Fatal Encephalitis Associated with Borna Disease Virus 1

Korn, Klaus; Coras, Roland; Bobinger, Tobias; Herzog, S.; Lücking, Hannes; Stöhr, Robert; Huttner, Hagen B.; Hartmann, Andréas; Ensser, Armin

doi:10.1056/nejmc1800724

Cited by 101 publications

(122 citation statements)

References 5 publications

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“…Testing an infectious contribution of BDV-1 to mental health, particularly depression, meant to be on a rocky path from the start, because human infection was doubted [25], despite evidence at different levels [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Recently, human BDV-1 infection became an incontrovertible fact by reports on its ability to even cause fatalities [18,19], emphasizing the broad capacity of BDV-1 as a human pathogen.…”

Section: Discussionmentioning

confidence: 99%

“…Although the majority of infections follows a sub-clinical course [15], even deadly outcomes are possible triggered by impaired immune defence [16,17]. Unexpectedly, BDV-1 caused fatal encephalitis recently occurred in transplant recipients who had received organs from a BDV-1 infected healthy donor [18], and another case was reported unrelated to transplantation [19].…”

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confidence: 99%

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Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial

Dietrich

Bode²,

Spannhuth

et al. 2020

BMC Pharmacol Toxicol

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Background: Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine.Methods: The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2-3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC). Results: Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (p = 0.003), a large clinical effect size (ES; Cohen's d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time (p < 0.001). In vitro, amantadine concentrations as low as 2.4-10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL).

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial

Dietrich

Bode²,

Spannhuth

et al. 2020

BMC Pharmacol Toxicol

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“…Aus den bisher vorliegenden Ergebnissen lässt sich kein Zusammenhang zwischen postulierten Bornavirusinfektionen und psychiatrischen Erkrankungen des Menschen belegen [12,16]. Die Beteiligung von klassischen und neu entdeckten Bornaviren an Enzephalitiden des Menschen ist jedoch nachgewiesen [1,2,4] [38]. Die Infektion kann auch mit einer Retinitis assoziiert sein [39][40][41].…”

Section: Wissensstand üBer Den Erregerunclassified

“…Als Auslöser der transplantationsassoziierten Infektionen konnte erstmals das klassische Bornavirus (Borna disease virus 1, BoDV-1) identifiziert werden [1]. Weitere nicht-transplantationsassoziierte Einzelfälle wurden in Bayern nachgewiesen und zoonotische Übertragungen für diese Infektionen vermutet [2,3].…”

unclassified

Bornavirus

2019

Bundesgesundheitsbl

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“…BoDV-1 is well known to cause severe and fatal neurological Borna disease in a variety of mammals, mainly horses and sheep. Recently BoDV-1 was identified as causal agent in fatal human encephalitis cases [3,4]. This underlines the need to unravel potential sources of infection in order to prevent further animal and human cases, especially since no curative therapy or vaccination exists [3,4].…”

Section: Introductionmentioning

confidence: 99%

No evidence for European bats serving as reservoir for Borna disease virus 1 or other known mammalian orthobornaviruses

Nobach

Herden

2020

Virol J

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Background: The majority of emerging infectious diseases are zoonotic in nature and originate from wildlife reservoirs. Borna disease, caused by Borna disease virus 1 (BoDV-1), is an infectious disease affecting mammals, but recently it has also been shown to cause fatal encephalitis in humans. The endemic character of Borna disease points towards a nature-bound reservoir, with only one shrew species identified as reservoir host to date. Bats have been identified as reservoirs of a variety of zoonotic infectious agents. Endogenous borna-like elements in the genome of certain bat species additionally point towards co-evolution of bats with bornaviruses and therefore raise the question whether bats could serve as a potential reservoir of orthobornaviruses. Methods: Frozen brain samples (n = 257) of bats of seven different genera from Germany were investigated by orthobornaviral RT-PCR. Additionally, tissue slides of formalin-fixed paraffin-embedded material of a subset of these bats (n = 140) were investigated for orthobornaviral phosphoprotein by immunohistochemistry. Results: The brain samples were tested by RT-PCR without any evidence of orthobornavirus specific amplicons. Immunohistochemistry revealed a faint immunoreaction in 3/140 bats but with an untypical staining pattern for viral antigen. Conclusions: RT-PCR-screening showed no evidence for orthobornaviral RNA in the investigated bats. However, immunohistochemistry results should be investigated further to elucidate whether the reaction might be associated with expressed endogenous bornaviral elements or other so far unknown bornaviruses.

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Fatal Encephalitis Associated with Borna Disease Virus 1

Cited by 101 publications

References 5 publications

Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial

Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial

Bornavirus

No evidence for European bats serving as reservoir for Borna disease virus 1 or other known mammalian orthobornaviruses

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