CASE REPORTS

Severe tick-borne encephalitis in a patient previously infected byWest Nile virus

EMOKE FERENCZI1, ENIKO BAN1, ANITA ABRAHAM2, TAMASNE KAPOSI1,

GABOR PETRANYI1, GYORGY BERENCSI1 & ANTTI VAHERI3

From the 1National Reference Laboratory for Viral Zoonoses, Department of Virology, National Centre for Epidemiology,

Budapest, 2St. Laszlo Central Hospital for Infectious Diseases, Budapest, Hungary, and 3Department of Virology, Haartman

Institute, University of Helsinki, Helsinki, Finland

AbstractWe describe severe tick-borne encephalitis (TBE) in a patient who had previously experienced West Nile fever, anotherflavivirus infection endemic in Hungary. Previous West Nile virus infection does not develop immunity either against TBEvirus infection or the disease, and it does not mitigate its clinical course. The possibility of antibody-dependentenhancement is considered.

Introduction

In the early 1960s it became obvious that tick-borne

encephalitis (TBE) is a significant public health

concern in Hungary. Endemic areas of TBE were

shaped through the systematic search for natural foci

of arboviruses between 1966 and 1986 [1], as well as

by viral diagnostics of suspected TBE patients [2].

The first indigenous human infections by West Nile

virus (WNV), characterized by neurological symp-

toms (meningitis, encephalitis), were diagnosed in

Hungary in 2003, but no animal cases had been

detected to date. 14 human cases were confirmed

serologically and a WNV outbreak at a goose farm

[3,4]. These events raised several questions: had the

virus already established itself in Hungary, did

migratory birds bring the virus to the country every

y, and what would be the consequences of consecu-

tive infections/immunizations of the 2 viruses, TBEV

and WNV, in humans? While the first 2 questions

remain unanswered, the present case report sheds

light on the third.

Case report

A 38-y-old female who lived in a small village in north-

eastern Hungary became seriously ill in the autumn of

2005 after a tick bite during an outing to the hills near

her village. She had a history of ulcerative colitis, had

not been vaccinated against TBE and had never been

abroad. 10 d after the tick bite she fell ill and was

admitted 1 d later to the Department of Neurology of

the local county hospital. Her initial symptoms were

malaise, nausea and generalized muscle pains. Be-

cause of her rapidly worsening condition she was

transferred to the Hungarian Central Hospital for

Infectious Diseases after 3 d of treatment. Upon her

second hospital admission, on d 14 after the tick bite,

the patient’s symptoms were fever, neck stiffness,

vertigo, severe neck pain radiating to the back and

difficulties in walking. During the next 3 d, hypotonia,

areflexia, and right upper limb paralysis developed.

There was no sensory involvement. Methylpredniso-

lone therapy (10 g total) was started and gradual

recovery followed. On d 27, mild paresis appeared in

the left upper limb. She recovered with sequelae�residual right arm weakness and right shoulder

muscle atrophy.

At the acute stage her cerebrospinal fluid had 525

WBC/l (95% polymorphonuclear cells), increased

protein (1.3 g/l) and normal glucose. An MRI scan

of the cervical spine excluded any compressive

lesion, but showed enlargement of the cervical cord

Correspondence: A. Vaheri, Department of Virology, Haartman Institute, POB 21, FIN-00014 University of Helsinki, Finland. Tel: �358 9 1912 6490.

E-mail: antti.vaheri@helsinki.fi

Scandinavian Journal of Infectious Diseases, 2008; 40: 759�766

(Received 14 February 2008; accepted 18 February 2008)

ISSN 0036-5548 print/ISSN 1651-1980 online # 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis As)

DOI: 10.1080/00365540801995386

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from C3 to C7 and signal disturbance due to

oedema and inflammation. Nerve conduction stu-

dies and concentric needle electromyography

showed severe damage of the right cervical anterior

horn cells (lower motor neurons) with concomitant

increase in distal latency of median nerve and signs

of denervation in the C5 and C6 myotomes.

The first serum sample was sent to the virus

laboratory with clinical diagnosis of TBE. Three

methods were used for the determination of specific

antibodies: 1) indirect fluorescent antibody assay

(IFA) on in-house slides; 2) haemagglutination in-

hibition test (HI) using in-house HA antigen pre-

pared from the first Hungarian TBEV isolate

(KEM1); and 3) a commercial ELISA test (Nova-

Tec). Reliability of the in-house tests was evaluated in

an external quality assurance (EQA) programme for

the serological diagnosis of TBEV infections, and the

tests proved to be suitable for this purpose [5].

Because of the difficulties in the detection of specific

IgM by the 3 methods used, the examinations were

extended to the detection of specific antibodies

directed against WNV. Both IFA and HI were

performed using in-house antigens, while the ELISA

was performed for IgM with a commercial ELISA kit

(PanBio). In spite of the very high titres of WNV-

specific IgG, IgM antibodies remained undetectable.

Results of specific IgM had been negative or doubtful

for both viruses. The kinetics of the immune response

indicated that she had earlier encountered WNV

infection (probably without severe symptoms) and

now suffered from a current TBEV infection. Table I

shows the serological results of the patient’s consecu-

tive 3 serum samples, except for the IgM results.

Historical data and conclusions

TBE-endemic foci in Hungary are well known since

the early 1960s, while WNV circulation and infec-

tions in human and animal individuals became

obvious only in 2003. The Transdanubian region

as well as the north-eastern part of Hungary are

endemic for TBE, the Hungarian Great Plains have

only very small TBE foci but seem to be endemic for

WNV. There are very few overlapping areas as yet.

Recent results have shown that WNV has established

itself in some parts of Hungary [4].

This is the first report on sequential natural

infections with WNV and TBEV in humans. The

case described here showed that the previous WNV

infection does not develop immunity against TBEV

infection or the disease, and does not mitigate the

clinical course of the disease.

Diagnostics of flavivirus infections are performed

centrally in Hungary. Since 1981 the IFA method

has been used as a daily routine and HI to confirm

the results. Using these 2 methods the laboratory can

diagnose most of the acute infections as well as

evaluate immunity after vaccination and, if not, an

additional virus neutralization test can be per-

formed. Typical antibody titres in the diagnostic

laboratory are 80�160 and 80�320 using IgG-IFA

and HI in sera taken on d 6�14, and 160�640 and

320�640 taken on d 15�42 after the onset of

symptoms. Specific IgM has been detectable during

this period by both methods in sera fractionated by

chromatography [6]. The IgM fraction corresponds

to about 1:10 dilution of the original serum and

contains also IgA. In primary WNV infections IgG

titres proved to be at least 4-fold higher than in

TBEV infections (data not shown).

During the past 25 y the National Reference

Laboratory has diagnosed about 30 TBE cases

with vaccination in their anamnestic data. The

immune response of most of these patients was

similar to the 1 described above. Notably, in most

patients the course of the disease has been more

severe than in the patients without former vaccina-

tion (Ferenczi, Mikola, Guseo, unpublished obser-

vations). Similar clinical observations have been

described in children who had developed severe

TBE despite post-exposure prophylaxis with specific

TBE immunoglobulin [7]. It is difficult to say

whether the present case is more severe than usual,

as the manifestations of TBEV infections can range

from asymptomatic to fatal illness. However, the

outcome of most TBE cases remains without seque-

lae in Hungary, and paresis and the consequent

muscular atrophy of the upper limbs are rare. Similar

data have been found in other European countries

Table I. Reciprocal virus serology titres of the patient infected consecutively by WNV and TBEV.

Antibodies to TBEV Antibodies to WNV

D after onset of symptoms Sample IgG-IFA HI IgG-IFA HI

6 Serum 640�1280 1280 1280�2560 ]10240

6 CSFa 2�4 8�16 2�4 16�32

8 Serum ]2560 2560�5120 ]2560 5120

43 Serum ]2560 ]10240 320 640

aCerebrospinal fluid.

760 Case Reports

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[8,9]. In this patient the very rapid transportation

from the local hospital to the Central Hospital for

Infectious Diseases (St. Laszlo Hospital, Budapest)

emphasizes the sudden onset of the severe disease,

which is not an everyday event in Hungary. The

short incubation period of 2 weeks to neurological

symptoms, compared to the usual 3 weeks, suggests

that antibody-dependent enhancement (ADE) may

have occurred.

Several factors (e.g. low antigen content in the

vaccine, negligence around the immunization sche-

dule, vaccination in the tick season, vaccination or

infection with another flavivirus, post-exposure pre-

vention with a small amount of specific immunoglo-

bulin preparation) could be traced as sources for the

suboptimal immune status [10]. In vitro studies on

ADE in TBE have suggested that the enhancement

might be group- rather than flavivirus-specific [11].

In our case the 2 viruses, WNV and TBEV, belong to

2 different serological groups but are still highly

cross-reactive. Model experiments in experimentally

infected animals might explain the events in the case

of consecutive infections by the 2 viruses.

Preventive measures, including vector control and

correct vaccination practice, are needed to avoid the

enhanced disease manifestation in flavivirus infec-

tions. More attention should be paid to the complete

flavivirus surveillance, especially in countries where

more than 1 flavivirus causes human illnesses.

References

[1] Molnar E. Occurrence of tick-borne encephalitis and other

arboviruses in Hungary. Geographia Medica 1982;/12:/78�120.

[2] Ferenczi E, Racz G, Faludi G, Czegledi A, Mezey I, Berencsi

G. Natural foci of classical and emerging viral zoonoses in

Hungary. In: Berencsi G, Khan AS, Halouzka J, editors.

NATO Science Series: Emerging Biological Threat. IOS

Press 2005;370:43�9.

[3] Glavits R, Ferenczi E, Ivanics E, Bakonyi T, Mato T, Zarka

P, et al. Co-occurrence of West Nile fever and circovirus

infection in a goose flock in Hungary. Avian Pathol 2005;/34:/

408�14.

[4] Bakonyi T, Ivanics E, Erdelyi K, Ursu K, Ferenczi E,

Weissenbock H, et al. Lineage 1 and 2 strains of encephalitic

West Nile virus, Central Europe. Emerg Infect Dis 2006;/12:/

618�23.

[5] Niedrig M, Avsic T, Aberle SW, Ferenczi E, Labuda M,

Rozentale B, et al. Quality control assessment for the

serological diagnosis of tick-borne encephalitis virus infec-

tions. J Clin Virol 2007;/38:/260�4.

[6] Nagy G, Mezey I. The use of ion exchange chromatography

for demonstration of rubella-specific IgM antibodies. Acta

Microbiol Acad Sci Hung 1977;/24:/189�94.

[7] Kluger G, Schottler A, Waldvogel K, Nadal D, Hinrichs W,

Wundisch GF, et al. Tick-borne encephalitis despite specific

immunoglobulin prophylaxis. Lancet 1995;/346:/1502.

[8] Kaiser R. The clinical and epidemiological profile of tick-

borne encephalitis in southern Germany 1994�1998: a

prospective study of 656 patients. Brain 1999;/122:/2067�78.

[9] Plısek S, Honegr K, Beran J. TBE infection in an incomplete

immunized person at risk who lives in a high-endemic area:

impact on current recommendations for immunization of

high-risk groups. Vaccine 2008;/26:/301�4.

[10] Ferenczi E, Jankovics A, Molnar E, Berencsi G. Does the

suboptimal antibody level aggravate the course of tick-borne

encephalitis? Acta Microbiol Immunol Hung 1999;/46:/394�5.

[11] Phillpotts RJ, Stephenson JR, Porterfield JS. Antibody-

dependent enhancement of tick-borne encephalitis virus

infectivity. J Gen Virol 1985;/66:/1831�7.

Six cases of Aerococcus sanguinicola infection: Clinical relevanceand bacterial identification

KRISTINA IBLER1, KJELD TRUBERG JENSEN2, CHRISTIAN ØSTERGAARD3,

UTE WOLFF SONKSEN4, BRITA BRUUN4, HENRIK C. SCHØNHEYDER5,

MICHAEL KEMP1, RIMTAS DARGIS1, KELD ANDRESEN1 &

JENS JØRGEN CHRISTENSEN1

From the 1Department of Bacteriology, Mycology and Parasitology, Statens Serum Institute, Copenhagen, and Departments of

Clinical Microbiology at 2Sydvestjysk Sygehus Esbjerg, 3Copenhagen University Hospital Herlev, 4Hillerød Hospital, and5Aalborg Hospital, Aarhus University Hospital, Denmark

Correspondence: K. Ibler, Department of Bacteriology, Mycology and Parasitology, Statens Serum Institute, Artillerivej 5, 2300 Copenhagen S, Denmark.

Tel: �45 32683647. Fax: �45 32683873. E-mail: Kristinaibler@hotmail.com

Case Reports 761

(Received 24 March 2008; accepted 25 March 2008)

ISSN 0036-5548 print/ISSN 1651-1980 online # 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis As)

DOI: 10.1080/00365540802078059

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