Tick-borne encephalitis epidemic in Hungary 1951-2021: The story and lessons learned.

The authors analysed epidemiological data of the Hungarian tick-borne encephalitis epidemic from the past seven decades. A total of 911 meningitis serosa cases were described from 1930-1950 s by local hospital physicians, indicating that the virus had been present in the country decades before its official identification in 1952. The virus spread freely in the 1950s-1960s, occupying almost all habitats where ticks occurred in large numbers. The increasing number of cases drove authorities to classify this illness as a notifiable disease in 1977 and to organize the first measures to stop the epidemic. Statistical analysis revealed that the large-scale vaccination launched from the 1990s was responsible for the sharp decrease in the number of human cases from 1997. A significant negative correlation was found between the number of vaccine doses sold and human cases 6 years later. The TBEV endemic area covers 16.57% of the territory and 16.65% of the population of the country. In the last 10 years, 186,000 vaccine doses/year in average were enough to keep the incidence of human TBEV infections between 0.45 and 0.06/100,000 persons. A 20-year-long study found evidence for easing clinical signs in TBEV-infected hospitalized patients. Statistics found a sharp decrease in the number of samples sent for TBEV diagnosis after 1989. Male dominance of patients was characteristic of the epidemics since the 1940s, but now analysis of detailed data from the 1981-2021 period (60.5%-87.5%) proved the statistical significance of this dominance. Obviously, the voluntary vaccination programme was the tool which broke the spread of the epidemic. Widespread public awareness of the disease and the tick vector, probable evolutionary spread of less pathogenic virus strains supplemented with the vaccination campaign led to a negligible level of human TBE cases in Hungary in the last years.

Oculoglandular Tularemia From Crushing an Engorged Tick.

We report on an unusual case of oculoglandular tularemia acquired after crushing a tick removed from a dog. As a droplet sprayed into the patient's eye the eyelids became inflamed, and on the fourth day, a high fever started. Prompt antibiotic treatment prevented serious complication.

[Borrelia miyamotoi: a recently identified human pathogenic tick-borne relapsing fever spirochete]. / Borrelia miyamotoi: egy újabb, humán patogén, kullancs által terjesztett, visszatéro lázat okozó baktérium.

Borrelia miyamotoi is a recently described relapsing fever spirochete transmitted by ticks of the Ixodes ricinus complex. This pathogen is different from Borrelia burgdorferi sensu lato (the Lyme borreliosis spirochetes) in its epidemiology, ecology and also genetics. Over 50 patients have been described worldwide with Borrelia miyamotoi disease, and three immunocompromised patients were reported with neurological symptoms. Our knowledge about Borrelia miyamotoi infection in ticks and its distribution in different habitats and also the mechanism of the infection is limited. The most common symptom is fever; thus it can be easily confused with other tick-borne diseases. Due to the intensive research in recent years, Borrelia miyamotoi infection in ticks and hosts has been reported from different regions and also the number of patients is increasing, thus this bacterium is considered as an emerging pathogen. In this literature review we would like to summarize the available knowledge about this spirochete. Orv Hetil. 2017, 158(29): 1124-1130.

[Bexsero, a novel vaccine against meningococcus]. / Bexsero, egy új, meningococcus elleni vakcina.

Meningococcus B is the most prevalent Neisseria meningitidis serogroup isolated in Hungary. Bexsero is one of the vaccines developed against it, which has been available in Hungary since the summer of 2014. The authors summarize the most important issues and open questions concerning the disease and the vaccine based on literature review. Based on immunological evidence, it is expected that Bexsero provides protection against this rare but very serious infection. However, the vaccine is extremely expensive, the clinical effectiveness has not yet been proven and it frequently causes fever, especially in infants where the vaccine is most needed. According to the opinion of the authors, the formulation of a Hungarian guideline concerning the application of Bexsero should be postponed until the accumulating international experience makes it possible to better judge the vaccine's benefits, risks and cost-effectiveness. For patients with asplenia, complement defect or other immunological defect, or in case of markedly increased individual risk of contracting the disease, the vaccination is already justified.

Transmission of Rickettsia slovaca and Rickettsia raoultii by male Dermacentor marginatus and Dermacentor reticulatus ticks to humans.

We analyzed rickettsial DNA of ticks from tick-borne lymphadenopathy (TIBOLA) patients. Dermacentor marginatus (9/17) and Dermacentor reticulatus (8/17) transmitted rickettsiae to a similar extent. Rickettsia raoultii was detected in more ticks than Rickettsia slovaca. We observed the development of TIBOLA symptoms after the bite of males of both tick species.

Contact with horses is a risk factor for tick-borne lymphadenopathy (TIBOLA): a case control study.

Tick-borne lymphadenopathy (TIBOLA) is an emerging infection caused by Rickettsia slovaca. We describe here the seasonal, age and gender characteristics as well as the association with horse contact as risk factors for acquiring TIBOLA in comparison with another, more frequent tick-borne disease, Lyme borreliosis.We analysed a dataset of 855 patients diagnosed with either Lyme (n = 805) or TIBOLA (n = 50) disease using Fisher's exact tests and generalized linear models. Then we performed a matched case-control study in which all TIBOLA patients were paired with one Lyme patient matching in age and gender. We identified the species of ticks collected from the TIBOLA patients (n = 16).We found that horse contact was significantly more frequent among TIBOLA (34/50; 68 %) than among Lyme patients (110/805; 13.7 %) (OR = 13.35, p < 0.001). The younger age and female gender associated with higher risk of acquiring TIBOLA (OR = 3.99, p < 0.001). Ten of the 16 ticks were D. marginatus, six were D. reticulatus suggesting that both species are responsible for transmitting R. slovaca. Two patients acquired the infection from male ticks. TIBOLA is a tick-borne zoonosis, which might have a specific association with horse contact.

The current perspective on tick-borne encephalitis awareness and prevention in six Central and Eastern European countries: report from a meeting of experts convened to discuss TBE in their region.

Tick-borne encephalitis (TBE) is a potentially life-threatening disease in humans and is caused by a flavivirus spread by infected ticks (Ixodes ricinus and Ixodes persulcatus). TBE is endemic across much of Central and Eastern Europe and the incidence is increasing, with numbers estimated to be as many as 8755 cases per year. The reasons for this increase are multi-faceted and may involve improvements in diagnosis and reporting of TBE cases, increases in recreational activities in areas inhabited by infected ticks and changes in climatic conditions affecting tick habitats. Vaccination is the most effective method of preventing TBE; following a successful nationwide vaccination campaign in Austria, the annual number of TBE cases fell to about 10% of those reported in the pre-vaccination era. This report describes the findings of a group of leading experts from six Central and Eastern European countries who convened to discuss TBE in their region during the 28th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID) Nice, France, 4-8 May 2010.

An integrated database on ticks and tick-borne zoonoses in the tropics and subtropics with special reference to developing and emerging countries.

Tick-borne zoonoses (TBZ) are emerging diseases worldwide. A large amount of information (e.g. case reports, results of epidemiological surveillance, etc.) is dispersed through various reference sources (ISI and non-ISI journals, conference proceedings, technical reports, etc.). An integrated database-derived from the ICTTD-3 project ( http://www.icttd.nl )-was developed in order to gather TBZ records in the (sub-)tropics, collected both by the authors and collaborators worldwide. A dedicated website ( http://www.tickbornezoonoses.org ) was created to promote collaboration and circulate information. Data collected are made freely available to researchers for analysis by spatial methods, integrating mapped ecological factors for predicting TBZ risk. The authors present the assembly process of the TBZ database: the compilation of an updated list of TBZ relevant for (sub-)tropics, the database design and its structure, the method of bibliographic search, the assessment of spatial precision of geo-referenced records. At the time of writing, 725 records extracted from 337 publications related to 59 countries in the (sub-)tropics, have been entered in the database. TBZ distribution maps were also produced. Imported cases have been also accounted for. The most important datasets with geo-referenced records were those on Spotted Fever Group rickettsiosis in Latin-America and Crimean-Congo Haemorrhagic Fever in Africa. The authors stress the need for international collaboration in data collection to update and improve the database. Supervision of data entered remains always necessary. Means to foster collaboration are discussed. The paper is also intended to describe the challenges encountered to assemble spatial data from various sources and to help develop similar data collections.

The positive predictive value of Borrelia burgdorferi serology in the light of symptoms of patients sent to an outpatient service for tick-borne diseases.

OBJECTIVE: By using the published incidence of Lyme borreliosis in endemic regions of the World, and the sensitivity and specificity data of the best Lyme serological tests, we computed the positive predictive value of Borrelia burgdorferi antibody testing. METHODS: The calculation of predictive value was based on Bayes' theorem. We also analyzed the frequency distribution of the specific and non-specific symptoms and complaints of 27,194 patients sent to the Centre for Tick-borne Diseases in Budapest from 1986 to 2008. RESULTS: This evaluation demonstrated that practitioners often use Lyme serology in a "trial and error" way, without any reasonable ground. According to our calculation the positive predictive value of the best Lyme antibody tests if applied in this way is <9.1%. CONCLUSION: Our study suggests that the present practice of applying Lyme serological tests may result in more harm than benefit.

Maternal Lyme borreliosis and pregnancy outcome.

BACKGROUND: There is disagreement regarding whether Lyme borreliosis is associated with adverse pregnancy outcome. METHODS: We performed a review of the data from 95 women with Lyme borreliosis during pregnancy, evaluated at the Center for Tick-borne Diseases, Budapest over the past 22 years. RESULTS: Treatment was administered parenterally to 66 (69.5%) women and orally to 19 (20%). Infection remained untreated in 10 (10.5%) pregnancies. Adverse outcomes were seen in 8/66 (12.1%) parentally treated women, 6/19 (31.6%) orally treated women, and 6/10 (60%) untreated women. In comparison to patients treated with antibiotics, untreated women had a significantly higher risk of adverse pregnancy outcome (odds ratio (OR) 7.61, p=0.004). While mothers treated orally had an increased chance (OR 3.35) of having an adverse outcome compared to those treated parenterally, this difference was not statistically significant (p=0.052). Erythema migrans did not resolve by the end of the first antibiotic course in 17 patients. Adverse pregnancy outcome was more frequent among these 'slow responder' mothers (OR 2.69), but this was not statistically significant (p=0.1425) . Loss of the pregnancy (n=7) and cavernous hemangioma (n=4) were the most prevalent adverse outcomes in our series. The other complications were heterogeneous. CONCLUSION: Our results indicate that an untreated maternal Borrelia burgdorferi s.l. infection may be associated with an adverse outcome, although bacterial invasion of the fetus cannot be proven. It appears that a specific syndrome representing 'congenital Lyme borreliosis' is unlikely.

[Lyme borreliosis--experience of the last 25 years in Hungary]. / Lyme-borreliosis--25 év hazai tapasztalatai.

We recognized the first Hungarian Lyme patients just 25 years ago, in 1984. It was exactly 20 years ago, when we opened the Lyme Disease Outpatient Service at the Central (László) Hospital for Infectious Diseases. 15 years ago we established the financially independent Center for Tick-borne Diseases. The milestones of this work at the Center for Tick-borne Diseases are the description of a new tick-borne rickettsial illness (tick-borne lymphadenopathy), development of a Lyme immunoblot kit and an automated immunoblot reader. We described a simple and reliable method for detection of intrathecal borrelia antibody synthesis which is necessary for the diagnosis of neuroborreliosis. We also developed and routinely apply the comparative immunoblot assay for the evaluation of serological progression and/or regression, which can help the clinicians to decide whether a serological reaction is resulted from a previous healed or an active borrelia infection. We studied the pregnancy outcome of borrelia infected mothers and provided that untreated borrelia infection is associated with higher chance of adverse pregnancy outcome.

Different B-cell populations are responsible for the peripheral and intrathecal antibody production in neuroborreliosis.

The diagnosis of neuroborreliosis (NB)--a serious complication of Lyme disease--relies on demonstration of intrathecal borrelia antibody production. We hypothesized that if a qualitative difference between the cerebrospinal fluid and the serum immunoblot-banding patterns was observed, then the borrelia antibodies found in the CSF could not be the result of leakage of serum antibodies to the CSF due to blood-brain barrier damage, but rather had to be produced intrathecally. CSF/serum pairs from 69 NB patients and from 85 control patients with other neurological disorders were investigated. All samples were tested blindly by immunoblot and a commercial capture ELISA kit for NB. The concordance between the two methods was 85.7%. When using the other method as reference, the accuracy of the two assays in the two patient materials was similar: 80% for sensitivity and 95% for specificity. Four types of comparative immunoblot-banding patterns that reflected intrathecal borrelia antibody synthesis were distinguished. The study showed that a simple comparison between the immunoblot pattern of serum and CSF samples allows for a reliable diagnosis of NB by demonstration of intrathecal antibody production. This is the first study to show that a qualitative difference of the antibody response between the immune response of serum and CSF is a rule. The findings also imply that partly different B-cell populations are responsible for the antibody production in the blood and in the central nervous system. In addition, our observation provides possible implications for other infectious diseases with CNS involvement.

Tick-borne lymphadenopathy (TIBOLA).

INTRODUCTION: From 1996 through 2000, we collected data on 86 patients with similar symptoms following a tick bite. The inclusion criteria were: enlarged regional lymph nodes and/or vesicular-ulcerative local reaction at the site of the tick bite. METHODS: Epidemiological and clinical data on these 86 patients were statistically analysed. All patients were tested for borrelia and 73 cases for Rickettsia slovaca antibodies by immunoblot. Fine-needle lymph node and/or skin biopsy was done in 13 patients. Gehomic PCR amplification was performed on these biopsy samples. RESULTS: Seventy-six patients described an "extremely big" tick, and/or recognised a Dermacentor spp. tick from a collection of several species indigenous to Hungary. The tick bite was usually (96%) located on the scalp region. The time from the recognition of the tick bite to the first symptom varied between 0 and 55 (mean nine) days. A characteristic local reaction (eschar) was seen in 70 (82%) patients. The eschar can be surrounded by a circular erythema (18 cases, 21%). The other main symptoms are the enlarged and sometimes painful lymph nodes in the region of the tick bite, characteristically in the occipital region and/or behind the sternocleidomastoideal muscle. The most frequent general symptoms were low-grade fever, fatigue, dizziness, headache, sweat, myalgia, arthralgia, and loss of appetite. Without treatment, the symptoms were seen to persist for as long as 18 months. One of the patients reported symptoms suggestive of encephalitis. The infection occurs most commonly in young children (age range: 2-57 years, mean: 12.6 years, 63% less than 10 years of age). A female predominance was registered (50/36). Doxycycline treatment can shorten the usually benign illness. R. slovaca PCR gave positive results from skin or lymph node biopsy samples in 10/13 (77%) patients. CONCLUSION: We have described a new and frequent tick-borne infection, most probably caused by R. slovaca.

Spotless rickettsiosis caused by Rickettsia slovaca and associated with Dermacentor ticks.

The pathogenic role of Rickettsia slovaca was first demonstrated in 1997 in a patient who presented with a single inoculation lesion of the scalp and enlarged cervical lymph nodes after receiving a bite from a Dermacentor tick. Subsequently, we evaluated the occurrence of R. slovaca infections among patients living in France and Hungary who presented with these symptoms. R. slovaca infections were confirmed by polymerase chain reaction (PCR) in 17 of 67 enrolled patients. Infections were most likely to occur in patients aged <10 years and in patients who were bitten during the colder months of the year. The median duration of incubation for the disease was 7 days. Fever was present in only 2 patients, and only 1 patient developed a rash. Sequelae included persistent asthenia (3 cases) and localized alopecia (4 cases). Immunofluorescence and/or Western blot analysis detected antibodies in 50% of tested patients. Three Dermacentor ticks obtained from patients revealed R. slovaca by PCR.