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1.  Ongoing Spillover of Hantaan and Gou Hantaviruses from Rodents Is Associated with Hemorrhagic Fever with Renal Syndrome (HFRS) in China 
Background
Longquan City, Zhejiang province, China, has been seriously affected by hemorrhagic fever with renal syndrome (HFRS) since the first cases were registered in 1974. To understand the epidemiology and emergence of HFRS in Longquan, which may be indicative of large parts of rural China, we studied long-term incidence patterns and performed a molecular epidemiological investigation of the causative hantaviruses in human and rodent populations.
Method/Principal Findings
During 1974–2011, 1866 cases of HFRS were recorded in Longquan, including 20 deaths. In 2011, the incidence of HFRS remained high, with 19.61 cases/100,000 population, despite the onset of vaccination in 1997. During 1974–1998, HFRS cases in Longquan occurred mainly in winter, while in the past decade the peak of HFRS has shifted to the spring. Notably, the concurrent prevalence of rodent-borne hantaviruses in the region was also high. Phylogenetic analyses of viral sequences recovered from rodents in Longquan revealed the presence of novel genetic variants of Gou virus (GOUV) in Rattus sp. rats and Hantaan virus (HTNV) in the stripe field mice, respectively. Strikingly, viral sequences sampled from infected humans were very closely related to those from rodents.
Conclusions/Significance
HFRS represents an important public health problem in Longquan even after years of preventive measures. Our data suggest that continual spillover of the novel genetic variant of GOUV and the new genetic lineage of HTNV are responsible for the high prevalence of HFRS in humans. In addition, this is the first report of GOUV associated with human HFRS cases, and our data suggest that GOUV is now the major cause of HFRS in this region.
Author Summary
Hemorrhagic fever with renal syndrome (HFRS) is a major public health problem in China despite human vaccination. We investigated the epidemiology and emergence of HFRS in Longquan (Zhejiang Province), a rural area with a high incidence of HFRS. During 1974–2011, a total of 1866 cases of HFRS were recorded in Longquan, including 20 deaths. Strikingly, phylogenetic analyses of viral sequences sampled from local rodents in Longquan revealed the presence of novel variants of Gou virus (GOUV) in Rattus sp. rats and Hantaan virus (HTNV) in the stripe field mice, respectively. Moreover, viral sequences sampled from infected humans in Longquan were very closely related to those from rodents. Overall, these data indicate that there is a continual spillover GOUV and HTNV from rodents to humans in Longquan, and this might be responsible for the high prevalence of HFRS. As well as highlighting the importance of the human-animal interface, these data also suggest that GOUV is now the major cause of HFRS in this region.
doi:10.1371/journal.pntd.0002484
PMCID: PMC3798614  PMID: 24147168
2.  Epidemiology of Hemorrhagic Fever with Renal Syndrome in Korea, 2001-2010 
Journal of Korean Medical Science  2013;28(10):1552-1554.
This study describes the epidemiology of hemorrhagic fever with renal syndrome (HFRS) in the past 10 yr (2001-2010) in Korea. During this period, a total of 3,953 HFRS patients and an average prevalence rate of 0.81 per 100,000 population were recorded, with a total of 40 fatal cases, corresponding to a case fatality rate of 1.01%. More HFRS cases were found in men than in women (57% vs 43%), and a higher prevalence rate of HFRS was observed in patients older than 40 yr (82.1%). The highest numbers of HFRS cases were found amongst farmers (35.6%). The majority of HFRS cases (71.3%) occurred in the last quarter of the calendar year (October to December). More HFRS cases occurred in the western part than in the eastern part of Korea (68.9% vs 31.1%). The incidence of HFRS was significantly higher (P < 0.001) in rural areas than in urban areas (80.3% vs 19.7%). HFRS still occurs commonly among men, in autumn, and in western rural area of Korea.
doi:10.3346/jkms.2013.28.10.1552
PMCID: PMC3792615  PMID: 24133366
Hemorrhagic Fever with Renal Syndrome; Epidemiology; Autumn; Rural Area
3.  Spatiotemporal Trends and Climatic Factors of Hemorrhagic Fever with Renal Syndrome Epidemic in Shandong Province, China 
Background
Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by Hantaviruses. It is endemic in all 31 provinces, autonomous regions, and metropolitan areas in mainland China where human cases account for 90% of the total global cases. Shandong Province is among the most serious endemic areas. HFRS cases in Shandong Province were first reported in Yutai County in 1968. Since then, the disease has spread across the province, and as of 2005, all 111 counties were reported to have local human infections. However, causes underlying such rapid spread and wide distribution remain less well understood.
Methods and Findings
Here we report a spatiotemporal analysis of human HFRS cases in Shandong using data spanning 1973 to 2005. Seasonal incidence maps and velocity vector maps were produced to analyze the spread of HFRS over time in Shandong Province, and a panel data analysis was conducted to explore the association between HFRS incidence and climatic factors. Results show a rapid spread of HFRS from its epicenter in Rizhao, Linyi, Weifang Regions in southern Shandong to north, east, and west parts of the province. Based on seasonal shifts of epidemics, three epidemic phases were identified over the 33-year period. The first phase occurred between 1973 and 1982 during which the foci of HFRS was located in the south Shandong and the epidemic peak occurred in the fall and winter, presenting a seasonal characteristic of Hantaan virus (HTNV) transmission. The second phase between 1983 and 1985 was characterized by northward and westward spread of HFRS foci, and increases in incidence of HFRS in both fall-winter and spring seasons. The human infections in the spring reflected a characteristic pattern of Seoul virus (SEOV) transmission. The third phase between 1986 and 2005 was characterized by the northeast spread of the HFRS foci until it covered all counties, and the HFRS incidence in the fall-winter season decreased while it remained high in the spring. In addition, our findings suggest that precipitation, humidity, and temperature are major environmental variables that are associated with the seasonal variation of HFRS incidence in Shandong Province.
Conclusions
The spread of HFRS in Shandong Province may have been accompanied by seasonal shifts of HTNV-dominated transmission to SEOV-dominated transmission over the past three decades. The variations in HFRS incidence were significantly associated with local precipitation, humidity, and temperature.
Author Summary
Hemorrhagic fever with renal syndrome (HFRS), a rodent-borne disease caused by Hantaviruses, is characterized by fever, acute renal dysfunction and hemorrhagic manifestations. At present, it is endemic in all 31 provinces, autonomous regions, and metropolitan areas in mainland China where human cases account for 90% of the total global cases. Historically Shandong Province bears the largest HFRS burden in China—the cumulative number of human cases accounted for 1/3 of the national total. Here we report a spatiotemporal analysis of human HFRS cases in Shandong using reported case data spanning 1973 to 2005. Through the analysis of seasonal incidences and use of velocity maps, three phases of seasonal shifts of HFRS epidemics and the expansion pattern of HFRS endemic areas were identified over the 33-year period. In addition, precipitation, humidity, and temperature were found to be significantly associated with the seasonal variation of HFRS incidence in Shandong Province. These findings offer insights in understanding possible causes of HFRS spread and distribution and may assist in informing prevention and control strategies.
doi:10.1371/journal.pntd.0000789
PMCID: PMC2919379  PMID: 20706629
4.  Hantaviruses in Rodents and Humans, Inner Mongolia Autonomous Region, China 
Emerging Infectious Diseases  2009;15(6):885-891.
Vigilance is needed to prevent hemorrhagic fever renal syndrome caused by Hantaan and Seoul viruses in this region.
Surveys were carried out in 2003–2006 to better understand the epidemiology of hantaviruses in the Inner Mongolia Autonomous Region of China (Inner Mongolia). Hemorrhagic fever with renal syndrome (HFRS) was first reported in this region in 1955 and has been an important public health problem here since then. During 1955–2006, 8,309 persons with HFRS were reported in Inner Mongolia (average incidence rate 0.89/100,000), and 261 (3.14%) died. Before the 1990s, all HFRS cases occurred in northeastern Inner Mongolia. Subsequently, HFRS cases were registered in central (1995) and western (1999) Inner Mongolia. In this study, hantaviral antigens were identified in striped field mice (Apodemus agrarius) from northeastern Inner Mongolia and in Norway rats (Rattus norvegicus) from middle and western Inner Mongolia. Phylogenetic analysis of hantaviral genome sequences suggests that HFRS has been caused mainly by Hantaan virus in northeastern Inner Mongolia and by Seoul virus in central and western Inner Mongolia.
doi:10.3201/eid1506.081126
PMCID: PMC2727351  PMID: 19523286
Viruses; zoonoses; hemorrhagic fever with renal syndrome; hantavirus; Hantaan virus; Seoul virus; China; Mongolia; research
5.  Spatial analysis of hemorrhagic fever with renal syndrome in China 
Background
Hemorrhagic fever with renal syndrome (HFRS) is endemic in many provinces with high incidence in mainland China, although integrated intervention measures including rodent control, environment management and vaccination have been implemented for over ten years. In this study, we conducted a geographic information system (GIS)-based spatial analysis on distribution of HFRS cases for the whole country with an objective to inform priority areas for public health planning and resource allocation.
Methods
Annualized average incidence at a county level was calculated using HFRS cases reported during 1994–1998 in mainland China. GIS-based spatial analyses were conducted to detect spatial autocorrelation and clusters of HFRS incidence at the county level throughout the country.
Results
Spatial distribution of HFRS cases in mainland China from 1994 to 1998 was mapped at county level in the aspects of crude incidence, excess hazard and spatial smoothed incidence. The spatial distribution of HFRS cases was nonrandom and clustered with a Moran's I = 0.5044 (p = 0.001). Spatial cluster analyses suggested that 26 and 39 areas were at increased risks of HFRS (p < 0.01) with maximum spatial cluster sizes of ≤ 20% and ≤ 10% of the total population, respectively.
Conclusion
The application of GIS, together with spatial statistical techniques, provide a means to quantify explicit HFRS risks and to further identify environmental factors responsible for the increasing disease risks. We demonstrate a new perspective of integrating such spatial analysis tools into the epidemiologic study and risk assessment of HFRS.
doi:10.1186/1471-2334-6-77
PMCID: PMC1471792  PMID: 16638156
6.  Hantavirus Infections in Humans and Animals, China 
Emerging Infectious Diseases  2010;16(8):1195-1203.
Hemorrhagic fever with renal syndrome is a serious public health problem in China.
Hemorrhagic fever with renal syndrome (HFRS) is a serious public health problem in the People’s Republic of China. Although 7 sero/genotypes of hantaviruses have been found in rodents, only Hantaan virus (carried by Apodemus agrarius mice) and Seoul virus (carried by Rattus norvegicus rats) reportedly cause disease in humans. During 1950–2007, a total of 1,557,622 cases of HFRS in humans and 46,427 deaths (3%) were reported in China. HFRS has been reported in 29 of 31 provinces in China. After implementation of comprehensive preventive measures, including vaccination, in the past decade in China, incidence of HFRS has dramatically decreased; only 11,248 HFRS cases were reported in 2007. Mortality rates also declined from the highest level of 14.2% in 1969 to ≈1% during 1995–2007. However, the numbers of HFRS cases and deaths in China remain the highest in the world.
doi:10.3201/eid1608.090470
PMCID: PMC3298307  PMID: 20678311
China; Hantavirus; Bunyaviridae; HFRS; natural hosts; viruses; zoonoses; perspective
7.  Forecasting incidence of hemorrhagic fever with renal syndrome in China using ARIMA model 
BMC Infectious Diseases  2011;11:218.
Background
China is a country that is most seriously affected by hemorrhagic fever with renal syndrome (HFRS) with 90% of HFRS cases reported globally. At present, HFRS is getting worse with increasing cases and natural foci in China. Therefore, there is an urgent need for monitoring and predicting HFRS incidence to make the control of HFRS more effective. In this study, we applied a stochastic autoregressive integrated moving average (ARIMA) model with the objective of monitoring and short-term forecasting HFRS incidence in China.
Methods
Chinese HFRS data from 1975 to 2008 were used to fit ARIMA model. Akaike Information Criterion (AIC) and Ljung-Box test were used to evaluate the constructed models. Subsequently, the fitted ARIMA model was applied to obtain the fitted HFRS incidence from 1978 to 2008 and contrast with corresponding observed values. To assess the validity of the proposed model, the mean absolute percentage error (MAPE) between the observed and fitted HFRS incidence (1978-2008) was calculated. Finally, the fitted ARIMA model was used to forecast the incidence of HFRS of the years 2009 to 2011. All analyses were performed using SAS9.1 with a significant level of p < 0.05.
Results
The goodness-of-fit test of the optimum ARIMA (0,3,1) model showed non-significant autocorrelations in the residuals of the model (Ljung-Box Q statistic = 5.95,P = 0.3113). The fitted values made by ARIMA (0,3,1) model for years 1978-2008 closely followed the observed values for the same years, with a mean absolute percentage error (MAPE) of 12.20%. The forecast values from 2009 to 2011 were 0.69, 0.86, and 1.21per 100,000 population, respectively.
Conclusion
ARIMA models applied to historical HFRS incidence data are an important tool for HFRS surveillance in China. This study shows that accurate forecasting of the HFRS incidence is possible using an ARIMA model. If predicted values from this study are accurate, China can expect a rise in HFRS incidence.
doi:10.1186/1471-2334-11-218
PMCID: PMC3169483  PMID: 21838933
8.  A novel Sin Nombre virus DNA vaccine and its inclusion in a candidate pan-hantavirus vaccine against hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS)☆ 
Vaccine  2013;31(40):4314-4321.
Sin Nombre virus (SNV; family Bunyaviridae, genus Hantavirus) causes a hemorrhagic fever known as hantavirus pulmonary syndrome (HPS) in North America. There have been approximately 200 fatal cases of HPS in the United States since 1993, predominantly in healthy working-age males (case fatality rate 35%). There are no FDA-approved vaccines or drugs to prevent or treat HPS. Previously, we reported that hantavirus vaccines based on the full-length M gene segment of Andes virus (ANDV) for HPS in South America, and Hantaan virus (HTNV) and Puumala virus (PUUV) for hemorrhagic fever with renal syndrome (HFRS) in Eurasia, all elicited high-titer neutralizing antibodies in animal models. HFRS is more prevalent than HPS (>20,000 cases per year) but less pathogenic (case fatality rate 1–15%). Here, we report the construction and testing of a SNV full-length M gene-based DNA vaccine to prevent HPS. Rabbits vaccinated with the SNV DNA vaccine by muscle electroporation (mEP) developed high titers of neutralizing antibodies. Furthermore, hamsters vaccinated three times with the SNV DNA vaccine using a gene gun were completely protected against SNV infection. This is the first vaccine of any kind that specifically elicits high-titer neutralizing antibodies against SNV. To test the possibility of producing a pan-hantavirus vaccine, rabbits were vaccinated by mEP with an HPS mix (ANDV and SNV plasmids), or HFRS mix (HTNV and PUUV plasmids), or HPS/HFRS mix (all four plasmids). The HPS mix and HFRS mix elicited neutralizing antibodies predominantly against ANDV/SNV and HTNV/PUUV, respectively. Furthermore, the HPS/HFRS mix elicited neutralizing antibodies against all four viruses. These findings demonstrate a pan-hantavirus vaccine using a mixed-plasmid DNA vaccine approach is feasible and warrants further development.
doi:10.1016/j.vaccine.2013.07.025
PMCID: PMC4010434  PMID: 23892100
Sin Nombre; virus Hantavirus; DNA vaccine; HPS; HFRS
9.  Epidemic characteristics of hemorrhagic fever with renal syndrome in China, 2006–2012 
BMC Infectious Diseases  2014;14:384.
Background
Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses is a serious public health problem in China. The National Notifiable Disease Surveillance System (NNDSS) was established online by China CDC in 2004 and rodent surveillance sites were adjusted to 40 sites in 22 provinces in 2005. Here we analyzed the surveillance data of both human cases and rodents host during 2006–2012 to examine the epidemic trends of HFRS in recent years in China.
Methods
Records on HFRS human cases and surveillance data of rodents host from 2006 to 2012 were analyzed. Phylogenetic tree based on complete sequence of M segment of 58 virus isolates was constructed and analyzed to make a better understanding of the molecular diversity of hantaviruses in China.
Results
During 2006–2012, a total of 77558 HFRS human cases and 866 deaths were reported with the average annual incidence rate of 0.83 cases/100,000 population and case fatality rate of 1.13%. 84.16% of the total cases were clustered in 9 provinces and mainly reported in spring and autumn-winter seasons. HFRS incidence in males was over 3 times higher than in females and farmers still accounted for the largest proportion. The average density of rodents was relatively stable from 2006 to 2012. Apodemus agrarius and Rattus norvegicus were predominant in wild field and residential area, respectively. Both hantaviruses carrying and infection rates in rodents had a rapid increase in 2012. Phylogenetic analysis showed that at least six clades of Hantaan virus and five of Seoul virus were prevalent in China.
Conclusion
HFRS in China was still a natural focal disease with relatively high morbidity and fatality and its distribution and epidemic trends had also changed. Surveillance measures, together with prevention and control strategies should be improved and strengthened to reduce HFRS infection in China.
doi:10.1186/1471-2334-14-384
PMCID: PMC4105051  PMID: 25012160
Hemorrhagic fever with renal syndrome (HFRS); Hantaviruses; Epidemics; Phylogenetic analysis
10.  Second External Quality Assurance Study for the Serological Diagnosis of Hantaviruses in Europe 
Hantaviruses are endemic throughout the world and hosted by rodents and insectivores. Two human zoonoses, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), are caused by hantaviruses and case fatality rates have reached 12% for HFRS and 50% for HPS in some outbreaks. Symptomatic hantavirus infections in Europe are summarised as HFRS mainly due to Puumala, Dobrava-Belgrade and Saaremaa virus. While HFRS has an overall low incidence in Europe, the number of cases varies from 100 per year in all Eastern and Southern Europe up to 1,000 per year only in Finland. To assess the quality of hantavirus diagnostics, the European Network for the Diagnostics of “Imported” Viral Diseases (ENIVD) organised a first external quality assurance (EQA) in 2002. The purpose of this second EQA study is to collect updated information on the efficiency and accurateness of hantavirus serological methods applied by expert laboratories. A serum panel of 14 samples was sent to 28 participants in Europe of which 27 sent results. Performance in hantavirus diagnosis varied not only on the method used but also on the laboratories and the subclass of antibodies tested. Commercial and in-house assays performed almost equally. Enzyme immunoassays were mainly used but did not show the best performances while immunoblot assays were the less employed and showed overall better performances. IgM antibodies were not detected in 61% of the positive IgM samples and IgM detection was not performed by 7% of the laboratories indicating a risk of overlooking acute infections in patients. Uneven performances using the same method is indicating that there is still a need for improving testing conditions and standardizing protocols.
Author Summary
Hantaviruses are endemic throughout the world and naturally hosted by rodents. The vast majority of human hantavirus infections are asymptomatic. In Europe, symptomatic hantavirus infections are summarised as hemorrhagic fever with renal syndrome (HFRS) mainly due to Puumala, Dobrava-Belgrade and Saaremaa virus. HFRS can cause fever, headache, and flank and abdominal pain. Moreover, renal dysfunction can lead to acute renal failure. Despite numerous research efforts, there is still no safe and effective vaccine or specific antiviral treatment against hantavirus infections. In this context, an accurate diagnosis as well as a reliable surveillance of hantavirus infections is essential. The diagnostics of hantavirus infections are based on serology using in-house or commercial assays. To assess the quality of hantavirus diagnostics, the European Network for the Diagnostics of “Imported” Viral Diseases organised a first external quality assurance (EQA) in 2002. In this publication we describe a second EQA study launched in 2011 with the objective to collect updated information on the efficiency and accurateness of hantavirus serological methods applied by expert laboratories. The study shows uneven performances indicating that there is still a need for improving testing conditions and standardizing protocols.
doi:10.1371/journal.pntd.0001607
PMCID: PMC3317902  PMID: 22509420
11.  Seroepidemiologic Survey for Coxiella burnetii Among US Military Personnel Deployed to Southwest and Central Asia in 2005 
We used a seroepidemiologic study to estimate Q fever (Coxiella burnetii) seroprevalence, seroincidence, and risk factors for seroconversion in two deployed military populations in 2005. The first study group resided in an area with a known Q fever outbreak history (Al Asad, Iraq). Of this population, 7.2% seroconverted for an incidence rate of 10.6 seroconversions per 1,000 person-months. The second population included personnel transiting through Qatar on mid-deployment leave from southwest/central Asia. In this group, we found 2.1% prevalence with 0.92 seroconversions per 1,000 person-months. However, no significant risk factors for Q fever seroconversion were found in either population.
doi:10.4269/ajtmh.12-0174
PMCID: PMC3820350  PMID: 24043692
12.  Trends in Meningococcal Disease in the United States Military, 1971–2010 
Emerging Infectious Diseases  2012;18(9):1430-1437.
When you consider the risks undertaken by US military personnel, do you include risk for disease? Public health officials do. Military personnel are at risk for infectious disease because of crowding, the rigors of physical training, and sometimes unhygienic field conditions. Meningococcal disease (usually manifested as bacterial meningitis or blood-borne infection) can be rapidly fatal. It has historically affected the military more than the general US population. One hundred years' worth of data support this trend from as long ago as World War I. However, in 1970, a policy requiring vaccination of military recruits started lowering the rate of infection, although the rate remained higher than that for the general population. Since 1982, improvements in vaccines have lowered rates even further. As a result of these vaccination efforts, the meningococcal disease rate among military personnel has reached a historic low, which now matches that of the general population.
Meningococci have historically caused extensive illness among members of the United States military. Three successive meningococcal vaccine types were used from 1971 through 2010; overall disease incidence dropped by >90% during this period. During 2006–2010, disease incidence of 0.38 (cases per 100,000 person-years) among members of the US military was not significantly different from the incidence of 0.26 among the age-matched US general population. Of the 26 cases in the US military, 5 were fatal, 15 were vaccine failures (e.g., illness in a person who had been vaccinated), and 9 were caused by Neisseria meningitidis serogroup Y. Incidences among 17- to 19-year-old basic trainees and among US Marines were significantly higher than among comparison military populations (p<0.05). No apparent change in epidemiology of meningococcal disease was observed after replacement of quadrivalent polysaccharide vaccine with conjugate vaccine in 2007. The data demonstrate that vaccination with meningococcal vaccine is effective.
doi:10.3201/eid1809.120257
PMCID: PMC3437735  PMID: 22932005
Neisseria meningitidis; meningococcal disease; infectious disease epidemiology; vaccines; military personnel; bacteria; United States; serogroups; vaccine effectiveness; conjugate; polysaccharide; meningococci; Suggested citation for this article: Broderick MP; Faix DJ; Hansen CJ; Blair PJ. Trends in meningococcal disease in the United States military; 1971–2010. Emerg Infect Dis [serial on the internet]. 2012 Sep [date cited]. http://dx.doi.org/10.3201/eid1809.120257
13.  Temporal trend and climate factors of hemorrhagic fever with renal syndrome epidemic in Shenyang City, China 
BMC Infectious Diseases  2011;11:331.
Background
Hemorrhagic fever with renal syndrome (HFRS) is an important infectious disease caused by different species of hantaviruses. As a rodent-borne disease with a seasonal distribution, external environmental factors including climate factors may play a significant role in its transmission. The city of Shenyang is one of the most seriously endemic areas for HFRS. Here, we characterized the dynamic temporal trend of HFRS, and identified climate-related risk factors and their roles in HFRS transmission in Shenyang, China.
Methods
The annual and monthly cumulative numbers of HFRS cases from 2004 to 2009 were calculated and plotted to show the annual and seasonal fluctuation in Shenyang. Cross-correlation and autocorrelation analyses were performed to detect the lagged effect of climate factors on HFRS transmission and the autocorrelation of monthly HFRS cases. Principal component analysis was constructed by using climate data from 2004 to 2009 to extract principal components of climate factors to reduce co-linearity. The extracted principal components and autocorrelation terms of monthly HFRS cases were added into a multiple regression model called principal components regression model (PCR) to quantify the relationship between climate factors, autocorrelation terms and transmission of HFRS. The PCR model was compared to a general multiple regression model conducted only with climate factors as independent variables.
Results
A distinctly declining temporal trend of annual HFRS incidence was identified. HFRS cases were reported every month, and the two peak periods occurred in spring (March to May) and winter (November to January), during which, nearly 75% of the HFRS cases were reported. Three principal components were extracted with a cumulative contribution rate of 86.06%. Component 1 represented MinRH0, MT1, RH1, and MWV1; component 2 represented RH2, MaxT3, and MAP3; and component 3 represented MaxT2, MAP2, and MWV2. The PCR model was composed of three principal components and two autocorrelation terms. The association between HFRS epidemics and climate factors was better explained in the PCR model (F = 446.452, P < 0.001, adjusted R2 = 0.75) than in the general multiple regression model (F = 223.670, P < 0.000, adjusted R2 = 0.51).
Conclusion
The temporal distribution of HFRS in Shenyang varied in different years with a distinctly declining trend. The monthly trends of HFRS were significantly associated with local temperature, relative humidity, precipitation, air pressure, and wind velocity of the different previous months. The model conducted in this study will make HFRS surveillance simpler and the control of HFRS more targeted in Shenyang.
doi:10.1186/1471-2334-11-331
PMCID: PMC3247297  PMID: 22133347
14.  Incidence of Carpal Tunnel Syndrome in the US Military Population 
Hand (New York, N.Y.)  2009;4(3):289-293.
Carpal tunnel syndrome (CTS) is a common disease. Its epidemiology has been evaluated previously, mostly in regional populations or in working groups, with an incidence between 1.5 and 3.5 per 1,000 person-years. We studied this diagnosis in the US military population, with the hypothesis that this young population would have a lower incidence of CTS than previously reported in general populations. The Defense Medical Epidemiology Database notes all medical encounters for all US military personnel and maintains the number of all personnel on active duty each year. We queried the database using the International Classification of Diseases, ninth revision, code 354.0 (CTS) and analyzed the personnel presenting for initial visits for the years 1998–2006. Multivariate Poisson analysis was performed, controlling for rank, gender, age, and race. The raw incidence of CTS in the US military was 3.98 per 1,000 person-years, in a population of 12,298,088 person-years. Females had a significantly higher incidence of CTS than males, with an adjusted incidence rate ratio of 3.29. CTS incidence increased by age, with the age group ≥40 years having a significantly higher incidence. Additionally, military rank was found to be an independent risk factor for CTS, with rates higher in senior officer and enlisted groups. This suggests that occupational requirements have an effect on CTS within the military. We showed a comparable incidence of CTS between the US military and general population, with a significantly higher female cohort with a diagnosis of CTS. Increased age and advanced rank were risk factors for CTS.
doi:10.1007/s11552-009-9166-y
PMCID: PMC2724617  PMID: 19172361
Carpal tunnel syndrome; Epidemiology; Military
15.  Geo-spatial Hotspots of Hemorrhagic Fever with Renal Syndrome and Genetic Characterization of Seoul Variants in Beijing, China 
Background
Hemorrhagic fever with renal syndrome (HFRS) is highly endemic in mainland China, and has extended from rural areas to cities recently. Beijing metropolis is a novel affected region, where the HFRS incidence seems to be diverse from place to place.
Methodology/Principal Findings
The spatial scan analysis based on geographical information system (GIS) identified three geo-spatial “hotspots” of HFRS in Beijing when the passive surveillance data from 2004 to 2006 were used. The Relative Risk (RR) of the three “hotspots” was 5.45, 3.57 and 3.30, respectively. The Phylogenetic analysis based on entire coding region sequence of S segment and partial L segment sequence of Seoul virus (SEOV) revealed that the SEOV strains circulating in Beijing could be classified into at least three lineages regardless of their host origins. Two potential recombination events that happened in lineage #1 were detected and supported by comparative phylogenetic analysis. The SEOV strains in different lineages and strains with distinct special amino acid substitutions for N protein were partially associated with different spatial clustered areas of HFRS.
Conclusion/Significance
Hotspots of HFRS were found in Beijing, a novel endemic region, where intervention should be enhanced. Our data suggested that the genetic variation and recombination of SEOV strains was related to the high risk areas of HFRS, which merited further investigation.
Author Summary
Hemorrhagic fever with renal syndrome (HFRS) is caused by Hantaviruses, the enzootic viruses with a worldwide distribution. In China, HFRS is a significant public health problem with more than 10,000 human cases reported annually and the endemic areas of the disease have extended from rural to urban areas and even to central cities in recent years. The HFRS incidence has increased recently and the morbidity seemed to be considerably diverse in different areas in Beijing, the capital of China. With the aim of gaining more information to control this disease, we carried out a spatial analysis of HFRS based on the data from human cases during 2004–2006 and investigated the genetic features of complete S and partial L segment sequences of Seoul virus from natural infected rodent hosts and patients. We found three geo-spatial clusters, i.e., “hotspots” of HFRS in Beijing, where intervention should be enhanced. Our data indicated that the genetic variation and recombination of SEOV might be related to the high risk areas of HFRS in Beijing, which was worthy of further investigation.
doi:10.1371/journal.pntd.0000945
PMCID: PMC3019113  PMID: 21264354
16.  The relationship between mosquito abundance and rice field density in the Republic of Korea 
Background
Japanese encephalitis virus (JEV), the causative agent of Japanese encephalitis (JE), is endemic to the Republic of Korea (ROK) where unvaccinated United States (U.S.) military Service members, civilians and family members are stationed. The primary vector of the JEV in the ROK is Culex tritaeniorhynchus. The ecological relationship between Culex spp. and rice fields has been studied extensively; rice fields have been shown to increase the prevalence of Cx. tritaeniorhynchus. This research was conducted to determine if the quantification of rice field land cover surrounding U.S. military installations in the ROK should be used as a parameter in a larger risk model that predicts the abundance of Cx. tritaeniorhynchus populations.
Mosquito data from the U.S. Forces Korea (USFK) mosquito surveillance program were used in this project. The average number of female Cx. tritaeniorhynchus collected per trap night for the months of August and September, 2002-2008, was calculated. Rice fields were manually digitized inside 1.5 km buffer zones surrounding U.S. military installations on high-resolution satellite images, and the proportion of rice fields was calculated for each buffer zone.
Results
Mosquito data collected from seventeen sample sites were analyzed for an association with the proportion of rice field land cover. Results demonstrated that the linear relationship between the proportion of rice fields and mosquito abundance was statistically significant (R2 = 0.62, r = .79, F = 22.72, p < 0.001).
Conclusions
The analysis presented shows a statistically significant linear relationship between the two parameters, proportion of rice field land cover and log10 of the average number of Cx. tritaeniorhynchus collected per trap night. The findings confirm that agricultural land cover should be included in future studies to develop JE risk prediction models for non-indigenous personnel living at military installations in the ROK.
doi:10.1186/1476-072X-9-32
PMCID: PMC2900240  PMID: 20573242
17.  Secular trends of chickenpox among military population in Israel in relation to introduction of varicella zoster vaccine 1979–2010 
Human Vaccines & Immunotherapeutics  2013;9(6):1303-1307.
Chickenpox is a contagious disease caused by the varicella zoster virus. There is scarce data on long-term trends of chickenpox and its relation to vaccinations practices. We aimed to evaluate trends of chickenpox in a military population during the period 1979–2010 and to assess temporal associations in relation with the introduction of varicella zoster vaccine to the civilian population in Israel in 2000. The archives of the Epidemiology Section of the Israel Defense Forces, where chickenpox is a notifiable disease, were reviewed for all cases of chickenpox from January 1, 1979–December 31, 2010. Annual and monthly incidence rates were calculated and analyzed in relation to vaccine introduction. Between 1979–2000, incidence rates fluctuated around 10 cases per 10,000 soldiers without a clear trend. Since 2000 there has been a dramatic 10-fold decline in incidence, especially notable since 2008, from eight per 10,000 soldiers in 2000 to the lowest rate ever recorded, in 2009, of 0.57 cases per 10,000 soldiers. A seasonal sinusoidal pattern was clearly demonstrated, with rising incidence from November to May followed by a gradual decline to October. The results of this long-term study suggest that the rates of chickenpox in the military population have significantly declined since the introduction of the vaccine to the civilian population in Israel and almost disappeared completely since 2008 as the vaccine was included in the state-funded routine childhood immunization schedule. These findings underscore the need for a strong surveillance system and will aid in determing vaccination policies.
doi:10.4161/hv.23943
PMCID: PMC3901821  PMID: 23412473
young adult; vaccine; vaccination policy; epidemiology; seasonality; chickenpox; varicella zoster virus
18.  Sex Differences in the Incidence and Case Fatality Rates From Hemorrhagic Fever With Renal Syndrome in China, 2004–2008 
Using retrospective hemorrhagic fever with renal syndrome (HFRS) cases in China, we determined that although the incidence of HFRS was higher among males, case fatality rates were higher among females and were age-dependent.
Background. Differences between male and female individuals in response to infectious diseases are an overlooked global health problem.
Methods. The relationship between sex and disease outcome was examined in populations of patients with hemorrhagic fever with renal syndrome (HFRS) in mainland China, where most cases of hantavirus exposure occur. HFRS in China is diagnosed on the basis of symptoms and is confirmed with serological testing. The geographical distribution, incidence, and case fatality rates (CFRs) of HFRS in China were estimated and compared by patient sex and age. In a subset of patients with HFRS, clinical manifestations of HFRS were assessed using latent class analysis and compared by sex.
Results. There were 80,671 HFRS cases reported during the period 2004–2008, with a majority of HFRS cases (39.2%) occurring among individuals 20–39 years of age. The incidence of HFRS was higher among male patients than among female patients for all individuals >10 years of age. There were 945 deaths (CFR, 1.17%) due to HFRS in China during the period 2004–2008. CFRs were higher among women than among men between the ages of 20–39 and ≥50 years of age. There were no sex differences in the geographical distribution of HFRS cases or deaths. Although the prevalence of each clinical marker did not differ by sex, 2 profiles of clinical markers were identified that were related to both severity of disease and sex.
Conclusions. These data illustrate a paradox in which the incidence of disease is greater for males, but the severity of disease outcome is worse for females. Several behavioral, societal, and biological factors are hypothesized to be involved.
doi:10.1093/cid/cir232
PMCID: PMC3146012  PMID: 21628481
19.  Plasmodium vivax Malaria: Status in the Republic of Korea Following Reemergence 
The Korean Journal of Parasitology  2009;47(Suppl):S39-S50.
The annual incidence of Plasmodium vivax malaria that reemerged in the Republic of Korea (ROK) in 1993 increased annually, reaching 4,142 cases in 2000, decreased to 864 cases in 2004, and once again increased to reach more than 2,000 cases by 2007. Early after reemergence, more than two-thirds of the total annual cases were reported among military personnel. However, subsequently, the proportion of civilian cases increased consistently, reaching over 60% in 2006. P. vivax malaria has mainly occurred in the areas adjacent to the Demilitarized Zone, which strongly suggests that malaria situation in ROK has been directly influenced by infected mosquitoes originating from the Democratic People's Republic of Korea (DPRK). Besides the direct influence from DPRK, local transmission within ROK was also likely. P. vivax malaria in ROK exhibited a typical unstable pattern with a unimodal peak from June through September. Chemoprophylaxis with hydroxychloroquine (HCQ) and primaquine, which was expanded from approximately 16,000 soldiers in 1997 to 200,000 soldiers in 2005, contributed to the reduction in number of cases among military personnel. However, the efficacy of the mass chemoprophylaxis has been hampered by poor compliance. Since 2000, many prophylactic failure cases due to resistance to the HCQ prophylactic regimen have been reported and 2 cases of chloroquine (CQ)-resistant P. vivax were reported, representing the first-known cases of CQ-resistant P. vivax from a temperate region of Asia. Continuous surveillance and monitoring are warranted to prevent further expansion of CQ-resistant P. vivax in ROK.
doi:10.3347/kjp.2009.47.S.S39
PMCID: PMC2769212  PMID: 19885334
Plasmodium vivax; malaria; Republic of Korea; reemergence; demilitarized zone; local transmission; unstable malaria; chemoprophylaxis; chloroquine-resistance
20.  Animal Reservoir, Natural and Socioeconomic Variations and the Transmission of Hemorrhagic Fever with Renal Syndrome in Chenzhou, China, 2006–2010 
Background
China has the highest incidence of hemorrhagic fever with renal syndrome (HFRS) worldwide. Reported cases account for 90% of the total number of global cases. By 2010, approximately 1.4 million HFRS cases had been reported in China. This study aimed to explore the effect of the rodent reservoir, and natural and socioeconomic variables, on the transmission pattern of HFRS.
Methodology/Principal Findings
Data on monthly HFRS cases were collected from 2006 to 2010. Dynamic rodent monitoring data, normalized difference vegetation index (NDVI) data, climate data, and socioeconomic data were also obtained. Principal component analysis was performed, and the time-lag relationships between the extracted principal components and HFRS cases were analyzed. Polynomial distributed lag (PDL) models were used to fit and forecast HFRS transmission. Four principal components were extracted. Component 1 (F1) represented rodent density, the NDVI, and monthly average temperature. Component 2 (F2) represented monthly average rainfall and monthly average relative humidity. Component 3 (F3) represented rodent density and monthly average relative humidity. The last component (F4) represented gross domestic product and the urbanization rate. F2, F3, and F4 were significantly correlated, with the monthly HFRS incidence with lags of 4 months (r = −0.289, P<0.05), 5 months (r = −0.523, P<0.001), and 0 months (r = −0.376, P<0.01), respectively. F1 was correlated with the monthly HFRS incidence, with a lag of 4 months (r = 0.179, P = 0.192). Multivariate PDL modeling revealed that the four principal components were significantly associated with the transmission of HFRS.
Conclusions
The monthly trend in HFRS cases was significantly associated with the local rodent reservoir, climatic factors, the NDVI, and socioeconomic conditions present during the previous months. The findings of this study may facilitate the development of early warning systems for the control and prevention of HFRS and similar diseases.
Author Summary
Hemorrhagic fever with renal syndrome (HFRS), a rodent-borne disease caused by hantaviruses, is characterized by fever, haemorrhage, headache, back pain, abdominal pain, and acute kidney injury. China has the highest incidence of HFRS worldwide. Reported cases account for 90% of the total global cases. Approximately 1.4 million HFRS cases were reported in China between 1950 and 2010. During the same time period, >46 000 people died from HFRS, and the fatality rate was 3.29%. A great deal of interest and excitement has developed recently for understanding the role of the environment in the transmission of HFRS. Our article provides evidence that rodent density and behavior depend on natural factors. Changes in animal reservoirs may lead to the emergence of new epidemics and threats to human health. However, economic development may promote a more residential environment, which could inhibit disease transmission from animals to humans by limiting their contact. We combined data about the rodent reservoir, the natural environment, and socioeconomic factors in the model. The results will be helpful for making and prioritizing preventive measures.
doi:10.1371/journal.pntd.0002615
PMCID: PMC3888453  PMID: 24421910
21.  Spatial Analysis of Hemorrhagic Fever with Renal Syndrome in Zibo City, China, 2009–2012 
PLoS ONE  2013;8(6):e67490.
Background
Hemorrhagic fever with renal syndrome (HFRS) is highly endemic in mainland China, where human cases account for 90% of the total global cases. Zibo City is one of the most serious affected areas in Shandong Province China with the HFRS incidence increasing sharply from 2009 to 2012. However, the hotspots of HFRS in Zibo remained unclear. Thus, a spatial analysis was conducted with the aim to explore the spatial, spatial-temporal and seasonal patterns of HFRS in Zibo from 2009 to 2012, and to provide guidance for formulating regional prevention and control strategies.
Methods
The study was based on the reported cases of HFRS from the National Notifiable Disease Surveillance System. Annualized incidence maps and seasonal incidence maps were produced to analyze the spatial and seasonal distribution of HFRS in Zibo City. Then spatial scan statistics and space-time scan statistics were conducted to identify clusters of HFRS.
Results
There were 200 cases reported in Zibo City during the 4-year study period. One most likely cluster and one secondary cluster for high incidence of HFRS were identified by the space-time analysis. And the most likely cluster was found to exist at Yiyuan County in October to December 2012. The human infections in the fall and winter reflected a seasonal characteristic pattern of Hantaan virus (HTNV) transmission. The secondary cluster was detected at the center of Zibo in May to June 2009, presenting a seasonal characteristic of Seoul virus (SEOV) transmission.
Conclusion
To control and prevent HFRS in Zibo city, the comprehensive preventive strategy should be implemented in the southern areas of Zibo in autumn and in the northern areas of Zibo in spring.
doi:10.1371/journal.pone.0067490
PMCID: PMC3696076  PMID: 23840719
22.  Atmospheric Moisture Variability and Transmission of Hemorrhagic Fever with Renal Syndrome in Changsha City, Mainland China, 1991–2010 
Background
The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by environmental determinants. This study aimed to explore the association between atmospheric moisture variability and the transmission of hemorrhagic fever with renal syndrome (HFRS) for the period of 1991–2010 in Changsha, China.
Methods and Findings
Wavelet analyses were performed by using monthly reported time series data of HFRS cases to detect and quantify the periodicity of HFRS. A generalized linear model with a Poisson distribution and a log link model were used to quantify the relationship between climate and HFRS cases, highlighting the importance of moisture conditions. There was a continuous annual oscillation mode and multi-annual cycle around 3–4 years from 1994 to 1999. There was a significant association of HFRS incidence with moisture conditions and the Multivariate El Niño–Southern Oscillation Index (MEI). Particularly, atmospheric moisture has a significant effect on the propagation of HFRS; annual incidence of HFRS was positively correlated with annual precipitation and annual mean absolute humidity.
Conclusions
The final model had good accuracy in forecasting the occurrence of HFRS and moisture condition can be used in disease surveillance and risk management to provide early warning of potential epidemics of this disease.
Author Summary
Hemorrhagic fever with renal syndrome (HFRS), a rodentborne disease caused by Hantaviruses, is characterized by fever, haemorrhage, headache, back pain, abdominal pain, and acute kidney injury. At present, it is endemic in all 31 provinces, autonomous regions, and metropolitan areas in mainland China where human cases account for 90% of the total global cases. Infection rates and population dynamics of hosts are thought to be influenced by climatic factors, especially humidity. Some studies have found that hantaviruses are limited in their spread to high-humidity environments for extended ex vivo stability. Here we provide the evidence that HFRS incidence was strongly associated with moisture conditions, including seasonal variation and annual situation, in Changsha, mainland China, 1991–2010. The results most likely indicate that moisture not only influences growth of food sources that determine rodent population size, thereby affecting the HFRS transmission, but also directly influences rodent activity and hantavirus infectivity. These findings offer insights in understanding possible causes of HFRS transmission, and can be used in disease surveillance and risk management to provide early warning of potential epidemics of this disease.
doi:10.1371/journal.pntd.0002260
PMCID: PMC3674989  PMID: 23755316
23.  Seroconversion for Infectious Pathogens among UK Military Personnel Deployed to Afghanistan, 2008–2011 
Emerging Infectious Diseases  2014;20(12):2015-2022.
Many exposures, and potentially infections, are unreported.
Military personnel are at high risk of contracting vector-borne and zoonotic infections, particularly during overseas deployments, when they may be exposed to endemic or emerging infections not prevalent in their native countries. We conducted seroprevalence testing of 467 UK military personnel deployed to Helmand Province, Afghanistan, during 2008–2011 and found that up to 3.1% showed seroconversion for infection with Rickettsia spp., Coxiella burnetii, sandfly fever virus, or hantavirus; none showed seroconversion for infection with Crimean-Congo hemorrhagic fever virus. Most seroconversions occurred in personnel who did not report illness, except for those with hantavirus (70% symptomatic). These results indicate that many exposures to infectious pathogens, and potentially infections resulting from those exposures, may go unreported. Our findings reinforce the need for continued surveillance of military personnel and for education of health care providers to help recognize and prevent illnesses and transmission of pathogens during and after overseas deployments.
doi:10.3201/eid2012.131830
PMCID: PMC4257834  PMID: 25418685
Afghanistan; serosurveillance; biosurveillance; hantavirus; Crimean-Congo hemorrhagic fever virus; CCHFV; Rickettsia; rickettsiae; Q fever; Coxiella burnetii; sandfly fever virus; undifferentiated fevers; United Kingdom; military; deployment; bacteria; viruses; seroconversion
24.  Clinical and Molecular Epidemiological Features of Hemorrhagic Fever with Renal Syndrome in Korea over a 10-year Period 
Background
Laboratory diagnosis of hemorrhagic fever with renal syndrome (HFRS), an infectious disease caused by rodent-borne hantaviruses in Asia and Europe, depends primarily on serological methods. Since the advent of such serodiagnostic tests, few reports are available about the clinical and molecular epidemiological features of HFRS.
Objectives
To investigate the epidemioclinical features of HFRS treated at a tertiary-care teaching hospital in Seoul over a 10-year period.
Study design
Medical records of HFRS patients, visited to a tertiary-care teaching hospital during February 2002 to February 2012, were reviewed. Sera from patients were tested for Hantaan virus (HTNV) and Seoul virus (SEOV) RNA using RT-PCR.
Results
Among 35 HFRS patients (mean age was 44.2 ± 14.7 years), 29 were male (82.9%). Acute renal failure developed in 27 patients (77.1%), and 12 patients (34.3%) were admitted to the intensive care unit (ICU). Conjunctival injection (OR 10.32, 95% CI 1.09–97.77, P = .04) and initial serum albumin less than 3 g/dL (OR 22.83, 95% CI 1.45–359.93, P = .03) were risk factors for ICU admission. Of 35 acute-phase sera, 11 (31.4%) were positive for HTNV RNA. None were positive for SEOV RNA.
Conclusions
HFRS was characterized by the clinical triad of fever, renal insufficiency and gastrointestinal symptoms. Conjunctival injection and serum albumin level were related to severity. Large scaled multi-center study is needed to enhance an insight to epidemioclinical characteristics of HFRS in Korea.
doi:10.1016/j.jcv.2013.06.027
PMCID: PMC4153883  PMID: 23871164
Hantaan virus; Hantavirus; Hemorrhagic fever with renal syndrome; Korea
25.  Incidence of insulin-requiring diabetes in the US military 
Diabetologia  2009;52(10):2087-2091.
Aims/hypothesis
The aim of the study was to determine age- and race-related, and overall incidence rates of insulin-requiring diabetes in adults in the US military.
Methods
Electronic records for admissions to US military and Tricare hospitals during 1990–2005 and visits to military clinics during 2000–2005 were identified using the Career History Archival Medical and Personnel System at the Naval Health Research Center, San Diego, CA, USA. Population data were obtained from the Defense Manpower Data Center and Defense Medical Epidemiology Database.
Results
In men there were 2,918 new cases of insulin-requiring diabetes in 20,427,038 person-years at ages 18–44 years (median age 28 years) for a total age-adjusted incidence rate of 17.5 per 100,000 person-years (95% CI 16.4–18.6). Incidence rates were twice as high in black men as in white men (31.5 vs 14.5 per 100,000, p < 0.001). In women there were 414 new cases in 3,285,000 person-years at ages 18–44 years (median age 27 years), for a total age-adjusted incidence rate of 13.6 per 100,000 (95% CI 12.4–14.9). Incidence rates were twice as high in black women as in white women (21.8 vs 9.7 per 100,000, p < 0.001). In a regression model, incidence of insulin-requiring diabetes peaked annually in the winter–spring season (OR 1.46, p < 0.01). Race and seasonal differences persisted in the multivariate analysis.
Conclusions/interpretation
Differences in incidence rates by race and season suggest a need for further research into possible reasons, including the possibility of a contribution from vitamin D deficiency. Cohort studies using prediagnostic serum 25-hydroxyvitamin D should be conducted to further evaluate this relationship.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-009-1449-x) contains supplementary material which is available to authorised users.
doi:10.1007/s00125-009-1449-x
PMCID: PMC2744779  PMID: 19629431
Incidence rates; Insulin-requiring diabetes; Race; Seasonality; Sex; Vitamin D; Young adults

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