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

journal homepage: www.elsevier.com/locate/ijid

A Case-control Study of Risk Sources for Severe Fever with

Thrombocytopenia Syndrome in Hubei Province, China

a,1 a,1 a a a a

Xuesen Xing , Xuhua Guan , Li Liu , Junqiang Xu , Guoming Li , Jianbo Zhan ,

a a a a a b

Gongping Liu , Xiaoqing Jiang , Xingfu Shen , Yongzhong Jiang , Yang Wu , Hao Zhang ,

c d a a a,

Jing Huang , Fan Ding , Sha Sha , Man Liu , Faxian Zhan *

Hubei Provincial Center for Disease Control and Prevention, Wuhan,China. No. 6 north Zhuodaoquan Road, Hongshan District,

Wuhan City, Hubei Province, China

b 3

Yichang City Center for Disease Control and Prevention, Yichang, China

c 4

Enshi County Center for Disease Control and Prevention, Enshi, China

d 5

Chinese Center for Disease Control and Prevention, Beijing, China

A R T I C L E I N F O A B S T R A C T

Article history: Background: Severe fever with thrombocytopenia syndrome (SFTS), an emerging infectious disease

Received 20 November 2016

caused by a novel bunyavirus, was discovered in rural areas of Central China in 2009.

Received in revised form 3 January 2017

Methods: A case-control study based on hospital data was applied to detect the potential risk sources for

Accepted 5 January 2017

SFTS in SFTS-endemic counties in Hubei Province. Cases were deﬁned as hospitalized SFTSV conﬁrmed

Corresponding Editor: Eskild Petersen,

patients. Controls were randomly selected from non-SFTSV patients in the same hospital ward within

Aarhus, Denmark

2 weeks of inclusion of the cases, and they were matched by age (+/À 5 years) and gender according to

1:2 matching condition.

Keywords:

Results: 68 cases and 136 controls participated in this study. In multivariate analysis, “Contact with cattle

case-control

tick” was the major risk source (Conditional Logistic Regression OR-MH = 8.62, 95% CI = 1.79-41.51),

severe fever with thrombocytopenia

syndrome outdoor activities and working in weeds or hillside ﬁelds could increase risk of cattle tick contact and

risk factors SFTS infection (Conditional Logistic Regression OR-MH = 8.82, 95% CI = 1.69-46.05, P value = 0.01).

tick exposure Conclusion: Our results suggested cattle might be dominant hosts in SFTS-endemic regions in Hubei

cattle tick

Province, which provided clues to transmission mechanism of “vectors, host animals, and humans”, thus

endemic

more effectively preventing and controlling the disease.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-

nc-nd/4.0/).

Introduction 23 provinces, of which 2750 (51.4%) were lab-conﬁrmed cases.

Henan, Shandong, Hubei, Anhui, Liaoning, Zhejiang, and Jiangsu

Severe Fever with Thrombocytopenia Syndrome (SFTS) is a reported 99.3% of those lab-conﬁrmed cases. The fatality rate of the

newly emerging infectious disease caused by the SFTS virus, a lab-conﬁrmed cases was 7.9%. Furthermore, SFTS has also been

1,2 5–7

genera in the family Bunyaviridae. Its major clinical symptoms recognized in Japan, South Korea, and the United States. In

are fever, thrombocytopenia, gastrointestinal symptoms, and recent years, it has become an increasingly important global health

leukocytopenia. SFTS was ﬁrst reported in the rural areas of threat.

Central China’s Hubei and Henan Provinces in 2009. with a case- The epidemic SFTS season appears to be between April and

fatality rate of up to 30%. During 2011 and 2014, 5352 suspected, October, and its peak occurs from May to July. The seasonal

probable, and lab-conﬁrmed SFTS cases were reported in distribution of SFTS cases is synchronous with the ecological habits

1–4

of ticks. Most (88.3% of) SFTS cases involved peasants living in

wooded or hilly areas or working in the ﬁelds. People between the

* Corresponding author. Tel.: +86 027 87652061. ages of 50 and 74 years accounted for 67.6% of all cases. Some

–

E-mail address: [email protected] (F. Zhan). 1 4,8

patients with an SFTS diagnosis reported a history of tick bite.

These authors contributed equally to this work: Xuesen Xing, Xuhua Guan.

2 In the study focusing on Jiangsu Province, a multiple variable

E-Mail: [email protected].

3 logistic regression analysis showed that raising goats, raising

E-Mail: [email protected].

E-Mail: [email protected]. cattle, farming, and grazing were risk factors for SFTSV 5

E-Mail: [email protected].

http://dx.doi.org/10.1016/j.ijid.2017.01.003

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

X. Xing et al. / International Journal of Infectious Diseases 55 (2017) 86–91 87

9,10

infection. Fan Ding et al. found that the odds ratio for SFTS was antigen cutoff value was 21.56PP (the mean +3 x SD PP values in

2.4 to 4.5 fold higher for patients who reported tick bites or the negative-control sera]].

presence of ticks in their living areas. Other independent risk

factors included cat or cattle ownership and the reported presence Data Collection

of weeds and shrubs in the working environment. SFTSV RNA has

been detected in ticks, animals, and SFTS cases, and the nucleic acid The professionals from provincial, city, and county CDCs were

1–4

sequences have high homology (93-100%) among them. These trained to interview and administer a standardized questionnaire

ﬁndings suggest that ticks are the insect vectors for transmitting to cases and controls. Participants/patients were asked for their

the virus to humans. However, several studies have provided demographic information (age, gender, ethnic group, home

evidence to highlight the risk of person-to-person transmission of address, occupation), and they were asked questions concerning

SFTSV through direct blood contact with the patient, especially their living environments (e.g., landform, environment, poultry, or

3,12,13

when the index patient has a high blood virus load. animal raising, house rats, wild animals), exposure history within

Until now, the mode of SFTSV transmission has remained 2 weeks prior to fever onset (e.g., travel history, tick touch or bite,

9,10

unclear. The risk factors for SFTS infection are diverse, did not contact with suspected SFTS patients, contact with similar cases),

clarify what kind of tick source exposure at high risk, and there is a and contact with animals and vectors (animal species and types of

lack of targeted prevention and control measures for use in the vectors). Completed questionnaires were systematically veriﬁed

regions of endemicity. Further investigations regarding the risk by provincial CDC study coordinators for data completeness. Data

sources are needed to effectively prevent and control the disease. were double entered into an EpiData 3.02 (the EpiData Association,

Here, we report the results of such a study conducted in Hubei Denmark, Europe) database, and this data entry was followed by

Province, China. 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

An individual matched case-control study design based on likelihood estimates for the matched odds ratios (ORs) and

hospital data was applied to detect the potential risk sources for corresponding 95% conﬁdence intervals (95%CIs) were calculated

SFTS. Cases were deﬁned as hospitalized patients with a fever using a conditional logistic regression model and the Wald test.

(body temperature 38 C) associated with thrombocytopenia SPSS version 12.0 (IBM, Armonk, NY, USA) was used for all the

(platelet count < 100 Â 10 /L) and leukopenia (peripheral white statistical analyses. All the tests were 2-tailed, and the statistical

blood cell count < 3.0 Â 10 /L), and who tested positive in the signiﬁcance level was set at P <0.05.

laboratory for SFTSV infection (i.e., qRT-PCR or IgM ELISA during

the acute illness phase). Controls were deﬁned as matched patients Ethical approval

with negative laboratory test results for SFTSV infection (i.e., qRT-

PCR, IgM and IgG ELISA during the acute phase). The controls were The National Health and Family Planning Commission deter-

randomly selected from a pool of patients who were ﬁrst mined it was necessary to collect SFTS data as part of a continuing

hospitalized in the same ward within 2 weeks of inclusion of public health investigation into an emerging outbreak. The study

the cases, and they were matched by age (+/À 5 years) and gender was approved by the institutional review board of the Hubei

according to a 1:2 matching condition. Provincial Center for Disease Control and Prevention. Written

All Level 2 and above hospitals including the national, informed consent was obtained from all the participants after they

provincial, municipal, county-level hospitals in Hubei Province were provided with detailed descriptions of the potential beneﬁts

carried out active surveillance of SFTS in the regions of endemicity of the study.

in Hubei Province in 2011. When a patient with fever (body

temperature 38 C) went to the hospital, the doctor conducted a Results

routine blood test. A patient suspected to have a fever (body

temperature 38 C) associated with thrombocytopenia and Characteristics of the study population

leukopenia had to be admitted to hospital, and all those cases

were reported to the Provincial Center for Disease Control and A total of 204 persons participated in this study, including

Prevention (CDC) via the electronic National Notiﬁable Diseases 68 cases and 136 matched controls; therefore, the matching ratio

Surveillance System. Field investigations of suspect patients were was about 1:2. The cases came from 13 counties. The most

completed as soon as they were reported by the investigators from frequently reported cases were from Guangshui county (23.5%, 16/

the local CDC, and the blood samples were gathered for further 68), followed by Macheng county (19.1%, 13/68) (Figure 1).

pathogenic identiﬁcation. Meanwhile, the investigators also Among the 68 cases, 34 had only positive PCR results, 6 had only

searched for the controls according to the matching requirements positive IgM ELISA results, and 28 had both positive PCR and IgM

and collected blood samples for further pathogenic identiﬁcation. 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

Experimental detection was 1.06:1 (35/33), and 92.6% were peasants (63/68) (Table 1). No

demographic differences (e.g., age, gender, ethnicity, and occupa-

TaqMan quantitative real-time reverse transcription PCR (qRT- tion) were observed between the cases and the controls (Table 1).

PCR) was performed on all samples using a certiﬁed real-time RT-

PCR kit for clinical diagnosis (SFDA registration no. 340166, China). Univariate analysis

The quantitative real-time RT-PCR assay was able to discriminate

SFTSV infection from other vector-borne viral diseases in humans, Matched case control analysis in this study was adjusted for age

with a potential detection limit of 10 viral RNA copies/ml or 10 TCID and sex matching. As shown in the univariate analysis, living

(50)/ml virus load. Serological antibodies against SFTSV were environments characterized by many weeds and much hillside

detected using a double-antigen sandwich ELISA (the double- ﬁeldwork were potential risk factors for SFTS (Table 2).

88 X. Xing et al. / International Journal of Infectious Diseases 55 (2017) 86–91

Table 1

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

Variable Classiﬁcation Number exposed ß P value

Cases Controls

N = 68 (%) N = 136(%)

Ethnicity Han 68(100.00) 133(97.79) 1.52 0.22

Other 0(0.00) 3(2.21)

Sex Male 33(48.53) 64(47.06) 0.04 0.84

Female 35(51.47) 72(52.94)

Age group 0-39 4(5.88) 5(3.68) 0.97 0.91

40-49 14(20.59) 34(25.00)

50-59 24(35.29) 45(33.09)

60-69 16(23.53) 33(24.26)

70 10(14.71) 19(13.97)

Occupation Peasant 63(92.60) 117(86.00) 1.91 0.17

Other 5(7.40) 19(14.00)

The tick exposure source was further classiﬁed into 4 bitten by environment ticks OR-MH = 12.00, 95% CI = 1.44-99.67)

subgroups; namely, “see ticks,” ‘contact with ticks,” “catch ticks,” (Table 3).

and “bitten by ticks” (Table 2). Among the different modes, “bitten On the basis of the multivariate conditional logistic regression

by ticks’ showed the highest risk of SFTS (OR-MH = 16.00, 95% analysis of tick exposure sources, the further multivariate

CI = 3.68-69.59), and these bites were mainly caused by animal conditional logistic regression analysis of the relationship between

ticks (animal tick indicates a tick that has bitten an animal) (OR- tick exposure (“contact with cattle ticks” and “bitten by environ-

MH = 20.00, 95% CI = 2.56-156.24). Among the various types of ment ticks”) and working and living conditions (work time

ticks, ‘cattle ticks’ were associated with the highest risk source of protection, skin damage at work, and so on) found that “cattle

SFTS (OR-MH for see ticks = 12.00, 95% CI = 2.97-48.50; OR-MH for tick contact” was independent risk source (Conditional Logistic

contact with ticks = 8.25, 95% CI = 2.48-27.42; OR-MH for catch Regression OR-MH = 8.82, 95% CI = 1.69-46.05, P value = 0.01)

ticks = 15.00, 95% CI = 1.81-124.35), followed by dog ticks and (Table 4).

environment ticks(Environment tick indicates a tick parasitic in

the grass, tea, or other environment.) (Table 2). Discussion

Multivariate analysis Previous studies have also shown that “tick exposure” is a major

1–4,8,11

risk factor for SFTS infection , but no study has yet shown

On the basis of the univariate analysis, the multivariate which source of tick exposure posed the greatest risk; i.e., animals,

conditional logistic regression analysis of tick exposure sources environment, etc. Our study found that “contact with cattle ticks”

found that “contact with cattle ticks” and “bitten by environment was a major risk source after adjusting for tick exposure, and

ticks” were risk sources after adjusting for tick exposure outdoor activities and working in weeds and in hillside ﬁelds could

(Conditional Logistic Regression OR-MH for contact with cattle increase the risk source of cattle tick contact and, therefore, SFTS

ticks = 7.70, 95% CI = 1.64-36.21; Conditional Logistic Regression for infection.

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

X. Xing et al. / International Journal of Infectious Diseases 55 (2017) 86–91 89

Table 2

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

Factor/source Classiﬁcation Number exposed OR-MH*(95%CI) ß MH P value

Cases Controls

N = 68(%) N = 136(%)

Weeds around residence 59(86.8) 74(54.4) 6.50(2.63-16.04) 22.51 <0.0001

working area 51(75.0) 64(47.1) 3.92(1.87-8.24) 15.04 0.0001

sit on grassland 40(58.8) 33(24.3) 5.27(2.52-11.04) 23.50 <0.0001

Field work hillside 32(47.1) 22(16.2) 6.25(2.74-14.27) 22.62 <0.0001

ﬂat 10(14.7) 26(19.1) 0.73(0.33-1.62) 0.62 0.43

woodland 4(5.9) 4(2.9) 2.00(0.50-8.00) 1.00 0.32

Pick yes 10(14.7) 10(7.4) 3.50(0.99-28.48) 3.85 0.050

Work time protection yes 1(1.5) 7(5.1) – – 0.33

Skin damage yes 17(25.0) 20(14.7) 2.17(0.97-4.83) 3.77 0.052

at work

See ticks yes 47(69.1) 30(22.1) 8.11(3.53-18.62) 41.80 <0.0001

cattle 21(30.9) 9(6.6) 12.00(2.97-48.50) 24.75 <0.0001

dog 13(19.1) 9(6.6) 3.13(1.25-7.79) 7.23 0.0072

pig 3(4.4) 2(1.5) 3.00(0.50-17.95) 1.60 0.21

poultry 5(7.4) 4(2.9) 2.65(0.58-12.37) 2.11 0.15

cat 1(1.5) 3(2.2) 0.67(0.069-6.41) 0.13 0.72

goat 1(1.5) 1(0.7) 2.0(0.13-31.98) 0.25 0.56

environment 23(33.8) 16(11.8) 4.00(1.79-8.95) 15.00 0.0001

Contact ticks yes 30(44.1) 14(10.3) 7.57(3.02-18.97) 32.06 <0.0001

dog 13(19.1) 5(3.7) 5.20(1.75-15.47) 12.97 0.0003

Cattle 19(27.9) 9(6.6) 8.25(2.48-27.42) 20.02 <0.0001

Catch ticks yes 16(23.5) 5(3.7) 7.75(2.57-23.41) 18.23 <0.0001

dog 9(13.2) 1(0.7) 18.00(2.28-142.08) 14.45 0.0001

cattle 8(11.8) 2(1.5) 15.00(1.81-124.35) 10.89 0.0010

Bitten by ticks yes 16(23.5) 2(1.5) 16.00(3.68-69.59) 25.00 <0.0001

animals 10(14.7) 1(0.7) 20.00(2.56-156.24) 16.41 0.0001

environment 6(8.8) 1(0.7) 12.00(1.44-99.68) 8.64 0.0033

Bitten by mosquitoes yes 15(22.1) 32(23.5) 0.88(0.38-2.07) 0.083 0.77

Bitten by other vectors yes 16(23.5) 33(24.3) 0.94(0.39-2.23) 0.022 0.88

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

See ticks 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 ticks indicates a person who has physically touched, caught, or been bitten by ticks without protection within 2 weeks prior to fever onset.

Cattle tick indicates a tick that bites cattle

Catch ticks 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 ticks indicates a person who has only been bitten by ticks without protection within 2 weeks prior to fever onset.

Animals tick indicates a tick that has bitten an animal.

Environment tick 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 buffaloes, goats, dogs and so on, thus exposing them to potential

no signiﬁcant occupational difference between the cases and tick bites. Previous studies have detected SFTSV in ticks collected

controls (P = 0.17). Peasants often labor, and they are commonly from several domestic animals, including cattle, buffaloes, goats,

inclined to touch the fur of domestic animals including cattle, 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.

90 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 on) showed that “cattle tick contact” was independent risk source

1,16–18

domestic animals in villages where the patients lived . (Conditional Logistic Regression OR-MH = 8.82, 95% CI = 1.69-46.05,

The differences in the rates of SFTSV infections among various P value = 0.01).In addition, previous studies have revealed that any

animal species and regions were statistically signiﬁcant. In Laizhou potential exposure to ticks, especially living and working with

and Penglai counties of the Shandong Province, 69.5% of sheep, domesticated animals presenting high SFTSV antibodies, including

60.5% of cattle, 37.9% of dogs, and 47.4% of chickens were goats, dogs, cattle, pigs, and chickens, increased SFTS incidence

10,11,17,19,23

seropositive for SFTSV, and the prevalence of SFTSV RNA was rates . In summary, our study provided further evidence

ranging from 1.7% to 5.3% . In Jiangsu Province, 66.8% of goats, that cattle might be major amplifying and reservoir hosts in SFTS-

28.2% of cattle, 7.4% of dogs, 4.7% of pigs, 1.2% of chickens, 1.7% of endemic regions in Hubei Province.

geese, 4.4% of rodents, and 2.7% of hedgehogs were seropositive for Haemaphysalis longicornis from domesticated animals are the

SFTSV, and the Multiple variable logistic regression analysis dominant species of tick in endemic regions, and the nucleic acid

showed that raising cattle and so on were risk factors for SFTS sequences of viruses isolated from ticks have high homology (93%–

10 8,19

virus infection among farmers . In Hubei Province, the 100%) with SFTSV isolated from patients . In Hubei Province, 4

seropositivity rate was the highest among cattle (73.7%-80.0%), tick species from cattle are found, including Haemaphysalis

followed by goats (36.7-59.1%) and dogs (55.0%), and the positive longicornis (70.8%), Hyalomma detritum (26.5%), Rhipicephalus

rate of SFTSV RNA was also highest in cattle (26.3%), followed by microplus (1.9%), and Ixodes sinensis (0.8%), but SFTSV RNA is only

20,21

goats (9.1%) . Our multivariate conditional logistic regression detected in Haemaphysalis longicornis[20].Thus, Haemaphysalis

analysis of tick exposure sources showed that “contact with cattle longicornis might be the major vector of SFTSV, and its geographic

ticks” including touching ticks, catching ticks, or bitten by ticks and distribution and density might play a central role in the risk of

“bitten by environment ticks” were risk sources for SFTSV infection SFTSV infection among humans.

(Conditional Logistic Regression OR-MH for contact with cattle The results of our study are subject to several limitations. First,

ticks = 7.70, 95% CI = 1.64-36.21; Conditional Logistic Regression for one fundamental selection/surveillance bias rests in the case

bitten by environment ticks OR-MH = 12.00, 95% CI = 1.44-99.67). deﬁnition of SFTS. In regions of endemicity, clinicians may be

Ticks are commonly found in humid scrubby forests, meadows, or inclined to only report or think about SFTS when the patient

peatlands, and there is an obvious seasonal distribution of SFTS presents with epidemiological links, such as tick bites or residing

cases. The endemic starts around March, peaks between May and in hilly areas, hence excluding explorations of risk factors in these

July, and ends around November, which is highly correlated with particular areas. In order to reduce this bias, we carried out strict

1–3,22

the ecological habits of ticks . Previous several studies showed training and ﬂow control. The clinicians had to conduct routine

that grazing, grass mowing, shrub, forest, and rainfed cropland blood tests for every patient with fever (38 C), and every patient

areas where the ticks commonly lived were associated with high with fever (38 C) associated with thrombocytopenia and

9,10,17

risk of SFTS incidence .but no study has yet showed which leukopenia had to be reported to the local CDC, which was

source of tick exposure posed the greatest risk; i.e., animals, responsible for the investigation of epidemiology and inquired into

environment, etc. On the basis of the multivariate conditional the patients’ exposure histories. The investigators from the local

logistic regression analysis of tick exposure sources, our further CDC ﬁrst checked medical records. The patients with epidemio-

multivariate conditional logistic regression analysis of the logical links, such as tick bites or residing in hilly areas, according

relationship between tick exposure (“contact with cattle ticks” to clinician reports, were not included in this study.

and “bitten by environment ticks”) and working and living Second, biases could have occurred since we only selected our

conditions (work time protection, skin damage at work, and so controls from hospitals. These controls may not have been drawn

X. Xing et al. / International Journal of Infectious Diseases 55 (2017) 86–91 91

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authors have approved the manuscript and agree with submission animals in Laizhou City, Shandong Province, China. Jpn J Infect Dis 2014;67

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to your esteemed journal. There are no conﬂicts of interest to

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environmental risk factors of severe fever with thrombocytopenia syndrome,

Xinyang, China. PLoS Negl Trop Dis 2014;8(5):e2820. doi:http://dx.doi.org/

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This study was supported by Hubei Province s Outstanding Microbiol Infect 2014;20(11):O870–878. doi:http://dx.doi.org/10.1111/1469-

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Medical Academic Leader program. We are grateful to the China

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CDC and all CDC levels and hospitals in Hubei Province for their

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