Abstract

The risk of tick-borne encephalitis (TBE) among U.S. military service members and beneficiaries residing in or traveling to Europe has not been assessed since the 1990s. The primary objective of this study was to assess the current risk of TBE in this population. Records of reportable medical events, inpatient and outpatient care, and laboratory test results were searched for TBE cases between 2006 and 2018. There were 8 individuals who met the case definition for TBE over the 13-year interval; 7 cases occurred during 2017 or 2018. Outpatient records did not identify any additional verified cases of TBE but revealed a large number of misclassified diagnoses. The risk of TBE among U.S. military service members and beneficiaries is low but may have increased in recent years. Military members and their dependents residing in Europe or Asia generally have a risk for TBE similar to that of other residents of the host nation. Additionally, there may be locations or activities that place certain individuals or units at increased risk for TBE, thus warranting additional control measures such as active surveillance, enhanced personal protective measures, and vaccination.

What Are the New Findings?

The risk of TBE among U.S. military service members and beneficiaries is low but not negligible. There were 8 cases of TBE among U.S. military service members and beneficiaries between 2006 and 2018, 7 of which occurred in 2017 or 2018. Case finding using outpatient data did not identify additional cases and revealed a large number of misclassified diagnoses.

What is the Impact on Readiness and Force Health Protection?

Although the risk of TBE among U.S. military personnel and their dependents is similar to residents of the host nation, there may be locations and activities that place individuals and military units at increased risk. U.S. military public health activities in Europe should ensure the implementation of TBE control measures, including accurate and timely surveillance, proper personal protective and tick avoidance measures, and risk-based vaccination.

Background

In 2012, tick-borne encephalitis (TBE) became a notifiable disease for health care professionals in Europe to report to public health agencies. Since then, the reported incidence of TBE in Europe has increased. The European Centre for Disease Prevention and Control (ECDC) has concluded that this increase is "consistent with a stable long-term trend" in the European Union, possibly related to environmental conditions.¹ However, it is also possible that this increase may be influenced by enhanced surveillance and diagnosis rather than (or in addition to) a true increase in the incidence of disease.

In 2016, there were 2,674 confirmed cases of TBE reported across the European Union and European Economic Area (EU/EEA), for an overall incidence of 0.6 per 100,000 population.¹ In Germany, the European country in which the greatest number of U.S. military service members and beneficiaries are stationed, surveillance for TBE (also called Frühsommer-Meningoenzephalitis [FSME] in German) by health authorities began much earlier—in 2001. The majority (89.0%) of TBE cases in Germany reported between 2001 and 2018 occurred in the southern states of Baden-Wurttemberg (BW) and Bavaria,² both of which contain U.S. military installations and personnel. The annual incidence rate of TBE in Germany during that time period ranged from 0.7 to 2.0 cases per 100,000 persons per year, but the average rate in high-risk areas such as BW and Bavaria was 3.7 (range: 0–48) cases per 100,000 persons per year.² While there was no significant change in TBE incidence noted between 2001 and 2016, the years of 2017 and 2018 were marked by an increase in rates compared to the previous years. Countries in the Baltic states had the highest reported rates of disease, although comparisons between countries are difficult because of differences in case definitions, laboratory diagnosis, and other surveillance capabilities.³

U.S. military personnel may engage in activities or behaviors that place them at risk for increased contact with the primary tick vector responsible for TBE transmission, Ixodes ricinus. These activities include hiking and camping and outdoor work activities such as forest work or military field exercises.^4,5 In the 1980s and 1990s, serological studies of U.S. military service members in areas felt to have high risk for TBE found a relatively low seroprevalence (7.2%) among soldiers stationed in Bavaria and Rheinland-Pfalz, Germany,⁶ and low rates of infection (0.9 and 0.7 seroconversions per 1,000 person-months) in Germany and Bosnia, respectively.^7,8 Only 1 reported case of symptomatic but unconfirmed TBE disease was found in a review of all inpatient medical records from facilities in central Europe from 1970 to 1983.⁷ Nevertheless, these historical data are not adequate to estimate the current risk to U.S. service members and their dependents, and no assessment of TBE incidence in U.S. military service members or beneficiaries has been published since the 1990s. Furthermore, most prior studies only assessed the risk of TBE in small, focally defined areas, and the risk to U.S. military personnel in the countries of eastern Europe and Asia is unknown.

The primary objective of this study was to determine the number of TBE cases among all U.S. military service members and other beneficiaries worldwide between 2006 and 2018, with a special focus on the risk of TBE in Europe, in order to inform current public health risk assessment and force health protection posture. Although TBE is reportable for all Department of Defense (DOD) beneficiaries in the military's reportable medical events (RMEs) system under the category "arboviral disease," ⁹ some cases might not be reported since TBE is not a reportable disease in the U.S. civilian public health system¹⁰ and because health care providers may not be aware of U.S. military and German reporting requirements. The secondary objectives of this study were to examine the completeness and accuracy of various data sources, evaluate existing case-finding algorithms, and determine a valid TBE surveillance case definition for future use.

Methods

This investigation was reviewed and approved by the Defense Health Agency's Human Research Protections Office as a public health surveillance activity. The population at risk was all U.S. military service members and beneficiaries between 1 Jan. 2006 and 31 December 2018. For the primary analysis, possible TBE cases were identified by examination of all outpatient and inpatient encounters and all RMEs in the Defense Medical Surveillance System (DMSS)¹¹ with a diagnosis of TBE (parent International Classification of Diseases, 9th [ICD-9] and 10th [ICD-10] Revision codes of 063 or A84, respectively). The TBE case definitions established by the ECDC were used to classify the cases.¹² The clinical criteria included any person with symptoms of inflammation of the central nervous system. To be a confirmed case, the patient had to meet the clinical criteria and have at least 1 of the following 5 laboratory findings: 1) TBE-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies in blood, 2) TBE-specific IgM antibodies in the cerebrospinal fluid, 3) seroconversion or 4-fold increase of TBE-specific antibodies in paired serum samples, 4) detection of TBE viral nucleic acid in a clinical specimen, or 5) isolation of TBE virus from a clinical specimen. A probable case was defined as any person who met the clinical criteria and had either 1) an epidemiological link or 2) detection of TBE-specific IgM antibodies in a unique serum sample. Only confirmed or probable cases were included in the analysis.

The data repository of the military's electronic medical record (EMR), the Armed Forces Health Longitudinal Technology Application (AHLTA), was reviewed to determine whether the subset of individuals with a record of a TBE diagnosis identified in DMSS records between 2016 and 2018 met the case definition. The review of AHLTA records included examination of all outpatient, inpatient, vaccine, and laboratory records from military treatment facilities (MTFs) in the EMR. Of note, the EMR also included scanned records of inpatient and outpatient encounters that occurred at non-MTFs. Information from hospitalizations at host nation medical facilities was obtained through English translations of the discharge summaries that had also been scanned and uploaded into the EMR. When records were not sufficiently complete to determine whether the patient had been a true TBE case, the patient was contacted via phone (if contact information was available) to obtain additional information.

To evaluate the completeness and accuracy of various alternative data sources and determine a surveillance case definition for future use, additional record reviews were performed. Laboratory records were available from 2006 through 2018 and included all TBE positive lab results from the EpiData Center (EDC) at the U.S. Navy and Marine Corps Public Health Center.^13,14 Of note, these laboratory data included only tests that were performed or reported by an MTF. Findings were also compared with those obtained from direct and purchased care data from TRICARE Europe found in the Military Health System Data Repository (MDR), again using inpatient and outpatient TBE diagnoses that occurred in Europe between 2016 and 2018. The sensitivity and positive predictive value (PPV) of these alternate data sources were estimated in accordance with U.S. Centers for Disease Control and Prevention (U.S. CDC) guidelines for the evaluation of surveillance systems.¹⁵ Because of the small number of cases and lack of appropriate denominators, rates were not calculated.

Results

During 2006–2018, a total of 8 individuals met the TBE case definition (4 confirmed and 4 probable) (Figure 1). Table 1 shows a list of the cases and their characteristics. Laboratory results and disease sequelae were inconsistently documented in the EMR. All cases had reported fever; other symptoms were variable. Five of the cases were service members and 3 were dependent children. Although the numbers are small, the number of cases in 2017–2018 (n=7) greatly exceeded the number from the previous 11 years (n=1), suggesting an increased TBE risk in recent years. The cases all occurred during the expected months of April through Nov. Of note, no cases were travelers to or residents of any location other than in Europe or in any German states other than BW and Bavaria. None of the cases had a prior history of TBE vaccine.

In order to assess the validity of the TBE definition, the medical records were reviewed for the 166 unique individuals with diagnoses of TBE identified from RMEs and outpatient and inpatient records in the DMSS between 2016 and 2018. Of these unique individuals, 157 had outpatient TBE diagnoses, 15 had inpatient diagnoses, and 5 had RMEs. Of the 166 individuals, 7 (4.2%) were determined to meet the case definition for confirmed (4) or probable (3) TBE. There was 1 additional record of TBE from Navy and Marine Corps Public Health Center laboratory data in an individual who had no TBE records in the DMSS, for a total of 167 individuals with a TBE record. The overlap of records among these different data sources is shown in Figure 2. The PPV and sensitivity of the types of records and diagnoses are listed in Table 2. All of the 7 cases were found to have either an inpatient (6) or an RME (5) diagnosis of TBE, and 4 had both. All 5 individuals with an RME were hospitalized, although 1 had an inpatient ICD-10 diagnosis code of A86 (viral encephalitis, unspecified). Of the 17 individuals who had either an RME, hospitalization, or lab record of TBE, 8 (47.1%) had no evidence of residence or medical care in Europe. Of the 9 hospitalized cases with a misclassified TBE diagnosis, 4 had a diagnosis of another tick-borne disease such as suspected Lyme disease, history of prior Lyme disease, or Rocky Mountain spotted fever. Of the remaining 5 individuals, 1 had long-standing headache symptoms and tested negative for TBE; the others had little or no documentation in their available health records to substantiate a diagnosis of TBE. Of the 157 outpatient diagnoses in the DMSS, 57 were diagnosed in Europe and 100 were either diagnosed outside of Europe or the place of care could not be determined. Of the 50 outpatient diagnoses from Europe that did not meet the case definition, 47 (94.0%) had an encounter for TBE vaccination on the date of TBE diagnosis, 1 (2.0%) had headache or other suggestive symptoms but did not meet the clinical case definition, and 2 (4.0%) had no visits in the EMR on or around the diagnosis date. Of the 100 outpatient cases diagnosed outside of Europe, none met the case definition. Most of these diagnoses occurred in the U.S. among retirees who had no record of care at an MTF. The few who did receive care at an MTF were seen for a tick or other insect bite.

For the period from 2006 through 2015, medical records were reviewed only for those 22 individuals who had an inpatient or RME diagnosis of TBE; only 1 of these individuals met the case definition. All 22 had an inpatient diagnosis of TBE and none had an RME.

Finally, the alternative data sources, including EDC laboratory and TRICARE Europe inpatient and outpatient data (from the MDR) were examined to identify additional cases of TBE. There were 2 individuals with a positive laboratory test for TBE between 2006 and 2018. One individual had already been identified as an RME, and the other did not meet the case definition (sensitivity=14.2%; PPV=50%). TRICARE Europe data from inpatient and outpatient care in Europe revealed 104 individuals with a TBE diagnosis between 2016 and 2018, 57 of whom were also ascertained from DMSS data. All 7 of the confirmed or probable TBE cases were included in this group (sensitivity=100%; PPV=6.7%). Of the additional 47 individuals identified with a TBE diagnosis who were not ascertained from DMSS data, all had only outpatient TBE diagnoses and none met the case definition for TBE. Thirty-seven (78.7%) of the 47 individuals had a medical encounter for TBE vaccine that was miscoded as TBE disease.

Editorial Comment

Of the 8 confirmed or probable cases of TBE among U.S. military service members and beneficiaries during the 13-year surveillance period, 7 occurred in 2017 or 2018. Five of the cases occurred in service members and 3 in children; all cases occurred in Germany in the states of BW or Bavaria. There were no cases of TBE identified among U.S. military service members or beneficiaries traveling to Europe. All but 1 of the cases were hospitalized in a host nation medical facility, and most of the case information was extracted from translations of those hospitalization records. RME surveillance identified 5 of the cases, while laboratory data identified only 1. This is not surprising, as only laboratory tests from MTFs could reliably be obtained and only 1 of the cases was treated in an MTF. Additional case finding using outpatient records revealed large numbers of misclassified cases regardless of data source, largely from medical encounters for TBE vaccine or tick bites that were miscoded as TBE disease. In summary, review of outpatient records identified no additional cases of TBE beyond those already found in RME and inpatient records.

This study provides an update to the current knowledge about the risk of TBE among service members and other beneficiaries. Two previous military studies examined the risk of infection in Germany and Bosnia by assessing seroconversion and found no cases of TBE disease.^6,8 Another military study reviewed military hospitalization data in Europe and found 1 case of unconfirmed TBE in military medical records between 1970 and 1983, a time when a much larger number of military personnel were living in Germany.⁷ The incidence rate of TBE in Germany was 2.0 per 100,000 in 2018, with a rate of 3.7 in higher-risk areas such as BW and Bavaria.² Given these rates and based on a population of approximately 50,000 U.S. military service members and beneficiaries dispersed throughout Germany, approximately 1 case per year would be expected. The current study found a very similar overall number of 8 cases over a 13-year period, with all but 1 case identified during the past 2 years. Although small numbers precluded formal statistical testing, the increased number of cases in 2017 and 2018 seen here is similar to the statistically significant increases reported in the German population. Additionally, the experiences in nearby Austria demonstrate the focal nature of TBE and the potential of TBE to emerge in previously unaffected populations despite high vaccination coverage.¹⁶ No cases among military-associated travelers to Europe were seen in the current study, consistent with prior assessments of low risk among most travelers.^5,17 While only 7 cases of TBE among non-military U.S. travelers were reported between 2000 and 2015, TBE is not a notifiable condition in the U.S., so additional cases may have occurred.⁵

The World Health Organization (WHO) recommends routine TBE vaccination in areas where the disease is highly endemic (defined as a rate of = 5 per 100,000 per year).¹⁸ In regions with lower incidence, WHO recommends targeting only those who are at higher than baseline risk and those that engage in extensive outdoor activities. The U.S. CDC suggests considering vaccination for those "anticipating high-risk exposures" as well as those "living in TBE-endemic countries for an extended period of time" but does not provide specific recommendations related to TBE vaccination.⁵ German policy among the civilian population is to vaccinate beginning at age 1 year if "substantial exposure" is anticipated but otherwise recommends deferring vaccination to age 3 years because of the risk of vaccine-related adverse events in the 1- to 2-year age group.¹⁹ Despite these recommendations, only 27% of the population is estimated to have been vaccinated against TBE, including only 37–40% in the higher-risk areas of BW and Bavaria.20 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 U.S. military has prior experience with TBE vaccine in Europe. As the vaccine is not licensed by the U.S. Food and Drug Administration (FDA), it must be obtained and administered by host nation providers in Europe outside the U.S. Military Health System. Although many service members and other U.S. military beneficiaries have obtained the vaccine, most of those residing in Germany never receive it. During deployment to Bosnia in the 1990s, the U.S. military's desire to mitigate TBE risk resulted in TBE vaccine being made available to all DOD personnel at high risk of tick exposure.⁸ Since the vaccine was not licensed by the FDA, it could not be made mandatory for service members, so the vaccine was administered on a voluntary basis under an investigational new drug protocol. After several years, the program was discontinued because of improper documentation and "significant deviation" from the protocol noted by the Government Accounting Office and FDA.21 The European Command (EUCOM) and DOD public health leadership are now considering ways to obtain FDA licensure in order to offer TBE vaccine to service members and other beneficiaries living in or traveling to Europe who would be at high risk for TBE exposure. The findings of this study support the current recommendations to vaccinate only those U.S. military service members and beneficiaries at higher risk for TBE acquisition because of residence in an area of high endemicity or participation in extensive outdoor activities.^5,17,18

Limitations of this study include a small number of cases and the potential for misclassification of outcome. Patients seeking care at host nation health care facilities may be undercounted in this report because these encounters and laboratory results may be insufficiently documented in AHTLA, thus not meeting the case definition applied here. This undercounting is expected to be modest in the active component because about 82% of these service members outpatient encounters and 68% of their inpatient encounters occur at MTFs.^22,23 Although about 90% of non-service member beneficiary encounters occur outside of MTFs,²⁴ potential undercounting is mitigated by the TRICARE Overseas Program contract requirement that the contractor translate medical documentation on request (S. Lynch, TRICARE Overseas Program Office, email communication, 24 July 2019). Many European MTFs appear to be actively engaged in obtaining/translating purchased care medical documentation and uploading it into the Health Artifact and Image Management Solution (HAIMS), which not only provides documentation for follow-up medical care but also allows for better public health surveillance and response.

Additionally, failure of health care providers to recognize TBE and comply with established diagnostic guidelines also may contribute to underestimation of disease.^19,25 Asymptomatic and subclinical infection and failure of infected individuals to seek care also contribute to the undercounting of cases. The prevalence of subclinical infection would best be assessed by repeating prior studies of seroconversion, which has not been done in Germany since the early 1990s.⁶ On the other hand, recent increases in cases seen in Germany could be attributable to increased surveillance and awareness related to the 2012 ECDC reporting requirement. However, because Germany has required TBE case notification since 2001, this seems less likely. Because many of the hospitalizations attributed to TBE were actually from other tick-borne diseases, further provider education on and awareness of these diseases is indicated, as is ensuring their proper prevention, detection, and response. Updated recommendations on the diagnosis and management of tick-borne diseases in the U.S. are summarized for providers and public health practitioners in a recent U.S. CDC publication.²⁶ Finally, the results from military populations may not be generalizable to U.S. travelers or other populations because of differences in occupational and other outdoor exposures.

Results of this study suggest that the RME case definition performs fairly well for routine surveillance of TBE. If a more precise estimate is desired, a modest improvement is possible by adding active surveillance of hospitalizations for TBE. However, because of a large proportion of misclassified diagnoses, record reviews are necessary to ascertain whether these additional diagnoses meet the case definition in order to accurately estimate the true TBE burden, assess public health risk, and inform force health protection posture. The ability to perform record review relies on the continuation of the current practice in EUCOM of entering records from care received at host nation medical facilities into the EMR. While the record review conducted in the current study indicated fairly complete documentation in the EMR of care received at host nation medical facilities in Germany, records from hospitalizations in the U.S. were uncommonly found in the EMR. Current surveillance for TBE can be further improved by increased awareness of clinical guidelines for prevention, diagnosis, and treatment in both adults and children.^17,19,25 Current TBE surveillance can also be improved by increased awareness of and adherence to DOD and host nation reporting requirements so that RMEs can be used to better detect changing trends in TBE incidence. Alternate case finding methods such as laboratory data and outpatient visits are likely to have minimal impact on TBE surveillance because of poor sensitivity and PPV, respectively. Human seroprevalence studies can be a useful complementary surveillance indicator but may be confounded from cross-reactivity to other flaviviruses or viruses of the TBE complex.^6–8 Virus prevalence in ticks has been found to be of questionable value in surveillance efforts,²⁷ a finding that is supported by the fact that only 4 of 1,153 ticks (0.3%) tested from passive surveillance at U.S. military installations in Europe from 2012 through 2018 were found to be infected with TBE (A. Cline, MAJ, U.S. Army Public Health Command-Europe, email communication, 20 May 2019).

The number of confirmed or probable TBE cases among U.S. military service members and beneficiaries is low but not negligible and has increased in recent years. Although military members and their dependents generally have the same risk for TBE as other residents of the host nation and should follow U.S. CDC guidance for travelers to these areas, there may be locations or activities that place these individuals at higher risk for disease. Commanders and U.S. military public health personnel in Europe should be familiar with and anticipate high-risk areas and activities U.S. personnel are likely to encounter. Furthermore, they should ensure that TBE control measures include accurate and timely surveillance, proper personal protective measures (PPMs), tick avoidance, and risk-based vaccination. There are several ways in which individuals and units can reduce their risk of TBE infection. Service members and dependents at risk for TBE should be counseled to avoid consuming unpasteurized dairy products, which can transmit TBE. Service members and dependents should also be counseled to use PPMs, particularly during field exercises and other outdoor activities and when stationed or visiting focal areas of increased TBE risk. PPMs include the DOD repellant system, which consists of maximally covering exposed skin with clothing, applying permethrin to clothing, and applying repellants to remaining exposed skin. Finally, service members and dependents should follow a risk-based strategy for vaccination consistent with national and international recommendations,^5,17,18,25 and the U.S. military should consider the risks and benefits of compulsory TBE vaccination of service members, similar to German military policy.

Author affiliations: Armed Forces Health Surveillance Branch, Public Health Division, Defense Health Agency, Silver Spring, MD

Acknowledgments: The authors would like to acknowledge Mr. Nicholas Seliga, EpiData Center, Navy and Marine Corps Public Health Center, for his assistance with the laboratory data; Mr. Shannon Lynch for his assistance obtaining data from the Military Health System Data Repository; Dr. Kay Erkens, Lt Col, Kommando Sanitätsdienst, UAbt VI 2.2, for consultation on German military vaccination policy; LTC Luke Mease for his review of and comments on an earlier version of this manuscript; and MAJ Amanda Cline, U.S. Army Public Health Command-Europe, for supplying the results from TBE tick surveillance in Europe.

Disclaimer: The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of Defense or of the U.S. Government.

Sources of support: Support was provided by the Armed Forces Health Surveillance Branch of the Public Health Division at the Defense Health Agency.

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