Orthohantaviruses are a group of zoonotic RNA viruses belonging to the family Hantaviridae of order Bunyavirales, which are the etiologic agents of hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans, depending on the virus species involved.1,2 At present, over 30 Orthohantaviruses species have been identified worldwide, 21 of which are pathogenic when transmitted from their rodent reservoirs to humans. Each Orthohantaviruses is predominantly related to a specific rodent carrier endemic to a given geographic area. Orthohantaviruses have co-evoluted with their dominant rodent hosts.3 The outbreaks and endemic occurrence of these zoonoses are closely related to the corresponding Orthohantaviruses dynamics, which are affected by the distribution and population density of the rodent species. Moreover, rodents are the most numerous and diverse order of small-mammal reservoirs in the world, which are extensively related to human rodent-borne disease and animal diseases; thus, becoming a threat to human and animal health.4 Thus, sufficient information on the distributional changes in rodent species is essential to develop appropriate surveillance and intervention strategies.
Because Orthohantaviruses are naturally rodent-borne viruses, Orthohantaviruses prevalence in human beings is strongly correlated with rodent ecology, dynamic changes in the species composition of rodent communities, and habitat composition.5 Thus, the course of Orthohantaviruses infection in both human and rodent reservoirs highly depends on the variability of rodent density due to environmental change and certain periodic characteristics over time. Voutilainen et al. demonstrated that populations of bank vole, the rodent host of Puumala hantavirus (PUUV), underwent a 3-year density cycle in northern Europe, and high abundances of PUUV-infected bank voles were related to HFRS epidemics in humans in these regions.6 In temperate Europe, where a minimum density of bank voles can effectively spread the hantavirus, the bank vole population showed modest seasonal variations, which led to sporadic PUUV epidemics.7
In China, HFRS is mainly caused by two types of Orthohantaviruses, Hantaan virus (HTNV) and Seoul virus (SEOV), each of which has co-evolved with a distinct rodent host. HTNV is carried by striped field mice (Apodemus agrarius), whereas SEOV is associated with Brown Norway rats (Rattus norvegicus) and causes a less severe form of HFRS.8,9 HFRS is common in China, cases have accounted for 90% of the total cases worldwide with more than 150,000 HFRS patients each year.10 Hubei Province, located in central-south China, was the most epidemic area for HFRS cases in China in the early 1980s,11 and epidemic outbreaks of HFRS infection have been observed approximately every decade since the first local occurrence of HFRS in 1957. The incidence and mortality of HFRS have declined after the peak year of 1983 and with sporadic HFRS cases since 2010.12 As a typical zoonotic infectious disease, the incidence and extent of HFRS are closely related to the presence and transmission of Orthohantaviruses, which depends on the distribution and infection of its animal hosts.8,12 Given this, our study reviewed the Orthohantaviruses infection in rodent reservoirs and humans in Hubei Province over a time span of 27 years (1984 to 2010) to analyze the relationship between the human cases of HFRS and anti-hantavirus antibody prevalence in the reservoirs as well as to identify possible reasons contributing to the decrease of the disease. Our results could provide a certain basis for predicting the epidemic characteristics of future rodent-borne diseases and developing effective prevention and control strategies for HFRS/similar virus disease, which may also be beneficial for pathogen carrying in both veterinary and human medicine.
Materials and Methods
Selection of monitoring site
The study area, Hubei Province, is located in central-south China (Figure 1). Hubei Province is divided geographically into 5 areas (the northwest mountains, southwest mountains, central hills, Jianghan plain, and northeast and southeast low hills) and administratively into 17 units (12 cities and 3 county-level cities directly managed by the provincial government, 1 autonomous prefecture, 1 forested region, among which include 21 county-level cities and 39 counties).12
Map of Hubei Province (China) and location of study sites.
Citation: American Journal of Veterinary Research 84, 8; 10.2460/ajvr.22.12.0215
According to the national unified classification standard of HFRS surveillance, the epidemic intensity of counties and cities was divided into high prevalence area (incidence >30/100,000), medium prevalence area (incidence 5 to 30/100,000), low prevalence area (incidence <5/100,000), and non-epidemic area (incidence 0). We selected eight monitoring sites for retrospective analysis, including Lichuan County-City (Enshi autonomous prefecture, southwest mountains, the medium epidemic intensity of HFRS), Baokang County (Xiangyang City, northwest mountains, low epidemic intensity of HFRS), Nanzhang County (Xiangyang City, northwest mountains and central hills, low epidemic intensity of HFRS), Tianmen City (Jianghan plain, high epidemic intensity of HFRS), Jiangxia District (Wuhan City, Jianghan plain, high epidemic intensity of HFRS), Xianning County-City (Xianning City, southeast low hills and Jianghan plain, high epidemic intensity of HFRS), Tongcheng County (Xianning City, southeast low hills, high epidemic intensity of HFRS), and Qichun County (Huanggang City, Jianghan plain, high epidemic intensity of HFRS).
Human sera and data collection
HFRS cases were recruited from 12 districts in Hubei Province from 1984 to 2010, and were diagnosed during their hospitalization according to standard clinical criteria: age ≥14 years, febrile time ≤4 days, typical HFRS symptoms and signs (eg, fever, proteinuria, and hematuria), and potential exposure history to wild rodents or other HFRS patients.13 Population data were based on the 2,000 population censuses for Hubei Province. Serologic identification was done by indirect IgM/IgG enzyme-linked immunosorbent assays (ELISAs) performed at the laboratory of the Hubei Provincial Center for Disease Control and Prevention (HBCDC) to confirm the clinical diagnosis. The clinical data were registered, including age, febrile time, typical HFRS symptoms and signs, and potential exposure history to wild rodents or other HFRS patients. All patients’ clinical data and blood samples were collected and stored in HBCDC. The serum samples from the healthy population in the endemic area were collected as a routine to investigate inapparent infection during the period. The blood specimens were indeed selected from those collected and archived multiple times per year throughout the 27-year study period, especially during the epidemic period. The results were recorded, reported, and summarized annually by HBCDC. For example, the screening number in 1989 was 8,000 (inapparent infection rate: 4.38%), and 1,477 (inapparent infection rate: 6.57%) in 2000. We summarized the data as a 5-year interval. The study participants were 10∼60-year-old residents in Hubei Province without HFRS history, who volunteered to offer a 5-mL blood sample for serological testing. Blood samples were centrifuged at 1100 X g for 15 minutes to separate the serum and then refrigerated for further processing and analysis.
Signed informed consent was obtained from all participants. The study was approved by the Research Ethics Committee of Wuhan University.
Rodents sample and data collection
We monitored rodent populations by trapping and screening antibodies in Hubei Province from 1984 to 2010, which were performed by HBCDC as routine work during this time. In the spring and autumn of April to May and September to October every year, the night trapping method was adopted at each monitoring outpost, and representative natural villages with previous HFRS cases were selected. Rat traps were distributed in residential areas and wild areas outside the natural villages within a 500-m radius. In residential districts, traps for rats were placed in areas with poor sanitation or disadvantaged living conditions, such as rubbish stations, construction sites, farmers’ markets, and mess halls. While in the neighborhood, traps were placed in the kitchen, warehouse, and garden. One trap was placed in every 15 m2 of the room. For field investigations, traps were placed along each side of canals, rivers, ridges, and roads, where rats may inhabit. Traps were set before dark and retrieved the next morning. Trapped animals were identified to species according to the previous criteria.14 After giving each one a unique number, the following information was collected: date and location of trapping, species, and sex. Sera and lung tissues were collected and stored immediately at −196 °C and then transported to the laboratory for processing. Rodent tissues were screened for Orthohantaviruses antigen using indirect immunofluorescence assay with mixed antigens of HTNV and SEOV. The procedures of IFA were conducted as previously described.15 The lung tissues of rodents were prepared for frozen sections. The primary antibody was diluted 1:200 in PBS for analysis. The secondary antibody was goat anti-rabbit IgG-FITC diluted 1:200 for testing. Scattered, granular fluorescence in the cytoplasm was considered a positive reaction.
Serological screening
Human serum samples were tested for the presence of IgG against Orthohantaviruses using IFA performed in our laboratory. Patient sera were diluted 1:50 in PBS and applied to slides precoated with mixed viral antigens (HTNV 76-118 strain/SEOV R22 strain, respectively). Slides were incubated for 1 h at 37 °C, and washed for 5 min in PBS 3 times and dried. Goat anti-human IgG fluorescein isothiocyanate (FITC) conjugate (A21050, 1:100, Abbkine) was applied to the slides, which were incubated for 1 h at 37 °C, washed 3 times, and dried. Each slide was examined for green scattered, granular fluorescence independently by 2 researchers using a microscope (Nikon TE2000).
Statistical analysis
Statistical analysis was performed using SPSS 17.0 software. The rodent density, virus carried rate, species of host animals, and human inapparent infection rate of HFRS were calculated, and their correlation was analyzed by Pearson correlation analysis. Statistical significance was set at P values <0.05. We calculated the species diversity of rodents using the Shannon Diversity Index (H'), following the Shannon method, where pi is the proportion of species I, and n is the number of species.
where H' is the Shannon-Weiner diversity index, ln (S) is the natural logarithm of species richness. And the equation used to calculate Simpson’s index is D = Σ (pi)2.
Results
Incidence and human asymptomatic infection rate of HFRS
The 5-year average annual HFRS incidence (1984 to 1990, 1991 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2010) and human asymptomatic infection are calculated and plotted to observe epidemic changes of HFRS in Hubei Province from 1984 to 2010 (Figure 2). From 1984 to 2010, 61,482 HFRS cases occurred in Hubei Province. We found that the annual average incidence was 6.42/100000 from 1984 to 1990, which was the highest recorded incidence in 27 years. The annual incidence of the disease decreased in the following four periods. As of 2000, the annual incidence of HFRS was <1/100,000.
Hemorrhagic fever with renal syndrome (HFRS) incidence and rate of latent infection in healthy people during 1986–2010.
Citation: American Journal of Veterinary Research 84, 8; 10.2460/ajvr.22.12.0215
Detection of seroprevalence in healthy people was conducted in Hubei Province from 1984 to 2010. A total of 43,753 people were tested, and 1,550 (3.54%) people were confirmed positive. The positive rate of healthy people was 4.67% from 1996 to 2000 (Table 1), which was the highest in the 5 periods. No apparent correlation existed between HFRS incidence and the human inapparent infection rate of HFRS (r = 0.7, P = .188).
Inapparent infection rate of Hantavirus in healthy people during 1984–2010, Hubei.
| Year | No. of human sample | No. positive | Tnapparent infection rate (%) |
|---|---|---|---|
| 1984–1990 | 16,400 | 697 | 4.25 |
| 1991–1995 | 10,382 | 286 | 2.75 |
| 1996–2000 | 6,838 | 319 | 4.67 |
| 2001–2005 | 9,519 | 235 | 2.47 |
| 2006–2010 | 614 | 13 | 2.12 |
| Total | 43,753 | 1,550 | 3.54 |
Monitoring of rodent
Rodent density—The rodent density, as estimated by capture frequency, for 27 years was detected (Figure 3). A total of 10,314 rodents were captured from trapping sites in Hubei Province between 1984 and 2010. The annual average rodent density was 4.14% and ranged from 2.14 to 16.65%. The rodent density in the 1990s declined sharply compared with its level in the 1980s. A continuous downtrend could be seen in the following time periods and the rodent density was significantly associated with the population HFRS incidence (r = 0.910, P = .032).
Rodent density in different time periods in Hubei Province.
Citation: American Journal of Veterinary Research 84, 8; 10.2460/ajvr.22.12.0215
Orthohantaviruses infection in rodents—Lung tissues were screened to detect Orthohantaviruses antigens by IFA, and 656 (6.36%) samples were identified as positive. We summarized the number of trapped and orthohantaviruses-antigen positive rodents during each period (Table 2). The virus carrier rates varied among different sampling periods, but the difference in rates were not clear from 1986 to 2005. We then observed a sharp decrease in seroprevalence thereafter.
Detection of Hantavirus in rodents captured at different periods in Hubei Province.
| Year | No. of traps | No. of captured | No. of positive samples | Virus carried rate (%) |
|---|---|---|---|---|
| 1984–1990 | 12,835 | 2,137 | 156 | 7.3 |
| 1991–1995 | 45,380 | 2,151 | 126 | 5.86 |
| 1996–2000 | 55,690 | 2,378 | 149 | 6.27 |
| 2001–2005 | 95,290 | 2,792 | 200 | 7.16 |
| 2006–2010 | 40,000 | 856 | 25 | 2.92 |
| Total | 249,195 | 10,314 | 656 | 6.36 |
The composition of Orthohantaviruses reservoir—We contrasted the composition of the Orthohantaviruses reservoir in 2000–2010 with that in the 1980s (Table 3). We found that Apodemus agrarius and Rattus norvegicus were dominant species in the 1980s that occupied 68.6% of the captured animals. Other species included Rattus losea, Mus musculus, Rattus flavipectus, and Suneus murinus (10.2%, 8.3%, 6.8%, and 2.9%, respectively). From 2000 to 2010, Apodemus agrarius and Rattus norvegicus remained the dominant species, which comprised 88.4% of the captured animals, and others were Mus musculus, Cricetulus triton, Rattus flavipectus, Suneus murinus, and Siberian weasel (6.2%, 1.1%, 0.8%, 0.6%, and 0.6%, respectively). Furthermore, the investigation showed that the Orthohantaviruses rate in all host animals has declined dramatically between 2000 and 2010, compared with the 1980s, the rate declined from 11.25% to 5.11% for Apodemus agrarius, from 8.06% to 5.95% for Rattus norvegicus, and the rates were 0 for others in 2000 to 2011.
The composition of the Hantavirus reservoir captured in Hubei Province and virus carrier rate (%) in different time periods.
| 2000∼2011 | 1984∼1987 | |||||
|---|---|---|---|---|---|---|
| Species name (common name) | Number of captured | Constituent ratio (%) | Positive rate (%) | Number of captured | Constituent ratio (%) | Positive rate (%) |
| Apodemus agrarius | 176 | 22.3 | 5.11 | 443 | 23.4 | 11.25 |
| Rattus norvegicus (Brown Norway rats) | 538 | 68.1 | 5.95 | 855 | 45.2 | 8.06 |
| Mus musculus | 49 | 6.2 | 0 | 157 | 8.3 | 13.1 |
| Suneus murinus (musk shrew) | 5 | 0.6 | 0 | 54 | 2.9 | 2.17 |
| Rattus flavipectus | 6 | 0.8 | 0 | 129 | 6.8 | 11.35 |
| Cricetulus triton | 9 | 1.1 | 0 | 0 | 0 | 0 |
| Siberian Weasel (yellow wease) | 5 | 0.6 | 0 | 0 | 0 | 0 |
| Rattus losea (Lesser Rice-field Rat) | 0 | 0 | 0 | 193 | 10.2 | 4.73 |
| Greater white-toothed shrew | 0 | 0 | 0 | 2 | 0.1 | 11.1 |
| Others | 2 | 0.3 | 0 | 59 | 3.1 | 10 |
Ecological analyses showed higher diversity in rodents in the 1980s, with a Shannon-Winner index (H) of 1.5382 distributed even with the Evenness index (E) as 0.668032, and the equation with Simpson’s index (D) as 0.28278. Subsequently, a lower level of species richness was found between 2000 and 2010 (H' = 0.9357, E = 0.406369, and D = 0.5176).
Discussion
Distinct Orthohantaviruses are naturally maintained in rodents or insectivorous species, and the transmission to humans occurs through inhalation, aerosolized excreta, or directly aggressive interaction. Furthermore, the distributions of the Orthohantaviruses epidemic area have obvious geographical features. The geographical distribution and migration of host animals determine the type and characteristics of Orthohantaviruses natural foci. Monitoring the density and virus-carrying rate of host animals could provide important information for understanding the prevalence of Orthohantaviruses in human beings.16
This study aimed to characterize the incidence of HFRS and latent infection, as well as the Orthohantaviruses infection in rodent reservoirs, through the use of the 27-year record in Hubei Province, which would further provide a better understanding of the epidemiology of Orthohantaviruses in Hubei area. Human Orthohantaviruses epidemics have often been explained by rodent host abundance.17 Some scholars studied the relationship between the dynamic density changes of wild rodents such as Apodemus agrarius and Trhamster and the incidence of HFRS in hilly areas of central and southern Shandong Province and found that the single species density and the total density of wild rodents were significantly correlated with the incidence of HFRS in the population.18 European scientists also found that the prevalence of PUUV is clearly consistent with the increase in the population density of its host voles.6,19 The explanation is based on the assumption that higher host densities increase both the number of infected individuals and the infection prevalence, as is expected with density-dependent pathogen transmission. In our study, the density of rats in Hubei Province was the highest during the HFRS pandemic period of the 1980s, followed by a downward trend. This phenomenon further confirmed that the HFRS incidence is significantly associated with rodent density (0.910; P < .05) in addition to the seroprevalence in rodents. This suggests that control of host density within the context of population activity is important in reducing the spread of HFRS.
The results also showed that there was no apparent correlation between the host density and rodent seropositivity. From 1985 to 2005, the host-virus carried rate fluctuated slightly between 5.86% and 7.3%, with an average virus carried rate of 6.65%. After 2005, the virus carried rate decreased to 2.92%, a decrease of 2.27 times. Olsson et al. concluded that PUUV transmission among rodents is independent of the bank vole density.20,21 Another study also showed that human orthohantaviruses epidemics could be predicted solely by the population dynamics of its carrier species.16 Studies on non-cyclic bank vole populations in temperate areas have demonstrated a threshold density is necessary for the maintenance of infection in a reservoir population, of which PUUV may not occur below the threshold density and no clear relationship between prevalence and bank vole density above the threshold density.19,22 This may explain the sharp decrease in virus carrier rates in rodents from before 2006 to the period of 2006 to 2010, and relatively stable seroprevalence between 1986 and 2005, although the rodent density consistently decreased each year.
HTNV and SEOV are 2 major pathogens of HFRS in China, which are mainly carried by striped field mice (Apodemus agrarius) and Brown Norway rats (Rattus norvegicus), respectively. The incidence of HFRS is linked to the serotype of orthohantaviruses and influenced by the infection of its animal hosts.23 The inapparent infection in healthy people of the 2 serotypes was different. The SEOV infections cause mild symptoms and have a higher inapparent rate than HTNV.24 In our study, although the average annual HFRS incidence rate from 1984 to 1990 was 6.42/100,000, which was the highest period, and incidence showed a declining trend in the following 4 time periods, with an average annual incidence of less than 1 in 100,000 after 2000, the inapparent infection rate in healthy people was higher during 1984 to 1990 and 1996 to 2000. Therefore, we infer that the percentage of SEOV infection has increased since the 1990s. This can also be proven by our previous study that most collected rodents in the Hubei area were Brown Norway rats, and the corresponding predominant SEOV was orthohantaviruses that circulate in the Hubei Province.11 Similar patterns were observed in other regions of China in recent years.25 Furthermore, the newly established HFRS endemic areas in mainland China are mostly related to SEOV with a characteristic spring peak of incidence since the 1990s.26,27 The change in the virus type of the epidemic area in recent years may be the main reason for the relatively small decline in the inapparent infection rate. In addition, we consequently isolated a new HTNV subtype (designated as HV004) from Apodemus agrarius in the epidemic area of Hubei Province from 2009 to 2011,28 which may indicate that the epidemic trend of HFRS has been changing over time, and systematic investigations and continuous surveillance should be executed.
Host population composition is an important factor in determining the epidemic characteristics of Orthohantaviruses. Comparing the composition of host animals after 2000 with those in the 1980s, the dominant species were Rattus norvegicus and Apodemus agrarius, although the population composition ratio changed. The proportion of the 2 species in the total host animals increased to 88.4% after 2000, compared with 68.6% in the 1980s, an increase of 1.29 folds, and the proportion of Rattus norvegicus increased from 45.2% to 68.1%, increasing by 1.51 folds. The number and type of other animals carrying Orthohantaviruses are significantly reduced due to the intervention of human activities in the natural ecological environment.3,29,30 HFRS are natural infectious diseases and their pathogenesis is characterized by natural dispersion. After the outbreak of HFRS in Hubei Province in the 1980s, a large-scale depopulation (rodenticide) of rats was adopted to reduce the prevalence of HFRS, which succeeded in the short term.12 However, biodiversity loss (increased wild reservoir population density and reduced small-mammal species diversity) would accelerate the transmission of zoonotic pathogens among wildlife hosts and cause augmented hantavirus prevalence.31,32 Furthermore, the widespread use of acute rodenticides has dramatically reduced the number of natural enemies of rats, such as owls and snakes, while the reproductive capacity and adaptability of rodents have increased, which worsens the ecological balance between wild animals.
There has been no pandemic of HFRS in Hubei Province in the past decade, which has been in a low-morbidity state. However, this state is not a natural emission state maintained by the ecological balance between host animals, but the results of the imbalance in rat ecology due to rodent control measures. Studies have shown that species diversity plays a “dilution” role in the transmission of Orthohantaviruses between host animals.32 Reducing the infection rate in host animals could also reduce the risk of population infection. Because of the slaughter of wild animals by humans and the large-scale encroachment of habitats, the species types and numbers were drastically reduced, which contributes to the spread of Orthohantaviruses in rats to some extent.31 In our study, although species richness dropped after 2000 compared with that in the 1980s, Rattus norvegicus and Apodemus agrarius were still the dominant species, and the rate of carrying the virus decreased. Our results emphasized the important balance between conservation biology and infectious disease management.
In this study, we present the epidemic characteristics of HFRS in the Hubei Province of China over a time span of 27 years (1984 to 2010). The change in host population composition and the increase in the proportion of Rattus norvegicus are potential risk factors in urban areas. Therefore, much attention must be given to the existing problems at the current stage. However, the present study may be limited because rodent capture locations may not be at the same accurate position over the entire study period due to labor overturn, which may cause surveillance variability or bias. In addition, this report does not address the data after 2010 as the investigation of Orthohantavirus infection in humans and the reservoir hosts were conducted separately. Nevertheless, according to the HFRS type in the epidemic area, the spatial and temporal dynamic distribution characteristics of the disease, and the main viral host animals, we should formulate targeted prevention and control measures to maintain the ecological balance between animals continuously.
Acknowledgments
This work was supported by the Foundation of Health and Family Planning Commission of Hubei Province (WJ2015MB113), the National High-Tech Research and Development Program of China (863 Program, No. 2007AA02Z465), and the National Natural Science Foundation of China (No. 81772186, No. 81971942 and No.82172274) to Hai-rong Xiong.
Yuan-Yuan Liu and An Yang contributed equally to the work.
The authors have nothing to declare.
We thank Li Liu and Xi-Xiang Huo from Hubei Provincial Center for Disease Control and Prevention for the data support.
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