The association between human herpesvirus infections and stroke: a systematic review protocol

Forbes, Harriet; Benjamin, Laura; Breuer, Judith; Brown, Martin M.; Langan, Sinéad; Minassian, Caroline; Smeeth, Liam; Thomas, Sara L; Warren‐Gash, Charlotte

doi:10.1136/bmjopen-2017-016427

Cited by 4 publications

(7 citation statements)

References 20 publications

(19 reference statements)

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“…Recurrent reactivation from this reservoir, which is peripheral ganglia, can cause debilitating and potentially life‐threatening disease 30 . Periodic virus reactivation can lead to serious inflammatory complications 31 …”

Section: Discussionmentioning

confidence: 99%

Assessment of anti‐HSV antibodies in patients with facial palsy in the course of neuroborreliosis

et al. 2020

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Aim There are many causes of facial nerve palsy. The most common causes are neuroborreliosis (NB), idiopathic paralysis or Herpes simplex virus (HSV) reactivation. The aim of this study was to characterize patients with facial palsy in the course of NB and to determine whether HSV‐1 reactivation takes place during the acute phase of NB. Methods A retrospective analysis of 66 patients with facial nerve palsy was performed. In 38 patients, facial palsy was caused by Borrelia burgdorferi sl infection. Immunological tests for HSV‐1, tick‐borne encephalitis virus and B burgdorferi sl in serum and cerebrospinal fluid (CSF) were performed. Results In this analysis, 55.2% of NB patients had right nerve palsy and 21% bilateral palsy; 15.8% of patients had erythema migrans (EM). Lymphocytic meningitis was diagnosed in 92% of patients and Bannwarth's syndrome was diagnosed in 47% of patients. IgM anti‐HSV‐1 antibodies were detected in four patients with NB and two patients with facial nerve palsy of other origin. IgM anti‐HSV‐1 antibodies were detected in the CSF of three patients (7.9%) with NB, and one of them had bilateral VII paresis and EM simultaneously. Treatment with ceftriaxone or doxycycline led to complete recovery. Conclusions Neuroborreliosis should always be considered as a cause of peripheral facial nerve palsy. Peripheral facial nerve palsy is a significant symptom in the course of NB, especially in patients accompanied by meningitis. Pathomechanism of facial nerve paresis has not been well explained so far and may depend on two independent mechanisms in NB, including HSV‐1 reactivation.

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Section: Discussionmentioning

confidence: 99%

Assessment of anti‐HSV antibodies in patients with facial palsy in the course of neuroborreliosis

et al. 2020

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“…The protocol was published[ 11 ] according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses Protocols guidelines (PROSPERO registration number:CRD42017054502).…”

Section: Methodsmentioning

confidence: 99%

Association of herpesviruses and stroke: Systematic review and meta-analysis

et al. 2018

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BackgroundHerpesviruses induce a range of inflammatory effects potentially contributing to an increased risk of stroke.ObjectivesTo investigate whether patients with infection, or reactivation of, human herpesviruses are at increased stroke risk, compared to those without human herpesviruses.Data sourcesSix medical databases and grey literature sources from inception to January 2017.Study eligibility criteriaStudies where the exposure was any human herpesvirus and the outcome was stroke. We included randomised controlled trials, cohort, case-control, case-crossover and self-controlled case series designs.MethodsMeta-analyses when sufficiently homogeneous studies were available. Quality of evidence across studies was assessed.ResultsWe identified 5012 publications; 41 met the eligibility criteria. Across cohort and self-controlled case series studies, there was moderate quality evidence that varicella infection in children was associated with a short-term increased stroke risk. Zoster was associated with a 1.5-fold increased stroke risk four weeks following onset (summary estimate: 1.55, 95%CI 1.46–1.65), which resolved after one year. Subgroup analyses suggested post-zoster stroke risk was greater among ophthalmic zoster patients, younger individuals and those not prescribed antivirals. Recent infection/reactivation of cytomegalovirus and herpes simplex viruses, but not past infection, was associated with increased stroke risk; however the evidence across studies was mainly derived from small, very low quality case-control studies.ConclusionsOur review shows an increased stroke risk following zoster and suggests that recent infection or reactivation of other herpesviruses increases stroke risk, although better evidence is needed. Herpesviruses are common and potentially preventable; these findings may have implications for reducing stroke burden.

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“…93,94 For other viruses, clotting factors may become depleted due to extensive activation and clearance, which contributes to the bleeding seen during infection of hemorrhagic viruses like dengue virus. 83,[95][96][97][98] To highlight the prevalence and importance of the virus-hemostasis association, in addition to the reports accumulating for SARS-CoV-2, other important and highly prevalent virus examples include the hepatitis C virus (HCV), 88,99,100 influenza virus, 101,102 Ebola virus, 89,103,104 Zika virus, 105 genital herpes (herpes simplex virus type 2 [HSV2]), 106,107 cytomegalovirus (CMV), 108,109 and the cold sore virus (herpes simplex virus type 2 [HSV1]). [110][111][112][113] We propose that a mutual molecular basis explains this diverse and extensive list.…”

Section: Tf and Virusesmentioning

confidence: 99%

“…Over two‐thirds of the world’s population is infected by HSV1, which is the leading cause of infectious blindness, 125 sporadic encephalitis, 126 and genital herpes 127,128 and is associated with intestinal dysregulation 129 . Although known as the cold sore virus and typically not life threatening, there are numerous correlations between HSV1 and other members of the herpesvirus family to cardiovascular disease, 130,131 suggesting links to TF: (i) HSV1 seropositivity is associated with a 2‐fold increase in myocardial infarction incidence and death due to coronary heart disease 113 ; (ii) fibrin deposits in the microvasculature are linked to HSV1 infection 132,133 ; (iii) DIC in neonates may occur during severe HSV1 infection 134 ; (iv) HSV2 is linked to ischemic and hemorrhagic stroke due to DIC 107,135 ; (v) a history of CMV infection is linked to subclinical and clinical arterial thickening 136‐138 ; (vi) CMV is strongly correlated to accelerated atherosclerosis in immunosuppressed organ transplant recipients 139‐142 ; and (vii) CMV infection is a strong risk factor for restenosis after angioplasty 143,144 . When paired with other known cardiovascular risk factors, viral correlation to vascular disease is strong 110‐113 .…”

Section: Tf On the Virus Envelopementioning

confidence: 99%

Antiviral anticoagulation

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Sutherland

Lin

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a novel envelope virus that causes coronavirus disease 2019 (COVID‐19). Hallmarks of COVID‐19 are a puzzling form of thrombophilia that has elevated D‐dimer but only modest effects on other parameters of coagulopathy. This is combined with severe inflammation, often leading to acute respiratory distress and possible lethality. Coagulopathy and inflammation are interconnected by the transmembrane receptor, tissue factor (TF), which initiates blood clotting as a cofactor for factor VIIa (FVIIa)‐mediated factor Xa (FXa) generation. TF also functions from within the nascent TF/FVIIa/FXa complex to trigger profound changes via protease‐activated receptors (PARs) in many cell types, including SARS‐CoV‐2–trophic cells. Therefore, aberrant expression of TF may be the underlying basis of COVID‐19 symptoms. Evidence suggests a correlation between infection with many virus types and development of clotting‐related symptoms, ranging from heart disease to bleeding, depending on the virus. Since numerous cell types express TF and can act as sites for virus replication, a model envelope virus, herpes simplex virus type 1 (HSV1), has been used to investigate the uptake of TF into the envelope. Indeed, HSV1 and other viruses harbor surface TF antigen, which retains clotting and PAR signaling function. Strikingly, envelope TF is essential for HSV1 infection in mice, and the FXa‐directed oral anticoagulant apixaban had remarkable antiviral efficacy. SARS‐CoV‐2 replicates in TF‐bearing epithelial and endothelial cells and may stimulate and integrate host cell TF, like HSV1 and other known coagulopathic viruses. Combined with this possibility, the features of COVID‐19 suggest that it is a TFopathy, and the TF/FVIIa/FXa complex is a feasible therapeutic target.

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The association between human herpesvirus infections and stroke: a systematic review protocol

Cited by 4 publications

References 20 publications

Assessment of anti‐HSV antibodies in patients with facial palsy in the course of neuroborreliosis

Assessment of anti‐HSV antibodies in patients with facial palsy in the course of neuroborreliosis

Association of herpesviruses and stroke: Systematic review and meta-analysis

Antiviral anticoagulation

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