In Europe, tick-borne encephalitis (TBE) is a common infection of the central nervous system with a 400% increase in reported cases during recent decades. TBE is caused by an RNA virus of the genus Flavivirus, also including the dengue, yellow fever, Japanese encephalitis, and West Nile viruses. The TBE virus (TBEV) is usually transmitted by bites of an infected tick. In most of Europe, the TBEV is endemic with seasonally distributed TBE cases due to temperature-dependant tick activity.1,2 Generally, TBE is characterized by a biphasic course after an incubation period of ∼1 to 2 weeks. Nonspecific flu-like symptoms 1 to 8 days are followed by an asymptomatic interval and thereafter symptoms from meningitis to meningoencephalomyelitis of varying severity occur.1,3,4 Childhood TBE is considered to be a relatively mild condition with favorable outcome compared with adult TBE.3,5,6 However, the general assumption of childhood TBE being insignificant is challenged by pediatric case-reports of severe acute TBE7 and deficits in attention and psychomotor activity combined with electroencephalogram abnormalities as sequelae.8 No specific treatment exists, but TBE is preventable by immunization.1,4,9,10
This study aimed to reevaluate symptomatology and clinical findings at diagnosis in childhood TBE. The algorithms for diagnostics are based on adult findings or studies in which children and adults are analyzed collectively. A better description of childhood TBE is essential for diagnostic accuracy and can lead to better understanding of the natural course of the disease in children.
PATIENTS AND METHODS
During 2003–2008, 3635 anti-TBE serologies were obtained at our hospital. These tests were requested by our own hospital, county hospitals, and general practitioners. Overall 998 patients (27%) were positive for anti-TBE immunoglobulin M (anti-TBE IgM) and/or G (anti-TBE IgG). These patients were asked retrospectively (May 2009) to fill in a questionnaire regarding symptoms prior to serology and to give consent to participate. Responses were obtained from 703 patients (70%), 32 (3.2%) were deceased and 13 (1.3%) could not be reached. Among respondents, 30 (4.3%) declined participation. Thus, 673 patients (67%), males/females 1/1.1, were available for further analysis. The study was approved by the Regional Ethics Review Board.
Serodiagnostic Testing for TBE.
Serum anti-TBE IgM and G were determined (accredited test procedures) by enzyme immunoassays (Siemens Healthcare Diagnostics, Deerfield, IL) at the Virology Laboratory, Department of Microbiology in Huddinge, Karolinska University Laboratory. The serodiagnostic criterion was a positive anti-TBE IgM or increased titer (≥4-fold) of anti-TBE IgG between acute and convalescent samples.
Laboratory results (ie, blood count, inflammatory indices, and cerebrospinal fluid [CSF] analysis) other than anti-TBE IgM and G were collected from patient charts. Tests were performed at accredited laboratories, mainly the Karolinska University Laboratory. The reference intervals are congruent with <5% variation.
Proportions were compared using Fisher exact test or, when sample size allowed, the χ2-test. Individual samples were analyzed using the Mann-Whitney U test or the Kruskal-Wallis test followed by Dunn multiple comparison test when appropriate. Statistical significance was set at P < 0.05.
Of 3635 anti-TBE serologies, 699 (19.2%) were obtained from patients <16 years (Tables 1, 2). Sampling occurred from spring to late autumn with a peak in August. In total, 296 (8.1%) anti-TBE serologies suggested TBE. Interpretation of serology in relation to clinical picture by responsible clinician resulted in 287 (7.9%) diagnoses. Of 3635 serologies, 692 (19.1%) displayed negative anti-TBE IgM but positive IgG. Data from 444 available questionnaires showed that 116 (26.3%) patients had no previous flavivirus infection and were nonimmunized against flaviviruses, suggesting subclinical infection (Tables 1, 2; and Table, Supplemental Digital Content 1, http://links.lww.com/INF/A634).
Epidemiologic and Clinical Findings in Childhood TBE.
Most children either resided in or visited TBE endemic areas and tick-bites were recalled by 75%. Nonspecific findings and symptoms (eg, elevated body temperature, headache, and malaise/fatigue) were more common in children, whereas those suggesting encephalitic origin (eg, cognitive dysfunction, impaired general appearance, and motor abnormalities) occurred more frequently in adults. Meningeal signs (eg, sensory disturbances and neck stiffness) were found in comparable frequencies in children and adults. Biphasic course was less frequent in preschool children than in schoolchildren and adults (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A634). Sensory disturbances, neck stiffness, vertigo/balance problems, and biphasic course were significantly more frequent in children with TBE than in non-TBE cases with completed questionnaires (Table, Supplemental Digital Content 2, http://links.lww.com/INF/A635). Duration of hospitalization was shorter in children than in adults. No deaths occurred in children (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A634).
Laboratory Findings in Childhood TBE.
Patients with TBE in different age groups displayed slightly elevated mean values in blood inflammatory indices without statistical difference—except for white blood cell count, which was significantly higher in children than in adults. Erythrocyte sedimentation rate and white blood cells were significantly elevated in children with TBE compared with non-TBE cases (Table, Supplemental Digital Content 2, http://links.lww.com/INF/A635). CSF analyses showed pleocytosis with mononuclear preponderance and a normal mean CSF glucose concentration in most patients, without statistically significant deviations between the age groups. Mean CSF albumin concentration was significantly higher in adults than in children. CSF glucose concentrations were significantly elevated in children with TBE compared with non-TBE cases (Table, Supplemental Digital Content 3, http://links.lww.com/INF/A636).
In the present study, anti-TBE serologies were consistent with the diagnosis in 5.5% of patients <16 years. Since the symptomatology is nonspecific, there is reason to believe that children and adults may elude diagnosis. Hence, 26.6% of patients with exclusively positive anti-TBE IgG had no medical history of flavivirus infection (N.B., TBEV is the only local Flavivirus) and were nonimmunized against flaviviruses. False positive anti-TBE serologies as an explanation in all these patients seem unlikely. Because the pitfalls and risk of bias when evaluating medical history retrospectively up to 6 years later, it can be argued that a significant number of patients might elude diagnosis due to subclinical infections.
The number of preschool children in this study is small. Since, according to the literature, childhood TBE is a rare disease particularly in preschool children,1,3,6,11 there is reason to suspect too infrequent consideration of the diagnosis. This is corroborated by the fact that during 2008, serologies (at our hospital) indicating Borrelia burgdorferi infection were 5 times more common (25.9% vs. 5.7%) in preschool children than schoolchildren and adults (C. Örvell, MD, PhD, unpublished data, 2010). Therefore, young children are evidently more exposed to ticks than can be concluded from the anti-TBE serologies. Whether this is a result of a better clinical awareness of B. burgdorferi infections than TBE infections in childhood needs to be elucidated.
Our data indicate that the clinical presentation and course of childhood TBE contrast in several aspects with the disease seen in adults. Symptoms are vague and nonspecific, and difficulties in verbalization of symptoms further emphasize the diagnostic challenge in children. The most prominent symptom was headache, reported in 60% of the preschool children compared with 74.3% to 85.2% in older individuals. This contrasts with previous studies where headache was reported in >90% children and adults.3–5,8,11 Furthermore, the biphasic course—a hallmark of TBE—was seen less frequently in preschool children than in older individuals.3–5,11 Generally, adults tended to be more affected and display motor abnormalities to a greater extent than children, as described by others.1,3,5 Again this indicates that childhood TBE is either characterized by vague symptoms easily eluding recognition or that symptoms usually described for adolescents/adults may be absent.
It has been hypothesized that TBEV induces a more pronounced encephalitic picture in adults than in children.5,11,12 This is corroborated by our findings of more frequent cognitive dysfunction, motor abnormalities, and elevated CSF albumin concentrations in adults. The medical history, clinical findings, and laboratory data indicate that the childhood TBE is a nonspecific inflammatory disease with a restricted encephalitic profile. Such an age-dependant symptomatology, also seen in other viral diseases, eg, Epstein-Barr virus and varicella-zoster virus infections, shows that immune responses can be different in children and adults.13,14
The diagnostic problems could be partly overcome by careful medical history and clinical examination. A comparison of children with and without TBE showed that biphasic course, vertigo/balance problems, and neck stiffness should prompt the clinician to consider TBE. In view of severe clinical courses of TBE in adults and the poorly described risk of sequelae in childhood TBE,1,3,4,7,8 there is reason to believe that children, in whom the diagnosis is probably missed to a large extent, would benefit from increased vigilance among medical care providers. Anti-TBE serologies should be performed more frequently because of the vague symptomatology and sparse clinical findings. Prospective studies are warranted to determine the incidence as well as morbidity and long-term consequences of childhood TBE.
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