Varicella-zoster virus vasculopathy

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. In varicella-zoster virus (VZV) vasculopathy, virus-infected regions are associated with a thickened intima composed of myofibroblasts, a paucity of smooth muscle cells in media, and disruption of internal elastic lamina.1 Similar morphologic changes have been found in other vascular diseases, such as pulmonary arterial hypertension (PAH) and atherosclerosis, 2 in which inflammation has emerged as a pathogenic component. For example, in PAH, inflammatory cells surrounding pulmonary artery lesions secrete CX3CL1, which induces vascular smooth muscle cell (VSMC) proliferation.3 In atherosclerosis, activated macrophages, in addition to other cells, secrete platelet-derived growth factor-BB and insulin-like growth factor-I, which promote VSMC migration 4 ; interleukin-1B also promotes VSMC proliferation. 5,6 We hypothesize that 1) after reactivation from trigeminal ganglia, virus spreads transaxonally to infect the adventitia, followed by transmural migration to the media 1,7 ; 2) inflammatory cells are recruited to virus-infected sites; and 3) inflammatory cells secrete factors that contribute to vessel wall changes seen in VZV vasculopathy. Characterization of immune cells involved in VZV vasculopathy could elucidate mechanisms of VZV-induced vascular remodeling and identify potential targets for therapy.

Inflammatory and Immune Responses in the Arterial Media

“…63 Although viral infection of large arteries in humans is rare, cerebral vasculopathy caused by infection with varicella zoster α-herpesvirus is similarly distinguished by viral antigen expression without inflammation of the media accompanied by accumulation of leukocytes in the intima and adventitia. 64,65 We have interpreted the medial sparing of leukocytic infiltrates in arteriosclerosis as consistent with immunoprivilege of this vascular compartment in noninfectious human diseases. Most atherosclerotic and transplant vasculopathy lesions display a paucity of infiltrating leukocytes and viable VSMCs within the media, although these benign features are overshadowed by the more impressive pathology of adjacent vascular compartments.…”

Varicella-Zoster Virus Downregulates Programmed Death Ligand 1 and Major Histocompatibility Complex Class I in Human Brain Vascular Adventitial Fibroblasts, Perineurial Cells, and Lung Fibroblasts

“…Persistent inflammation with a predominance of T cells and macrophages can be seen even up to 10 months after disease onset and is associated with pathological vascular remodeling (10). The mechanism(s) by which inflammatory cells persist to cause vascular damage in VZV-infected arteries is unknown.…”

Herpes zoster ophthalmicus and varicella zoster virus vasculopathy

“…Since then, there have been numerous reports of infarcts in the cerebrum, cerebellum, midbrain, and pons after HZ or varicella infection (30) . More recently, active viral infection has been shown in large and small arteries of patients with VZV vasculopathy (31) , leading to the clinical spectrum expanding beyond typical hemiplegia to include other signs and symptoms, such as headache, fever, cognitive changes, transient ischemic attacks (TIAs), temporal arteritis (32) , and focal neurologic deficits (17) (Table 2). However, specific vascular involvement varies widely, and associated TIAs may also evolve into a variety of vascular events, including single, bilateral, or multiple ischemic/hemorrhagic infarcts; aneurysms; cerebral or subarachnoid hemorrhages (33)(34)(35) ; or infarcts of the basal ganglia or internal capsule (36) .…”