Publications by authors named "Anna Grahn"

21 Publications

  • Page 1 of 1

Genetic variants and immune responses in a cohort of patients with varicella zoster virus encephalitis.

J Infect Dis 2021 May 11. Epub 2021 May 11.

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.

Background: Infection with varicella zoster virus (VZV) may involve different central nervous system (CNS) manifestations, including meningitis, encephalitis, and vasculitis. In cases where otherwise healthy individuals are affected, an inborn error of immunity may underlie increased susceptibility or severity of infection.

Methods: We collected a cohort of 17 adults who experienced VZV encephalitis and performed whole exome sequencing. Patient PBMCs were infected with VZV and innate antiviral interferon and cytokine responses as well as viral replication was evaluated. Data were analyzed by Mann Whitney U test.

Results: We identified a total of 21 different potentially disease-causing variants in a total of 13 of the 17 patients included. These gene variants were within two major functional clusters: i) innate viral sensors and immune pathways and ii) autophagy pathways. Antiviral interferon (IFN) and cytokine responses were abnormal in the majority of patients, whereas viral replication was increased in only 2/17.

Conclusion: This study identifies a list of variants of pathogenic potential, which may serve as a platform for generating hypotheses for future studies addressing genetic and immunological factors associated with susceptibility to VZV encephalitis. Collectively, these data suggest that disturbances in innate sensing and autophagy pathways may predispose to VZV encephalitis.
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http://dx.doi.org/10.1093/infdis/jiab254DOI Listing
May 2021

Cognitive impairment without altered levels of cerebrospinal fluid biomarkers in patients with encephalitis caused by varicella-zoster virus: a pilot study.

Sci Rep 2020 12 28;10(1):22400. Epub 2020 Dec 28.

Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Varicella-zoster virus (VZV) is one of the most common agents causing viral infections of the central nervous system (CNS). VZV encephalitis is associated with severe neurological sequelae, despite antiviral treatment. Cognitive impairment has been reported and VZV has been associated with dementia. Our aim was to investigate the cognitive impairment and cerebrospinal fluid biomarkers in a follow-up study of patients with VZV encephalitis. Thirteen patients with VZV encephalitis, diagnosed by detection of VZV DNA in cerebrospinal fluid (CSF) by PCR and concomitant symptoms of encephalitis, were included. Neuropsychological assessment in parallel with a lumbar puncture to obtain CSF was performed 1.5-7 years after acute disease. The CSF biomarkers neurofilament light chain (NFL), S100B, glial fibrillary acidic protein (GFAP), amyloid-β (Aβ) 40 and Aβ42, total tau (t-tau) and phosphorylated tau (p-tau) were analysed and compared to controls (n = 24). Cognitive impairment was shown in the domains of executive functions and speed/attention and to a minor degree in the domains of learning/memory and language, indicated by a significantly poorer performance on seven neuropsychological test variables. No convincing evidence of alterations in concentrations of biomarkers in the CSF were shown. Our results indicate that patients with VZV encephalitis suffer from cognitive impairment long time after acute disease. Importantly, these impairments do not seem to be accompanied by biomarker evidence of ongoing neuronal or astrocytic injury/activation or induction of dementia-related brain pathologies by the infection.
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http://dx.doi.org/10.1038/s41598-020-79800-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769988PMC
December 2020

Serum and cerebrospinal fluid neurofilament light chain in patients with central nervous system infections caused by varicella-zoster virus.

J Neurovirol 2020 10 20;26(5):719-726. Epub 2020 Aug 20.

Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Varicella-zoster virus (VZV) is a common cause of viral central nervous system (CNS) infection, and patients may suffer from severe neurological sequelae. The biomarker neurofilament light chain (NFL) is used for assessment of neuronal damage and is normally measured in cerebrospinal fluid (CSF). Novel methods have given the possibility to measure NFL in serum instead, which could be a convenient tool to estimate severity of disease and prognosis in VZV CNS infections. Here, we investigate the correlation of serum and CSF NFL in patients with VZV CNS infection and the association of NFL levels in serum and CSF with different VZV CNS entities. NFL in serum and CSF was measured in 61 patients who were retrospectively identified with neurological symptoms and VZV DNA in CSF detected by PCR. Thirty-three herpes zoster patients and 40 healthy blood donors served as control groups. NFL levels in serum and CSF correlated strongly in the patients with VZV CNS infection. Encephalitis was associated with significantly higher levels of NFL in both serum and CSF compared with meningitis and Ramsay Hunt syndrome. Surprisingly, herpes zoster controls had very high serum NFL levels, comparable with those shown in encephalitis patients. We show that analysis of serum NFL can be used instead of CSF NFL for estimation of neuronal injury in patients with VZV CNS infection. However, high levels of serum NFL also in patients with herpes zoster, without signs of CNS involvement, may complicate the interpretation.
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http://dx.doi.org/10.1007/s13365-020-00889-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532135PMC
October 2020

CXCL13 in patients with facial palsy caused by varicella zoster virus and Borrelia burgdorferi: a comparative study.

Diagn Microbiol Infect Dis 2020 Sep 30;98(1):115095. Epub 2020 May 30.

Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.

High cerebrospinal fluid (CSF) concentrations of the chemokine CXCL13 have been associated with Lyme neuroborreliosis (LNB), and have recently been studied as a potential diagnostic marker. It has proven difficult to establish a reliable diagnostic cut-off, possibly in part due to heterogenicity of case-control groups. Our purpose was to investigate CSF CXCL13 concentrations in patients with similar clinical presentations, facial palsy. We retrospectively included patients with facial palsy associated with LNB (n = 21), or varicella zoster virus (VZV) (n = 26). Median CXCL13 concentrations were significantly higher in patients with LNB facial palsy compared to VZV facial palsy. Receiver-operating characteristic analyses yielded an optimal cut-off concentration at 34.5 pg/mL (sensitivity 85.7%, specificity of 84.6%), lower than that in previous studies. Although the analysis has potential, it is still not adequately established that CXCL13 provides additional, clinically useful, diagnostic information over current recommendations.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115095DOI Listing
September 2020

An unexpectedly high occurrence of aciclovir-induced neuropsychiatric symptoms in patients treated for herpesvirus CNS infection: a prospective observational study.

J Antimicrob Chemother 2019 12;74(12):3565-3572

Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Aciclovir is effective in herpesvirus infections of the CNS. Aciclovir-induced neuropsychiatric symptoms (AINS) have been reported and are associated with high CSF concentrations of aciclovir metabolite 9-carboxymethoxymethylguanine (CMMG). Risk factors except for renal failure have not been explored, and disruption of the blood-brain barrier (BBB) in acute CNS infection may be of interest.

Objectives: To investigate the impact of risk factors on aciclovir and CMMG concentrations, and to relate the results to AINS.

Methods: We investigated 21 consecutively included, consenting patients treated with aciclovir or valaciclovir for herpesvirus CNS infection. Regression models were constructed to study the impact of risk factors including BBB disruption, as measured with CSF:serum albumin ratio, on CSF aciclovir and CMMG concentrations. Medical records were assessed retrospectively to identify patients with AINS.

Results: Increased CSF:serum albumin ratio, as well as decreased renal function and high aciclovir doses, was associated with increased aciclovir and CMMG concentrations in the CSF. We identified five patients with new neuropsychiatric symptoms; four of those were considered to have AINS and had increased CSF CMMG concentrations. Only one patient without suspicion of AINS had an increased CSF CMMG concentration.

Conclusions: In patients with herpesvirus CNS infections, BBB disruption is associated with increasing aciclovir and CMMG CSF concentrations. We also found an unexpectedly high number of patients with AINS. Evaluation of CSF:serum albumin ratios, renal function and CSF concentrations of aciclovir and CMMG may all contribute to the optimization of aciclovir dosing and avoidance of AINS.
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http://dx.doi.org/10.1093/jac/dkz357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857197PMC
December 2019

Chemokines and matrix metalloproteinases in cerebrospinal fluid of patients with central nervous system complications caused by varicella-zoster virus.

J Neuroinflammation 2019 Feb 18;16(1):42. Epub 2019 Feb 18.

Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Varicella-zoster virus (VZV) is a common viral agent causing central nervous system (CNS) infections including encephalitis, meningitis, and Ramsay Hunt syndrome. Neurological complications occur frequently despite antiviral treatment. Matrix metalloproteinases (MMPs) and cytokines are involved in the neuroinflammatory response during CNS infection. Their role in VZV CNS infections and how they differ between different CNS entities caused by VZV are poorly investigated.

Methods: We analyzed the levels of 30 chemokines and 9 MMPs in cerebrospinal fluid (CSF) and serum from 66 patients with VZV CNS infections diagnosed by detection of VZV DNA in CSF and concomitant neurological symptoms and compared with a control group (n = 24).

Results: Levels of CCL19, CXCL8, CXCL9, and CXCL10 were significantly increased and surpassing the levels in serum when analyzing all patients with VZV CNS infections whereas CXCL11 was only increased in CSF of patients with VZV meningitis. MMP-2-levels were highly elevated in CSF of all 66 VZV patients. The patients with encephalitis had the most significantly increased levels of MMPs in CSF, and MMP-3, MMP-8, and MMP-12 were exclusively increased in this group, whereas MMP-9 in CSF was increased in the patients with VZV meningitis.

Conclusions: We show that both chemokines and MMPs are elevated in the CSF of patients with VZV CNS infections. Encephalitis and meningitis patients differed with respect to other chemokines (CXCL11) and MMPs (MMP-3, MMP-8, MMP-9, and MMP-12), indicating that different location of the virus gives rise to qualitative differences in the ensuing inflammatory response. In addition, the pronounced increase of MMPs in CSF of the patients with encephalitis suggests an association to the severity of this manifestation, compared to VZV meningitis and Ramsay Hunt syndrome. The role of MMPs in association to chemokines should be further investigated to evaluate their significance in the neuropathogenesis of VZV CNS infections and as a potential target for new treatment alternatives.
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http://dx.doi.org/10.1186/s12974-019-1428-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378740PMC
February 2019

Absence of Nosocomial Transmission of Imported Lassa Fever during Use of Standard Barrier Nursing Methods.

Emerg Infect Dis 2018 06;24(6):978-987

Nosocomial transmission of Lassa virus (LASV) is reported to be low when care for the index patient includes proper barrier nursing methods. We investigated whether asymptomatic LASV infection occurred in healthcare workers who used standard barrier nursing methods during the first 15 days of caring for a patient with Lassa fever in Sweden. Of 76 persons who were defined as having been potentially exposed to LASV, 53 provided blood samples for detection of LASV IgG. These persons also responded to a detailed questionnaire to evaluate exposure to different body fluids from the index patient. LASV-specific IgG was not detected in any of the 53 persons. Five of 53 persons had not been using proper barrier nursing methods. Our results strengthen the argument for a low risk of secondary transmission of LASV in humans when standard barrier nursing methods are used and the patient has only mild symptoms.
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http://dx.doi.org/10.3201/eid2406.172097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004835PMC
June 2018

Imported Case of Lassa Fever in Sweden With Encephalopathy and Sensorineural Hearing Deficit.

Open Forum Infect Dis 2016 Oct 20;3(4):ofw198. Epub 2016 Sep 20.

Departments of Infectious Medicine.

We describe an imported case of Lassa fever with both encephalopathy and bilateral sensorineural hearing deficit. Absence of fever during hospitalization, initially nonspecific symptoms, and onset of hearing deficit in a late stage of disease probably contributed to delayed diagnosis (14 days after admittance to hospital). The pathogenesis of neurological manifestations of Lassa fever is poorly understood and no specific treatment was given. A total of 118 personnel had close contact with the patient, but no secondary cases occurred. This case highlights the importance of considering Lassa fever as a differential diagnosis in patients with recent travel to endemic areas.
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http://dx.doi.org/10.1093/ofid/ofw198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152670PMC
October 2016

Cerebrospinal fluid viral load and biomarkers of neuronal and glial cells in Ramsay Hunt syndrome.

Eur J Neurosci 2016 12 1;44(11):2944-2949. Epub 2016 Oct 1.

Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Diagnosvägen 21, Gothenburg, SE-416 85, Sweden.

Reactivation of varicella zoster virus (VZV) can manifest with facial palsy diagnosed as Ramsay Hunt Syndrome (RHS) or Ramsay Hunt Syndrome zoster sine herpete (RHS-ZSH). These syndromes are associated with poor prognosis despite treatment with antivirals and corticosteroids. Concentrations of biomarkers such as neurofilament protein (NFL), S-100β protein and glial fibrillary acidic protein (GFAp) have previously been measured in cerebrospinal fluid (CSF) to assess neuronal damage and glial pathology. We employed immunochemical methods to measure concentrations of NFL, S-100β protein and GFAp in CSF from patients with RHS (n = 15) and RHS-ZSH (n = 13) diagnosed by detection of VZV DNA in the CSF by quantitative PCR, and compared with a control group (n = 52). The biomarker concentrations were correlated with CSF viral load and outcome measured by House-Brackmann score. NFL and GFAp concentrations were increased compared with controls (P = 0.008 and P = 0.04), while S-100β levels were decreased. This pattern was more pronounced in patients with RHS compared to the patients with RHS-ZSH (NS and P = 0.028). The amount of viral DNA in CSF correlated with increased GFAp (P = 0.003) and NFL (P = 0.006). No correlations were found between biomarker concentrations and patient outcome. Patients with facial palsy caused by VZV had biochemical signs of neuronal damage and astrogliosis. High amounts of viral DNA may be associated with the degree of damage on neuronal and astroglial cells. Prospective studies are warranted to elucidate the association of elevated biomarkers in the CSF and outcome assessed by more sensitive tests.
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http://dx.doi.org/10.1111/ejn.13403DOI Listing
December 2016

Varicella-zoster virus (VZV) DNA in serum of patients with VZV central nervous system infections.

J Infect 2016 09 15;73(3):254-60. Epub 2016 Jun 15.

Department of Infectious Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

Objectives: Varicella-zoster virus (VZV) is a common viral agent causing central nervous system (CNS) infections, normally diagnosed by detection of VZV DNA in cerebrospinal fluid (CSF). Our aim was to investigate trends in VZV DNAemia in VZV CNS infections, which could potentially contribute to diagnosis and secondly, correlate the amount of VZV DNA in serum to severity of disease.

Methods: Seventy-two patients with VZV CNS infections diagnosed by detection of VZV DNA in CSF and concomitant neurological symptoms were included. The amount of VZV DNA was measured by real-time PCR in paired serum and CSF samples and compared to a control group of herpes zoster (n = 36).

Results: An increased amount of VZV DNA was detected in serum in patients with encephalitis compared to patients with meningitis or Ramsay-Hunt syndrome, respectively (p = 0.003 and p = 0.024). A greater proportion of patients with VZV CNS infections and detectable VZV DNA in serum had ongoing rash compared to those without detectable VZV DNA in serum (p ≤ 0.001). The viral load in serum of patients with neurological symptoms was lower compared to in patients with herpes zoster without neurological symptoms (p ≤ 0.001) and only 32/72 of the patients with VZV CNS disease had VZV DNA detected in serum.

Conclusion: Increased amount of VZV DNA in serum of patients with VZV CNS infections seems associated with encephalitis and ongoing rash. Additionally, viral DNA analysis by PCR in serum may be a helpful diagnostic tool although viral DNA analysis by PCR in CSF is the method of choice for diagnosis.
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http://dx.doi.org/10.1016/j.jinf.2016.04.035DOI Listing
September 2016

Varicella-zoster virus infections of the central nervous system – Prognosis, diagnostics and treatment.

J Infect 2015 Sep 12;71(3):281-93. Epub 2015 Jun 12.

Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Infectious Diseases, Sahlgrenska University Hospital, Östra, SE 416 85 Göteborg, Sweden. Electronic address:

Both varicella and herpes zoster that are caused by varicella-zoster virus (VZV), are associated with central nervous system disease. Since the introduction of polymerase chain reaction, the opportunity to detect the virus in cerebrospinal fluid (CSF) has improved dramatically. As a result VZV is diagnosed as one of the most common viruses causing CNS disease and it has become evident that this disease includes a wide spectrum of different CNS manifestations. The most evaluated CNS manifestations are encephalitis which is associated with both varicella and herpes zoster and, cerebellitis which occurs predominantly in children with varicella. Other manifestations have been less widely investigated. The incidence of cerebrovascular disease caused by VZV has been only scarcely studied and, in addition, some data indicate that vasculitis might also be involved in other VZV CNS manifestations such as herpes zoster-associated encephalitis. For this reason, VZV CNS infection must be suspected in several CNS syndromes and diagnostics should be based on CSF analysis for detection of VZV DNA by PCR and/or intrathecal antibody production. The prognosis is reported as favourable in children but few follow-up studies are available. Moreover, in adults, the prognosis is reported to be good in overall terms, but later studies indicate more serious neurological sequelae including cognition. Despite considerable mortality and morbidity, so far also in vaccinating countries, few treatment studies are available. Further treatment studies including assessments of neurological and cognitive sequelae, are warranted.
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http://dx.doi.org/10.1016/j.jinf.2015.06.004DOI Listing
September 2015

Recombination of Globally Circulating Varicella-Zoster Virus.

J Virol 2015 Jul;89(14):7133-46

Unlabelled: Varicella-zoster virus (VZV) is a human herpesvirus, which during primary infection typically causes varicella (chicken pox) and establishes lifelong latency in sensory and autonomic ganglia. Later in life, the virus may reactivate to cause herpes zoster (HZ; also known as shingles). To prevent these diseases, a live-attenuated heterogeneous vaccine preparation, vOka, is used routinely in many countries worldwide. Recent studies of another alphaherpes virus, infectious laryngotracheitis virus, demonstrate that live-attenuated vaccine strains can recombine in vivo, creating virulent progeny. These findings raised concerns about using attenuated herpesvirus vaccines under conditions that favor recombination. To investigate whether VZV may undergo recombination, which is a prerequisite for VZV vaccination to create such conditions, we here analyzed 115 complete VZV genomes. Our results demonstrate that recombination occurs frequently for VZV. It thus seems that VZV is fully capable of recombination if given the opportunity, which may have important implications for continued VZV vaccination. Although no interclade vaccine wild-type recombinant strains were found, intraclade recombinants were frequently detected in clade 2, which harbors the vaccine strains, suggesting that the vaccine strains have already been involved in recombination events, either in vivo or in vitro during passages in cell culture. Finally, previous partial and complete genomic studies have described strains that do not cluster phylogenetically to any of the five established clades. The additional VZV strains sequenced here, in combination with those previously published, have enabled us to formally define a novel sixth VZV clade.

Importance: Although genetic recombination has been demonstrated to frequently occur for other human alphaherpesviruses, herpes simplex viruses 1 and 2, only a few ancient and isolated recent recombination events have hitherto been demonstrated for VZV. In the present study, we demonstrate that VZV also frequently undergoes genetic recombination, including strains belonging to the clade containing the vOKA strain.
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http://dx.doi.org/10.1128/JVI.00437-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473579PMC
July 2015

Cognitive impairment 3 years after neurological Varicella-zoster virus infection: a long-term case control study.

J Neurol 2013 Nov 31;260(11):2761-9. Epub 2013 Jul 31.

Department of Infectious Diseases, Sahlgrenska University Hospital, Östra, SE-416 85, Göteborg, Sweden,

Varicella-zoster virus (VZV) is one of the most common viruses causing central nervous system (CNS) infection, sometimes with severe neurological complications and sequelae despite appropriate antiviral treatment. Whether the neurological sequelae of VZV CNS infections include long-term cognitive impairment and how this impairment might affect the patients is still largely unknown. In this study, 14 patients with predominant CNS manifestations caused by VZV infection underwent cognitive testing 3 years (median 39.5 months, range 31-52 months) after acute disease. The results were compared with those for 28 controls, matched for age and gender. The tests covered the cognitive domains of speed and attention, memory and learning, visuospatial function, language and executive function. To further assess the cognitive dysfunction caused by neurological VZV infection, patients were classified into the concept of mild cognitive impairment (MCI), which is associated with development of dementia in other pathologies. The VZV patients performed significantly worse than controls on four tests covering the domains of speed and attention, memory and learning and executive function. The cut-off was set at 1.5 SD below mean age. In addition, a greater proportion of VZV patients were classified with MCI as compared with controls. In conclusion, patients with previous VZV infection affecting the brain had signs of long-term cognitive impairment in the domains of speed and attention, memory and learning and executive function. However, larger study populations are needed to confirm these results.
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http://dx.doi.org/10.1007/s00415-013-7057-1DOI Listing
November 2013

Cerebrospinal fluid biomarkers in patients with varicella-zoster virus CNS infections.

J Neurol 2013 Jul 8;260(7):1813-21. Epub 2013 Mar 8.

Department of Infectious Diseases, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Östra, SE-416 85 Göteborg, Sweden.

Varicella-zoster virus (VZV) is one of our most common viruses causing central nervous system (CNS) infection with sometimes severe neurological complications. Glial fibrillary acidic protein (GFAp), light subunit of neurofilament protein (NFL) and S-100β protein are cerebrospinal fluid (CSF) biomarkers that have been used to estimate the severity of brain damage and outcome in various CNS diseases. So far, these biomarkers have not been utilised to investigate glial pathology and neuronal damage in patients with VZV CNS infections. In this prospective study, we measured CSF GFAp, NFL and S-100β as markers of brain damage in 24 patients with acute neurological manifestations and VZV DNA detected in CSF by PCR and compared with a control group (n = 14). Concentrations of CSF NFL and GFAp were increased in patients with VZV CNS infection compared with controls (p = 0.002 and p = 0.03) while levels of S-100β were reduced. In patients with VZV encephalitis the elevations of CSF NFL and GFAp were more pronounced compared with patients with other VZV CNS syndromes. No correlations between the levels of biomarkers and viral load, neurological sequels or clinical outcome were found in this limited number of patients. These results indicate that VZV induces neuronal damage and astrogliosis with more severe brain damage in patients with VZV encephalitis than in patients with other neurological complications caused by this virus.
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http://dx.doi.org/10.1007/s00415-013-6883-5DOI Listing
July 2013

Varicella-zoster virus (VZV) glycoprotein E is a serological antigen for detection of intrathecal antibodies to VZV in central nervous system infections, without cross-reaction to herpes simplex virus 1.

Clin Vaccine Immunol 2011 Aug 22;18(8):1336-42. Epub 2011 Jun 22.

Department of Infectious Diseases, Sahlgrenska University Hospital, Östra, SE-416 85 Gothenburg, Sweden.

Herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) cause serious central nervous system (CNS) diseases that are diagnosed with PCR using samples of cerebrospinal fluid (CSF) and, during later stages of such infections, with assays of intrathecal IgG antibody production. However, serological diagnoses have been hampered by cross-reactions between HSV-1 and VZV IgG antibodies and are commonly reported in patients with herpes simplex encephalitis (HSE). In this study we have evaluated VZV glycoprotein E (gE) as a new antigen for serological diagnosis of VZV-induced CNS infections. Paired samples of CSF and serum from 29 patients with clinical diagnosis of VZV CNS infection (n = 15) or HSE (n = 14), all confirmed by PCR, were analyzed. VZV gE and whole VZV were compared as antigens in enzyme-linked immunosorbent assays (ELISAs) for serological assays in which the CSF/serum sample pairs were diluted to identical IgG concentrations. With the gE antigen, none of the HSE patients showed intrathecal IgG antibodies against VZV, compared to those shown by 11/14 patients using whole-VZV antigen (P < 0.001). In the patients with VZV infections, significantly higher CSF/serum optical density (OD) ratios were found in the VZV patients using the VZV gE antigen compared to those found using the whole-VZV antigen (P = 0.001). These results show that gE is a sensitive antigen for serological diagnosis of VZV infections in the CNS and that this antigen was devoid of cross-reactivity to HSV-1 IgG in patients with HSE. We therefore propose that VZV gE can be used for serological discrimination of CNS infections caused by VZV and HSV-1.
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http://dx.doi.org/10.1128/CVI.05061-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147344PMC
August 2011

Recombinant glycoprotein E produced in mammalian cells in large-scale as an antigen for varicella-zoster-virus serology.

J Virol Methods 2011 Jul 22;175(1):53-9. Epub 2011 Apr 22.

Mammalian Protein Expression Core Facility, Sahlgrenska Academy, University of Gothenburg, Box 440, 405 30 Gothenburg, Sweden.

A recombinant glycoprotein E (gE) from varicella-zoster virus (VZV) was generated and produced in Chinese Hamster Ovary (CHO) cells, in the development of a specific antigen for analysis of IgG antibodies to VZV. Several stable gE-secreting clones were established and one clone was adapted to growth in serum-free suspension culture. When the cells were cultured in a perfusion bioreactor, gE was secreted into the medium, from where it could be easily purified. The recombinant gE was then evaluated as a serological antigen in ELISA. When compared to a conventional whole virus antigen, the VZV gE showed similar results in ELISA-based seroprevalence studies of 854 samples derived from blood donors, students, ischemic stroke patients and their controls, including samples with border-line results in previous analyses. Eight samples (0.9%) were discordant, all being IgG-negative by the VZV gE ELISA and positive by the whole virus ELISA. The sensitivity and specificity of the VZV gE ELISA were 99.9% and 100%, respectively, compared to 100% and 88.9% for the VZV whole virus ELISA. The elderly subjects showed similar reactivities to both antigens, while VZV gE gave lower signals in the younger cohorts, suggesting that antibodies to gE may increase with age. It was concluded that the recombinant VZV gE from CHO cells was suitable as a serological antigen for the detection of IgG antibodies specific for VZV.
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http://dx.doi.org/10.1016/j.jviromet.2011.04.014DOI Listing
July 2011

Nodule detection in digital chest radiography: summary of the RADIUS chest trial.

Radiat Prot Dosimetry 2005 ;114(1-3):114-20

Department of Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.

As a part of the Europe-wide research project 'Unification of physical and clinical requirements for medical X-ray imaging'-governed by the Radiological Imaging Unification Strategies (RADIUS) Group-a major image quality trial was conducted by members of the group. The RADIUS chest trial aimed at thoroughly examining various aspects of nodule detection in digital chest radiography, such as the effects of nodule location, system noise, anatomical noise, and anatomical background. The main findings of the RADIUS chest trial concerning the detection of a lung nodule with a size in the order of 10 mm can be summarised as: (1) the detectability of the nodule is largely dependent on its location in the chest, (2) the system noise has a minor impact on the detectability at the dose levels used today, (3) the disturbance of the anatomical noise is larger than that of the system noise but smaller than that of the anatomical background and (4) the anatomical background acts as noise to a large extent and is the major image component affecting the detectability of the nodule.
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http://dx.doi.org/10.1093/rpd/nch574DOI Listing
September 2005

Nodule detection in digital chest radiography: part of image background acting as pure noise.

Radiat Prot Dosimetry 2005 ;114(1-3):102-8

Department of Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.

There are several factors that influence the radiologist's ability to detect a specific structure/lesion in a radiograph. Three factors that are commonly known to be of major importance are the signal itself, the system noise and the projected anatomy. The aim of this study was to determine to what extent the image background acts as pure noise for the detection of subtle lung nodules in five different regions of the chest. A receiver operating characteristic (ROC) study with five observers was conducted on two different sets of images, clinical chest X-ray images and images with a similar power spectrum as the clinical images but with a random phase spectrum, resulting in an image background containing pure noise. Simulated designer nodules with a full-width-at-fifth-maximum of 10 mm but with varying contrasts were added to the images. As a measure of the part of the image background that acts as pure noise, the ratio between the contrast needed to obtain an area under the ROC curve of 0.80 in the clinical images to that in the random-phase images was used. The ratio ranged from 0.40 (in the lateral pulmonary regions) to 0.83 (in the hilar regions) indicating that there was a large difference between different regions regarding to what extent the image background acted as pure noise; and that in the hilar regions the image background almost completely acted as pure noise for the detection of 10 mm nodules.
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http://dx.doi.org/10.1093/rpd/nch523DOI Listing
September 2005

Nodule detection in digital chest radiography: introduction to the RADIUS chest trial.

Radiat Prot Dosimetry 2005 ;114(1-3):85-91

Department of Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.

Most digital radiographic systems of today have wide latitude and are hence able to provide images with a small constraint on dose level. This opens up for an unprejudiced dose optimisation. However, in order to succeed in the optimisation task, good knowledge of the imaging and detection processes is needed. As a part of the European-wide research project 'unification of physical and clinical requirements for medical X-ray imaging'-governed by the Radiological Imaging Unification Strategies (RADIUS) Group-a major image quality trial was conducted by members of the group. The RADIUS chest trial was focused on the detection of lung nodules in digital chest radiography with the aims of determining to what extent (1) the detection of a nodule is dependent on its location, (2) the system noise disturbs the detection of lung nodules, (3) the anatomical noise disturbs the detection of lung nodules and (4) the image background and anatomical background act as pure noise for the detection of lung nodules. The purpose of the present paper is to give an introduction to the trial and describe the framework and set-up of the investigation.
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http://dx.doi.org/10.1093/rpd/nch575DOI Listing
September 2005

A software tool for increased efficiency in observer performance studies in radiology.

Radiat Prot Dosimetry 2005 ;114(1-3):45-52

Department of Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.

Observer performance studies are time-consuming tasks, both for the participating observers and for the scientists collecting and analysing the data. A possible way to optimise such studies is to perform them in a completely digital environment. A software tool-ViewDEX (Viewer for Digital Evaluation of X-ray images)-has been developed in Java, enabling it to function on almost any computer. ViewDEX is designed to handle several types of studies, such as visual grading analysis (VGA), image criteria scoring (ICS) and receiver operating characteristics (ROC). The results from each observer are saved in a log file, which can be exported for further analysis in, for example, a special software for analysing ROC results. By using ViewDEX for an ROC experiment, an evaluation rate of approximately 200 images per hour can be achieved, compared to approximately 25 images per hour using hard copy evaluation. The results are obtained within minutes of completion of the viewing. The risk of human errors in the process of data collection and analysis is also minimised. The viewer has been used in a major trial containing approximately 2700 images.
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http://dx.doi.org/10.1093/rpd/nch550DOI Listing
September 2005
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