Since 1998, the HFRS incidence in Changchun has increased dramatically. The HFRS hotspot has been located at Shuangyang County in southeastern Changchun. Two epidemic phases were identified by examining the seasonal pattern of HFRS incidence. One phase was characterized by a single epidemic peak at the end of each year during 1988–1997. The other phase had two separate epidemic peaks, which occurred at the end and the beginning of each year since 1998. The peak at the beginning of each year could be associated with the emergence of SEOV. The transmission of hantaviruses through A. agrarius mice peaks during the fall-winter period, while R. norvegicus rat-associated infections mainly occur in spring
[11, 12, 16, 19]. Given the well-documented evidence, and the two-phase pattern observed in the present study, we infer that the HFRS phase I (1988–1997) pattern was primarily caused by HTNV infections. HFRS phase II (since 1998) pattern was caused by both HTNV and SEOV infections. Noticeably, the newly established and re-emerging HFRS endemic areas in mainland China since the 1990s that included Beijing City, Shandong Province, Huludao City, and Changchun, could be associated with SEOV (e.g. peridomestic rodents-associated) infections indicated by a characteristic spring peak in human cases
[10, 16, 20]. In mainland China, antigen-positive A. agrarius, Apodemus peninsulae, and R. norvegicus rats are predominant in rural, forest, and urban areas, respectively
. The results suggest that prioritizing control efforts on peridomestic rodent populations in residential areas in spring and on sylvatic rodent populations in late autumn and early winter might provide an effective means of targeting the specific hantaviruses that cause HFRS.
The Poisson regression analysis revealed that livestock husbandry, especially deer cultivation, was significantly associated with spatial and temporal distributions of HFRS incidence. Hantaviruses are primarily transmitted from rodent hosts to humans by aerosols generated from contaminated excreta (e.g., urine and feces) of rodents, and to a lesser extent by contaminated food or rodent bites
. The incidence of HFRS is mainly determined by infection rate and distribution of rodent hosts; host distribution is affected by the natural habitat structure (e.g., human buildings, landscape composition, landscape configuration, annual mean temperature, and seasonal variation)
[21, 22]. Environmental changes that include climate, human agriculture, and social-economic conditions can lead to a change in virus transmission risk from infected rodents to humans
[3, 23]. The results of a study in Elunchun and Molidawahaner counties of Inner Mongolia indicated that climate variability (including rainfall, land surface temperature, relative humidity and the multivariate El Niño Southern Oscillation index) had a significant role in HFRS transmission in northeastern China
. The results of a study on hantavirus pulmonary syndrome in the Four Corners region of United States revealed that environmental factors (e.g., the dramatic increase in precipitation associated with the 1992 to 1993 El Niño) could indirectly increase the risk for Sin Nombre virus exposure
. Furthermore, heterogeneity in the effects of environmental factors on hantavirus diseases between different areas could result from differences in biotopes, climatic conditions, viruses, and the rodent reservoirs
. In this study, time-series Poisson regression analysis was used to account for the complex associations between HFRS incidence and influencing factors during a long period of time. Compared with climatic factors, livestock husbandry (mainly deer density) seemed to have a greater effect on HFRS incidence. The analysis of the factors relating to spatial heterogeneity of HFRS incidence also indicated that deer density could play a role in the distribution of HFRS cases, especially for the SEOV-dominated HFRS that occurred from 1998 to 2012. Livestock husbandry has been one of key driving forces of emerging infectious diseases and has also modified the transmission of endemic infections
[27, 28]. Traditional livestock husbandry was reinstituted at the end of the 1980s and extended into the mid-1990s in Changchun. Deer cultivation and production of deer-related products has been prominent in northeastern China, especially in Changchun. As the numbers of livestock increased, more farms were established and more feed was needed. This additional feed has provided habitats and food for rodents. Farming activities that are related to livestock husbandry can also increase the probability of exposure to infective rodents
[12, 29]. The authors of a case–control study in Sichuan Province in China suggested that farming activities related to livestock husbandry (e.g., having haystacks for livestock in the yard or indoors in barns) can increase the risk of HFRS transmission
. Rodents on pig and chicken farms are considered to be a potential threat to human and animal health, and at least 20 pathogens (e.g., hantaviruses and Leptospira species) can be found on the rodents caught on pig or chicken farms and in the surrounding area
. Livestock husbandry could have an intermediate role in HFRS incidence by affecting rodent populations and increasing human exposure to aerosols and secretions from infected rodents. The observed association between HFRS incidence and deer cultivation was statistically significant, but it does not prove causality. Further field investigations on rodent population density and hantavirus infection status in rodents living around livestock farms are needed to improve our understanding of the underlying mechanism.
The results of this study indicated that the HFRS incidence was associated with yearly average relative humidity. Rodent population size increase rapidly in response to favorable weather conditions
. The relationship between rodent population dynamics and meteorological factors is complex, and varies by rodent species and climate regions
[10, 24, 32]. These complicated relationships may have different effects on disease transmission, and usually display nonlinear patterns between diseases and climate factors in a large geographical area. The association between HFRS and relative humidity that was found in this study was consistent with the result reported for a nearby area of Changchun
. Higher humidity levels affect the infectivity and stability of the virus in the ex vivo environment
[33, 34]. However, the underlying mechanisms for the positive correlations between HFRS incidence and relative humidity are not yet clear. Our study results indicated that livestock cultivation rather than climatic factors likely has a more important role in the emergence of HFRS outbreaks in Changchun. In addition, we have not found significant associations between the spatial distribution of HFRS incidence and land cover. It is likely that the land cover differences between counties in this study area were not significant.
The reemergence of HFRS was also affected by multiple factors including prevention measures, and other human activities
[35–37]. As the official documents preserved in Changchun CDC indicate, enhanced measures that include epidemiological surveillance, deratization, vaccination and health education have been implemented for prevention and control of the disease since incidence increased at the end of 1990s. These measures were improved further in 2005. The vaccine mostly used was a univalent HTNV vaccine. It was used in Shuangyang, Jiutai, and Yushu from 1999 to 2004, in the town populations with high HFRS incidence (>5/100,000 population). A bivalent purified inactivated vaccine against HTNV and SEOV infections has been used in these areas since 2005. A significant decline in HFRS incidence has occurred since 2006 (Figure
2). One limitation of this study was that we did not examine vaccination efficacy, but this omission was the result of a lack of detailed information. Another study limitation was that we could not confirm the shifts in virus transmission because the information on the classification of hantaviruses in HFRS patients and infected rodents was missing. Future studies on the classification of hantaviruses are needed. The results of this study indicated that prevention and control of HFRS in Changchun will benefit from targeting control measures at R. norvegicus populations, especially at livestock husbandry sites. The need for vaccination of farmers involved in livestock husbandry in early spring should also be emphasized.