Emergency prevention of tick-borne viral encephalitis in remote regions of the Russian Federation

Introduction

Tick-borne viral encephalitis (TBE) is one of the most common natural focal diseases of the nervous system transmitted by ixodid ticks, which are obligate bloodsuckers and, as a rule, attack humans in natural biotopes. TBE is an epidemically significant infection in the Russian Federation (RF).

The nosoareal of TBE almost completely coincides with the habitat of two species of ixodid ticks: Ixodes persulcatus (Urals, Siberia, Far East, partially the European part) and Ixodes ricinus (European part) [1]. In the natural foci of TVE on the territory of the Russian Federation, variants of the TBE virus of four subtypes circulate: Far Eastern (prototype strain Sof'in), European (Neudoerfl), Siberian (Vasilchenko and Zausaev) and Baikal (group "886-84" of similar virus variants) [2].

Tick attacks occur not only in natural biotopes (in forest and taiga regions), but also in city parks, squares, summer cottages, garden plots and homesteads, and in suburban cottages. Approximately 70% of those infected with TBE are city dwellers, often unvaccinated [3].

In the Russian Federation, over the course of two decades of the 21st century, a decrease in the incidence of TBE has been recorded. Moreover, this is happening in the absence of a decrease in the number of people who have suffered from the bite of ixodid ticks seeking medical help, which suggests that the epidemic process is waning. At the same time, the spread of the risk indicators for TBE incidence across the country’s administrative regions is very large [4].

However, thousands of cases of infection are registered annually, and a significant portion of them occur in remote areas, where high tick activity is combined with low availability of medical infrastructure. In the north of our country, there is an increase in contacts of the population with ixodid ticks, which can be carriers and reservoirs of TBE. The decisive role in the formation of TBE morbidity in the Russian Federation is played by (in descending order): Siberian, Ural, Northwestern, and Far Eastern Federal Districts [1].

The incidence of TBE also depends on the level of collective immunity, which in turn depends on the volume of vaccination of the population [5, 6].

TBE begins to affect the cells of the brain and spinal cord within 24 h after the tick bites [7].

A feature of the clinical manifestations of TBE is their diversity. TBE can have an acute course with a large number of different symptoms and a favorable outcome, but often acquires a progressive fulminant or chronic protracted process (up to 20%) with a severe course, leading to the development of disability and death (1.4–9%) [8]. 

In the structure of the clinical manifestations of TBE in 2021, febrile (59.7%) and meningeal (24.3%) forms prevailed. Then, in descending order: meningoencephalitic (11.2%), subclinical (2.6%), poliomyelitis (2.1%), and polyradiculoneuritic (0.25%). A comparative analysis of the materials on the clinical manifestations of TBE for 2019–2021 shows that their structure has remained virtually unchanged over this period. In total, 14 fatal outcomes were recorded [1]. 

The outcome of the disease largely depends on the correct extraction of the tick using the «КЛЕЩАМНЕТ» ("TICK-NOT") kit, the serotype of the virus, the number of viral particles that have entered the body, and is also determined by the nature of the body's immune response to contact with the pathogen, the effectiveness of emergency prevention and drug treatment [9]. Therefore, it is necessary to perform early emergency prevention of TBE (from the moment the tick attaches), etiotropic antiviral and complex pathogenetic therapy.

In this article, we will consider the use of preventive measures against TBE in the remote regions of the Russian Federation: the Siberian, Ural, Northwestern, and Far Eastern Federal Districts, which have the highest incidence rates.

Prevention of tick-borne viral encephalitis

Preventive measures aimed at preventing infection with the TBE virus include [1, 10]:

• Acaricidal treatment of the territories of socially significant objects;
• Vaccination of the population according to the epidemiological indications;
• Seeking medical help from specialists and removing the tick;
• Laboratory express diagnostics: polymerase chain reaction (PCR) and enzyme immunoassay (ELISA) for the TBE antigen in the tick and/or in the blood serum of the victim of TBE;
• Emergency (post-exposure) prophylaxis for people affected by the bite of virus-containing ticks and previously unvaccinated by administering human immunoglobulin against TBE;
• Use of iodophenazone;
• Dispensary observation of convalescents of tick-borne infections.

The volume of all preventive measures increases from year to year [1]. However, in the remote regions of the Russian Federation, where access to medical care is limited, disease prevention becomes critically important.

Vaccination. It is generally recognized that the most effective measure for preventing TBE is vaccination, which in most cases prevents the development of severe forms of the disease. However, despite the high immunogenicity of modern vaccines, they do not provide 100% protection of vaccinated people from the development of TBE [11]. In most of the territories of the Russian Federation enzootic for TBE, vaccination is not carried out on a sufficient scale [12]. 

In 2021, 2,889,515 people (including 1,433,850 children) were vaccinated in the country, of whom 41,807 reported tick bites, with 14 falling ill (0.03%). At the same time, the rate of manifest cases of the disease among unvaccinated individuals was 0.25% (1,004 cases out of 403,438 victims of tick bites and unvaccinated individuals). Thus, the incidence of TBE among vaccinated individuals is 8.3 times lower than that among unvaccinated individuals [1].

Among those vaccinated, a milder course of the disease was noted; the proportion of the meningeal form did not exceed 2.0% (OR=0.385; 95% CI 0.306–0.486) (see table) [13].

Emergency etiotropic seroprophylaxis.The introduction of human immunoglobulin against TBE is carried out only after receiving positive PCR and/or ELISA results for the TBE antigen in the tick and/or in the blood serum of the victim [14].

In 2021, specific immunoglobulin was used in the Russian Federation to prevent the manifest development of infection in 100,704 people, which is 22.6% of those affected by tick bites (30.6% among children) [1].

The introduction of human immunoglobulin against TBE is possible within 96 h from the moment of the tick bite. The use of specific immunoglobulin later is not effective enough since it can have an immunosuppressive effect, suppressing the synthesis of its own antibodies [15]. It is administered once at a dose of 0.1 ml/kg (maximum 8 ml) in the absence of contraindications such as allergic reactions or severe systemic reactions to the administration of human blood products in the anamnesis, hypersensitivity to the components of the drug [13]. Specific immunoglobulins have an immunosuppressive effect; therefore, it is not advisable to administer immunoglobulin more than 2-3 times to the same person throughout life. In addition, human immunoglobulin against TBE is not advisable in case of repeated tick bites during one epidemic season. The drug is not effective in case of infection with other pathogens of arbovirus infections [9]. 

It has been established that among people who received human immunoglobulin against TBE, the disease was milder, and the proportion of meningeal forms did not exceed 7.0% (OR = 1.429; 95% CI 1.241–1.645) (see table) [13].

It has been proven that the effectiveness of the prophylactic action of this drug is directly dependent on the timing of its administration from the moment of TBE virus infection. Moreover, only about 6% of the population has specific immunity against TBE [16], and the shortage and high cost of specific immunoglobulin against TBE do not allow for the coverage of emergency prevention for all those in need.

In this regard, an area for the emergency prevention and treatment of TBE has become the use of the drug iodophenazone.

Iodophenazone. Since 1996, the antiviral drug iodophenazone (Iodantipyrine^®) has been used for the emergency prevention of tick-borne encephalitis in the Russian Federation. It has anti-inflammatory, immunostimulating and interferonogenic properties; stabilizes biological membranes and delays the penetration of the virus into the cell; is an active inducer of α- and β-interferon, stimulates cellular and humoral immunity; is active against tick-borne encephalitis virus and hemorrhagic fever with renal syndrome.

A number of authors have demonstrated the effectiveness of Iodantipyrine^® when used in areas endemic for TBE [17-21]. It has been established that Iodantipyrine^® has interferon-inducing, immunomodulatory, antiviral and anti-inflammatory activity; high therapeutic efficacy, particularly in the febrile and meningeal forms of TBE. The drug can be used not only in the first 96 h after tick attachment but also at a later date, and unlike anti-tick immunoglobulin, this does not lead to the suppression of the specific immune response to the TBE antigen [18-22].

The use of Iodantipyrine^® made it possible to avoid the development of the meningeal form of TBE, while the risk of developing the disease in people who received the drug was significantly lower (OR = 0.162; 95% CI 0.101–0.262) (see table) [13].

In addition, Iodantipyrine^® is effective as a preventive measure immediately before visiting areas enzootic for TBE [13].

Thus, the obtained research results indicate the high epidemiological effectiveness of Iodantipyrine^®. Its use is more effective compared with the use of specific human immunoglobulin against TBE (see table), traditionally used for the emergency prevention of TBE.

From the point of view of pharmacoeconomics, Iodantipyrine^® is not inferior to immunoglobulin against TBE in terms of its effectiveness and safety of use, and cost analysis showed that in the case of using Iodantipyrine^®, the costs of the healthcare budget associated with the treatment of developed TBE are 2.2 times lower than those of immunoglobulin against TBE; the costs of emergency prophylaxis with Iodantipyrine^® are 11.3 times lower [23].

It is advisable to use Iodantipyrine^®:

• If there are contraindications to the administration of immunoglobulin against TBE;
• In case of multiple administrations of immunoglobulin against TBE: throughout a person’s life, it is not advisable to administer immunoglobulin more than 2-3 times to the same person;
• In case of repeated tick bites during one epidemic season, when multiple administration of immunoglobulin against TBE is not indicated;
• Previously completed a full course of vaccination against TBE as an additional preventive measure;
• Victims who sought medical care at a later stage — later than 96 h after the tick bite, when the administration of human immunoglobulin against TBE is no longer indicated;
• if it is impossible to perform PCR and/or ELISA to detect the TBE antigen in a tick or in the blood serum of the victim when the patient is in an area remote from specialized medical institutions or at health care facilities (HCF) where diagnostics of tick-borne infections are not performed.

The main advantages of Iodantipyrine^®:

• High efficiency in the prevention of tick-borne encephalitis;
• The possibility of application both before and after a tick bite;
• Relatively low cost and availability;
• Minimal side effects.

The drug is available in tablet form, which makes it convenient for use in remote regions of Russia (Siberian, Ural, Northwestern, Far Eastern Federal Districts), where injectable forms of drugs may be unavailable. First, in rural areas, where there is traditionally a shortage of pharmacies, feldsher-obstetric stations, healthcare facilities, and most importantly, medical personnel. In these regions, there remains a large number of settlements, residents of which still have to travel a long way even for pre-hospital care, and as a rule, there is no possibility of administering immunoglobulin against TBE, due to the following:

• Lack of availability of a laboratory with the ability to conduct PCR and/or ELISA tests for the TBE antigen in the tick and/or in the blood serum of the victim;
• Lack of funds both among the population and at healthcare facilities and feldsher-obstetric stations to purchase immunoglobulin against TBE;
• Difficulty in maintaining the cold chain during the transportation and storage of the immunoglobulin against TBE;
• Lack of medical specialists to assess the condition of the victim and administer immunoglobulin against TBE.

Therefore, in remote areas of Russia, where medical care is often unavailable, Iodantipyrine^® is becoming the only available drug of choice for the emergency prevention of tick-borne encephalitis due to the following: 

• Its over-the-counter dispensing from pharmacies, which is important for areas where access to doctors is limited;
• Convenient-release tablet form and ease of use for self-administration by the patient without special medical training;
• Significant reduction in the time for emergency prevention;
• No need to comply with special cold chain conditions during transportation, as well as during storage, which allows you to take it with you in a field first aid kit, which is especially important in expeditions and other similar situations throughout the season, and use it immediately after detecting an attached tick;
• Affordable price for the family budget, which makes it attractive to wide sections of the population and healthcare institutions;
• Minimum contraindications: the drug is well tolerated by most patients, except people with individual intolerance to iodine.

Therefore, in remote regions of the Russian Federation, where vaccination and immunoprophylaxis with human immunoglobulin against TBE may be unavailable or difficult, oral drugs for emergency prophylaxis, such as Iodantipyrine^®, are of particular importance and can be used in the following situations:

• Routine prevention: people living in endemic areas or planning trips to such regions are recommended to start taking Iodantipyrine^® a few days before possible contact with ticks. This allows the body to create a protective barrier against the virus;
• Emergency prevention: it has been scientifically proven that during the first day after a tick bites, the tick-borne encephalitis virus penetrates the brain through the blood-brain barrier, which is dangerous due to damage to brain cells and its consequences. Therefore, it is extremely important to speed up the start of emergency TBE prevention as much as possible, without waiting for positive PCR and/or ELISA results for the TBE antigen in the tick and/or in the blood serum of the victim to prescribe immunoglobulin against TBE, and in the first hours to start taking Iodantipyrine^® according to the emergency prevention scheme, which significantly reduces the risk of developing the disease;
• Treatment at the early stages: when the first symptoms of tick-borne encephalitis appear (fever, headache, weakness), Iodantipyrine^® can be used as part of the complex pathogenetic therapy;
• Treatment of vaccinated persons: mandatory administration of Iodantipyrine^® to those vaccinated against tick-borne encephalitis to reduce morbidity and increase the effectiveness of preventive vaccination measures among the population.

For maximum effectiveness of the drug, it is important to follow the following practical recommendations for the use of Iodantipyrine^®:

• dosage: 

- routine prevention: it is recommended to take 1 tablet (0.1 g) 3 times a day for 2 days before visiting an endemic area, then continue taking it for the entire period of stay in the danger zone;

- emergency prevention: in the first 96 h after a tick bite after a tick bite - 3 tablets 3 times a day for the first 2 days, then 2 tablets 3 times a day for the next 2 days;

• storage:

- Iodantipyrine^® should be stored in a dry, dark place at a temperature not exceeding 25°C. This is especially important in remote regions where climatic conditions may be extreme.

Informing the public

In remote areas of the Russian Federation, it is important to conduct educational programs that talk about the risks of TBE and methods of its prevention.

In addition to starting to take medications, one of the most important emergency measures immediately after a tick has attached is its correct extraction. Common folk remedies for tick removal are often ineffective and even harmful to the body. A reliable and safe choice is the «КЛЕЩАМНЕТ» ("TICK-NOT") kit, which includes a device for extracting a tick and a test tube for transporting the tick to the laboratory. It will allow you to promptly and completely remove the attached tick and reduce the likelihood of TBE infection.

Local residents should be aware of the existence of Iodantipyrine^® and the rules for its use. 

Conclusion

Tick-borne viral encephalitis remains a serious threat to the health of the population of the Russian Federation, especially in remote regions: the Siberian, Ural, Northwestern and Far Eastern Federal Districts.

The warm winter of 2024-2025 and the early start of spring in Russia will contribute to the activation of ticks and, consequently, to the early start of the epidemic season in 2025.

In conditions of limited access to medical care in remote regions of the Russian Federation, disease prevention is becoming a key element in the fight against it.

Over decades of experience in the use of Iodantipyrine^®, extensive data have been obtained on its effectiveness, safety, and clinical and economic benefits.

Due to its availability and ease of use, Iodantipyrine^® is an important tool for preventing the development of tick-borne viral encephalitis.

Widespread public awareness of the possibilities of its use, as well as ensuring the availability of the drug in endemic areas of the Russian Federation, will help reduce the incidence and maintain the health of thousands of people. Iodantipyrine^® deserves attention as an effective means of preventing tick-borne viral encephalitis, especially in remote regions of the Russian Federation, where other methods of protection may be unavailable.

With the combined use of the «КЛЕЩАМНЕТ» ("TICK-NOT") kit and Iodantipyrine^®, the likelihood of contracting tick-borne viral encephalitis was significantly reduced.

The active implementation of Iodantipyrine^® as a means of preventing tick-borne viral encephalitis will help optimize the costs of the healthcare system budget at various levels, as well as improve the quality of medical prevention of such a socially significant pathology as tick-borne viral encephalitis.