Benefit of detecting tick-borne encephalitis viremia in the first phase of illness

Abstract

In Switzerland, reports of tick-borne encephalitis virus (TBEV) infections to the Federal Office of Public Health have increased by 100% in 2005 compared to the annual mean from 1999 to 2004. This might be partly due to unspecificity in serological testing. In order to make diagnostics more specific and to improve patient management, we recommend to consider the first phase of the biphasic course of TBE, that can be suspected in a trias of tick bite, followed by a feverish illness associated with thrombocytopenia and/or leucocytopenia. In this phase, detection of viremia by TBEV-specific polymerase chain reaction assay (PCR) will enable diagnosis as well as prediction of the second phase of TBEV infection, developing in the majority of patients. Circumstances suggesting detection of TBE viremia are exemplified by two case reports.

Introduction

Tick-borne encephalitis virus (TBEV) is an important arbovirus transmitted mainly by the ticks Ixodes ricinus in Europe and by I. persulcatus in the Urals, Siberia, far-eastern Russia, and also in parts of Estonia and Latvia (Charrel et al., 2004). In Switzerland, incidence of TBEV infections increased by 100% to 202 cases in 2005 compared to the annual mean from 1999 to 2004 (Anonymous, 2006a).

TBE can only be diagnosed accurately by means of laboratory techniques, as the clinical symptoms are not specific for the disease (Charrel et al., 2004, Kunze et al., 2004). The clinical course of Western subtype of TBEV usually happens in a biphasic manner (Gritsun et al., 2003). The first phase consists of an unspecific illness with fever, headache, malaise and myalgia (Kaiser, 1999, Kunz, 1992). This phase is commonly characterised by thrombocytopenia and leukocytopenia. After a symptom-free interval of 1–33 days, this viremic phase is followed by the second phase of TBE in 74–100% of cases. In the remaining individuals the disease resolves without a second phase (Günther et al., 1997, Kaiser, 1999, Lotrič-Furlan et al., 2000). In the second phase, at least four clinical features of different severity are observed: meningitis, meningoencephalitis, meningoencephalomyelitis, meningoradiculoneuritis (Charrel et al., 2004, Kunze et al., 2004). During this phase, etiological diagnosis may be difficult mainly for two reasons. First, virus cannot be detected in CSF neither by culture nor by TBEV-PCR (Haglund and Günther, 2003). Second, diagnosis of TBE by detection of IgM alone is hampered, since IgM antibodies can persist for up to 10 months in vaccinees or individuals who acquired the infection naturally (Hofmann et al., 1983). Thus, confirmation by detection of specific IgG is required, but may turn out negative in the early phase of infection, and monitoring an increase of TBEV-specific IgG 1–2 weeks later is only done in a minority of patients (Kaiser, 2000, Niedrig et al., 2001). Furthermore, cross-reacting antibodies to other flaviviruses by prior infection or vaccination (e.g. Dengue virus, Yellow fever virus, Japanese encephalitis virus) should be taken into account when using commercial ELISAs for detection of TBEV IgG (Niedrig et al., 2001). Thus, verification of positive results by neutralisation assay is advised by some experts (Holzmann, 2003), and a patient's meticulous medical history might help in estimating the specificity of positive TBEV IgG results.

In Switzerland, 88.6% of 202 TBEV infections or suspected TBE in 2005 were reported due to positive TBEV-IgM, 5.9% of cases with reference to an increase of TBEV-IgG, and no cases with seroconversions of TBEV-IgG. The remaining cases were suspected TBE, reported without specification of method or on pure clinical suspicion (personal communication by Dr. Hans-Peter Zimmermann, Federal Office of Public Health, Berne).

Taken together, serological diagnosis of TBE is hampered by long persistence of TBEV-IgM and by unspecificity of TBEV-IgG. Thus, despite positive TBEV-IgM additional diagnostics of pathogens associated with similar clinical features that geographically overlap with TBEV is mandatory (Dumpis et al., 1999, Kennedy, 2004).

A new approach to diagnose infections by Western TBEV subtype can be detection of viremia in the first phase of illness, thereby anticipating diagnosis of later TBE, as 74–100% of these patients will encounter the second phase (Günther et al., 1997, Kaiser, 1999, Lotrič-Furlan et al., 2000).