THE MOST COMMON ANTHROPOZOONOSES IN THE REPUBLIC OF SRPSKA IN THE PERIOD 2015 – 2020

Zoonotic diseases are increasingly becoming an emerging public health threat, partially due to the risk of spillover events at the human-wildlife interface. Th eir potential for infecting people with exotic pathogens originating from unusual pets should not be overlooked. Th e aim of the study is to present and analyze the trend of zoonoses in the 2015-2020 period using the descriptive method. Th e source of data is reports of single cases of infectious diseases, which is in accordance with the applicable legislation governing this area. Th e incidence of anthropozoonoses was the highest in 2017 amounting 16.5/100,000, while the lowest value in this fi ve-year period was in 2020, with 1.1/100,000. Th e share of anthropozoonoses in the total incidence of infectious diseases was also the lowest in 2020, with the value of 0.02%, while the highest share of this group of diseases was recorded in 2017 with a value of 1.42%. In the specifi ed period, the three most commonly reported anthropozoonoses are Q-febris, leptospirosis, and brucellosis. In 2020, the most frequently registered anthropozoonosis was toxoplasmosis, while in the previous 5 years, this disease was not reported among the three most common. It is necessary to raise awareness about the presence of zoonoses in the overall incidence of infectious diseases in the Republic of Srpska, because due to the common non-specifi c clinical picture, zoonoses are not the fi rst to be considered in diff erential diagnosis. In the fi ght against zoonoses, a coordinated approach to “One Health” is necessary, which will enable design and implementation of programs, policies, legislation and research in the area of public health.


NAJČEŠĆE ANTROPOZOONOZE U REPUBLICI SRPSKOJ U PERIODU 2015 -2020 INTRODUCTION
Six in ten human cases of infectious disease arise from animal transmission (Center for Disease Control, 2018). Fift y years ago, following the wide-scale manufacture and use of antibiotics and vaccines, it seemed that the battle against infections was being won for the human population. Since then, however, and in addition to increasing antimicrobial resistance among bacterial pathogens, there has been an increase in the emergence of zoonotic diseases originating from wildlife, sometimes causing fatal outbreaks of epidemic proportions. Zoonosis is defi ned as any infection naturally transmissible from vertebrate animals to humans. In addition, many of the newly discovered diseases have a zoonotic origin. Due to globalization and urbanization, some of these diseases have already spread all over the world, caused by the international fl ow of goods, people and animals. However, special attention should be paid to farm animals since, apart from the direct contact, humans consume their products, such as meat, eggs, and milk. Th erefore, zoonoses such as salmonellosis, campylobacteriosis, tuberculosis, swine and avian infl uenza, Q fever, brucellosis, STEC infections, and listeriosis are crucial for both veterinary and human medicine. Consequently, in the suspicion of any zoonoses outbreak, the medical and veterinary services should closely cooperate to protect the public health (Libera et al., 2022). Zoonotic diseases, particularly those associated with livestock and poultry, are becoming an increasing threat for public health for various reasons. For example, the predictions suggest that the global human population will constantly increase and reach almost 10 billion by 2050. Consequently, it will result in a higher food demand (United Nations, 2019). One Health is an eff ective approach for the management of zoonotic disease in humans, animals and environments. Examples of the management of bacterial zoonoses in Europe and across the globe demonstrate that One Health approaches of international surveillance, information-sharing and appropriate intervention methods are required to successfully prevent and control disease outbreaks in both endemic and non-endemic regions. Additionally, One Health approach enables eff ective preparation and response to bioterrorism threats (Cross, 2018).
Diagnostics plays a key role in disease surveillance. Misdiagnosis results in inappropriate treatment, or missed opportunities to prevent further disease transmission. Th e zoonoses discussed in this paper oft en present as undiff erentiated febrile illnesses, and so a detailed history is key to diagnosis. More common ailments with similar symptoms are initially suspected, and diagnosis may be missed altogether in self-limiting cases (Gunaratnam et al, 2014).
It is almost certain that large-scale zoonotic disease outbreaks will almost certainly continue to occur regularly in the future. Th erefore, a better general understanding of the factors aff ecting variation in the severity of outbreaks is critical for well-being of the global community (Stephens et al, 2021). En-demic zoonoses continue to be relatively neglected, oft en with a lack of local and international realization of the extent to which they impact human health and well-being. Th is is partly due to the issues surrounding local capacity and knowledge and partly because, unlike emerging infectious diseases, they are not seen as a threat to people in the developed world. Both EIDs and endemic zoonoses, however, can be tackled using the One Health approach, which includes the identifi cation and mitigation of human activities that lead to disease emergence and spread (Cunningham et al, 2017). In the fi ght against zoonoses, a coordinated approach to "One Health" is necessary, as it will enable the design and implementation of programs, policies, legislation and research in the fi eld of public health.
Th e aim of the study is to present and analyze the trend in zoonoses during the 2015-2020 period using the descriptive method. Th e source of data is reports of single cases of infectious diseases, which is in accordance with the applicable legislation governing this area.

MATERIAL AND METHODS
No ethical approval was obtained because this study did not involve laboratory animals. Only non-invasive procedures were used.
As part of epidemiological surveillance, an analysis of the data obtained from monitoring the trend of anthropozoonosis according to European Union (EU) case defi nitions was performed (European Commission, 2018). EU definitions have been part of the national legislation for years now, and they are regulated by law. Using the descriptive method, the data obtained from all 54 primary health centers, as well as 10 hospitals in Republic of Srpska, were analyzed. Th e data were obtained through the Notifi cation of Infectious Diseases, which is an offi cial and binding document for every doctor who registers and thus reports an infectious disease, which is regulated by regulations and law. Th e disease reports are sent from these institutions to the Public Health Institute of the Republic of Srpska which analyzes the data and generates offi cial reports. Th e trend of anthropozoonoses in the mentioned period is described and the three most common anthropozoonoses for each year are determined. Th e case of each disease is classifi ed as possible -probable -confi rmed on the basis of the national case defi nition criteria. Using statistical analysis with statistical soft ware SPSS 23, we compared the incidences of these diseases, while patient demographics were analyzed and statistically processed using chi-squared (χ 2 ) test. Th is test was used to determine whether there is a statistically signifi cant diff erence between the observed frequencies of the three diseases in the observed groups and the frequencies of the same groups in the general population.

RESULTS
Th e incidence of anthropozoonoses was the highest in 2017 with 16.5/100,000, while th e lowest value in this six-year period was in 2020, amounting to 1.1/100,000 ( Figure 1). Th e share of anthropozoonoses in the total incidence of infectious diseases was also the lowest in 2020 and amounted to 0.02%, while the highest share of this group of diseases was recorded in 2017 with a value of 1.42%. In the specifi ed period, the three most commonly reported anthropozoonoses were Q-febris, leptospirosis, and brucellosis.
Th e analysis of the collected data from epidemiological surveillance in the mentioned period, showed that there was a total of 283 cases of these three diseases, and the incidence trend shows that the incidence was the highest in 2017, high in 2016, 2018 and 2019, while in 2020 the incidence was very low (Table 1). If we separate the incidence for each of these three diseases individually, we come to the following information: a total of 83 cases of brucellosis were reported in that period, and the incidence trend shows that the incidence of brucellosis was the highest in 2018 (2.96% 000), and signifi cantly lower in other seasons. In the observed period, a total of 86 cases of leptospirosis were reported, and the incidence trend was the highest in 2017, with the incidence of 2.78% 000, high in the 2019 season with the incidence of 2.1% 000 and signifi cantly lower in other seasons. 114 cases of Q-fever were reported in the same period, with the incidence trend that was highest in the 2016 season and an incidence of 2.76% 000, high in the 2017 (2.43% 000) and 2019 seasons (2.45% 000) and signifi cantly lower in other seasons ( Figure 2). Based on the results of the χ ^ 2 test (χ ^ 2 = 56.993; p = 0.000), it can be concluded that there was a statistically signifi cant diff erence in the total number of patients of all three diseases by sex. Statistically signifi cant (p =0.000, < 0.05) there was a higher number of male patients than the number of female patients, compared to the number of men and women in general population observed for all three diseases together as well as for each of the diseases individually ( Figure 3). Th e data obtained from epidemiological population surveillance from 2015 to 2020 in the Republic of Srpska show that out of a total of 283 patients with brucellosis, leptospirosis and Q-fever, 155 or 54.77% live in urban areas and 128 or 45.23% in rural areas. However, statistical analysis of data for each of the diseases separately reveals that there are signifi cant diff erences in this regard between these three diseases. Namely, the results of the χ ^ 2 test for brucellosis (χ ^ 2 = 1.157; p = 0.282) and leptospirosis (χ ^ 2 = 2.110; p = 0.146) show that there was no statistically signifi cant diff erence in the number of patients according to the type of settlement in which they lived, while in patients with Q fever (χ ^ 2 = 33,778; p = 0,000) this statistical diff erence is signifi cant, as indicated by the relatively high value of the χ ^ 2 test and the high probability (p = 0.000, <0.05) for the accuracy of that statistical diff erence (Figure 4).  Th e analysis of the regional distribution of patients by each of the three diseases, and in total, we come to the result that the largest number of reported cases was registered in the Banja Luka region, and lowest in the Trebinje region. When it comes to the reports on the outbreaks of these three infectious diseases in the given period, one epidemic of Q fever was reported in 2016 in Banja Luka, where 30 patients were registered and that correlates with the trend. According to data from population surveillance, the diagnosis of brucellosis, leptospirosis and Q-fever was clinically established in 184 cases (65.02%) (probable cases), which is signifi cantly more than 99 cases (34.98%) in which the diagnosis was confi rmed in the laboratory (confi rmed cases). Th ere is a similar relationship in terms of the method of establishing the diagnosis for each of the three diseases, with the number and share of clinically made diagnoses (probable cases) being highest in patients with Q fever (81 cases and 71.05%) while there were 33 confi rmed cases (28.95%). Th e number and share of laboratory confi rmed cases is the highest in patients with leptospirosis (35 cases and 40.7%), while there were 51 probable cases (59.3%). Th e number and share of probable cases of brucellosis was 52 (62.65%), while there were 31 confi rmed cases (37.35%) ( Figure 6).

DISCUSSION
Communicable disease epidemiology is closely linked to pathogen ecology, environmental and social determinants, economic factors, access to care, as well as the state of country development (McMichael, 2012). Climate change continues to have both direct and indirect eff ects on communicable diseases, oft en in combination with other drivers, such as increased global travel and trade. Th e frequency, duration, and intensity of heat waves has increased across Europe, and the last decade was the warmest ever recorded (World Meteorological Organization, 2013).
A global, integrated zoonotic disease surveillance system needs to detect disease emergence in human or animal populations anywhere in the world at the earliest time possible. An eff ective global, integrated zoonotic disease surveillance system requires eff ective surveillance at national, regional, and international levels, because information from outbreak investigations is used by human and animal health offi cials at all levels to implement response measures and evaluate the eff ectiveness of those responses.
Emerging zoonotic diseases can occur any time in any part of the world. Th erefore, it is diffi cult to predict which pathogens may emerge, which human and or animal populations it may aff ect, or how these pathogens may spread. From a growing number of experiences, the world has learned that it is crucial to detect and report emerging zoonotic disease outbreaks that occur in a single country or region. Early detection and reporting at the local level give the international community an opportunity to assist national authorities and implement eff ective response measures (Keusch et al, 2009). Q fever is a severe, zoonotic disease spread worldwide and caused by Cox-iella burnetii. Th is disease was fi rst described by Derrick in 1937 following an epidemic fever outbreak among employees at a slaughterhouse in Brisbane, Australia (Derrick, 1937). Q fever can manifest as an acute disease, usually as a self-limited febrile illness, pneumonia, or hepatitis. It may also occur as a persistent focalized infection with endocarditis. Th e main reservoirs of C. burnetii are cattle, sheep, and goats, but infections were detected in other animals such as domestic mammals, marine mammals, reptiles, birds, and ticks (Eldin et al, 2017). C. burnetii is most abundant in aborted fetuses, amniotic fl uid and placenta aft er stillbirth or normal birth of off spring from infected mothers, and in the urine, feces and milk of infected animals. Transmission to humans most commonly occurs through inhalation of aerosolized bacteria from the placenta (delivery or abortion), feces, or urine of infected animals. Human-to-human transmission is extremely rare. Leptospirosis is a widespread bacterial zoonosis occurring most commonly in low-income populations living in tropical and subtropical regions, both in urban and in rural environments. Rodents are known as the main reservoir animals, but other mammals may also signifi cantly contribute to human infections in some settings. Clinical presentation of leptospirosis is nonspecifi c and variable, and most of the early signs and symptoms point to the so-called 'acute fever of unknown origin' (Goarant, 2016;Adler et al, 2009).
Th e implementation of the case defi nition is signifi cant because all reported cases need to be categorized in the same way in accordance with international regulations (Nichols et al, 2014). Th e introduction of a case defi nition facilitated the early recognition of these diseases as well as the appropriate direction in their diagnosis and confi rmation. Th is also enables the evaluation of surveillance system through the analysis of the report of each individual case Standards for good laboratory practices overlap with standards for good laboratory network operations. Good laboratory practice principles are simply applied to laboratory facilities that meet proper standards for testing, safety, and security; employ a trained and profi ciency-tested staff ; have standardized operating procedures, validated test protocols, and properly functioning equipment; and use a communication system that relies on common platforms and accurately and reliably reports test results in a timely manner.
Th e Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (WOAH -ex OIE), and the World Health Organization (WHO) recognize a joint responsibility to minimize the health, social and economic impact of diseases arising at the human-animal interface by preventing, detecting, controlling, eliminating or reducing disease risks to humans originating directly or indirectly from domestic or wild animals, and their environments. An important aspect of eff orts to mitigate potential health threats at the human-animal ecosystems interface is early warning, supported by robust risk assessment to inform decisions, actions, and timely communication between agencies and sectors responsible for human health, animal health, wildlife, and food safety. In 2006, in response to health threats such as H5N1 highly pathogenic avian infl uenza (HPAI) and the severe acute respiratory syndrome (SARS), the three organizations consolidated their eff orts to establish a Global Early Warning System for Major Animal Diseases Including Zoonosis (GLEWS). GLEWS became one of the mechanisms used by the WOAH, FAO, and WHO together for monitoring data from existing event-based surveillance systems and track and verify relevant animal and zoonotic events (FAO-WOAH-WHO, 2010).
Based on the results of the study, it can be seen that the incidence of these diseases was the lowest in 2020. Th e cause of this drastic decline is largely the outbreak of the COVID 19 pandemic and the fact that it cast a shadow on other diseases due to the enormous burden it imposed on the health system. Pandemic certainly did not change the course of these diseases, but it did make their reporting, adequate diagnosis and anti-epidemic action very diffi cult. But despite the epidemic, doctors who are the fi rst to receive and treat patients do not consider zoonoses as the fi rst option in diff erential diagnosis, especially because most of them do not have specifi c symptoms at the beginning of the disease, and in the most severe clinical phase fever, malaise, headache, muscle aches, pneumonia or even meningitis are the symptoms of many other nonzoonotic diseases. Our doctors were somewhat more cautious about zoonoses in the fi rst few years aft er the catastrophic fl oods that hit this region in 2014, but that has changed over time due to the impact of several factors.
In the observed period, out of the three most reported diseases, namely brucellosis, leptospirosis and Q fever, the largest number of reported cases were Q fever cases, with the highest incidence in 2016. Th e reason for this is the registered outbreak of this disease in the area of Banja Luka. Furthermore, a signifi cantly higher number of people with disease fell ill in urban areas than in rural areas. Th ese data may lead to the conclusion that contact of the urban population with the villages through excursions, hiking, visits to rural families and many other activities that bring this population into contact with the rural area, allows immunologically incompetent population contact with Coxiella spores. Th e fact is close contact with the reservoir animals of this disease is not necessary-it is enough to breathe air with spores that carry this causative agent. Th us, in the area of the city of Banja Luka, there were several outbreaks of this disease in the period before 2010.
A statistically signifi cantly higher number of men contracted these three diseases than women, which traditionally described these zoonoses as "male diseases", mostly because men are more likely to engage in livestock, agriculture and other activities in the nature and with animals.
In terms of age groups, the largest number of patients falls in the range of 20-64 year olds, which leads us to the conclusion that these diseases aff ected the working population the most, namely those who come into contact with animals and their products through agriculture, livestock, etc.
Based on the results of the analysis, the largest number of patients was registered in the region of Banja Luka, which is also the most populated area in the Republic of Srpska. Hospital and diagnostic capacities are the largest in this region, so the increased reporting of these diseases can be related to that fact.
A signifi cantly higher percentage of reported cases of brucellosis, leptospirosis and Q fever was reported based on clinical criteria. Th is is certainly something that makes a weak point of the system of control over anthropozoonoses and represents a link that requires signifi cant improvements. Adequate and precise diagnostics are necessary to confi rm the case of any infectious disease, which makes the system of supervision and control of these diseases stronger and more reliable. Another weakness of the system is the absence of a unique electronic system for reporting of infectious diseases-health institutions are not connected into IT network which would obtain a fl ow of information on reports of infectious diseases, outbreaks and all other data that is necessary to analyze the situation or other unexpected health events. For this reason, it is impossible to get all the information about each patient, because most of the reporting and data sharing is paper based or via e-mail at our request. Th at is why establishing a network of health institutions with the Public Health Insti-tute of the Republic of Srpska would be one of the main factors of the improvement and strengthening of the infectious disease surveillance system.

CONCLUSIONS
Th e incidence of anthropozoonoses in the Republic of Srpska in the 2015-2020 period was highest in 2017, and the lowest in 2020. Th e three most commonly reported diseases were brucellosis, leptospirosis, and Q fever. Th e reported cases of these three diseases were more common among urban population, the patients being mostly male and a majority of them belonged to the working population. Th e largest number of cases has been reported as probable without microbiological confi rmation, which is stated in the case defi nition for each disease. It is necessary to improve the reporting of zoonoses in the Republic of Srpska in terms of case confi rmation, as well as raising awareness of the frequency and importance of anthropozoonoses of all physicians, especially those who fi rst treat patients.

АCKNOWLEDGEMENT
Th is study is independent research of the above mentioned authors and is not part of any fi nancially supported project.