Patients with breakthrough tick‐borne encephalitis suffer a more severe clinical course and display extensive magnetic resonance imaging changes
Authors: J Panholzer
J N Wagner
A Hauser
A Troescher
M Sonnberger
T J von Oertzen
I Krehan
Journal: European journal of neurology (2020)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: encephalitis; magnetic resonance imaging; tick-borne encephalitis virus; vaccination.
Affiliations: Department of Neurology 1, Kepler University Hospital, Johannes Kepler University Linz, Linz, Austria., Department of Neuroradiology, Kepler University Hospital, Johannes Kepler University Linz, Linz, Austria., Department of Neurology 2, Kepler University Hospital, Johannes Kepler University Linz, Linz, Austria.

Abstract:  Background and purpose: Tick-borne encephalitis (TBE) is a common viral disease in central Europe and Asia. Severe or even lethal neurological symptoms may ensue. With limited therapeutic options, active vaccination against the TBE virus (TBEV) is strongly recommended in endemic areas. A systematic analysis of the clinical picture and cerebral imaging findings associated with TBE was conducted with particular focus on patients who acquired TBE despite previous vaccination. Methods: A cohort of 52 patients with serologically proven TBE treated at our centre in a 10-year period who received at least one cerebral magnetic resonance imaging (MRI) was retrospectively described. Extension of MRI changes was systematically assessed by an experienced neuroradiologist. Standard statistical procedures were performed. Results: Fifty-two patients with a definite serological diagnosis of TBE were included. The most common presentation was encephalitis (67%). MRI showed TBE-associated parenchymal lesions in 33% of all patients. Sites of predilection included the periaqueductal grey, the thalamus and the brainstem. Ten patients had received at least one prior active or passive TBEV immunization. All of these had a maximal Rankin Scale score of at least 4. The median number of affected anatomical regions on MRI was significantly higher than in the non-vaccinated cohort. Conclusions: To our knowledge, this is the first study systematically describing the peculiarities of MRI in patients vaccinated against TBE. In addition to a severe clinical course, they exhibit more extensive MRI lesions than a non-vaccinated cohort. Possible reasons for these findings include incomplete seroconversion, more virulent TBEV strains or antibody-dependent enhancement. 

Retracted: No

PubPeer comments:
 **No retraction despite significant flaws in study design and interpretation of the data.** **Ignorance or arrogance?** Readers response to: Patients with breakthrough tick-borne encephalitis suffer a more severe clinical course and display extensive MRI changes Heinz-J. Schmitt, Wilhelm Erber, Farid Khan https: doi.org 10.1111 ene.14449 Dear Editor, With much interest we read the article by Wagner et al.,(1) however, their claim that u201cpatients with breakthrough tick-borne encephalitis suffer a more severe clinical courseu201d is not supported by their data as the scientific evidence necessary to substantiate this claim would generally be a double-blind randomized study, not a retrospective case series from a tertiary care center. Specifically: First, u201cvaccine failuresu201d suggests that TBE occurred despite all recommended doses administered according to the licensed schedule. Only 3 patients (cases 8, 9, 10 in Table 2) met this criterion, however 2 of them (cases 8 and 10) suffered from an autoimmune disease. In immunosuppressed subjects, uninhibited viral replication leads to brain destruction, which explains the disease severity in these patientsu2014without the need for speculative antibody-mediated disease enhancement (ADE). Second, 6 of 9 actively vaccinated patients had received their last vaccine dose up to 30 years ago. Patient number 2 was last vaccinated around 1986 and had TBE in 2016. Given immunosenescence observed with TBE vaccination, necessitating booster doses every 3 years (as of age 60 years),(2) ADE can be excluded for this patient due to the lack of any anti-TBEV-antibody. Similarly for patient 3 having only had passive vaccination 19 years prior. Third, to compare disease severity, an appropriate study design would use unselected patients as the denominator. However, this study presented a case series of 52 tertiary care TBE patients with MRI imaging. Thus, the study population was biased by referral and by selection: 46% of patients had myelitis compared with 3.1% in a study of 6063 unselected patients from Germany (3) and 8.9% for encephalitis, myelitis, and radiculitis among TBE patients in Latvia.(4) Further, data on underlying diseases in the unvaccinated patients were not presented for a comparison of severity. Fourth, classification bias is another concern. It appears that the actual vaccine was not mentioned for 5 of 10 patients classified as u201cTBE vaccinatedu201d. Furthermore, for 2 patients only the approximate time of vaccination was given. Given the articleu2019s title of u201cPatients with breakthrough statusu201d, there was little discussion of the validation of the vaccination status nor availability of the source data. Prior studies have identified significant inaccuracies of vaccination status derived from patient recall, including as recorded in medical records if only sourced from intake interviews.5 Most interestingly, 43 52 patients (82%) had never received active vaccination (1 passively)u2014an excellent indication of high vaccine effectiveness. Even with these selective data, effectiveness is as high as 96% (calculation below). Though this case series may support that patients with autoimmune diseases may have severe illnesses despite past TBE vaccination, the theoretical concern that TBE vaccination may cause ADE (first raised in 1985 (6) has not been supported in this study or over 35 years with more than one hundred million vaccine doses distributed. Following the guidelines from WHO and ECDC, we strongly recommend TBE vaccination to all persons exposed to the TBEV based on the established safety and effectiveness of TBE vaccines from well-controlled studies. References 1. Wagner JN, Sonnberger M, Troescher A, et al. Patients with breakthrough tick-borne encephalitis suffer a more severe clinical course and display extensive MRI changes. Eur J Neurol. 2020. 2. Konior R, Brzostek J, Poellabauer EM, Jiang Q, Harper L, Erber W. Seropersistence of TBE virus antibodies 10 years after first booster vaccination and response to a second booster vaccination with FSME-IMMUN 0.5mL in adults. Vaccine. 2017. 3. Dobler G, Kaier K, Hehn P, Bohmer MM, Kreusch TM, Borde JP. Tick-borne encephalitis virus vaccination breakthrough infections in Germany: a retrospective analysis from 2001 to 2018. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2019. 4. Zavadska D, Odzelevica Z, Karelis G, et al. Tick-borne encephalitis: A 43-year summary of epidemiological and clinical data from Latvia (1973 to 2016). PLoS One. 2018;13(11):e0204844. 5. Miles M, Ryman TK, Dietz V, Zell E, Luman ET. Validity of vaccination cards and parental recall to estimate vaccination coverage: a systematic review of the literature. Vaccine. 2013;31(12):1560- 1568. 6. Kayser M, Klein H, Paasch I, Pilaski J, Blenk H, Heeg K. Human antibody response to immunization with 17D yellow fever and inactivated TBE vaccine. Journal of medical virology. 1985;17(1):35-45. Disclosure of conflicts of interest: All authors are full-time employees of Pfizer Vaccines and may own stock stock options. ,