International Journal of Infectious Diseases 25 (2014) e180–e185

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

jou rnal homepage: www.elsevier.com/locate/ijid

Epidemiological characteristics of severe fever with thrombocytopenia

syndrome in Zhejiang Province, China

a,1 a,1 a,1 a b a

Jimin Sun , Chengliang Chai , Huakun Lv , Junfen Lin , Chengwei Wang , Enfu Chen ,

a a a a, a,

Yanjun Zhang , Zhiping Chen , Shelan Liu , Zhenyu Gong *, Jianmin Jiang *

a

Zhejiang Provincial Centre for Disease Control and Prevention, Hangzhou, 310051, China

b

Daishan Centre for Disease Control and Prevention, Daishan, China

A R T I C L E I N F O S U M M A R Y

Article history: Objectives: To summarize the epidemiological characteristics of severe fever with thrombocytopenia

Received 29 January 2014

syndrome (SFTS) in Zhejiang Province, China.

Received in revised form 25 February 2014

Methods: A standardized questionnaire was used to collect information on demographic features,

Accepted 25 February 2014

exposure history, clinical symptoms, and timelines of medical visits. Descriptive statistics were used to

Corresponding Editor: Eskild Petersen,

analyze the characteristics of SFTS.

Aarhus, Denmark

Results: A total of 65 cases of SFTS were identified in Zhejiang Province from 2011 to 2013, of whom 34

were male and 31 were female. The median age was 66 years and 60 cases occurred in persons aged 50

Keywords: years. The majority (91%) of SFTS cases occurred between May and August. With regard to exposure

Fever with thrombocytopenia syndrome

history, patients had pursued outdoor activities (63%), had a history of exposure to a tick (68%) or tick

Epidemiological characteristic

bite (29%), bred domestic animals (31%), or had a history of exposure to a mouse (57%), and some patients

Clinical characteristics

had a multi-exposure history. Approximately 98.46% of patients were hospitalized, and symptoms of the

Family cluster

illness included fever (98%), fatigue (71%), chills (51%), etc. Two family clusters occurred, although there

was no person-to-person transmission.

Conclusions: In Zhejiang Province, SFTS is prevalent between May and August among elderly persons

who live in hilly areas, and clinical features are not specific. More emphasis should be given to this

disease and further training of medical personnel should be carried out to prevent misdiagnosis.

ß 2014 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/3.0/).

1. Introduction In 2011–2012, 2047 cases of SFTS and 129 deaths were reported

4

in over 206 counties of eastern and central China. Cases of SFTS

Severe fever with thrombocytopenia syndrome (SFTS) is an were also identified in Zhejiang Province, and a total of 65 cases

emerging infectious disease discovered in China and is caused by a were reported in recent years according to the information system

5–7

novel bunyavirus, SFTS virus (SFTSV). SFTSV is classified in the for disease control and prevention. Here, we analyze the

family Bunyaviridae, genus Phlebovirus, and is believed to be epidemiological and clinical characteristics of SFTS in Zhejiang

transmitted by ticks because the virus has been detected in Province to provide scientific information for the control and

1

Haemaphysalis longicornis ticks. The major clinical symptoms and prevention of SFTS.

laboratory abnormalities of SFTS are fever, thrombocytopenia,

leukopenia, and elevated serum hepatic enzymes, and death in

1 2. Methods

SFTS patients is usually the result of multiple organ failure. The

clinical symptoms, however, are less specific and need to be

2.1. Case definition

differentiated from those of various other infectious diseases, in

particular from hemorrhagic fever with renal syndrome (HFRS)

2,3 In accordance with the document entitled ‘‘The diagnosis and

caused by hantavirus and human anaplasmosis.

treatment programs of severe fever with thrombocytopenia

8

syndrome’’ issued by the Chinese Ministry of Health, an acutely

ill person with acute onset of fever (38.0 8C) and other symptoms

* Corresponding authors. Tel.: +86 571 87115009; fax: +86 571 87115009.

(e.g., gastrointestinal symptoms, bleeding), epidemiological risk

E-mail addresses: [email protected] (Z. Gong), [email protected] (J. Jiang).

1

These authors contributed equally to this paper. factors (being a farmer or being exposed to ticks 2 weeks before

http://dx.doi.org/10.1016/j.ijid.2014.02.022

1201-9712/ß 2014 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/3.0/).

J. Sun et al. / International Journal of Infectious Diseases 25 (2014) e180–e185 e181

12

illness onset), and laboratory data showing thrombocytopenia and

2013 2012 2011

leukocytopenia, was defined as a suspected case of SFTSV.

10

Confirmed cases of SFTSV infection were defined as those who

met the criteria for a suspected case of SFTSV and who also met one

8

or more of the following criteria: (1) detection of SFTSV RNA by a

molecular method, (2) seroconversion or 4-fold increase in 6

antibody titers between two serum samples collected at least 2

weeks apart, and (3) isolation of SFTSV in cell culture. 4

Number of cases

2.2. Laboratory test assays 2

0

Serum samples obtained from the patients with suspected SFTS

30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80-

were sent to the laboratory of the Zhejiang Provincial Center for

Age groups

Disease Control and Prevention (CDC). Laboratory measurements

of SFTSV RNA by real-time reverse-transcription PCR (RT-PCR), of

Figure 1. Age distribution of SFTS in Zhejiang Province, China.

SFTSV-specific immunoglobulin M (IgM) and immunoglobulin G

(IgG) antibodies, and isolation of SFTSV were performed as

6

described previously. numbers of reported cases were Zhoushan (69%) and Ningbo (18%).

Of note, 63% (41/65) of cases were identified in Daishan County,

2.3. Data collection which is a part of Zhoushan located in eastern Zhejiang Province.

Daishan County is comprised of seven towns, and SFTS was

The aims of our study were explained to all patients and their indentified in five of them (Figure 4). Gaoting town and Dongsha

consent was obtained prior to inclusion in this study. A town accounted for 68% (28/41) of patients in Daishan County.

standardized questionnaire was used to collect information on All cases lived in hilly areas within a month before illness onset

demographic features (age, gender, occupation, and residential and 63% (41/65) of cases had performed outdoor activities within 2

address), exposure history, clinical signs and symptoms, date of weeks before illness onset. Of these, 36 cases farmed, 10 cases

onset, date of first medical visit, and date of confirmation. Exposure mowed, and three cases grazed (Table 1). Six cases had a history of

history collected included habitats of their place of residence, farming and mowing, and one case had a history of farming,

outdoor activities within 2 weeks before illness onset, exposure to mowing, and grazing. Among the 65 cases, 27 of 40 with data

a tick within a month before illness onset, history of tick bite available had a history of exposure to a tick in the month before

within 2 weeks before illness onset, skin breakdown within 2 illness onset, but only 12 of 41 cases with data available had a

weeks before illness onset, breeding domestic animals, contact history of a tick bite before illness onset. In addition, 14% (9/65)

with wildlife, and history of exposure to a mouse within a month of cases had skin breakdown within 2 weeks before illness onset,

before illness onset. 31% (20/65) of cases bred domestic animals, and 57% (30/53) of

cases had a history of exposure to a mouse within a month before

2.4. Data analysis illness onset. However, no case had a history of contact with

wildlife. Of note, nine cases had a multi-exposure history to

Descriptive statistics were used to analyze the epidemiological domestic animals and mice; four cases had a multi-exposure

characteristics and clinical characteristics of SFTS in Zhejiang history of tick bite and mouse contact; two cases had a multi-

Province, China. We used the Wilcoxon Rank Sum W test to exposure history of tick bite and contact with domestic animals;

compare the age distribution of patients with SFTS who survived two cases had a multi-exposure history of tick bite and contact

and those who died. The Chi-square test or Fisher’s exact test were with domestic animals and mice. The estimated median incubation

used to compare symptoms between survivors and those who period for 12 confirmed cases with a history of tick bite was 12

died. The difference was considered statistically significant when days (range 2–47 days).

p < 0.05. The statistical analysis was performed using SPSS

software (SPSS 17.0; SPSS Inc., Chicago, IL, USA). 3.2. Clinical characteristics

3. Results Approximately 99% of patients were hospitalized, and symp-

toms of the illness included fever (98%), fatigue (71%), chills (51%),

3.1. Epidemiological characteristics

A total of 65 laboratory confirmed cases of SFTS were identified in 14 2011 2012 2013

Zhejiang Province from 2011 to 2013, of whom 34 were male and 31

12

were female. All patients lived in wooded, hilly areas and the

majority of them were farmers (92%). The median age of confirmed

10

patients was 66 years (range 31–84 years), and 60 cases (92%)

occurred in persons aged 50 years (Figure 1). Moreover, nine 8

deaths occurred (case fatality rate, 14%) and the age distribution of

6

patients who died was significantly different to that of survivors

Numer of cases

(Z = À 2.034, p = 0.042 (<0.05)). The majority (91%) of SFTS cases 4

during 2011–2013 in Zhejiang Province occurred yearly between

2

May and August (Figure 2). However, two cases were reported in

March and two cases were reported in October in 2013.

0

All cases occurred in 13 counties that were members of five Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

cities, and the number of counties in which SFTS was identified

increased from 2011 to 2013 (Figure 3). The cities with the highest Figure 2. Monthly distribution of SFTS in Zhejiang Province, China.

e182 J. Sun et al. / International Journal of Infectious Diseases 25 (2014) e180–e185

Figure 3. Geographical distribution of SFTS in Zhejiang Province from 2011 to 2013.

Table 1

Exposure history of 65 SFTS cases in Zhejiang Province

Living in a hilly area a month before illness 65/65 (100)

onset (%)

Outdoor activities within 2 weeks before 41/65 (63)

illness onset (%)

Farming (%) 36/65 (55)

Mowing (%) 10/65 (15)

Grazing (%) 3/65 (5)

History of exposure to a tick within a month 27/40 (68)

before illness onset (%)

History of tick bite within 2 weeks before 12/41 (29)

illness onset (%)

Skin breakdown within 2 weeks before illness 9/65 (14)

onset (%)

Breeding domestic animals (%) 20/65 (31)

Contact with wildlife (%) 0/65 (0)

History of exposure to a mouse within a month 30/53 (57)

before illness onset (%)

Figure 4. Geographical distribution of SFTS in Daishan County from 2011 to 2013. SFTS, severe fever with thrombocytopenia syndrome.

J. Sun et al. / International Journal of Infectious Diseases 25 (2014) e180–e185 e183

Son

Table 2

Illness onset Visited a clinic Serum colle cted Confirmed

Clinical symptoms of SFTS cases in Zhejiang Province

Symptom Patients Patients Patients p-Value

with who who died

18/5 19/5 26/5 27/5

symptoms survived (n = 9)

Visited a hospital,

(n = 65) (n = 56) Mother hospitalization and serum

Illness onset Visited a clinic collected Confirmed

Fever (%) 64 (98) 55 (98) 9 (100)

Fatigue (%) 46 (71) 39 (70) 7 (78) 0.618

Chills (%) 33 (51) 29 (52) 4 (44) 0.683

20/5 21/5 26/5 27/5

Headache (%) 31 (47) 27 (48) 4 (44) 0.834

201 2

Lymphadenopathy (%) 29 (45) 26 (46) 3 (33) 0.463

Anorexia (%) 26 (40) 22 (39) 4 (44) 0.769

Nausea (%) 26 (40) 21 (38) 5 (56) 0.305 Wife

Myalgia (%) 23 (35) 20 (36) 3 (33) 0.890

Illness onset and visited a clinic Serum collected and confirmed

Diarrhea (%) 19 (29) 14 (25) 5 (56) 0.061

Vomiting (%) 15 (23) 13 (23) 2 (22) 0.948

Abdominal pain (%) 15 (23) 10 (18) 5 (56) 0.013 20/7 23/7

Gingival hemorrhage (%) 12 (18) 10 (18) 2 (22) 0.754

Husband Visited a hospital,

Conjunctival congestion (%) 10 (15) 8 (14) 2 (22) 0.54 hospitalization, serum collected Transferred to

Illness onset another hospital

Petechiae (%) 9 (14) 5 (9) 0 and confirmed

SFTS, severe fever with thrombocytopenia syndrome.

21/7 23/7 24/7

2013

headache (47%), lymphadenopathy (45%), anorexia (40%), nausea

Figure 5. Timelines of events in two family clusters of SFTS cases in Zhejiang

(40%), myalgia (35%), diarrhea (29%), vomiting (23%), abdominal Province.

pain (23%), gingival hemorrhage (18%), conjunctival congestion

(15%), and petechiae (14%). Symptoms were similar between

survivors and those who died except abdominal pain (Table 2). The history of tick bite and had not pursued outdoor activities within

median temperature of patients was 38.9 8C (range 37.3–40 8C). 2 weeks before illness onset.

Laboratory abnormalities included thrombocytopenia (97%), leu- The second family cluster also included two confirmed SFTS

kocytopenia (92%), neutropenia (88%), and lymphocytopenia patients. The first case was a 75-year-old woman who had onset of

(83%). The minimum white blood cell, platelet, neutrophil, and fever, fatigue, and anorexia on July 20, 2013. She visited a hospital

9 9

lymphocyte counts in the acute phase were 0.6 Â 10 /l, 3.5 Â 10 /l, in Daishan County and was hospitalized on July 20, 2013. She did

9 9

0.01 Â 10 /l, and 0.02 Â 10 /l, respectively (Table 3). The median not have history of tick exposure or tick bite. The secondary patient

time from illness onset to first medical visit was 1 day (range 0–16 was her husband who lived with her and did farm work in daily life.

days) and the median time from illness onset to confirmation was 9 He had the onset of clinical symptoms similar to those of his wife

days (range 1–52 days). Sixty percent (39/65) of patients first on July 21 and visited a hospital on July 23, 2013. Serum samples

visited a village or town clinic and 37% (24/65) of cases first visited were collected from these two persons on July 23 and they were

a county hospital. confirmed on the same day. The husband’s symptoms worsened

and he was transferred to a hospital in Zhoushan City for better

3.3. Family clusters treatment on July 24, 2013 (Figure 5).

A total of two family clusters were identified in Zhejiang

Province. One family cluster was identified in 2012 and the 4. Discussion

other was identified in 2013. The first family cluster comprised

two persons with confirmed SFTSV infection. The index case Zhejiang Province is located in southeastern China, adjacent to

patient was male, 50 years old, and had onset of fever, headache, Jiangsu and Anhui where SFTS is endemic. Although SFTSV was first

nausea, abdominal pain, and diarrhea on May 18, 2012. He then isolated in 2009, SFTSV has probably been prevalent for some time

visited a clinic on May 19, 2012. He had a history of tick bite in China as the virus was found in serum samples from Anhui

9

within 2 weeks before illness onset. The secondary patient was Province collected in 2006. In this study, 65 patients including 34

his mother who was 85 years old and lived with him. She had males and 31 females were identified. All patients lived in wooded,

onset of fever, abdominal pain, diarrhea, and lymphadenopathy hilly areas and the majority of cases were sporadic, except for two

on May 20, 2012 and visited a clinic on May 21, 2012. She then family clusters. Nine deaths occurred and the case fatality rate was

visited a hospital in Daishan County on May 26, 2012 as her very high. However, we suspect that these confirmed cases

condition had worsened. Serum samples of these two persons represent the tip of the iceberg and that there are many more as yet

were collected on May 26 and both were confirmed with SFTS on undetected mild and asymptomatic infections. The real case

May 27, 2012 (Figure 5). The secondary patient did not have a fatality rate might therefore be lower than shown in our data.

Table 3

Laboratory findings in the acute phase of SFTS in patients from Zhejiang Province

Normal Increased Decreased Average Minimum Maximum

level level level (Â109/l) (Â109/l) (Â109/l)

White cell count (%) 4 (6) 1 (2) 60 (92) 2.04 0.6 11.1

Platelet count (%) 2 (3) 0 63 (97) 47.54 3.5 134

Neutrophil count (%) 7 (11) 1 (2) 57 (88) 1.19 0.01 10.5

Lymphocyte count (%) 10 (15) 1 (2) 54 (83) 0.62 0.02 7.5

SFTS, severe fever with thrombocytopenia syndrome.

e184 J. Sun et al. / International Journal of Infectious Diseases 25 (2014) e180–e185

Most SFTS cases occurred yearly between May and August. The identify and cure SFTSV infection. As a result, the patients then

reasons for this might include lots of outdoor activities, a high tick have to attend hospitals with better facilities for further care. Also,

density, and the fact that ticks usually absorb their subjects’ blood the majority of samples are transported to the Zhejiang Provincial

in order to grow and proliferate between May and August. CDC for testing. It is possible that there are many other patients

However, two cases were reported in March and two cases were with infections in rural areas who do not have the opportunity to

reported in October in 2013, months when the tick density is low, seek further care at better hospitals with laboratory capacity to

indicating that there might be other transmission routes apart identify SFTSV.

from tick bites. A few clusters of SFTS cases have been identified in the

The majority of cases occurred among persons aged 50 years or provinces of Shandong, Jiangsu, Hubei, and Anhui, and virological

older and fatality increased with age. These findings are in investigations have verified limited human-to-human transmis-

1,4,10–14 9,21–23

agreement with corresponding data from other studies. The sion of SFTSV. In our study, we also identified two family

high proportion of elderly patients may be due to physiological clusters in Daishan County. However, given the fact that the

factors related to ageing, such as decreased immune function and secondary patient lived together with the index patient in two

the presence of comorbidities with chronic diseases. However this family clusters and the time intervals of illness onset between the

may also be related to demographic features of residents in index patient and the secondary patient were within the median

wooded or hilly areas where SFTS occurs. Generally, young adults incubation period of SFTS, suggests that the index patient and the

from wooded or hilly areas go to cities to earn better money and secondary patient were infected from the same infectious source

then return to their hometown for the spring festival. As a result, rather than transmission being person-to-person.

the majority of residents of rural areas between the months of In summary, we have summarized the epidemiological and

March and November are elderly people and children. clinical characteristics of SFTS in Zhejiang Province, which will be

SFTS cases were identified in 13 counties from 2011 to 2013 and useful for the prevention and treatment of SFTS. A total of 65 SFTS

most cases were from Daishan County. However one case from Anji cases were identified and the majority of them occurred in elderly

and another case from Pujiang were identified in 2013. Both cases persons from wooded, hilly areas between May and August. Most

visited a hospital in Hangzhou and were confirmed in Hangzhou. patients pursued outdoor activities, had a history of exposure to

This informs us that some SFTS cases may be misdiagnosed ticks (with some patients having a history of tick bites), and bred

because no county-level CDC has the capacity to identify SFTSV domestic animals; some patients had a multi-exposure history.

infection except Daishan CDC. Moreover, SFTSV seroprevalence is Clinical features of SFTS were not specific and were consistent with

found in the general populations of Hubei Province, Shandong many other diseases, indicating that some cases of SFTS might be

Province, and Jiangsu Province, suggesting that subclinical SFTSV misdiagnosed. Family clusters occurred, although they were not as

infections or a relatively mild form of SFTS illness may occur in a result of person-to-person transmission. More emphasis should

15–17

humans. be given to this disease and further training of medical personnel

Some patients performed outdoor activities within 2 weeks should be carried out to prevent misdiagnosis. Laboratory capacity

before illness onset or had a history of exposure to a tick within a and the surveillance of ticks, domestic animals, and mice should be

month before illness onset. However, only 29% of patients had a strengthened for the control and prevention of SFTS in Zhejiang

history of tick bite within 2 weeks before illness onset. The reason Province.

for this may be that they did not find a tick bite or that there are

other transmission routes. It is notable that 31% of cases bred Acknowledgements

domestic animals and 57% of cases had a history of exposure to a

mouse within a month before illness onset. We postulate that We thank the physicians and staff at the centers for disease

domestic animals and rodents living in close contact with humans control and prevention of the 13 counties in which SFTS was

are reservoirs for SFTSV, whereas ticks are the vectors that transmit identified for their support and assistance. This research was

the virus from animal hosts to humans. Some studies on SFTSV supported by a grant from Zhejiang Province Major Science and

prevalence among domestic animals confirm this hypothesis. Niu Technology Program (2012C13016-2), a grant from the Project of

et al. detected SFTSV-specific antibodies in 69.5% of sheep, 60.5% of the State Scientific & Technological Development of the 12th Five

18

cattle, 37.9% of dogs, 3.1% of pigs, and 47.4% of chickens. Another Year Plan (2012ZX10004219), and the Medical Research Program

study in Shandong Province showed 111/134 goats to be of Zhejiang Province (2012KYA045, 2014RCA002).

16

seropositive for SFTSV, and a serosurvey of domesticated animals Ethical standards: The experimental research reported in this

conducted in Jiangsu Province found SFTSV antibody positivity study was performed with the approval of the ethics committee of

rates of 57% in goats, 32% in cattle, 6% in dogs, 5% in pigs, and 1% in Zhejiang Provincial Centre for Disease Control and Prevention

17

chickens, but no antibodies in geese or mice. (Zhejiang CDC). Human research was carried out in compliance

The clinical presentation of SFTS includes fever, fatigue, chills, with the Declaration of Helsinki.

headache, lymphadenopathy, anorexia, nausea, myalgia, diarrhea, Conflict of interest: No conflict of interest exists in the

vomiting, and abdominal pain. These symptoms are not specific submission of this manuscript.

and are consistent with many infectious causes including bacteria

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