Lessons from Epstein-Barr virus DNA detection in cerebrospinal fluid as a diagnostic tool for EBV-induced central nervous system dysfunction among HIV-positive patients

Wang, Yanli; Yang, Jun; Wen, Ying

doi:10.1016/j.biopha.2021.112392

Cited by 11 publications

(13 citation statements)

References 93 publications

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“…Viruses are abundant, ubiquitous in nature, and may be deleterious to human health. Prior viral infections, including Epstein-Barr virus (EBV) [1,2], Herpes Simplex virus (HSV) [3,4], Human immunodeficiency virus (HIV) [5,6], poliovirus [7,8], Zika virus [9,10], and many others have been associated with subsequent neurological damage [11]. Comorbidities and predisposing genetic risk factors for neurological and immunological dysfunction often vary among individuals in natural populations.…”

Section: Introductionmentioning

confidence: 99%

Serum Cytokines Predict Neurological Damage in Genetically Diverse Mouse Models

Gómez

Karmakar

Carroll

et al. 2022

Cells

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Viral infections contribute to neurological and immunological dysfunction driven by complex genetic networks. Theiler’s murine encephalomyelitis virus (TMEV) causes neurological dysfunction in mice and can model human outcomes to viral infections. Here, we used genetically distinct mice from five Collaborative Cross mouse strains and C57BL/6J to demonstrate how TMEV-induced immune responses in serum may predict neurological outcomes in acute infection. To test the hypothesis that serum cytokine levels can provide biomarkers for phenotypic outcomes of acute disease, we compared cytokine levels at pre-injection, 4 days post-injection (d.p.i.), and 14 d.p.i. Each strain produced unique baseline cytokine levels and had distinct immune responses to the injection procedure itself. Thus, we eliminated the baseline responses to the injection procedure itself and identified cytokines and chemokines induced specifically by TMEV infection. Then, we identified strain-specific longitudinal cytokine profiles in serum during acute disease. Using stepwise regression analysis, we identified serum immune markers predictive for TMEV-induced neurological phenotypes of the acute phase, e.g., IL-9 for limb paralysis; and TNF-α, IL-1β, and MIP-1β for limb weakness. These findings indicate how temporal differences in immune responses are influenced by host genetic background and demonstrate the potential of serum biomarkers to track the neurological effects of viral infection.

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Section: Introductionmentioning

confidence: 99%

Serum Cytokines Predict Neurological Damage in Genetically Diverse Mouse Models

Gómez

Karmakar

Carroll

et al. 2022

Cells

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“…HIV-infected patients are vulnerable to CNS opportunistic infections, the most common disease among which are cerebral toxoplasmosis, progressive multifocal leukoencephalopathy, tuberculous meningitis, cryptococcal meningitis, and cytomegalovirus encephalitis ( Tan et al, 2012 ; Bowen et al, 2016 ; Thakur, 2020 ). CNS lymphoma, although not an infectious disease, has been associated with CNS EBV infection ( Bossolasco et al, 2002 ; Wang et al, 2022 ). In the present study, those pathogens were also the major contributors to CNS disorders, suggesting that priority should be given to those pathogens when making a differential diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…The related clinical disorders tend to occur in patients with higher blood viral loads ( Spector et al, 1998 ; Kanakry et al, 2016 ). In HIV-infected patients, detection of EBV DNA in CSF sample doses not prove EBV associated neurological diseases, although high CSF EBV DNA level is associated with CNS lymphoma ( Wang et al, 2022 ). The low number of sequences CMV or EBV reads reported by CSF mNGS, in our study, may be a reflection of CMV or EBV persistence other than active diseases.…”

Section: Discussionmentioning

confidence: 99%

Metagenomic next-generation sequencing for identification of central nervous system pathogens in HIV-infected patients

et al. 2022

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Although considerable interest in metagenomic next-generation sequencing (mNGS) has been attracted in recent years, limited data are available regarding the performance of mNGS in HIV-associated central nervous system (CNS) infection. Here, we conducted a retrospectively analyzing of the cerebrospinal fluid (CSF) mNGS reports and other clinical data from 80 HIV-infected patients admitted to the Second Hospital of Nanjing, China from March, 2018 to March, 2022. In our study, CSF mNGS reported negative result, mono-infection, and mixed infection in 8.8, 36.2, and 55% of the patients, respectively. Epstein–Barr virus (EBV), positive in 52.5% of samples, was the most commonly reported pathogen, followed by cytomegalovirus (CMV), John Cunningham virus (JCV), torque teno virus (TTV), cryptococcus neoformans (CN), toxoplasma Gondii (TE), and mycobacterium tuberculosis (MTB). 76.2% of the EBV identification and 54.2% of the CMV identification were not considered clinically important, and relative less sequence reads were reported in the clinical unimportant identifications. The clinical importance of the presence of TTV in CSF was not clear. Detection of JCV, CN, or TE was 100% suggestive of specific CNS infection, however, 60% of the MTB reports were considered contamination. Moreover, of the 44 (55%) mixed infections reported by mNGS, only 4 (5%) were considered clinical important, and mNGS failed to identify one mixed infection. Additionally, except for MTB, CSF mNGS tended to have high sensitivity to identify the above-mentioned pathogens (almost with 100% sensitivity). Even all the diagnostic strategies were evaluated, the cause of neurological symptoms remained undetermined in 6 (7.5%) patients. Overall, our results suggest that mNGS is a very sensitive tool for detecting common opportunistic CNS pathogen in HIV-infected patients, although its performance in CNS tuberculosis is unsatisfactory. EBV and CMV are commonly detected by CSF mNGS, however, the threshold of a clinical important detection remains to be defined.

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“…Several reviews have been conducted on the presence of EBV-DNA in the CSF of HIV patients with lymphoma, with various conclusions drawn on its use, especially in PCNSL [ 25 ]. However, very few studies have described the presence of EBV-DNA in non-lymphoma HIV patients.…”

Section: Discussionmentioning

confidence: 99%

“…It is thought that under these circumstances, EBV occurs in the CNS as an opportunistic infection [ 18 , 21 ]. EBV-DNA in the CNS is often detected together with other pathogens but more frequently than others, especially in patients with suspected meningitis and with HIV [ 24 , 25 , 26 ]. Currently, limited data have been shown on the presence of EBV-DNA in meningitis and indeed in the absence of lymphoma.…”

Section: Introductionmentioning

confidence: 99%

Epstein–Barr Virus Detection in the Central Nervous System of HIV-Infected Patients

et al. 2022

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Simply detecting Epstein–Barr virus deoxyribonucleic acid (EBV-DNA) is insufficient to diagnose EBV-associated diseases. The current literature around EBV-DNA detection from cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV)-positive non-lymphoma patients was systematically reviewed and a meta-analysis reporting the estimated pooled prevalence in this population when PCR methods are employed, targeting different sequence segments within the EBV genome, was conducted. Using a combination of three key concepts—Epstein–Barr virus detection, central nervous system disease, and human cerebrospinal fluid—and their MeSH terms, the PubMed database was searched. A total of 273 papers reporting the detection of EBV in CNS were screened, of which 13 met the inclusion criteria. The meta-analysis revealed a pooled prevalence of EBV-DNA in CSF of 20% (CI: 12–31%). The highest pooled prevalence was from studies conducted on the African population at 39% (CI: 27–51%). The investigation of the presence of EBV-DNA in the CSF was also very varied, with several gene targets used. While most patients from the articles included in this review and meta-analysis were symptomatic of CNS disorders, the pathogenicity of EBV in non-lymphoma HIV patients when detected in CSF has still not been determined. The presence of EBV-DNA in the CNS remains a concern, and further research is warranted to understand its significance in causing CNS disorders.

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Lessons from Epstein-Barr virus DNA detection in cerebrospinal fluid as a diagnostic tool for EBV-induced central nervous system dysfunction among HIV-positive patients

Cited by 11 publications

References 93 publications

Serum Cytokines Predict Neurological Damage in Genetically Diverse Mouse Models

Serum Cytokines Predict Neurological Damage in Genetically Diverse Mouse Models

Metagenomic next-generation sequencing for identification of central nervous system pathogens in HIV-infected patients

Epstein–Barr Virus Detection in the Central Nervous System of HIV-Infected Patients

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