A Case-control Study of Risk Sources for Severe Fever with Thrombocytopenia Syndrome in Hubei Province, China

A Case-control Study of Risk Sources for Severe Fever with Thrombocytopenia Syndrome in Hubei Province, China

International Journal of Infectious Diseases 55 (2017) 86–91 Contents lists available at ScienceDirect International Journal of Infectious Diseases ...

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International Journal of Infectious Diseases 55 (2017) 86–91

Contents lists available at ScienceDirect

International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid

A Case-control Study of Risk Sources for Severe Fever with Thrombocytopenia Syndrome in Hubei Province, China Xuesen Xinga,1, Xuhua Guana,1, Li Liua , Junqiang Xua , Guoming Lia , Jianbo Zhana , Gongping Liua , Xiaoqing Jianga , Xingfu Shena , Yongzhong Jianga , Yang Wua , Hao Zhangb , Jing Huangc, Fan Dingd, Sha Shaa , Man Liua , Faxian Zhana,* a Hubei Provincial Center for Disease Control and Prevention, Wuhan,China. No. 6 north Zhuodaoquan Road, Hongshan District, Wuhan City, Hubei Province, China2 b Yichang City Center for Disease Control and Prevention, Yichang, China3 c Enshi County Center for Disease Control and Prevention, Enshi, China4 d Chinese Center for Disease Control and Prevention, Beijing, China5

A R T I C L E I N F O

A B S T R A C T

Article history: Received 20 November 2016 Received in revised form 3 January 2017 Accepted 5 January 2017 Corresponding Editor: Eskild Petersen, Aarhus, Denmark

Background: Severe fever with thrombocytopenia syndrome (SFTS), an emerging infectious disease caused by a novel bunyavirus, was discovered in rural areas of Central China in 2009. Methods: A case-control study based on hospital data was applied to detect the potential risk sources for SFTS in SFTS-endemic counties in Hubei Province. Cases were defined as hospitalized SFTSV confirmed patients. Controls were randomly selected from non-SFTSV patients in the same hospital ward within 2 weeks of inclusion of the cases, and they were matched by age (+/ 5 years) and gender according to 1:2 matching condition. Results: 68 cases and 136 controls participated in this study. In multivariate analysis, “Contact with cattle tick” was the major risk source (Conditional Logistic Regression OR-MH = 8.62, 95% CI = 1.79-41.51), outdoor activities and working in weeds or hillside fields could increase risk of cattle tick contact and SFTS infection (Conditional Logistic Regression OR-MH = 8.82, 95% CI = 1.69-46.05, P value = 0.01). Conclusion: Our results suggested cattle might be dominant hosts in SFTS-endemic regions in Hubei Province, which provided clues to transmission mechanism of “vectors, host animals, and humans”, thus more effectively preventing and controlling the disease. © 2017 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Keywords: case-control severe fever with thrombocytopenia syndrome risk factors tick exposure cattle tick endemic

Introduction Severe Fever with Thrombocytopenia Syndrome (SFTS) is a newly emerging infectious disease caused by the SFTS virus, a genera in the family Bunyaviridae.1,2 Its major clinical symptoms are fever, thrombocytopenia, gastrointestinal symptoms, and leukocytopenia. SFTS was first reported in the rural areas of Central China’s Hubei and Henan Provinces in 2009. with a casefatality rate of up to 30%.3 During 2011 and 2014, 5352 suspected, probable, and lab-confirmed SFTS cases were reported in

* Corresponding author. Tel.: +86 027 87652061. E-mail address: [email protected] (F. Zhan). 1 These authors contributed equally to this work: Xuesen Xing, Xuhua Guan. 2 E-Mail: [email protected]. 3 E-Mail: [email protected]. 4 E-Mail: [email protected]. 5 E-Mail: [email protected].

23 provinces, of which 2750 (51.4%) were lab-confirmed cases. Henan, Shandong, Hubei, Anhui, Liaoning, Zhejiang, and Jiangsu reported 99.3% of those lab-confirmed cases. The fatality rate of the lab-confirmed cases was 7.9%.4 Furthermore, SFTS has also been recognized in Japan, South Korea, and the United States.5–7 In recent years, it has become an increasingly important global health threat. The epidemic SFTS season appears to be between April and October, and its peak occurs from May to July. The seasonal distribution of SFTS cases is synchronous with the ecological habits of ticks.1–4 Most (88.3% of) SFTS cases involved peasants living in wooded or hilly areas or working in the fields. People between the ages of 50 and 74 years accounted for 67.6% of all cases.4 Some patients with an SFTS diagnosis reported a history of tick bite.1–4,8 In the study focusing on Jiangsu Province, a multiple variable logistic regression analysis showed that raising goats, raising cattle, farming, and grazing were risk factors for SFTSV

http://dx.doi.org/10.1016/j.ijid.2017.01.003 1201-9712/© 2017 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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infection.9,10 Fan Ding et al. found that the odds ratio for SFTS was 2.4 to 4.5 fold higher for patients who reported tick bites or the presence of ticks in their living areas. Other independent risk factors included cat or cattle ownership and the reported presence of weeds and shrubs in the working environment.11 SFTSV RNA has been detected in ticks, animals, and SFTS cases, and the nucleic acid sequences have high homology (93-100%) among them.1–4These findings suggest that ticks are the insect vectors for transmitting the virus to humans. However, several studies have provided evidence to highlight the risk of person-to-person transmission of SFTSV through direct blood contact with the patient, especially when the index patient has a high blood virus load.3,12,13 Until now, the mode of SFTSV transmission has remained unclear.9,10 The risk factors for SFTS infection are diverse, did not clarify what kind of tick source exposure at high risk, and there is a lack of targeted prevention and control measures for use in the regions of endemicity. Further investigations regarding the risk sources are needed to effectively prevent and control the disease. Here, we report the results of such a study conducted in Hubei Province, China.

The professionals from provincial, city, and county CDCs were trained to interview and administer a standardized questionnaire to cases and controls. Participants/patients were asked for their demographic information (age, gender, ethnic group, home address, occupation), and they were asked questions concerning their living environments (e.g., landform, environment, poultry, or animal raising, house rats, wild animals), exposure history within 2 weeks prior to fever onset (e.g., travel history, tick touch or bite, contact with suspected SFTS patients, contact with similar cases), and contact with animals and vectors (animal species and types of vectors). Completed questionnaires were systematically verified by provincial CDC study coordinators for data completeness. Data were double entered into an EpiData 3.02 (the EpiData Association, Denmark, Europe) database, and this data entry was followed by consistency checking.

Materials and Methods

Statistical Analysis

Study design

Pearson Chi-Squared and Fisher’s exact tests were used to compare the categorical variables, when appropriate. Maximum likelihood estimates for the matched odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated using a conditional logistic regression model and the Wald test. SPSS version 12.0 (IBM, Armonk, NY, USA) was used for all the statistical analyses. All the tests were 2-tailed, and the statistical significance level was set at P <0.05.

An individual matched case-control study design based on hospital data was applied to detect the potential risk sources for SFTS. Cases were defined as hospitalized patients with a fever (body temperature 38  C) associated with thrombocytopenia (platelet count < 100  109/L) and leukopenia (peripheral white blood cell count < 3.0  109/L), and who tested positive in the laboratory for SFTSV infection (i.e., qRT-PCR or IgM ELISA during the acute illness phase). Controls were defined as matched patients with negative laboratory test results for SFTSV infection (i.e., qRTPCR, IgM and IgG ELISA during the acute phase). The controls were randomly selected from a pool of patients who were first hospitalized in the same ward within 2 weeks of inclusion of the cases, and they were matched by age (+/ 5 years) and gender according to a 1:2 matching condition. All Level 2 and above hospitals including the national, provincial, municipal, county-level hospitals in Hubei Province carried out active surveillance of SFTS in the regions of endemicity in Hubei Province in 2011. When a patient with fever (body temperature 38  C) went to the hospital, the doctor conducted a routine blood test. A patient suspected to have a fever (body temperature 38  C) associated with thrombocytopenia and leukopenia had to be admitted to hospital, and all those cases were reported to the Provincial Center for Disease Control and Prevention (CDC) via the electronic National Notifiable Diseases Surveillance System. Field investigations of suspect patients were completed as soon as they were reported by the investigators from the local CDC, and the blood samples were gathered for further pathogenic identification. Meanwhile, the investigators also searched for the controls according to the matching requirements and collected blood samples for further pathogenic identification. Experimental detection TaqMan quantitative real-time reverse transcription PCR (qRTPCR) was performed on all samples using a certified real-time RTPCR kit for clinical diagnosis (SFDA registration no. 340166, China). The quantitative real-time RT-PCR assay was able to discriminate SFTSV infection from other vector-borne viral diseases in humans, with a potential detection limit of 10 viral RNA copies/ml or 10 TCID (50)/ml virus load.14 Serological antibodies against SFTSV were detected using a double-antigen sandwich ELISA (the double-

antigen cutoff value was 21.56PP (the mean +3 x SD PP values in negative-control sera]].15 Data Collection

Ethical approval The National Health and Family Planning Commission determined it was necessary to collect SFTS data as part of a continuing public health investigation into an emerging outbreak. The study was approved by the institutional review board of the Hubei Provincial Center for Disease Control and Prevention. Written informed consent was obtained from all the participants after they were provided with detailed descriptions of the potential benefits of the study. Results Characteristics of the study population A total of 204 persons participated in this study, including 68 cases and 136 matched controls; therefore, the matching ratio was about 1:2. The cases came from 13 counties. The most frequently reported cases were from Guangshui county (23.5%, 16/ 68), followed by Macheng county (19.1%, 13/68) (Figure 1). Among the 68 cases, 34 had only positive PCR results, 6 had only positive IgM ELISA results, and 28 had both positive PCR and IgM ELISA results. Participants between the ages of 40 and 69 years old made up the majority (79.4%) of the cases, the female to male ratio was 1.06:1 (35/33), and 92.6% were peasants (63/68) (Table 1). No demographic differences (e.g., age, gender, ethnicity, and occupation) were observed between the cases and the controls (Table 1). Univariate analysis Matched case control analysis in this study was adjusted for age and sex matching. As shown in the univariate analysis, living environments characterized by many weeds and much hillside fieldwork were potential risk factors for SFTS (Table 2).

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Table 1 Demographic characteristics of the 68 cases and 136 controls in Hubei Province, China, 2011. Variable

Ethnicity Sex Age group

Occupation

Classification

Han Other Male Female 0-39 40-49 50-59 60-69 70 Peasant Other

Number exposed Cases N = 68 (%)

Controls N = 136(%)

68(100.00) 0(0.00) 33(48.53) 35(51.47) 4(5.88) 14(20.59) 24(35.29) 16(23.53) 10(14.71) 63(92.60) 5(7.40)

133(97.79) 3(2.21) 64(47.06) 72(52.94) 5(3.68) 34(25.00) 45(33.09) 33(24.26) 19(13.97) 117(86.00) 19(14.00)

ß2

P value

1.52

0.22

0.04

0.84

0.97

0.91

1.91

0.17

The tick exposure source was further classified into 4 subgroups; namely, “see ticks,” ‘contact with ticks,” “catch ticks,” and “bitten by ticks” (Table 2). Among the different modes, “bitten by ticks’ showed the highest risk of SFTS (OR-MH = 16.00, 95% CI = 3.68-69.59), and these bites were mainly caused by animal ticks (animal tick indicates a tick that has bitten an animal) (ORMH = 20.00, 95% CI = 2.56-156.24). Among the various types of ticks, ‘cattle ticks’ were associated with the highest risk source of SFTS (OR-MH for see ticks = 12.00, 95% CI = 2.97-48.50; OR-MH for contact with ticks = 8.25, 95% CI = 2.48-27.42; OR-MH for catch ticks = 15.00, 95% CI = 1.81-124.35), followed by dog ticks and environment ticks(Environment tick indicates a tick parasitic in the grass, tea, or other environment.) (Table 2).

bitten by environment ticks OR-MH = 12.00, 95% CI = 1.44-99.67) (Table 3). On the basis of the multivariate conditional logistic regression analysis of tick exposure sources, the further multivariate conditional logistic regression analysis of the relationship between tick exposure (“contact with cattle ticks” and “bitten by environment ticks”) and working and living conditions (work time protection, skin damage at work, and so on) found that “cattle tick contact” was independent risk source (Conditional Logistic Regression OR-MH = 8.82, 95% CI = 1.69-46.05, P value = 0.01) (Table 4).

Multivariate analysis

Previous studies have also shown that “tick exposure” is a major risk factor for SFTS infection 1–4,8,11, but no study has yet shown which source of tick exposure posed the greatest risk; i.e., animals, environment, etc. Our study found that “contact with cattle ticks” was a major risk source after adjusting for tick exposure, and outdoor activities and working in weeds and in hillside fields could increase the risk source of cattle tick contact and, therefore, SFTS infection.

On the basis of the univariate analysis, the multivariate conditional logistic regression analysis of tick exposure sources found that “contact with cattle ticks” and “bitten by environment ticks” were risk sources after adjusting for tick exposure (Conditional Logistic Regression OR-MH for contact with cattle ticks = 7.70, 95% CI = 1.64-36.21; Conditional Logistic Regression for

Discussion

Figure 1. Distribution of patients and controls in different cities. This map was created by MapInfo 7.0.

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Table 2 Variables associated with SFTS and the univariate analysis of 68 cases and 136 controls in Hubei Province, China, 2011. Factor/source

Weeds

Field work

Pick Work time protection Skin damage at work See ticksa

Contact ticksb

Catch ticksd

Bitten by tickse

Bitten by mosquitoes Bitten by other vectors

Classification

Number exposed

OR-MH*(95%CI)

ß2-MH

P value

Cases N = 68(%)

Controls N = 136(%)

around residence working area sit on grassland hillside flat woodland yes yes yes

59(86.8) 51(75.0) 40(58.8) 32(47.1) 10(14.7) 4(5.9) 10(14.7) 1(1.5) 17(25.0)

74(54.4) 64(47.1) 33(24.3) 22(16.2) 26(19.1) 4(2.9) 10(7.4) 7(5.1) 20(14.7)

6.50(2.63-16.04) 3.92(1.87-8.24) 5.27(2.52-11.04) 6.25(2.74-14.27) 0.73(0.33-1.62) 2.00(0.50-8.00) 3.50(0.99-28.48) – 2.17(0.97-4.83)

22.51 15.04 23.50 22.62 0.62 1.00 3.85 – 3.77

<0.0001 0.0001 <0.0001 <0.0001 0.43 0.32 0.050 0.33# 0.052

yes cattle dog pig poultry cat goat environment yes dog Cattlec yes dog cattle yes animalsf environmentg yes yes

47(69.1) 21(30.9) 13(19.1) 3(4.4) 5(7.4) 1(1.5) 1(1.5) 23(33.8) 30(44.1) 13(19.1) 19(27.9) 16(23.5) 9(13.2) 8(11.8) 16(23.5) 10(14.7) 6(8.8) 15(22.1) 16(23.5)

30(22.1) 9(6.6) 9(6.6) 2(1.5) 4(2.9) 3(2.2) 1(0.7) 16(11.8) 14(10.3) 5(3.7) 9(6.6) 5(3.7) 1(0.7) 2(1.5) 2(1.5) 1(0.7) 1(0.7) 32(23.5) 33(24.3)

8.11(3.53-18.62) 12.00(2.97-48.50) 3.13(1.25-7.79) 3.00(0.50-17.95) 2.65(0.58-12.37) 0.67(0.069-6.41) 2.0(0.13-31.98) 4.00(1.79-8.95) 7.57(3.02-18.97) 5.20(1.75-15.47) 8.25(2.48-27.42) 7.75(2.57-23.41) 18.00(2.28-142.08) 15.00(1.81-124.35) 16.00(3.68-69.59) 20.00(2.56-156.24) 12.00(1.44-99.68) 0.88(0.38-2.07) 0.94(0.39-2.23)

41.80 24.75 7.23 1.60 2.11 0.13 0.25 15.00 32.06 12.97 20.02 18.23 14.45 10.89 25.00 16.41 8.64 0.083 0.022

<0.0001 <0.0001 0.0072 0.21 0.15 0.72 0.56* 0.0001 <0.0001 0.0003 <0.0001 <0.0001 0.0001 0.0010 <0.0001 0.0001 0.0033 0.77 0.88

OR-MH*: Matched case control analysis was adjusted for age and sex matching. See ticksa indicates a person who has seen ticks, but has not touched, caught, or been bitten by ticks without protection within 2 weeks prior to fever onset. Contact ticksb indicates a person who has physically touched, caught, or been bitten by ticks without protection within 2 weeks prior to fever onset. Cattle tickb indicates a tick that bites cattle Catch ticksd indicates a person who has only physically caught ticks or been bitten by ticks without protection within 2 weeks prior to fever onset. Bitten by tickse indicates a person who has only been bitten by ticks without protection within 2 weeks prior to fever onset. Animals tickf indicates a tick that has bitten an animal. Environment tickg indicates a tick parasitic in the grass, tea, or other environment. * indicates Fisher exact.

Although 92.6% of our cases (63/68) were peasants, there was no significant occupational difference between the cases and controls (P = 0.17). Peasants often labor, and they are commonly inclined to touch the fur of domestic animals including cattle,

buffaloes, goats, dogs and so on, thus exposing them to potential tick bites. Previous studies have detected SFTSV in ticks collected from several domestic animals, including cattle, buffaloes, goats, dogs, and cats. Furthermore, serology positive for IgM antibodies

Table 3 Risk Sources associated with SFTS in a tick exposure multivariate analysis of 68 cases and 136 controls in Hubei Province, China, 2011.

* OR-MH*: Matched case control analysis was adjusted for age and sex matching.

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X. Xing et al. / International Journal of Infectious Diseases 55 (2017) 86–91 Table 4 Risk Sources associated with SFTS in the relationship multivariate analysis between tick exposure and working and environment exposure of 68 cases and 136 controls in Hubei Province, China, 2011.

* OR-MH*: Matched case control analysis was adjusted for age and sex matching. # indicates Fisher exact.

against SFTSV has been observed in dogs, cattle, and other domestic animals in villages where the patients lived 1,16–18. The differences in the rates of SFTSV infections among various animal species and regions were statistically significant. In Laizhou and Penglai counties of the Shandong Province, 69.5% of sheep, 60.5% of cattle, 37.9% of dogs, and 47.4% of chickens were seropositive for SFTSV, and the prevalence of SFTSV RNA was ranging from 1.7% to 5.3% 19 . In Jiangsu Province, 66.8% of goats, 28.2% of cattle, 7.4% of dogs, 4.7% of pigs, 1.2% of chickens, 1.7% of geese, 4.4% of rodents, and 2.7% of hedgehogs were seropositive for SFTSV, and the Multiple variable logistic regression analysis showed that raising cattle and so on were risk factors for SFTS virus infection among farmers 10 . In Hubei Province, the seropositivity rate was the highest among cattle (73.7%-80.0%), followed by goats (36.7-59.1%) and dogs (55.0%), and the positive rate of SFTSV RNA was also highest in cattle (26.3%), followed by goats (9.1%) 20,21. Our multivariate conditional logistic regression analysis of tick exposure sources showed that “contact with cattle ticks” including touching ticks, catching ticks, or bitten by ticks and “bitten by environment ticks” were risk sources for SFTSV infection (Conditional Logistic Regression OR-MH for contact with cattle ticks = 7.70, 95% CI = 1.64-36.21; Conditional Logistic Regression for bitten by environment ticks OR-MH = 12.00, 95% CI = 1.44-99.67). Ticks are commonly found in humid scrubby forests, meadows, or peatlands, and there is an obvious seasonal distribution of SFTS cases. The endemic starts around March, peaks between May and July, and ends around November, which is highly correlated with the ecological habits of ticks 1–3,22. Previous several studies showed that grazing, grass mowing, shrub, forest, and rainfed cropland areas where the ticks commonly lived were associated with high risk of SFTS incidence 9,10,17.but no study has yet showed which source of tick exposure posed the greatest risk; i.e., animals, environment, etc. On the basis of the multivariate conditional logistic regression analysis of tick exposure sources, our further multivariate conditional logistic regression analysis of the relationship between tick exposure (“contact with cattle ticks” and “bitten by environment ticks”) and working and living conditions (work time protection, skin damage at work, and so

on) showed that “cattle tick contact” was independent risk source (Conditional Logistic Regression OR-MH = 8.82, 95% CI = 1.69-46.05, P value = 0.01).In addition, previous studies have revealed that any potential exposure to ticks, especially living and working with domesticated animals presenting high SFTSV antibodies, including goats, dogs, cattle, pigs, and chickens, increased SFTS incidence rates 10,11,17,19,23. In summary, our study provided further evidence that cattle might be major amplifying and reservoir hosts in SFTSendemic regions in Hubei Province. Haemaphysalis longicornis from domesticated animals are the dominant species of tick in endemic regions, and the nucleic acid sequences of viruses isolated from ticks have high homology (93%– 100%) with SFTSV isolated from patients 8,19. In Hubei Province, 4 tick species from cattle are found, including Haemaphysalis longicornis (70.8%), Hyalomma detritum (26.5%), Rhipicephalus microplus (1.9%), and Ixodes sinensis (0.8%), but SFTSV RNA is only detected in Haemaphysalis longicornis[20].Thus, Haemaphysalis longicornis might be the major vector of SFTSV, and its geographic distribution and density might play a central role in the risk of SFTSV infection among humans. The results of our study are subject to several limitations. First, one fundamental selection/surveillance bias rests in the case definition of SFTS. In regions of endemicity, clinicians may be inclined to only report or think about SFTS when the patient presents with epidemiological links, such as tick bites or residing in hilly areas, hence excluding explorations of risk factors in these particular areas. In order to reduce this bias, we carried out strict training and flow control. The clinicians had to conduct routine blood tests for every patient with fever (38  C), and every patient with fever (38  C) associated with thrombocytopenia and leukopenia had to be reported to the local CDC, which was responsible for the investigation of epidemiology and inquired into the patients’ exposure histories. The investigators from the local CDC first checked medical records. The patients with epidemiological links, such as tick bites or residing in hilly areas, according to clinician reports, were not included in this study. Second, biases could have occurred since we only selected our controls from hospitals. These controls may not have been drawn

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from the same environments (e.g., they may only reside in low-risk areas), which would have overpowered the transmission risks associated with ticks or outdoor activities. However, this variable may have been indirectly controlled in our analysis because most of our selected study hospitals were located in hilly areas. It is therefore likely that controls and cases came from the same areas surrounding the study hospitals. In conclusion, our study results revealed that “cattle tick exposure” including touching ticks, catching ticks, or bitten by ticks was a major risk source for SFTS infection, and that cattle might be the dominant hosts in the regions of SFTS-endemicity in Hubei Province. Hopefully, we will provide clues to transmission mechanism of “vectors, host animals, and humans” that can be used for further study, thus more effectively preventing and controlling the disease. Conclusions Our results suggested cattle might be dominant hosts in SFTSendemic regions in Hubei Province, which provided clues to transmission mechanism of “vectors, host animals, and humans”, thus more effectively preventing and controlling the disease. Conflicts of Interest This manuscript has not been published or presented elsewhere in part or in entirety, and is not under consideration by another journal. All study participants provided informed consent, and the study design was approved by the institutional review board of the Hubei Provincial Center for Disease Control and Prevention. All the authors have approved the manuscript and agree with submission to your esteemed journal. There are no conflicts of interest to declare. Acknowledgments This study was supported by Hubei Province’s Outstanding Medical Academic Leader program. We are grateful to the China CDC and all CDC levels and hospitals in Hubei Province for their help in our field investigations and study design. References 1. Yu XJ, Liang MF, Zhang SY, Liu Y, Li JD, Sun YL, et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 2011;364(16):1523–32. doi:http://dx.doi.org/10.1056/NEJMoa1010095. 2. Xu B, Liu L, Huang X, Ma H, Zhang Y, Du Y, et al. Metagenomic analysis of fever, thrombocytopenia and leukopenia syndrome (FTLS) in Henan Province, China: discovery of a new bunyavirus. PLoS Pathog 2011;7(11):e1002369. doi:http:// dx.doi.org/10.1371/journal.ppat.1002369. 3. Li D. A highly pathogenic new bunyavirus emerged in China. Emerg Microbes Infect 2013;2(1):e1. doi:http://dx.doi.org/10.1038/emi.2013.1. 4. Li Yi, Zhou Hang, Mu Di, Yin Wenwu, Yu H. Epidemiological analysis on severe fever with thrombocytopenia syndrome under the national surveillance data from 2011 to 2014,China. Zhonghua Liu Xing Bing Xue Za Zhi 2015;6(36):598– 602.

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