Toscana Virus Meningoencephalitis in Upper Bavaria

Sandfly-transmitted Toscana virus (TOSV), a phlebovirus of the Phenuiviridae family, is one of the most common causative agents of meningoencephalitis (ME) in endemic areas (1). Knowledge of regional pathogens is of particular importance for initial treatment. Recently, reports of the spread of sandflies have increased (2), so that endemic circulation of TOSV is also conceivable in Germany.

Methods

A retrospective, single-center observational study identified TOSV cases and all patients with aseptic ME without pathogen identification during the period 2007 to 2021. TOSV meningitis was assumed if TOSV RNA was detected in cerebrospinal fluid (CSF) or if antibody detection was successful from serum samples in a two-step procedure (indirect immunofluorescence test and immunoblot). Evidence of acute infection was defined as the identification of TOSV IgM and IgG antibodies in combination with a fourfold increase in specific antibody titer after repeated testing at intervals of 2–3 weeks. Patients over 18 years of age with proven meningitis, as defined by a symptom complex of fever, headache, and neck stiffness, without any neurological focal symptom beyond that, and by a CSF pleocytosis of >5 cells/µL, were included in the aseptic meningitis cohort without pathogen detection. We defined concomitant encephalitic involvement as the presence of an additional focal neurological deficit. We defined the evidence or presence of a competing cause of CSF pleocytosis as an exclusion criterion. Preserved CSF and serum samples from the aseptic ME cohort without pathogen identification were subsequently tested at the Institute of Microbiology of the German Armed Forces for the presence of TOSV RNA or TOSV IgG/IgM antibodies (positive ethical vote 292/19 S). Clinical, laboratory, and CSF parameters were collected from the TOSV cohort and the aseptic ME cohort without pathogen identification. No statistical comparison of the two groups was made in view of the small number of cases and the resulting limited statistical power.

Results

During the period from 2007 to 2021, eight patients were identified with TOSV ME (Table 1). TOSV RNA was detected in the CSF of six patients, and two patients demonstrated seroconversion. All patients had previously visited Italy, seven patients within the previous two weeks; for one patient, the time interval could not be accurately reconstructed. The majority of cases had occurred in the previous seven (7/8) and two years (4/8) and had taken place between July and September (Table 1). Rapid recovery soon followed subacute onset of disease associated with typical meningitic and encephalitic symptoms. However, we did not observe any other complications.

Table 1

Parameters of the TOSV meningoencephalitis cohort and the aseptic meningoencephalitis cohort without pathogen identification

In total, we identified 426 aseptic ME cases during the above period, of which 195 cases remained without pathogen identification. Of these 195 aseptic ME cases, we were able to identify and retrospectively test for TOSV in a total of 52 preserved serum and CSF samples in our biobank. However, we found no constellation suggestive of acute TOSV infection. Thus, the proportion of TOSV ME in our cases of diagnosed aseptic meningoencephalitides was 1.9% [1.0; 3.7] (8/426). We also examined the CSF and serum samples for West Nile virus (WNV) on an exploratory basis, again failing to detect a positive result (data not shown).

Discussion

In our Department of Neurology, we identified eight patients with TOSV meningoencephalitis during the past 15 years who had previously been to Italy. Very few studies are known to date that have investigated transmission of TOSV in Germany. In a recent publication, the seroprevalence for TOSV IgG antibodies was 2% in patients with aseptic ME in Baden-Wurttemberg from 2006 to 2016 and 4% for TOSV IgM antibodies, but direct pathogen identification by polymerase chain reaction (PCR) was not successful in any patient (3). None of the patients had a history of travel to an endemic area, and it remained uncertain whether and how the patients had been exposed to TOSV.

In Italy, a national health survey estimated an annual incidence of 0.1 per 100 000 for TOSV (4). There was no increase in TOSV cases from 2018 to 2020, with the high incidence in 2018 being attributed by the authors to the higher-than-average temperatures that year which favored the proliferation of sandflies (4). Estimates for Germany have not yet been made. However, as a result of globalization and increasing travel, a rise in TOSV infections can be expected in the coming years, even in our latitudes. The increasing number of cases of TOSV meningoencephalitis in our hospital in recent years already reflects this. Furthermore, global warming plays a significant role in the spread of virus-carrying vectors. Table 2 shows the seroprevalence of TOSV in regions where TOSV-carrying sandflies are already endemic (1, 2). Modeling studies show that climate change can be expected to further spread certain sandfly species in central Europe as well (5).

Table 2

Toscana virus: Seroprevalences in endemic areas

A limitation of our study is its retrospective analysis and testing of serum and CSF samples. Testing for TOSV could only be carried out on specimens preserved in the biobank which, bearing in mind that the CSF tests were performed only in some cases during office hours, resulted in the low number of cases of specimens tested.

In summary, based on our retrospective observational study, we do not currently suspect endemic TOSV circulation; possible TOSV infection should be considered especially among travelers returning from endemic areas with signs of meningitis/meningoencephalitis. Nevertheless, the increase in vector-borne infections in Germany illustrates that the spread of TOSV in our latitudes cannot be ruled out in the coming years and calls for increased vigilance. Diagnosing patients with TOSV is of clinical importance, given that the favorable course of the disease avoids prolonged hospitalization and antiviral therapies.

Martina Wenzel*, Ali Maisam Afzali*, Dieter Hoffmann, Sabine Zange,
Enrico Georgi, Bernhard Hemmer

Clinic and Polyclinic for Neurology at the Rechts der Isar Hospital, Technical University, Munich (Wenzel, Afzali, Hemmer), [e-mail]

Institute for Experimental Neuroimmunology (Afzali)

Munich Cluster for Systems Neurology (SyNergy), Munich (Afzali, Hemmer)

Institute of Virology, Technical University and Helmholtz Center Munich (Hoffmann)

Institute of Microbiology of the German Armed Forces, Munich (Zange, Georgi)

*The authors contributed equally to this paper.

Conflict of interest statement

The authors confirm that there are no conflicts of interest.

Manuscript received on 06 March 2022, revised version accepted on 09 May 2022

Translated from the original German by Dr. Grahame Larkin, MD

Cite this as:
Wenzel M, Afzali AM, Hoffmann D, Zange S, Georgi E, Hemmer B:
Toscana virus meningoencephalitis in Upper Bavaria.
Dtsch Arztebl Int 2022; 119: 546–7. DOI: 10.3238/arztebl.m2022.0224

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