Tickborne encephalitis virus, northeastern Italy.

To the Editor: Approximately 3,000 cases of tickborne encephalitis virus (TBEV) disease are registered annually in Europe (1). In Italy, indigenous TBEV infection cases have been only sporadically recorded from 1975 through 2001; in addition, serologic investigations in populations at risk in northern Italy have shown only a low prevalence of specific antibodies (0.6%-5%) (2,3). A surveillance system for TBEV infections was started after autochthonous TBEV was recognized in late summer and fall 2003 in Friuli-Venezia Giulia (FVG), a small region of northeastern Italy with nearly 1 million inhabitants (4). Surveillance is based on systematic microbiologic screening of all patients referred to the emergency departments of regional hospitals for suspected community-acquired central nervous system infections or fever and headache with a history of tick bite in the past 6 weeks. Screening for TBEV was performed on sera or cerebrospinal fluid (CSF) by enzyme immunoassay (Enzygnost Anti-TBE virus Ig, Dade Behring Marburg GmbH, Marburg, Germany) and repeated on convalescent-phase sera. Demonstration of specific immunoglobulin M (IgM) in serum or CSF in the acute phase or [greater than or equal to] 4-fold rise in serum antibody titer in the convalescent phase was interpreted as an indicator of recent TBEV infection. For surveillance purposes, TBEV infection was defined when hemagglutination inhibition antibody test and neutralization assay by a reference laboratory confirmed ELISA results (5). Data were collected at a regional reference center, where cases were classified as possible, probable, and confirmed, according to the new TBEV case definition (6).

From July 2003 through November 2005, 20 cases of TBEV infection were detected; their demographic, epidemiologic, and clinical characteristics are given in the Table. Cases occurred throughout the year, with a biphasic peak in June and September-November. A biphasic clinical course was reported in 10 patients. The median period between tick bite and date of referral to hospital was 22 days (range 15-46 days). Seventeen cases were classified as confirmed, 2 as probable, and 1 case could not be classified because symptoms started after tick season (December) (6). Two patients were coinfected with Borrelia burgdorferi.

The most common symptoms were fever, headache, nausea, vomiting, and myalgia; the most common central nervous system signs were stiff neck, irritability, and limb paresis. Five patients only reported headache and fever without neurologic signs. Lumbar puncture, performed in 15 patients, showed mild pleocytosis with neutrophil predominance in 13 patients, elevated protein level in 14 patients, and normal glucose level in all.

The clinical syndrome was classified, in accordance with Kaiser et al., into febrile form (4 cases), aseptic meningitis (3 cases), encephalitis (2 cases), meningoencephalitis (8 cases), and meningoencephalomyelitis (3 cases) (7). None of the patients died, but 3 required respiratory support in the intensive care unit. Outcome was favorable for 9 patients; major neurologic sequelae were observed in 6 and minor sequelae in 5.

During the past 20 years, TBEV has reemerged in several European areas that had been disease free (1,8). In FVG, which borders disease-endemic areas such as Slovenia and Austria, the first cases of TBEV infection were documented recently (4). Several explanations, in addition to the well-established role of climate change, can be proposed (1). First, in Slovenia, after the end of the Communist regime, recreational activities increased considerably, with the creation of natural parks and hunting grounds, densely populated with deer, chamois, rodents, foxes, and other wild animals that can easily cross national borders (9). Second, after the 1976 earthquake that destroyed a large number of mountain villages in FVG, economic activities were progressively concentrated in the plains of the region, which rapidly increased urbanization of the plains towns. As a consequence, the mountains in the northern part of the region were progressively abandoned by humans and returned to wilderness. A final possible explanation is that TBEV cases were undiagnosed because awareness among local physicians was low; however, this variable likely played a minor role, since a recent serologic survey of persons at high risk (forest rangers) yielded a low positivity ratio (3). If even workers at risk had a low sero-prevalence, TBEV cases were likely uncommon in the region.

The implementation of a regional active surveillance system allows the highest sensitivity in assessing the epidemiologic features of TBEV infections, which are characterized by highly disease-endemic microfoci in areas free of the problem (10). Precisely defining areas where risk is particularly will lead to optimal use of prevention programs and design of educational programs for residents, tourists, and healthcare workers.

Acknowledgments

We are grateful to Maria Grazia Ciuffolini for TBEV serologic testing (hemagglutination-inhibition antibody test and neutralization assay).

Anna Beltrame, * Maurizio Ruscio, ([dagger]) Barbara Cruciatti, ([double dagger]) Angela Londero, * Vito Di Piazza, ([section]) Roberto Copetti, ([section]) Valentino Moretti, ([dagger]) Paolo Rossi, ([paragraph]) Gian Luigi Gigli, ([paragraph]) Luigia Scudeller, * and Pierluigi Viale *

* University of Udine, Udine, Italy; ([dagger]) Hospital of San Daniele, San Daniele, Italy; ([double dagger]) Hospital of Pordenone, Pordenone, Italy; ([section]) San Antonio Abate Hospital, Tolmezzo, Italy; and ([paragraph]) Hospital of Udine, Udine, Italy

References

(1.) Gunther G, Haglund M. Tick-borne encephalopathies: epidemiology, diagnosis, treatment and prevention. CNS Drugs. 2005;19:1009-32.

(2.) Cristofolini A, Bassetti D, Schallenberg G. Zoonoses transmitted by ticks in forest workers (tick-borne encephalitis and Lyme borreliosis): preliminary results. Med Lav. 1993;84:394-402.

(3.) Cinco M, Barbone F, Ciufolini M, Mascioli M, Anguero Rosenfeld M, Stefanel P, et al. Seroprevalence of tick-borne infections in forestry rangers from northeastern Italy. Clin Microbiol Infect. 2004;10:1056-61.

(4.) Beltrame A, Cruciatti B, Ruscio M, Scudeller L, Cristini F, Rorato G, et al. Tick-borne encephalitis in Friuli Venezia Giulia, northeastern Italy. Infection. 2005;33:158-9.

(5.) Holzmann H, Kundi M, Stiasny K, Clement J, McKenna P, Kunz C, et al. Correlation between ELISA, hemagglutination inhibition, and neutralization tests after vaccination against tick-borne encephalitis. J Med Virol. 1996;48:102-7.

(6.) Stefanoff P, Eidson M, Morse DL, Zielinski A. Evaluation of tickborne encephalitis case classification in Poland. Euro Surveill. 2005;10:23-5.

(7.) Kaiser R. The clinical and epidemiological profile of tick-borne encephalitis in southern Germany 1994-98: a prospective study of 656 patients. Brain. 1999;122:2067-78.

(8.) Skarpaas T, Ljostad U, Sundoy A. First human cases of tickborne encephalitis, Norway. Emerg Infect Dis. 2004;10: 2241-3.

(9.) Lesnicar G, Poljak M, Seme K, Lesnicar J. Pediatric tick-borne encephalitis in 371 cases from an endemic region in Slovenia, 1959 to 2000. Pediatr Infect Dis J. 2003;22:612-7.

(10.) Zeman P. Objective assessment of risk maps of tick-borne encephalitis and Lyme borreliosis based on spatial patterns of located cases. Int J Epidemiol. 1997;26: 1121-9.

Address for correspondence: Anna Beltrame, Clinic of Infectious Diseases, University of Udine, Via Colugna no. 50, 33100 Udine, Italy; email: [e-mail]

Table. Demographic, epidemiologic, and clinical data for 20 patients
with TBEV infection in Friuli-Venezia Giulia *

                                              Hospitalization date
                                           (length of hospitalization
Patient    Sex    Age (y)     Tick bite               [d])

1           F        36          Yes            2003 Jul 28 (31)
2           M        58          Yes            2003 Oct 13 (15)
3           F        42          Yes            2003 Oct 17 (19)
4           F        27           No            2003 Dec 30 (25)
5           M        16          Yes            2004 Apr 28 (21)
6           F        53          Yes            2004 Jun 21 (18)
7           M        43          Yes            2004 Jul 17 (0)
8           M        62          Yes            2004 Oct 10 (10)
9           M        35          Yes            2004 Nov 8 (15)
10          F        77          Yes            2004 Nov 22 (0)
11          F        36          Yes            2005 May 8 (19)
12          M        12          Yes            2005 May 13 (27)
13          M        64          Yes            2005 Jun 10 (11)
14          M        59          Yes            2005 Jun 20 (12)
15          M        15          Yes            2005 Sep 1 (10)
16          F        39          Yes            2005 Sep 8 (8)
17          M        70          Yes            2005 Sep 16 (53)
18          M        75           No            2005 Oct 18 (10)
19          M        20           No            2005 Nov 2 (7)
20          M        61          Yes            2005 Nov 26 (13)

           Definitive
Patient    diagnosis                     Sequelae

1             MEM                       UL paresis
2              E                          Absent
3              ME                         Absent
4              ME        UL paresis, paresis of VII cranial nerve
5              ME                       UL tremors
6              ME                        Diplopia
7              FF                         Absent
8              ME                     UL paresthesia
9              ME                         Absent
10             FF                         Absent
11            MEM                       UL paresis
12             ME                         Absent
13             FF           UL paresthesia, hearing impairment
14             M                          Absent
15             ME                         Absent
16             M                          Absent
17            MEM                  UL paresis, RI, VAP
18             FF                       UL tremors
19             M                        UL tremors
20             E             UL tremors, ataxia, opsoclonus

* TBEV, tickborne encephalitis virus; MEM, meningoencephalomyelitis;
UL, upper limbs; E, encephalitis; ME, meningoencephalitis; FF, febrile
form; M, meningitis; RI, respiratory insufficiency; VAP,
ventilator-associated pneumonia.