Abstract

Tick-borne encephalitis (TBE) is caused by a flavivirus usually transmitted to humans via the bite of an infected Ixodes ricinus tick. The disease is endemic to central Europe, including Germany where it is a potential threat to U.S. service members and other beneficiaries. This report describes 3 cases of TBE in persons living during 2017 and 2018 in the region of Germany with the highest incidence of TBE: a 36-year-old active duty service member and 2 non-service member beneficiaries aged 17 and 7 years. Each patient presented with debilitating symptoms and, following recovery from their acute illnesses, experienced troubling sequelae for months afterward. The nature of their initial illnesses varied from one another, as did the length and nature of their sequelae. The criteria for diagnosing TBE based upon clinical symptoms and laboratory test results are described. Preventive strategies for protecting residents in Germany from TBE include measures to avoid tick bites. The potential for use of the TBE virus vaccine, not Food and Drug Administration-approved in the U.S. but available in Europe, is discussed.

Background

Tick-borne encephalitis (TBE) is caused by tick-borne encephalitis virus (TBEV), a flavivirus distributed throughout Eurasia. Germany has a relatively high incidence of TBE; in 2016, Germany reported 348 of the 1,534 total cases reported in Europe.¹ There are 3 TBEV subtypes; the subtype most prevalent in Germany is the European subtype, most commonly transmitted by the tick Ixodes ricinus. Rarely, TBEV can be transmitted through the ingestion of contaminated dairy products, such as unpasteurized milk.² TBE (known as Frühsommer-Meningoenzephalitis in German) can cause debilitating meningoencephalitis and long-term sequelae; as such, it poses a health threat to U.S. service members and beneficiaries residing in Germany.³

Typical risk factors for TBE include living in a known risk area and engaging in activities in wooded/forested areas, such as hiking, camping, mushroom gathering, and military field exercises.^4,5 About half of patients diagnosed with TBE recall a tick bite.⁶ The majority of TBE cases are among males, in both pediatric and adult populations.^7–9

TBEV infection can cause a spectrum of illness ranging from subclinical (about one-third of cases) to death (0–1.4%).² Differences in clinical severity are believed to be due to varying virulence of the pathogen and individual factors, most prominently age (older age is associated with increased severity of disease) and comorbidities (especially immunosuppresion).¹ Presentation is typically biphasic (72–87% of patients), with a generally subclinical, viremic prodromal phase followed by a more severe second phase. The early phase is characterized by non-specific symptoms such as fever, anorexia, muscle aches, nausea, and vomiting.¹⁰ The most common laboratory findings during the first phase of TBE include leukopenia and thrombocytopenia. It is estimated that 30–50% of symptomatic TBE patients experience only the initial phase of illness, while the remainder experience both phases.¹ Remission between the first and second phases typically lasts about 8 days. The second phase of TBE involves the central nervous system. Patients may have symptoms of meningitis (fever, headache, neck stiffness), encephalitis (drowsiness, confusion, sensory or motor disturbance), or meningoencephalitis.¹⁰ The most common laboratory findings during the second phase include an elevated white blood cell count, white blood cells in the cerebrospinal fluid (CSF), and increased protein in the CSF. It is common to see an initial predominance of granulocytes in CSF that shifts to a predominance of lymphocytic cells later in the illness. An abnormal electroencephalogram (EEG) is seen in 77% of patients.¹ Sequelae following acute infection are relatively common; 26–46% of patients reported some form of remaining symptoms, such as headache and difficulties with concentration or memory, 6–12 months following acute infection.²

The current report describes 3 cases of TBE that occurred among U.S. Military Health System beneficiaries living in Germany in 2017 and 2018. A large portion of this U.S. population resides in Bavaria and Baden-Wurttemberg, the German states where 80–90% of German TBE cases occur. There is 1 large U.S. military installation located in a county ("Landkreis" in German) that consistently reports some of the highest incidence rates of TBE in Germany.¹¹ Cases of TBE described here were identified through the U.S. military's reportable medical event reporting system—the Disease Reporting System internet (DRSi)—and case details were extracted from Armed Forces Health Longitudinal Technology Application (AHLTA) electronic medical records. Case ascertainment also used inpatient documents from German hospitals, translated and scanned into AHLTA. Individuals were included as cases if they met the European Centre for Disease Prevention and Control (ECDC) definition of TBE requiring 1) clinically apparent disease of the central nervous system and 2) valid laboratory documentation of current TBEV infection in the patient. ECDC laboratory criteria for confirmation of current TBEV infection include at least 1 of the following 5: TBE-specific immunoglobulin M and G (IgM and IgG, respectively) antibodies in blood, TBE-specific IgM antibodies in CSF, seroconversion or 4-fold increase of TBE-specific antibodies in paired serum samples, detection of TBE viral nucleic acid in a clinical specimen, or isolation of TBEV from a clinical specimen.^3,12 Diagnosis with TBE-specific IgM and IgG antibodies in blood is the most common method of laboratory confirmation in Germany given the clinical course of TBE (IgM and IgG last longer in serum than the virus does) and clinical simplicity (a single serum sample is easier to draw than CSF or multiple sera samples).¹³

Case 1

In November 2017, a 36-year-old male, active duty service member presented to a German hospital with fever and delirium. The patient had no known history of a tick bite and was unimmunized against TBE. The patient lived and worked near Hohenfels, Bavaria, Germany, and was frequently in forested, woody, and grassy areas (always in the local region) as part of his military duties.

A companion reported that the patient had experienced fever for approximately 1 week, altered personality at work (including falling asleep there), and left-sided hemiparesis, which appeared on the day of presentation. This is consistent with the published literature, with focal, unilateral, and upper body areas being the most commonly affected by neurological abnormalities, when present.1 At the hospital, the patient complained of headaches, retrobulbar pain, and recurring numbness of the left arm and exhibited several episodes of confusion. Rash (not further described in the hospital record) was noted on physical exam.

The patient was too agitated for lumbar puncture (LP) to be performed; accordingly, he was sedated, after which LP was successful. CSF showed moderate pleocytosis consistent with viral meningoencephalitis. An EEG showed a moderately severe, generalized alteration with encephalitic involvement due to known meningitis.

Initially admitted to intensive care, the patient was moved to regular care as he improved. The patient had persistent headaches and what the hospital record described as "general psychomotor slowing and reactions." Upon admission, the patient was promptly treated with antibacterial and antiviral medications, initially ampicillin, acyclovir, and ceftriaxone. As results of testing became available, the antimicrobials were stopped in a stepwise manner. The patient was diagnosed with TBE on the basis of the compatible clinical presentation and positive serum TBE IgG and IgM antibodies. The patient gradually improved over 10 days of hospitalization. Upon discharge, 2 weeks of rest at home were recommended.

Following discharge, this soldier reported generalized fatigue, weakness in arms and shoulders, imbalance, headaches, and trouble with memory/focus lasting for several months. Although the fatigue and weakness gradually improved after 4–5 months, headaches persisted for over 6 months. These symptoms mostly resolved; however, he reported intermittent difficulties with memory, focus, and persistent headaches.

Case 2

In June 2018, a 17-year-old male presented to a U.S. military hospital emergency department (ED) with right-sided frontal headache. The patient lived near Stuttgart, Baden-Wurttemberg, Germany. The patient noted no tick bite, was unimmunized for TBE, and reported no pertinent outdoor activities. He had a multiyear history of recurrent headaches and reported that his current headache was greater in intensity but in the same location as previous headaches. The patient denied nausea, vomiting, sensitivity to light or sounds, numbness, focal weakness, stiff neck, and fever. He was treated with intramuscular ketorolac (an antiinflammatory drug used to treat pain), intravenous fluids (IV), and IV antiemetics. Computed tomography (CT) scan showed no acute abnormalities. The patient improved significantly with treatment and was diagnosed with tension headache, prescribed butalbital/acetaminophen/caffeine, and released from the ED.

The following day, the patient presented to his regular outpatient clinic for a recommended follow-up. Since discharge from the ED, he had developed fever (39.3°C), worsened headache, neck stiffness, vomiting, photophobia, muscle aches, and dizziness. He reported having a cold recently, but symptoms of his cold had reportedly resolved before the onset of the headache and were mild enough that he did not seek care for them. These symptoms could be consistent with biphasic presentation, reported in about 80% of cases in Germany.¹

The patient was referred to a local German hospital and admitted for possible meningitis. Upon presentation, he was still febrile (39.7°C), with meningismus and mild throat inflammation. Blood tests showed leukocytosis, elevated C-reactive protein, and low overall IgG. CSF showed leukocytosis, pleocytosis, and increased protein. Magnetic resonance imaging (MRI) showed no evidence of meningitis or encephalitis. Chest x-ray findings were consistent with bronchopneumonia with left basal consolidation. Urinalysis was positive for protein, ketones, bilirubin, and urobilirubin. An EEG was normal.

On the third day of hospitalization, the patient had low oxygen saturation values (down to 84%) and was transferred to intensive care. The following day, the patient's oxygen saturation improved and he was transferred back to regular care.

Upon admission, the patient was promptly treated with antibacterial and antiviral medications (initially ampicillin, acyclovir, ceftriaxone) and analgesia (ibuprofen, paracetamol, metamizole, and tramadol). On the same day as his intensive care unit transfer, the patient received a one-time, high dose of systemic corticosteroids. He was diagnosed with TBE based on his clinical presentation and positive serum TBE IgG and IgM antibodies. Of note, there was no evidence of TBE IgG or IgM in the CSF.

Following 9 days of hospitalization with gradual improvement, the patient was discharged from the hospital in stable condition. After discharge, the patient experienced fatigue that was disruptive to his work and led to medical follow-up. The fatigue persisted for approximately 3 months before complete resolution.

Case 3

In Sept. 2018, a 7-year-old female developed worsening headache, photophobia, fever (reported 40°C), nausea, vomiting, and diarrhea over 2 days. She lived near Stuttgart, Baden-Wurttemberg, Germany, and was unimmunized against TBE. Her family reported hiking in Germany twice (in May and Sept. of 2018), with no known tick bite or other pertinent travel. Outpatient evaluation yielded a diagnosis of unspecified viral illness for which she was prescribed oral rehydration therapy and antipyretics. Of note, nausea and vomiting are common presenting symptoms of TBE, especially among pediatric patients.⁹

Upon outpatient follow-up the next day, the patient had experienced no improvement. The patient's parents were instructed to go to a local German hospital, where the patient was admitted with the complaints described above and neck stiffness. On hospital day 1, her condition continued to deteriorate.

LP was performed on hospital day 1. The patient's CSF showed pleocytosis, leukocytosis, and an increased albumin ratio, indicative of a breakdown in the blood-brain barrier consistent with meningitis. The patient's CSF had a positive TBE IgG index. The TBE IgG index is a diagnostic calculation that compares TBE IgG concentrations in the CSF to TBE IgG concentrations in the serum, controlling for total IgG concentrations in both the CSF and serum. A positive TBE IgG index (higher levels of TBE IgG in the CSF than in the serum) demonstrates intrathecal production of TBE antibodies, an indicator of active TBE infection.¹³ Serum was positive for TBE IgG and IgM. Of note, serum was also IgM positive for herpes simplex virus and enterovirus; however, upon expert consultation, no other good evidence for another (non-TBE) etiology was found among the diseases for which the patient was tested, and this case is consistent with a typical TBE infection in childhood (G. Dobler, MD, Lt Col, Bundeswehr, email communication, 09 April 2019).

An EEG (hospital day 3) was abnormal with right temporo-parieto-occipital slowing and a one-time spike-wave complex on the right frontal side. MRI (hospital day 3) showed prominent superficial cranial vessels and sphenoidal and maxillary sinusitis but no evidence of encephalitis. An EEG (hospital day 7) was normal.

Despite aggressive antipyretic treatment, the patient had persistent fevers during the first 4 inpatient days (ranging between 38° and 40°C) before defervescing on hospital day 4. She received IV glucose/electrolyte solutions for 7 days. Upon admission, she was promptly treated with antibacterial and antiviral medications, initially ampicillin, acyclovir, and ceftriaxone. There appears to have been no significant delay in treatment or diagnosis in this case.

Following 8 days of hospitalization, the patient was discharged in stable condition. Following hospital discharge she suffered significant difficulties with focus (in general) and school. Before infection, she was doing better in school than a twin sister. After infection, her twin was doing better and the patient had significant school difficulties. As of March 2019, the patient continued to have persistent, periodic headaches and to be much less energetic than before the infection. She was reported to be much more socially withdrawn.

The patient was unimmunized against TBE; however, 1 week before the patient first developed symptoms, her family had contacted the military clinic to seek TBE vaccination. The referral process was started; however, given multiple steps in the process, the actual appointment for vaccination with a German clinic was set for 3–4 weeks later. In the interim, the patient developed TBE.

Editorial Comment

Although cases of TBE among U.S. travelers to Europe and Asia have been described previously, this is the first report to describe such cases among U.S. service members and beneficiaries living in Europe.¹⁴ The cases illustrate the significant acute debilitation that TBE can cause. For example, case 1, an active duty soldier, experienced dramatically altered mental status, the most common neurological symptom.¹ TBE infection in this patient caused a 10-day hospitalization, 2 weeks of convalescence, and months of headaches, decreased energy, and difficulty with concentration; ultimately, there was a significant negative impact on his readiness and deployability. Moreover, all patients reported some degree of sequelae following resolution of TBEV infection, which is well described in the literature.^1,8 For example, case 3 (a 7-year-old female) experienced cognitive issues. Pediatric patients often recover physically more quickly from TBE, but cognitive sequelae represent a prominent concern.⁹ This report also documents that those residing in a risk area (e.g., in Bavaria and Baden-Wurttemberg, Germany) are potentially more likely to contract TBE. Two of 3 cases reported participation in traditionally high-risk outdoor activities; however, none recalled a tick bite.

These cases also highlight the potential for under diagnosis of TBE in the U.S. population stationed in Germany. Under diagnosis occurs in the European health care system and is thought to be due to lack of knowledge of the disease and the relative rarity of "classical" clinical presentation of TBE.⁵ If TBE is underdiagnosed by European providers, it is likely also underdiagnosed by U.S. providers in Europe. Lack of education and awareness of this Eurasian zoonosis could preclude its consideration in a differential diagnosis. Furthermore, there are challenges accessing diagnostics in the U.S. health care system. Serum testing for TBE IgG and IgM is available; however, it is not included as a standard test and requires direct coordination with the laboratory and a specific request for the test. Failure to appropriately diagnose TBE could lead to unnecessary testing, the lack of a definitive diagnosis, and an unclear prognosis. Such uncertainty might prevent a patient from accessing or utilizing appropriate specialty services during and after the acute phase of the disease. Delays in diagnosis could also contribute to similar problems. Although cases 2 and 3 did have to visit a U.S. provider twice before referral, review of the clinical details (especially the lack of meningeal signs during the first visit for both) suggest there was no delay in appropriate referral to the German system; similarly, there appears to be no delay in appropriate diagnosis once in the German system.

Efforts should be made to prevent TBE in the U.S. military population in Europe. These efforts could mirror the German, Austrian, or World Health Organization (WHO) public health approaches, which include promoting avoidance of ticks/TBE (i.e., through behavior, appropriate clothing, repellants, and early detection of ticks) and vaccination (either targeted or in the general population).⁵ The Austrian national government recommends and financially supports generalized vaccination for all residents.¹⁵ German military personnel are all required to receive TBE vaccine in order to be prepared to support national emergency response efforts in endemic areas (K. Erkens, MD, Lt Col, Bundeswehr, email communication, 13 Nov. 2019). The WHO recommends vaccination of all age groups in areas of high pre-vaccination prevalence (defined as = 5/100,000 per year).^16,17 The German government recommends vaccination for all individuals 1 year or older in risk areas defined by the Robert Koch Institute.³ One study showed overall TBE vaccination in Germany at 27%, with higher rates in the highest-risk areas (i.e., 37–40% in Bavaria and Baden-Wurttemberg).¹⁸

None of the cases reported here had been immunized against TBEV. Vaccination is safe and effective in preventing TBE. Unfortunately, no TBE vaccines are U.S. Food and Drug Administration (FDA) approved, so purchase or administration by the U.S. government, including U.S. military medical facilities, is legally restricted. Administration of TBE vaccine is, however, now covered by insurance for U.S. military members in Europe. It is administered only at the level of individual patients, not at the level of military units or as a public health effort. Through the efforts of the European Command (EUCOM) and medical providers in Germany, TBE vaccine was approved for all active duty beneficiaries through TRICARE Eurasia in May 2014. Before that (starting in Feb. 2008), it was identified as a TRICARE eligible benefit for dependents and retirees. Currently, obtaining TBE vaccination among the U.S. military population requires a multistep process. The patient must first visit their military provider, who verifies the patient will be in country long enough to complete the series (at least 1 year longer). A referral to a German provider is then made. The patient then makes an appointment and visits the German provider. The patient receives the initial dose then arranges to receive the additional doses 3 and 9 months later. Given the requirement to obtain a special referral and arrange for and make multiple visits to an off-post provider, it is possible this process is sufficiently onerous to deter some from seeking the vaccine. Department of Defense (DOD) civilian employees with private (non-TRICARE) health insurance receive health care through the German medical system. Accordingly, for DOD civilians, TBE vaccine has been covered for as long as it has been standard of care in the German health care system.

Also, because the vaccine is not offered through the U.S. Military Health System or as part of any force health protection efforts, it is possible that U.S. military personnel may simply not be aware of the vaccine or indications for seeking it. There have been efforts by EUCOM and the Defense Health Agency to obtain FDA approval for TBE vaccine. FDA approval would likely simplify the process of obtaining vaccine and would allow it to be considered as a force health protection and/or public health measure. For example, the U.S. military could explore mirroring the German military model of requiring TBE vaccination for all military personnel stationed in Bavaria and Baden-Wurttemberg. Cost-benefit analysis of TBE vaccination of U.S. military personnel would inform this consideration.

This case study has several limitations. Many clinical details were derived from German medical records; all were translated by certified medical translators in an approved but imperfect process. Sequelae and preceding symptoms were ascertained up to a year after TBE infection and were likely subject to recall bias.

U.S. Military Health System beneficiaries living in Germany are at risk of TBE. It is important for providers caring for military service members in Europe to be proficient in the recognition and treatment of TBE. The U.S. military health care system in Europe should educate providers and patients regarding TBE risk, prevention, diagnosis, and treatment. The U.S. military health care system should also strive to make TBE diagnostics readily available to its providers and beneficiaries either internally or through enhanced cooperation with the German health care system.

Author affiliations: U.S. Army Medical Department Activity-Bavaria, Department of Preventive Medicine (LTC Mease, MAJ Maddox, Ms. Whitman); Madigan Army Medical Center (LTC Mease); Fort Hood Public Health (MAJ Maddox); 18th Military Police Brigade (MAJ Noss)

Acknowledgments: The authors thank Prof. Dr. Gerhard Dobler (Lt Col, Bundeswehr) for his thoughtful consultation, MAJ Daniel Weinstein for his valuable operational perspective, Mr. Joey Scaletta for his consistent support, and COL James Mancuso for his excellent guidance.

Funding: All work described herein was performed as part of paid regular duties as part of employment by the U.S. Government.

Disclaimer: The views expressed are those of the author(s) and do not reflect the official policy of the Department of the Army, the Department of Defense, or the U.S. Government.

References

1. Erber W, Schmitt H-J, Vukovic Jankovic T. Epidemiology by country—an overview. In: Dobler G, Erber W, Schmitt H-J, eds. Tick-Borne Encephalitis (TBE). Singapore: Global Health Press;2018:114–127.
2. Lindquist L, Vapalahti O. Tick-borne encephalitis. Lancet. 2008;371(9627):1861–1871.
3. Borde JP, Zajkowska J. TBE in adults. In: Dobler G, Erber W, Schmitt H-J, eds. Tick-Borne Encepahlitis (TBE). Singapore: Global Health Press;2018:70–85.
4. European Centre for Disease Prevention and Control. Factsheet about tick-borne encephalitis (TBE). https://ecdc.europa.eu/en/tick-borneencephalitis/facts/factsheet. Accessed 28 Aug. 2019.
5. Kunze M, Haditsch M. TBE as a matter of public health. In: Dobler G, Erber W, Schmitt H-J, eds. Tick-Borne Encephalitis (TBE). Singapore: Global Health Press;2018:283–289.
6. Hellenbrand W, Kreusch T, Bohmer MM, et al. Epidemiology of tick-borne encephalitis (TBE) in Germany, 2001–2018. Pathogens. 2019;8(2).
7. Dobler G, Tkachev S. General epidemiology of tick-borne encephalitis. In: Dobler G, Erber W, Schmitt H-J, eds. Tick-Borne Encephalitis (TBE). Singapore: Global Health Press;2018:103–113.
8. Logar M, Arnez M, Kolbl J, Avsic-Zupanc T, Strle F. Comparison of the epidemiological and clinical features of tick-borne encephalitis in children and adults. Infection. 2000;28(2):74–77.
9. Sundin M. TBE in children. In: Dobler G, Erber W, Schmitt H-J, eds. Tick-Borne Encephalitis (TBE). Singapore: Global Health Press;2018:85–91.
10. Centers for Disease Control and Prevention. Tick-borne encephalitis: signs and symptoms. https://www.cdc.gov/vhf/tbe/symptoms/index.html. Accessed 27 Aug. 2019.
11. Mackenstedt U, Dobler G. TBE in Germany. In: Dobler G, Erber W, Schmitt H-J, eds. Tick-Borne Encephalitis (TBE). Singapore: Global Health Press;2018:170–174.
12. European Centre for Disease Prevention and Control. Surveillance and disease data for tickborne encephalitis. https://ecdc.europa.eu/en/tickborne-encephalitis/surveillance-and-disease-data. Accessed 20 May 2019.
13. Dobler G. Diagnosis. In: Dobler G, Erber W, Schmitt H-J, eds. Tick-Borne Encephalitis (TBE). Singapore: Global Health Press;2018:276–282.
14. Centers for Disease Control and Prevention. Tick-borne encephalitis among U.S. travelers to Europe and Asia—2000–2009. MMWR Morb Mortal Wkly Rep. 2010;59(11):335–338.
15. Heinz FX, Stiasny K, Holzmann H, et al. Vaccination and tick-borne encephalitis, central Europe. Emerg Infect Dis. 2013;19(1):69–76.
16. Poellabauer EM, Kollartisch H. Prevention—vaccines and immunoglobulins. In: Dobler G, Erber W, Schmitt H-J, eds. Tick-Borne Encephalitis (TBE). Singapore: Global Health Press;2018:290–304.
17. World Health Organization. Vaccines against tick-borne encephalitis: WHO position paper—recommendations. Vaccine. 2011;29(48):8769–8770.
18. Erber W, Schmitt H-J. Self-reported tick-borne encephalitis (TBE) vaccination coverage in Europe: results from a cross-sectional study. Ticks Tick Borne Dis. 2018;9(4):768–777.