after protracted neurologic disease (late). Methods: VZV-infected temporal artery obtained 3 days after onset of ischemic optic neuropathy from an 80-year-old man, VZV-infected middle cerebral artery (MCA) obtained 10 months after protracted disease from a 73-year-old man, and 5 MCAs and 1 temporal artery from normal subjects, age 22–60 years, were examined histologically and immunohistochemically using antibodies against VZV and inflammatory cell subsets. Results: In both early and late VZV vasculopathy, T cells, activated macrophages, and rare B cells were found in adventitia and intima. In adventitia of early VZV vasculopathy, neutrophils and VZV antigen were abundant and a thickened intima was associated with inflammatory cells in vaso vasorum vessels. In media of late VZV vasculopathy, viral antigen, but not leukocytes, was found. VZV was not seen in inflammatory cells. Inflammatory cells were absent in control arteries. Conclusions: Both VZV and neutrophils exclusively in adventitia in early VZV vasculopathy indicate that disease begins there. Late VZV vasculopathy is distinguished by viral antigen without inflammation in media, revealing a human virus in an immunoprivileged arterial media. Association of thickened intima and inflammation in vaso vasorum vessels in early VZV vasculopathy support the role of virus-induced inflammation in vessel wall remodeling.

Restricted varicella-zoster virus transcription in human trigeminal ganglia obtained soon after death

ABSTRACT We analyzed the varicella-zoster virus (VZV) transcriptome in 43 latently infected human trigeminal ganglia (TG) with postmortem intervals (PMIs) ranging from 3.7 to 24 h. Multiplex reverse transcriptase PCR (RT-PCR) revealed no VZV transcripts with a PMI of <9 h. Real-time PCR indicated a significant increase (P = 0.02) in VZV ORF63 transcript levels but not the virus DNA burden with longer PMI. Overall, both the breadth of the VZV transcriptome and the VZV ORF63 transcript levels in human cadaver TG increased with longer PMI.

Varicella zoster virus in the temporal artery of a patient with giant cell arteritis

We recently detected varicella zoster virus (VZV) in the temporal arteries (TA) of 5/24 patients with clinically suspect giant cell arteritis (GCA) whose TAs were GCA-negative pathologically; in those GCA-negative, VZV+TAs, virus antigen predominated in the arterial adventitia, but without medial necrosis and multinucleated giant cells. During our continuing search for VZV antigen in GCA-negative TAs, in the TA of one subject, we found abundant VZV antigen, as well as VZV DNA, in multiple regions (skip areas) of the TA spanning 350 μm, as well as in skeletal muscle adjacent to the infected TA. Additional pathological analysis of sections adjacent to those containing viral antigen revealed inflammation involving the arterial media and abundant multinucleated giant cells characteristic of GCA. Detection of VZV in areas of the TA with pathological features of GCA warrants further correlative pathological-virological analysis of VZV in GCA.

Editor's Choice: Persistence of Varicella Zoster Virus DNA in Saliva After Herpes Zoster

Analysis of saliva samples from individuals aged ≥ 60 years who had a history of zoster (group 1), zoster and postherpetic neuralgia (PHN; group 2), or no history of zoster (group 3) revealed varicella zoster virus (VZV) DNA in saliva samples from 11 of 17 individuals in group 1, 10 of 15 individuals in group 2, and 2 of 17 individuals in group 3. The frequency of VZV DNA detection was significantly higher (P = .001) in saliva of subjects with a history of zoster, with or without PHN (21 [67%] of 32 subjects in groups 1 and 2), than in saliva of age-matched subjects with no zoster history (2 [12%] of 17 subjects in group 3). Thus, persistence of VZV DNA in saliva is the outcome of zoster, independent of PHN. Because VZV infection can produce neurological and ocular disease without zoster rash, future studies are needed to establish whether VZV DNA can be detected in the saliva of such patients.

VZV multifocal vasculopathy with ischemic optic neuropathy, acute retinal necrosis and temporal artery infection in the absence of zoster rash

We describe a 54-year-old diabetic woman who developed ischemic optic neuropathy followed by acute retinal necrosis and multiple areas of focal venous beading. Vitreous fluid contained amplifiable VZV DNA but not HSV-1, CMV or toxoplasma DNA. The clinical presentation was remarkable for jaw claudication and intermittent scalp pain, prompting a temporal artery biopsy that was pathologically negative for giant cell arteritis, but notable for VZV antigen. The current case adds to the clinical spectrum of multifocal VZV vasculopathy. The development of acute VZV retinal necrosis after ischemic optic neuropathy supports the notion that vasculitis is an important additional mechanism in the development of VZV retinal injury.

Frequency and Abundance of Alphaherpesvirus DNA in Human Thoracic Sympathetic Ganglia

ABSTRACT Alphaherpesvirus reactivation from thoracic sympathetic ganglia (TSG) and transaxonal spread to target organs cause human visceral disease. Yet alphaherpesvirus latency in TSG has not been well characterized. In this study, quantitative PCR detected varicella-zoster virus (VZV), herpes simplex virus 1 (HSV-1), and HSV-2 DNA in 117 fresh TSG obtained postmortem from 15 subjects. VZV DNA was found in 76 (65%) ganglia from all subjects, HSV-1 DNA was found in 5 (4%) ganglia from 3 subjects, and no HSV-2 was found.