Human surveillance of TOSV neuroinvasive infections M.Paola Landini Unit of Clinical Microbiology - Regional Center for microbiological emergencies,

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1 Human surveillance of TOSV neuroinvasive infections M.Paola Landini Unit of Clinical Microbiology - Regional Center for microbiological emergencies, St Orsola Hospital, University of Bologna

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3 Toscana virus(tosv) was first isolated in 1971 from Phlebotomus perniciosus in Monte Argentario (Grosseto, Tuscany) and characterized by Paola Verani (ISS Rome)

4 TOSCANA VIRUS Transmission: phlebotomus bites (Phlebotomus perniciosus, P. Perfiliewi) Reservoir: Phlebotomus? Transmissine s cycle: Phlebotomus man/woman- Phlebotomus? - Isolated from the brain of a bat (Pipistrellus kuhli) - Specific IgG found in some animal species (all asymptomatic)

5 TOSV was recognized as a causative agent of neurological disease in humans only in 1983, when it was isolated for the first time from a young woman with lymphocytic meningitis TOSV is the major cause of aseptic meningitis (95%) and meningoencephalitis (4.5%)

6 Asymptomatic infection and infection without central nervous system involvement due to TOSV, such as febrile erythema or influenza-like illness, have also been described Unusual clinical manifestations or severe sequelae, such as hydrocephalus, epididimo-orchitis and ischemic complications, have been recently reported

7 TOSV: EUROPE TOSV is endemic in Mediterranean Europe lineage B lineage A Depaquit et al. 2010

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9 Seroprevalence studies in Italy, show large variations ranging from 3% in northern Italy (Torino), to 16% in Umbria and 22% in central Italy. The virus is widespread in several regions including Tuscany, Piedmont, the Marches, Umbria and Emilia- Romagna. A recent retrospective study on the antibody prevalence rates of TOSV among children and adults was performed in a population (n=2737) living in Tuscany during The seroprevalence rate was 19.8% in adults and 5.8% in children, showing an age-dependent increase in TOSV specific immunity. Moreover, correlating seroprevalence to the clinical profile, the study indicated that asymptomatic TOSV infection is more frequent in young people (91%) than in adults (31.4%), in whom a higher incidence of severe signs of neurological disorders correlated to TOSV infection are present

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11 TOSV distribution in Italy Emilia Romagna Region: /120 cases (15%) 14 aseptic meningitis 2 meningoencephalitis 2 encephalitis = human cases of TOSV infection Modified from Vocale et al, 2011

12 Vocale et al, 2011 INFEZIONI ACUTE DA TOSV (anno 2010)

13 No correlation with age or gender Mean duration of symptoms: 8 days Most frequent symptoms: fever, headache 100% positive prognosis 11/18 TOSV acute infections were in the Bologna province 13/18 cases are autoctonous; 5/18 cases? Vocale et al, 2011

14 TOSV distribution in Italy Emilia Romagna Region: /137 cases (9.5%) = human cases of TOSV infection 11 aseptic meningitis 1 meningoencephalitis 1 encephalitis

15 TOSV-2011 TOSV ACUTE INFECTION: 13/137 (9.5%) PCR+Ab-: 0/13 PCR+Ab+: 11/13 PCR-IgG+IgM+: 0/13 PCR-IgG-IgM+: 0/13 PCR (not performed)igg+igm+: 2/13 ACUTE INFECTION 11/13 (84.6%) RECENT INFECTION 2/13 (15.4%)

16 TOSV distribution in Italy Emilia Romagna Region: = human cases of TOSV infection 30/120 cases (25%) 19 aseptic meningitis 4 encephalitis 7 meningoencephalitis (2 severe cases, coma ICU) Pierro et al, submitted

17 TOSV-2012 TOSV ACUTE INFECTIONS 2012: 30/120 (25%) PCR+Ab-: 7/30 PCR+Ab+: 20/30 PCR-IgG+IgM+: 2/30 PCR-IgG-IgM+: 1/30 ACUTE INFECTIONS 27/30 RECENT INFECTIONS 3/30

18 TOSV in Emilia Romagna 2010 Among 120 cases 18 positives (15%) (Vocale et al. 2011) 2011 Among 137 cases 13 positives (9.5%) 2012 Among 120 aseptic meningitis 30 positives (25%) (Pierro et al submitted manuscript )

19 TOSV neuroinvasive infections Emilia-Romagna AGE FEMALES MALES TOTAL TOTAL From: Regione Emilia-Romagna

20 TOSV seems an emerging human pathogen

21 : The lab testing for TOSV was done once per week and only to samples negative for WNV and USUV What do we do today? From 2012: all the samples entering the regional surveillance system for WNV are tested in parallel for TOSV

22 WNV RT-PCR (CSF, serum/plasma) PCR+ PCR-, IgM+, IgG- PCR-, IgM+, IgG+ WNV neuroinvasive infection USUV neuroinvasive infection Samples from patients with neurological symptoms TOSV Serology IgG-IgM (CSF, serum/plasma) RT-PCR (CSF) Serology IgG-IgM (serum/plasma) PCR-, IgM-, IgG+ PCR-, IgM-, IgG- (WNV and TOSV) PCR+ PCR-, IgM+, IgG- PCR-, IgM+, IgG+ PCR-, IgM-, IgG+ Past infection with WNV or another flavivirus Neuroinvasive infection with TOSV Past infection with TOSV USUV PCR+ RT-PCR (CSF, serum/plasma) PCR- Absence of acute WNV, TOSV and USUV infection FLOW CHART FOR INFECTIONS BY TOSV, WNV, USUV

23 Conclusions From 2010 to 2012 neuroinvasive infections by TOSV RER are increased in In our setting TOSV should be considered an emerging virus There is the need to increase the awarenes of family doctors and emergency personnel More studies are necessary in order to understand the reservoir and the transmission cycle