Epidemiologic Characteristics of Domestic Patients with Hemorrhagic Fever with Renal Syndrome in Taiwan: A 19-Year Retrospective Study

Background: Hemorrhagic fever with renal syndrome (HFRS) is an illness caused by hantaviruses. Numerous factors modify the risk of hantavirus transmission. This study explored the epidemiological characteristics, differences, and trends in terms of gender, age, season, and living areas of those diagnosed with domestically acquired HFRS in Taiwan from 2001 to 2019. Methods: We examined publicly available annual summary data on the domestic cases with HFRS from 2001 to 2019; these data were obtained from the web database of Taiwan’s Centers for Disease Control (CDC). Results: This study analyzed 21 domestic cases with HFRS from Taiwan’s CDC databases. In this study of the cases of HFRS in Taiwan, a gradual increase in the cases of those aged ≥40 years acquiring the disease was noted, and a distinct pattern of seasonal variation (spring) was observed. Furthermore, more men had domestically acquired HFRS, and living in Taipei metropolitan area (6 cases [28.6%]) and the rural areas (Gao-Ping region, 9 cases [42.9%]) was identified as a potential risk factor. This study represents the first report of confirmed cases of domestically acquired HFRS from surveillance data from Taiwan’s CDC, 2001–2019. Conclusion: This study highlights the importance of longitudinal studies covering a wide geographical area, particularly for highly fluctuating pathogens, to understanding the implications of the transmission of zoonotic diseases in human populations. Important data were identified to inform future surveillance and research efforts in Taiwan.


Introduction
Due to factors such as frequent international exchanges as well as a global climate and living environment changes, different emerging and re-emerging diseases are spreading rapidly. Incidence rates are increasing, particularly for vector-borne diseases. Hantavirus syndrome is a disease caused by The incubation period of HFRS is approximately 12 to 16 days; however, this can vary from 5 to 42 days. The typical initial symptoms are a sudden fever lasting 3 to 8 days, and this may by followed by conjunctival hyperemia, weakness, backache, headache, abdominal pain, anorexia, vomiting, and facial flushing [13]. Hemorrhagic symptoms appear on the third to sixth day; later symptoms may include proteinuria, hypotension, shock, and mild kidney diseases. Over the course of the disease, acute kidney failure may arise and lasts several weeks, with a corresponding fatality rate of 5% to 15%. The course of HFRS is divided into five stages: febrile, hypotensive, oliguric, polyuric, and convalescent. Stages may occasionally overlap.
Taiwan is an island nation; therefore, infectious diseases are mostly transmitted through seaports and airports, with rodent-borne viruses being one transmission source. In 1995, Taiwan discovered its first HFRS case that originated from China. Cases since 2001 have been regarded as sporadic, with massive outbreaks rarely seen. Additionally, Taiwan's Centers for Disease Control (CDC) established the Taiwan National Infectious Disease Statistics System (TNIDSS) in 2001 [14], providing the public, academics, and those in the media with access to the latest domestic epidemic updates related to HFRS. Accordingly, this study used the system to investigate the epidemiological characteristics, differences, and trends in terms of sex, age, season, and living areas related to domestic HFRS cases in Taiwan from 2001 to 2019.

Ethical Policy
Studies using information that is freely available in the public domain and that analyze open data sets where data have been properly anonymized do not require ethical approval. The authors are sure about the added value of this study that conforms with the public use of the government reports.

Definition of Confirmed Cases
The central competent authority in Taiwan classified HFRS as a Category 3 communicable disease, as listed in the Communicable Control Act in 2001. It was reclassified as a Category 2 disease in 2004. The following procedure should be followed for communicable diseases listed in this Act's documentation. Whenever infection with a disease occurs in an individual, doctors or medical institutions should report this to health authorities within legal time limits. Appropriate treatment should be administered, and isolation measures can be applied in accordance with the Act's stipulations. The listed communicable diseases usually have a rapid transmission speed as well as high hazard severity and fatality rates. Therefore, when the following conditions are observed or suspected during inspection, doctors should report information to relevant health authorities within 24 h, as stipulated in the regulations below: Acute fever along with varying severity levels of hemorrhagic diseases and abnormal renal function, and having two or more of the following symptoms: headache, muscle soreness or backache, nausea or vomiting, diarrhea, and blurred vision; having a relevant travel history; having contact with rodents or their excreta and secretion; having probable or confirmed contact with contaminants or a history of such contact; having conducted experiments on hantaviruses or relevant specimens. Furthermore, patients having undergone inspections in hospitals and received positive results from the following analyses: (1) molecular biology analysis of clinical specimens, (2) hantavirus-specific antibodies IgM in acute-phase serum, (3) antivirus-specific antibodies IgM or IgG (either one) having seroconversion or a 4-fold (or higher) increase, (4) disease confirmed by immunohistochemical analysis from a biopsy. Reports from Taiwan's CDC have indicated that a confirmation of an HFRS case should be made in accordance with the receipt of positive results in any of inspections (1), (3), or (4).

Data Source
This study employed TNIDSS, a public database established by Taiwan's CDC [14]. The public TNIDSS database includes data on five categories of communicable diseases listed in the Communicable Control Act literature. The website is updated with the latest epidemic information early each morning, providing the latest charts (e.g., run charts), reports (in Excel format), distributions (in county, city, or township), and encyclopedias of different disease types. This allows for epidemic information to become more transparent and up to date. To ensure information security and privacy, the public database includes only secondary data (i.e., notification date, onset date, confirmation date, and the number of confirmed domestic and imported cases imported of HFRS) without case details. The database does not contain the medical history of patients, their signs and symptoms, or the results of laboratory data.

Data Analysis
This is a retrospective historical study of all domestic HFRS cases since 2001. We confirmed the number of people diagnosed as having HFRS from 2001 to 2010 and from 2011 to September, 2019 and examined the distribution of their epidemiological characteristics (sex, age, time of diagnosis, living area), differences, and results. Next, we emphasized sex, age, time of diagnosis, living area change, trends, and related results in our analysis of cases of HFRS from 2001 to 2006, from 2007 to 2012, and from 2013 to 2019. Descriptive data are shown as mean and summary, where appropriate. Categorical variables were compared using the chi-square test. All statistical analyses were performed using SPSS (IBM SPSS version 21; Asia Analytics Taiwan Ltd., Taipei, Taiwan). All statistical tests were 2-sided with an α value of 0.05. p values of < 0.05 were considered to represent statistical significance.

Study Population
During the study period, 21 adults (Table 1) had confirmed diseases, 18 (85.7%) of which were men. Among them, 20 (95.2%) patients were 20-64 years old and 1 (4.8%) was >65 years old. The patients (10 in spring, 5 in summer, and 6 in winter) were examined and screened for HFRS. The characteristics of patients with confirmed cases (including habitual residence) are shown in Table 2.    Figure  1).   HFRS infections were identified throughout the year except during fall, with the highest incidence in spring followed by winter ( Figure 3). HFRS infections were identified in all residential regions in Taiwan (highest incidence in the Taipei and Gao-Ping areas; Figure 4 and Figure 5). HFRS infections were identified throughout the year except during fall, with the highest incidence in spring followed by winter ( Figure 3). HFRS infections were identified throughout the year except during fall, with the highest incidence in spring followed by winter ( Figure 3). HFRS infections were identified in all residential regions in Taiwan (highest incidence in the Taipei and Gao-Ping areas; Figure 4 and Figure 5).

Discussion
Zoonoses are diseases that can spread from animals to humans and from humans to animals [15]. Pathogens can be transmitted directly between humans and animals or carried by vectors to enter another organism [16]. Zoonoses can be categorized into viruses, bacteria, molds, parasitic worms, and protozoa; they can be transmitted though contact, inhalation, or consuming foods and drinks that contain pathogens [17]. Transmission of zoonoses can be a threat to human health. HFRS is a zoonotic disease transmitted by rodent hosts [18]. From 2001 to the time of writing, 21 confirmed domestic cases of HFRS (Table 1) and 1 imported (from China) confirmed case (December, 2007) have been reported. In the past 10 years, 0-4 cases were reported yearly, which can be considered to be sporadic, especially in terms of the patients' occupation; accordingly, the susceptible population cannot be determined. In general, the number of cases depends on rodent distribution in the surrounding area and the likelihood of contacting hantaviruses directly or indirectly. Based on the prevalence in Taiwan literature [19][20][21], various rodent species serve as potential hosts of hantaviruses, including Rattus flavipectus, Rattus losea, Rattus norvegicus, Rattus tanezumi, Bandicota indica, Mus musculus, and Apodemus agrarius of the order Rodentia, along with Suncus murinus of the order Insectivora. Of these eight species, Suncus murinus, Rattus norvegicus, Mus musculus, and Rattus tanezumi are easily found in environments (residences) where human activities take place. According to an investigation on rodent-borne diseases within the five metropolises in Taiwan, the dominant rodent species in markets and night markets are Suncus murinus (52.9%) and Rattus norvegicus (45.4%). The larger the rodents are, the more likely their HFRS antibodies being tested positive becomes. Rattus norvegicus rodents possess the highest HFRS antibody sensitivity (20.1%); those captured in Taipei City had the highest sensitivity (23.9%). Seoul serotypes (100%) are the main HFRS antibodies. Through molecular biology analysis, it was revealed that the hantavirus carrier rates of Rattus norvegicus and Suncus murinus were 80.0% and 40.0%, respectively [21]. Suncus murinus (the house shrew) as a hantavirus carrier, the soricid-borne hantavirus Thottapalayam virus (TPMV), has not been proven so far to be pathogenic for humans [22]. This study suggested that the Seoul virus is the main pathogenic hantavirus prevalent in Taiwan. No statistical differences were found between rodent species and their geographical distribution. However, people unfamiliar with rodent-borne diseases are less willing to participate in deratting, which increases difficulty of prevention work. The public health interventions are currently that the government promotes autonomous environmental management and biological control in Taiwan (for example: Milvus migrans). Large-scale rat prevention measures can function as urgent precautions against outbreaks [23]. Market management teams should include waste removal, setting up rat bait and traps, and clearing out garbage shortly

Discussion
Zoonoses are diseases that can spread from animals to humans and from humans to animals [15]. Pathogens can be transmitted directly between humans and animals or carried by vectors to enter another organism [16]. Zoonoses can be categorized into viruses, bacteria, molds, parasitic worms, and protozoa; they can be transmitted though contact, inhalation, or consuming foods and drinks that contain pathogens [17]. Transmission of zoonoses can be a threat to human health. HFRS is a zoonotic disease transmitted by rodent hosts [18]. From 2001 to the time of writing, 21 confirmed domestic cases of HFRS (Table 1) and 1 imported (from China) confirmed case (December, 2007) have been reported. In the past 10 years, 0-4 cases were reported yearly, which can be considered to be sporadic, especially in terms of the patients' occupation; accordingly, the susceptible population cannot be determined. In general, the number of cases depends on rodent distribution in the surrounding area and the likelihood of contacting hantaviruses directly or indirectly. Based on the prevalence in Taiwan literature [19][20][21], various rodent species serve as potential hosts of hantaviruses, including Rattus flavipectus, Rattus losea, Rattus norvegicus, Rattus tanezumi, Bandicota indica, Mus musculus, and Apodemus agrarius of the order Rodentia, along with Suncus murinus of the order Insectivora. Of these eight species, Suncus murinus, Rattus norvegicus, Mus musculus, and Rattus tanezumi are easily found in environments (residences) where human activities take place. According to an investigation on rodent-borne diseases within the five metropolises in Taiwan, the dominant rodent species in markets and night markets are Suncus murinus (52.9%) and Rattus norvegicus (45.4%). The larger the rodents are, the more likely their HFRS antibodies being tested positive becomes. Rattus norvegicus rodents possess the highest HFRS antibody sensitivity (20.1%); those captured in Taipei City had the highest sensitivity (23.9%). Seoul serotypes (100%) are the main HFRS antibodies. Through molecular biology analysis, it was revealed that the hantavirus carrier rates of Rattus norvegicus and Suncus murinus were 80.0% and 40.0%, respectively [21]. Suncus murinus (the house shrew) as a hantavirus carrier, the soricid-borne hantavirus Thottapalayam virus (TPMV), has not been proven so far to be pathogenic for humans [22]. This study suggested that the Seoul virus is the main pathogenic hantavirus prevalent in Taiwan. No statistical differences were found between rodent species and their geographical distribution. However, people unfamiliar with rodent-borne diseases are less willing to participate in deratting, which increases difficulty of prevention work. The public health interventions are currently that the government promotes autonomous environmental management and biological control in Taiwan (for example: Milvus migrans). Large-scale rat prevention measures can function as urgent precautions against outbreaks [23]. Market management teams should include waste removal, setting up rat bait and traps, and clearing out garbage shortly after business hours as stallholder contract stipulations; vendors should seal food and gutters should be covered with lids of appropriate apertures to lower rodent density and reduce the likelihood of human-rodent contact. Public health education should also be emphasized to help people understand the importance of rat prevention, learn more about rodent-related diseases, and maintain high sanitation levels in their surroundings. The public should ensure no rat infestation, no rat dwelling, and no rat feeding to fundamentally prevent rodent density from increasing and thus ensure public health and safety [24].
HFRS is a highly infectious viral disease. Humans can be infected by inhaling droplets containing rodents' urine, saliva, and droppings. Fleas, ticks, and mosquitos do not transmit hantaviruses. Domestic HFRS cases are reported in Taiwan. With the increase of international travel, import-related threats remain, particularly from neighboring regions where HFRS is prevalent, including China and Southeast Asian countries. Since 2001, only 1 imported case has been reported [14]. To prevent imported infectious diseases from spreading and affecting people's health, epidemic prevention inspectors stand guard at all international seaports and airports on public holidays and remind outbound travelers to cooperate with fever inspection personnel when returning. Furthermore, travelers with fever, cough, vomiting, diarrhea, rash, and jaundice should report to inspectors. Foreign travelers who have symptoms within 15 days after returning home should seek medical advice immediately; travel and contact history should be provided for diagnosis references so that diagnosis can be confirmed as soon as possible, treatments can be conducted in a timely manner, and epidemics can be avoided.
A previous study indicated that HFRS infections are most often diagnosed in those of the male sex. It is suggested that this is due to increased exposure as a result of men's occupational and recreational activities [25]. According to data on domestic HFRS cases over the years, more men work as butchers, fisherpersons, fishmongers, and in the industries of stock farming, aquaculture, and agriculture. Among these occupations, recognition and notification of symptoms are well established. Fewer cases of female infections have been identified, which may be due to more women working in indoor environments; similar results have been identified in international studies [26,27]. No statistically significant differences were noted in terms of sex, which accords with the findings of international foreign studies [28,29]. Cases of male exposure outnumbered those of female exposure from 2013 to 2019. During this time, the male incidence rate was 80% (8/10), which also corresponds with the results of international studies [30,31].
A related study confirmed a high lifetime risk for both women and men for acquiring HFRS infections in endemic areas [30]. The present study demonstrated that no significant differences were observed in a comparison of HFRS cases over the years in terms of age, only that number of HFRS cases in patients aged 40 to 49 years increased over the past 6 years. Furthermore, HFRS cases in patients aged 50 to 65 years reached a peak during 2013-2019, indicating results similar to those of international studies [30,[32][33][34].
Climate could also influence the population abundance of host rodent and hantavirus transmission dynamics. Temperature might also affect reproduction and survival rates of small rodents as well as the length of time that the virus remains infectious in the environment [35]. No statistical differences were observed when domestic HFRS cases were compared in terms of seasons. More cases were reported in spring and winter than in other seasons, and the largest number of cases identified was during 2001-2006 and 2013-2019, which corresponds with results of related international studies [32,33].
Furthermore, in accordance with previous findings, a strong relationship was observed between living in rural, stock farming areas or close to farms and being at risk of hantavirus infection [36,37]. Risk factors such as living in close contact with rodents, agriculture, and stock farming are more likely in rural areas [37,38]. Although most HFRS cases have been reported in rural settings and in Europe or Asia, there are important exceptions. In fact, the Seoul serotype has been reported mainly during urban, rather than rural outbreaks [39]. No significant differences were observed in a comparison of domestic HFRS cases in terms of living area, although more cases were reported in the Taipei metropolitan area and the rural Gao-Ping area than in other regions; furthermore, the cases reported during 2013 to 2019 account for 48% of all HFRS cases, the highest proportion over the years of monitoring. This is similar to the result in international literature: metropolitan areas and rural agricultural or stock farming areas have a higher risk of having HFRS outbreaks [30,34,40,41]. Because these counties are distributed throughout Taiwan, we can assume that infected individuals are found throughout the island nation, which suggests that hantavirus diseases could be an emerging health problem.
Evidence is required to determine the next actions and decisions to ensure the execution of appropriate public health policy [42]. For example, in this study, researchers observed and recorded HFRS relevant data on the TNIDSS public database and selected credible information from large medical databases by employing epidemiological and statistical methods. The researchers applied all acquired medical evidence on public health services. As a result, it is expected that the outbreaks of acute infectious diseases (e.g., HFRS) will be minimized or eliminated. Through the enactment of preventive healthcare standards based on public health science, high-quality health risk assessments were provided to reduce unnecessary medical resource expenditure. Furthermore, the core value of public health policy is disease prevention. According to the natural history of a disease, the preventive health care strategy is divided into three levels (primary, secondary, and tertiary prevention) and five stages. The researchers of this study conducted primary prevention, explored epidemiological characteristics and trends, assessed exposure risk, and attempted to modify the lifestyles of the susceptible population to enhance public health.
The concept of "one health" relates to the relationship between the health of humans and animals [43]. In terms of HFRS, if rodents carry pathogens or are infected with hantavirus diseases, humans may also be infected. Furthermore, with environment changes and deterioration caused by human activities, the growth and decline of species, or their health conditions, may also affect human society. Each organism has a role in the interconnected Earth; once a link is broken, it affects the ecosystem and human survival. These visionary public health concepts can become references for governments and public health experts worldwide for enacting health policies or distributing health care resources.
Three limitations of this study should be noted. First, the Taiwan's CDC data only provide the basic epidemic data of patients with HFRS and not any clinical data, and did not provide any detailed experimental procedures. However, this study is convinced of the authenticity of the positive confirmed cases announced by Taiwan's CDC. However, the researchers could not compare clinical data to determine differences or trends related to HFRS symptoms. Second, public databases do not offer the genotypes of hantavirus virus strains; therefore, the virus strain that is currently prevalent or phylogenetic differences between domestic and imported virus strains could not be determined. Third, public health policy changes are not being proposed based on the results from this study. However, this study is unique, owing to the abundant data the government network platform provides (even in the early construction stage). Public databases have been properly maintained over the years; this facilitates research and increases the value of the data. Related institutions also conduct monitoring related to disease types or symptoms and lead to further follow-up studies.

Conclusions
This is the first report in Taiwan concerning the epidemiological characteristics and trends of HFRS cases from 2001 to 2019. In this study on the incidence of HFRS in Taiwan, a gradual increase in incidence was noted with patient age and a distinct pattern of seasonal variation was determined. Furthermore, more men were diagnosed as having domestically acquired HFRS than women, and living in the Taipei metropolitan area or rural areas was suggested as a potential risk factor. Furthermore, it is highly recommended to extend HFRS vaccination to people older than 50 years to better protect them against the disease. This information will be of value to policymakers and clinical experts for direct prevention and control activities related to hantaviruses that cause the most severe illnesses and have the greatest burden on the Taiwanese health care system. This study highlights the importance of longitudinal studies encompassing wide geographical areas, particularly for highly fluctuating pathogens and their reservoirs, to understanding the implications of the transmission of zoonotic diseases in human populations. Crucial data were identified to inform future surveillance and research efforts in Taiwan.