Zoonotic spillover infections with Borna disease virus 1 leading to fatal human encephalitis, 1999–2019: an epidemiological investigation - 27/03/20

Doi : 10.1016/S1473-3099(19)30546-8

Hans Helmut Niller, MD ^a,^{^{†
Contributed equally}}, Klemens Angstwurm, MD ^e,^{^{†
Contributed equally}}, Dennis Rubbenstroth, DVM ^g,^h,^{^{†
Contributed equally}}, Kore Schlottau, PhD ^g, Arnt Ebinger, MSc ^g, Sebastian Giese, PhD ^h, Silke Wunderlich, MD ⁱ, Bernhard Banas, ProfMD ^b, Leonie F Forth, PhD ^g, Donata Hoffmann, DVM ^g, Dirk Höper, PhD ^g, Martin Schwemmle, ProfPhD ^h, Dennis Tappe, ProfMD ^k, Jonas Schmidt-Chanasit, ProfMD ^k,^l, Daniel Nobach, DVM ^m, Christiane Herden, ProfDVM ^m, Christoph Brochhausen, ProfMD ^f, Natalia Velez-Char, MD ^f, Andreas Mamilos, MD ^f, Kirsten Utpatel, MD ^f, Matthias Evert, ProfMD ^f, Saida Zoubaa, MD ^c, Markus J Riemenschneider, ProfMD ^c, Viktoria Ruf, MD ⁿ, Jochen Herms, ProfMD ⁿ, Georg Rieder, MD ^p, Mario Errath, MD ^p, Kaspar Matiasek, ProfDVM ^o, Jürgen Schlegel, ProfMD ^j, Friederike Liesche-Starnecker, MD ^j, Bernhard Neumann, MD ^e, Kornelius Fuchs, MD ^e, Ralf A Linker, ProfMD ^e, Bernd Salzberger, ProfMD ^d, Tobias Freilinger, MD ^q,^r, Lisa Gartner, MD ^q, Jürgen J Wenzel, ProfMD ^a, Udo Reischl, ProfPhD ^a, Wolfgang Jilg, ProfMD ^a, André Gessner, ProfMD ^a, Jonathan Jantsch, ProfMD ^a, Martin Beer, ProfDVM ^g,^{^{†
Contributed equally},}⁎ , Barbara Schmidt, ProfMD ^a,^{^{†
Contributed equally}}

^a Institute of Clinical Microbiology and Hygiene, Regensburg University Hospital, Regensburg, Germany

^b Department of Nephrology, Regensburg University Hospital, Regensburg, Germany

^c Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany

^d Infectious Diseases, Regensburg University Hospital, Regensburg, Germany

^e Department of Neurology, University of Regensburg, Regensburg, Germany

^f Institute of Pathology, University of Regensburg, Regensburg, Germany

^g Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany

^h Institute of Virology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

ⁱ Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany

^j Department of Neuropathology, Technical University of Munich, Munich, Germany

^k Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany

^l Faculty of Mathematics, Informatics and Natural Sciences, University of Hamburg, Hamburg, Germany

^m Institute of Veterinary Pathology, Justus-Liebig-University Giessen, Giessen, Germany

ⁿ Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, Munich, Germany

^o Section of Clinical & Comparative Neuropathology, Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

^p Department of Neurology, Klinikum Traunstein, Traunstein, Germany

^q Department of Neurology, Klinikum Passau, Passau, Germany

^r Hertie-Institute for Clinical Brain Research, University Tuebingen, Tuebingen, Germany

^* Correspondence to: Prof Martin Beer, Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany Institute of Diagnostic Virology Friedrich-Loeffler-Institut 17493 Greifswald-Insel Riems Germany

Summary

Background

In 2018–19, Borna disease virus 1 (BoDV-1), the causative agent of Borna disease in horses, sheep, and other domestic mammals, was reported in five human patients with severe to fatal encephalitis in Germany. However, information on case frequencies, clinical courses, and detailed epidemiological analyses are still lacking. We report the occurrence of BoDV-1-associated encephalitis in cases submitted to the Institute of Clinical Microbiology and Hygiene, Regensburg University Hospital, Regensburg, Germany, and provide a detailed description of newly identified cases of BoDV-1-induced encephalitis.

Methods

All brain tissues from 56 encephalitis cases from Bavaria, Germany, of putative viral origin (1999–2019), which had been submitted for virological testing upon request of the attending clinician and stored for stepwise diagnostic procedure, were systematically screened for BoDV-1 RNA. Two additional BoDV-1-positive cases were contributed by other diagnostic centres. Positive results were confirmed by deep sequencing, antigen detection, and determination of BoDV-1-reactive antibodies in serum and cerebrospinal fluid. Clinical and epidemiological data from infected patients were collected and analysed.

Findings

BoDV-1 RNA and bornavirus-reactive antibodies were detected in eight newly analysed encephalitis cases and the first human BoDV-1 isolate was obtained from an unequivocally confirmed human BoDV-1 infection from the endemic area. Six of the eight BoDV-1-positive patients had no record of immunosuppression before the onset of fatal disease, whereas two were immunocompromised after solid organ transplantation. Typical initial symptoms were headache, fever, and confusion, followed by various neurological signs, deep coma, and severe brainstem involvement. Seven of nine patients with fatal encephalitis of unclear cause were BoDV-1 positive within one diagnostic centre. BoDV-1 sequence information and epidemiological analyses indicated independent spillover transmissions most likely from the local wild animal reservoir.

Interpretation

BoDV-1 infection has to be considered as a potentially lethal zoonosis in endemic regions with reported spillover infections in horses and sheep. BoDV-1 infection can result in fatal encephalitis in immunocompromised and apparently healthy people. Consequently, all severe encephalitis cases of unclear cause should be tested for bornaviruses especially in endemic regions.

Funding

German Federal Ministry of Education and Research.

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Plan

Introduction

Methods

Sample retrieval

RNA extraction and detection of BoDV-1 RNA

High-throughput sequencing

Phylogenetic analysis

Detection of bornavirus-reactive antibodies

Immunohistochemistry and in-situ hybridisation

Virus isolation

Role of the funding source

Results

Discussion

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Vol 20 - N° 4

P. 467-477 - avril 2020 Retour au numéro

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Zoonotic spillover infections with Borna disease virus 1 leading to fatal human encephalitis, 1999–2019: an epidemiological investigation - 27/03/20

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