Varicella zoster virus (VZV) reactivation results in zoster, which may be complicated by postherpetic neuralgia, myelitis, meningoencephalitis, and VZV vasculopathy. This review highlights the ...clinical features, laboratory abnormalities, imaging changes, and optimal treatment of each of those conditions. Because all of these neurological disorders produced by VZV reactivation can occur in the absence of rash, the virological tests proving that VZV caused disease are discussed.
After primary infection, VZV becomes latent in ganglionic neurons along the entire neuraxis. With a decline in VZV-specific cell-mediated immunity, VZV reactivates from ganglia and travels anterograde to the skin to cause zoster, which is often complicated by postherpetic neuralgia. VZV can also travel retrograde to produce meningoencephalitis, myelitis, and stroke. When these complications occur without rash, VZV-induced disease can be diagnosed by detection of VZV DNA or anti-VZV antibody in cerebrospinal fluid and treated with intravenous acyclovir.
Awareness of the expanding spectrum of neurological complications caused by VZV reactivation with and without rash will improve diagnosis and treatment.
Abstract Varicella zoster virus (VZV) is a ubiquitous, human alphaherpesvirus that produces varicella on primary infection then becomes latent in ganglionic neurons along the entire neuraxis. In ...elderly and immunocompromised individuals, VZV reactivates and travels along nerve fibers peripherally resulting in zoster. However, VZV can also spread centrally and infect cerebral and extracranial arteries (VZV vasculopathy) to produce transient ischemic attacks, stroke, aneurysm, sinus thrombosis and giant cell arteritis, as well as granulomatous aortitis. The mechanisms of virus-induced pathological vascular remodeling are not fully elucidated; however, recent studies suggest that inflammation and dysregulation of programmed death ligand-1 play a significant role.
PURPOSE OF REVIEWVaricella zoster virus (VZV) causes varicella, establishes latency, then reactivates to produce herpes zoster. VZV reactivation can also cause central nervous system (CNS) disease ...with or without rash. Herein, we review these CNS diseases, pathogenesis, diagnosis, and treatment.
RECENT FINDINGSThe most common CNS manifestation of VZV infection is vasculopathy that presents as headache, cognitive decline, and/or focal neurological deficits. VZV vasculopathy has also been associated with cerebral amyloid angiopathy and moyamoya syndrome. Rarely, VZV will produce a meningitis, encephalitis, cerebellitis, and myelopathy. Pathogenic mechanisms include direct VZV infection of affected tissue, persistent inflammation, and/or virus-induced hypercoagulability. Diagnosis is confirmed by the temporal association of rash to disease onset, intrathecal synthesis of anti-VZV antibodies, and/or the presence of VZV DNA in CSF. Most cases respond to intravenous acyclovir with corticosteroids.
SUMMARYVZV produces a wide spectrum of CNS disorders that may be missed as some cases do not have an associated rash or a CSF pleocytosis. Clinicians must be vigilant in including VZV in their differential diagnosis of CNS infections as VZV is a ubiquitous pathogen; importantly, VZV CNS infections are treatable with intravenous acyclovir therapy and corticosteroids.
Varicella Zoster Virus Vasculopathy Nagel, Maria A; Bubak, Andrew N
The Journal of infectious diseases,
09/2018, Letnik:
218, Številka:
suppl_2
Journal Article
Recenzirano
Odprti dostop
Varicella zoster virus (VZV) is a ubiquitous, exclusively human alphaherpesvirus that produces varicella then becomes latent in ganglionic neurons. In elderly and immunocompromised individuals, VZV ...reactivates and typically produces herpes zoster. Studies of patients with VZV vasculopathy have identified key clinical, imaging, and laboratory features to assist in diagnosis and treatment. Complementary studies have further expanded the spectrum of VZV vasculopathy to include the extracranial circulation and identified mechanisms contributing to its pathogenesis. Given our increasing aging population and recognition that VZV reactivation manifesting as zoster is a risk factor for stroke and myocardial infarction, recognition of VZV as a potential cause of vascular disease with or without associated zoster rash is essential to decrease associated morbidity and mortality because VZV vasculopathy can be treated with antiviral therapy.
Summary Vasculopathies caused by varicella zoster virus (VZV) are indicative of a productive virus infection in cerebral arteries after either reactivation of VZV (shingles) or primary infection ...(chickenpox). VZV vasculopathy can cause ischaemic infarction of the brain and spinal cord, as well as aneurysm, subarachnoid and cerebral haemorrhage, carotid dissection, and, rarely, peripheral arterial disease. VZV vasculopathy in immunocompetent or immunocompromised individuals can be unifocal or multifocal with deep-seated and superficial infarctions. Lesions at the grey–white matter junction on brain imaging are a clue to diagnosis. Involvement of both large and small arteries is more common than that of either alone. Most patients have a mononuclear cerebrospinal fluid pleocytosis, often with red blood cells. Cerebrospinal fluid pleocytosis and rash are absent in about a third of cases. Anti-VZV IgG antibody in the cerebrospinal fluid is found more frequently than VZV DNA. In recent years, the number of recognised VZV vasculopathies has grown, and accurate diagnosis is important for the effective treatment of these disorders.
PURPOSE OF REVIEWGiant cell arteritis (GCA) is a severe form of vasculitis in the elderly. The recent discovery of varicella zoster virus (VZV) in the temporal arteries and adjacent skeletal muscle ...of patients with GCA, and the rationale and strategy for antiviral and corticosteroid treatment for GCA are reviewed.
RECENT FINDINGSThe clinical features of GCA include excruciating headache/head pain, often with scalp tenderness, a nodular temporal arteries and decreased temporal artery pulsations. Jaw claudication, night sweats, fever, malaise, and a history of polymyalgia rheumatica (aching and stiffness of large muscles primarily in the shoulder girdle, upper back, and pelvis without objective signs of weakness) are common. ESR and CRP are usually elevated. Diagnosis is confirmed by temporal artery biopsy which reveals vessel wall damage and inflammation, with multinucleated giant cells and/or epithelioid macrophages. Skip lesions are common. Importantly, temporal artery biopsies are pathologically negative in many clinically suspect cases. This review highlights recent virological findings in temporal arteries from patients with pathologically verified GCA and in temporal arteries from patients who manifest clinical and laboratory features of GCA, but whose temporal artery biopsies (Bx) are pathologically negative for GCA (Bx-negative GCA). Virological analysis revealed that VZV is present in most GCA-positive and GCA-negative temporal artery biopsies, mostly in skip areas that correlate with adjacent GCA pathology.
SUMMARYThe presence of VZV in Bx-positive and Bx-negative GCA temporal arteries indicates that VZV triggers the immunopathology of GCA. However, the presence of VZV in about 20% of temporal artery biopsies from non-GCA postmortem controls also suggests that VZV alone is not sufficient to produce disease. Treatment trials should be performed to determine if antiviral agents confer additional benefits to corticosteroids in both Bx-positive and Bx-negative GCA patients. These studies should also examine whether oral antiviral agents and corticosteroids are as effective as intravenous acyclovir and corticosteroids. Appropriate dosage and duration of treatment also remain to be determined.
Macrophage accumulation is not only a characteristic hallmark but is also a critical component of pulmonary artery remodeling associated with pulmonary hypertension (PH). However, the cellular and ...molecular mechanisms that drive vascular macrophage activation and their functional phenotype remain poorly defined. Using multiple levels of in vivo (bovine and rat models of hypoxia-induced PH, together with human tissue samples) and in vitro (primary mouse, rat, and bovine macrophages, human monocytes, and primary human and bovine fibroblasts) approaches, we observed that adventitial fibroblasts derived from hypertensive pulmonary arteries (bovine and human) regulate macrophage activation. These fibroblasts activate macrophages through paracrine IL-6 and STAT3, HIF1, and C/EBPβ signaling to drive expression of genes previously implicated in chronic inflammation, tissue remodeling, and PH. This distinct fibroblast-activated macrophage phenotype was independent of IL-4/IL-13-STAT6 and TLR-MyD88 signaling. We found that genetic STAT3 haplodeficiency in macrophages attenuated macrophage activation, complete STAT3 deficiency increased macrophage activation through compensatory upregulation of STAT1 signaling, and deficiency in C/EBPβ or HIF1 attenuated fibroblast-driven macrophage activation. These findings challenge the current paradigm of IL-4/IL-13-STAT6-mediated alternative macrophage activation as the sole driver of vascular remodeling in PH, and uncover a cross-talk between adventitial fibroblasts and macrophages in which paracrine IL-6-activated STAT3, HIF1α, and C/EBPβ signaling are critical for macrophage activation and polarization. Thus, targeting IL-6 signaling in macrophages by completely inhibiting C/EBPβ or HIF1α or by partially inhibiting STAT3 may hold therapeutic value for treatment of PH and other inflammatory conditions characterized by increased IL-6 and absent IL-4/IL-13 signaling.
Varicella zoster virus (VZV) is a lymphotropic alpha-herpesvirinae subfamily member that produces varicella on primary infection and causes zoster, vascular disease and vision loss upon reactivation ...from latency. VZV-infected peripheral blood mononuclear cells (PBMCs) disseminate virus to distal organs to produce clinical disease. To assess immune evasion strategies elicited by VZV that may contribute to dissemination of infection, human PBMCs and VZV-specific CD8+ T cells (V-CD8+) were mock- or VZV-infected and analyzed for immunoinhibitory protein PD-1, PD-L1, PD-L2, CTLA-4, LAG-3 and TIM-3 expression using flow cytometry. All VZV-infected PBMCs (monocytes, NK, NKT, B cells, CD4+ and CD8+ T cells) and V-CD8+ showed significant elevations in PD-L1 expression compared to uninfected cells. VZV induced PD-L2 expression in B cells and V-CD8+. Only VZV-infected CD8+ T cells, NKT cells and V-CD8+ upregulated PD-1 expression, the immunoinhibitory receptor for PD-L1/PD-L2. VZV induced CTLA-4 expression only in V-CD8+ and no significant changes in LAG-3 or TIM-3 expression were observed in V-CD8+ or PBMC T cells. To test whether PD-L1, PD-L2 or CTLA-4 regulates V-CD8+ effector function, autologous PBMCs were VZV-infected and co-cultured with V-CD8+ cells in the presence of blocking antibodies against PD-L1, PD-L2 or CTLA-4; ELISAs revealed significant elevations in IFNγ only upon blocking of PD-L1. Together, these results identified additional immune cells that are permissive to VZV infection (monocytes, B cells and NKT cells); along with a novel mechanism for inhibiting CD8+ T cell effector function through induction of PD-L1 expression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Varicella zoster virus (VZV) is a highly neurotropic human herpesvirus. Primary infection usually causes varicella (chicken pox), after which virus becomes latent in ganglionic neurons along the ...entire neuraxis. VZV reactivation results in zoster (shingles) which is frequently complicated by chronic pain (postherpetic neuralgia). VZV reactivation also causes meningoencephalitis, myelitis, ocular disorders, and vasculopathy, all of which can occur in the absence of rash. This review focuses on the association of VZV and stroke, and on the widening spectrum of disorders produced by VZV vasculopathy in immunocompetent and immunocompromised individuals, including recipients of varicella vaccine. Aside from ischemic stroke, VZV infection of cerebral arteries may lead to development of intracerebral aneurysms, with or without hemorrhage. Moreover, recent clinical-virological case reports and retrospective pathological-virological analyses of temporal arteries positive or negative for giant cell arteritis (GCA) indicate that extracranial VZV vasculopathy triggers the immunopathology of GCA. While many patients with GCA improve after corticosteroid treatment, prolonged corticosteroid use may potentiate VZV infection, leading to fatal vasculopathy in the brain and other organs.
Varicella zoster virus (VZV) vasculopathy is caused by productive virus infection of cerebral arteries, leading to inflammation, pathological vascular remodeling, and ischemic or hemorrhagic stroke. ...VZV vasculopathy occurs in immunocompetent and immunocompromised individuals and involves both large and small vessels. MRI abnormalities include more deep-seated than superficial lesions, particularly at gray–white matter junctions, and lesions may enhance. Diagnosis is challenging, since stroke can occur months after zoster rash and in the absence of rash or CSF pleocytosis. The best virological test for diagnosis is detection of anti-VZV IgG antibody in the CSF. Pathological studies of VZV-infected arteries from patients with VZV vasculopathy reveal that the arterial adventitia is the initial site of infection, after which virus spreads transmuraly towards the lumen. Histological and immunohistochemical studies of VZV-infected arteries show a thickened intima, disrupted internal elastic lamina, and loss of smooth muscle cells, that likely contribute to weakening of the vessel wall and occlusion. Early in disease, VZV-infected arteries contain CD4+ and CD8+ T cells, macrophages, and rare B cells, in addition to abundant neutrophils in early disease. Importantly, perivascular inflammatory cells underlie the areas of thickened intima, raising the possibility that soluble factors secreted by these cells contribute to arterial remodeling. This review discusses the clinical features of VZV vasculopathy and potential mechanisms of VZV-induced cerebrovascular remodeling and stroke.
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