Review
Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis Quan Liu, Biao He, Si-Yang Huang, Feng Wei, Xing-Quan Zhu
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging haemorrhagic fever that was first described in rural areas of China. The causative agent, SFTS virus (SFTSV), is a novel phlebovirus in the Bunyaviridae family. Since the first report in 2010, SFTS has been found in 11 provinces of China, with about 2500 reported cases, and an average case-fatality rate of 7·3%. The disease was also reported in Japan and Korea in 2012; Heartland virus, another phlebovirus genetically closely related to SFTSV, was isolated from two patients in the USA. The disease has become a substantial risk to public health, not only in China, but also in other parts of the world. The virus could undergo rapid evolution by gene mutation, reassortment, and homologous recombination in tick vectors and vertebrate reservoir hosts. No specific treatment of SFTS is available, and avoiding tick bites is an important measure to prevent the infection and transmission of SFTSV. This Review provides information on the molecular characteristics and ecology of this emerging tick-borne virus and describes the epidemiology, clinical signs, pathogenesis, diagnosis, treatment, and prevention of human infection with SFTSV.
Introduction In May, 2007, three patients with high fever, gastrointestinal bleeding, abdominal pain, bloating, nausea, vomiting, and high concentrations of aminotransferases were diagnosed as having acute gastroenteritis in a local hospital in Xinyang, Henan province, China. A relative of one patient reported the disease to the Henan Centre for Disease Control and Prevention; a special investigation by the centre showed the clinical characteristics of acute onset with fever, low counts of white blood cells and platelets, high concentrations of alanine and aspartate aminotransferases, and proteinuria. On the basis of these features, the centre ruled out gastrointestinal disorders and started to search for similar cases. 79 cases, with ten deaths (a case-fatality rate of 12·7%), were found in Henan in 2007.1 At that time, there were outbreaks of Tsutsugamushi (scrub typhus), caused by Orientia tsutsugamushi, in this area2,3 and human granulocytic anaplasmosis, caused by Anaplasma phagocytophilum, in neighbouring Anhui province.4,5 These diseases have similar clinical features. Rickettsial diseases, such as human granulocytic anaplasmosis, Tsutsugamushi, and human monocytic ehrlichiosis, caused by Ehrlichia chaffeensis, were thus regarded as possible causes of the Henan outbreak. However, only six (3%) of 206 suspected cases were confirmed as A phagocytophilum infection, and no pathogen was isolated in the 3 years from 2007.1 Patients with severe fever with thrombocytopenia syndrome (SFTS) were also reported in the provinces of Shandong, Jiangsu, Hubei, Anhui, and Liaoning.6 In 2010, a novel bunyavirus, designated as SFTS virus (SFTSV) or Huaiyangshan virus,7 was isolated from patients with SFTS. It was regarded as the causative agent of the lifethreatening illness associated with fever and thrombocytopenia in China.1,2 In 2012, the disease was also described in Japan8 and Korea,9,10 and another phlebovirus, named Heartland virus, was reported as the cause of two cases of severe
febrile illness with thrombocytopenia in Missouri, USA.11 Heartland virus is genetically closely related to SFTSV. The disease was traced back to 2009 for the USA, and the summer of 2012 for Japan and Korea, and no evidence was found that the patients had travelled to China. These viruses might have different origins, but cause similar or even identical symptoms and clinical outcomes. The newly emerged SFTSV actually originated in China about 50–150 years ago.12 Perhaps this pathogen has also been present in Japan and Korea, and Heartland virus in the USA, for a long time. In this review, we discuss the molecular characteristics and ecology of SFTSV and describe the epidemiology, clinical signs, pathogenesis, diagnosis, treatment, and prevention of this emergent tick-borne zoonosis.
Lancet Infect Dis 2014 Published Online May 16, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70718-2 State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China (Q Liu PhD, S-Y Huang PhD, Prof X-Q Zhu PhD); Military Veterinary Institute, Academy of Military Medical Sciences, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun, China (Q Liu, B He PhD); and College of Life Science, Jilin Agricultural University, Changchun, China (F Wei PhD) Correspondence to: Prof Xing-Quan Zhu, State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province 730046, China [email protected]
Causative agent Classification SFTSV is a phlebovirus of the family Bunyaviridae. Bunyaviridae includes the largest group of RNA viruses, with more than 350 viruses classified in five genera: the orthobunyaviruses (eg, Bunyamwera,13 Schmallenberg,14 Oropouche,15 and La Crosse16 viruses), the nairoviruses (eg, Crimean-Congo haemorrhagic fever virus and Nairobi sheep disease virus17,18), the tospoviruses (eg, tomato spotted wilt virus19), the phleboviruses (eg, Rift Valley fever,20 Candiru,21 sandfly fever Naples,22 Punta Toro,22 sandfly fever Sicilian,23 and Toscana24 viruses), and the hantaviruses (eg, Hantaan and Sin Nombre viruses25,26). Except for the rodent-borne hantaviruses, the Bunyaviridae are transmitted by arthropod vectors.27 Bunyaviruses can infect various animals and plants,25 and many viruses of this family have caused febrile infections in people, with encephalitis and haemorrhagic fevers. They are regarded as emerging pathogens of public health importance, owing to the increased incidence of late in new hosts and geographical locations.28–30 The phleboviruses are about 70 antigenically distinct serotypes, classed in two groups. The phlebotomus fever
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group are transmitted by phlebotominae sandflies or mosquitoes, and the Uukuniemi group by ticks.31 Genetically, SFTSV is grouped in the phlebovirus branch, but it differs from other known phleboviruses and probably is a third distinct group within the genus.1,2 Although SFTSV and Heartland virus have limited sequence similarity to other members of the Uukuniemi group, they were assigned to that group because they lack the small non-structural protein on their M segment, have certain serological characteristics, and have ticks as the common arthropod vector.32–34 Matsuno and colleagues34 have identified a new species of phlebovirus, the Bhanja group, which includes Bhanja, Forecariah, and Palma viruses.32 SFTSV and Heartland virus are more closely related to the Bhanja group than to the Uukuniemi group.34
Genome and structure SFTSV particles are spherical, measure 80–100 nm in diameter, and have a unit membrane envelope, from which protrude polypeptide spikes 5–10 nm long.2 The genome consists of three negative-stranded RNA segments: small, medium, and large. The small RNA segment has 1744 nucleotides and encodes the nucleoprotein and a non-structural protein by the ambisense strategy. The non-translated regions at the 3ʹ and 5ʹ termini are highly conserved, and show extensive nucleotide complementarity, forming a panhandle-like structure.1,2 The nucleoprotein encapsidates and packages genomic RNA into ribonucleoprotein complexes to protect it from degradation by exogenous nucleases or immune systems in the host cell.35 Despite the similar functions of nucleoprotein, the crystal structure of SFTSV nucleoprotein processes a stable hexameric ring to facilitate viral RNA encapsidation, a crucial step in replication of the virus. The four residues, A8, F11, A25, and L28, are essential for its oligomerisation, which differs substantially from that of other members of the Bunyaviridae.36–38 In addition, nucleoprotein has an active role in RNA transcription and replication and virion assembly.39,40 Both the nucleoprotein and the non-structural protein of SFTSV inhibit the antiviral immune response in host cells by suppressing the activation of interferon β and nuclear factor κB signalling.41–44 The medium RNA segment is 3378 nucleotides long and contains a single open reading frame encoding 1073 aminoacids for the precursor of the glycoprotein, which has crucial roles in virus assembly, formation of the virus particle, and attachment to new target cells.27 The glycoprotein binds to non-muscle myosin heavy chain IIA of cell surface protein, contributing to the efficiency of early infection by SFTSV.45 The large RNA segment is 6368 nucleotides long, and encodes 2084 aminoacids of the large protein, the viral RNA-dependent RNA polymerase, which brings about replication and transcription of the viral RNA.27 The 2
influenza-like endonuclease domain within its N-terminal is essential for viral cap-dependent transcription.46
Genetic diversity Despite more than 90% sequence similarity of SFTSV isolates irrespective of their broad geographical distribution, they are grouped into five sublineages A–E. Those isolated from animals (dogs, cats, goats, buffalo, and cattle) are in lineage A and do not show a geographical clustering pattern,12 which is distinct from other zoonotic viruses, such as rabies virus and hantavirus.47,48 Heartland virus and SFTSV share a common ancestor among viruses in the Bhanja group.12,34 The molecular mechanism of genetic diversity of SFTSV has not been completely elucidated, but several studies have shown that the virus can undergo rapid evolution by gene mutation, natural reassortment, and homologous recombination.12 Because its RNA-dependent RNA polymerase has no proof-reading function, SFTSV has a high mutation rate (about 10–⁴ substitutions per site each year) during its replication, the basis of its genetic diversity.12 Reassortment is a very efficient evolutionary force in segmented-genome viruses, which is associated with high pathogenicity and transmissibility among vectors and hosts and even results in new outbreaks.49 Phylogenetic evidence for natural reassortment has been reported in members of the genus phlebovirus, such as Rift Valley fever and Candiru viruses.12,21,50 Ding and colleagues51 have identified two SFTSV strains with reassortment in the small segment, which suggests that this process is the force to drive rapid change in SFTSV. Although homologous recombination is thought to be rare in negative-strand RNA viruses, it has been found in the medium segment of SFTSV52 and in other negative-sense RNA viruses, such as influenza,53–55 Ebola,56 and hantaviruses,57,58 which suggests that intragenic recombination has a role in the rapid evolution of the virus. The tick vector of SFTSV, Haemaphysalis longicornis, and the vertebrate reservoir hosts could provide the place of the coinfection by homologous recombination and natural reassortment for the virus.
Epidemiology SFTS was first reported in rural regions in Henan and Hubei provinces of central China between March and July, 2009.6 However, the first case occurred in Dingyuan County, Chuzhou, Anhui province, in September, 2006.59 From June, 2009, to September, 2010, 171 patients were identified as having SFTSV infection in Henan, Hubei, Shandong, Liaoning, Anhui, and Jiangsu provinces.1 By the end of 2012, the disease had been found in 11 provinces: Henan, Hubei, Anhui, Shandong, Jiangsu, Zhejiang, Jiangxi, Guangxi, Yunnan, Shaanxi, and Liaoning (figure 1). During 2011–12, 2047 cases occurred in China (with 129 deaths), mainly distributed in 206 counties of eastern and central China. The highest numbers of
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reported cases were in Henan (48% of the total), Hubei (22%), and Shandong (16%). Serosurveillance showed that 1·0–3·8% of the examined population in hilly areas had SFTSV antibodies, which suggests that SFTSV has circulated widely in China and that a very small proportion of infected individuals develop disease.60–72 The incidence of SFTS ranged from 0·03 per 1000 in Hubei province to 0·05 per 1000 in Shandong province.63 The first case of SFTS outside China was in North Korea in 2009.10 A fatal case was identified in South Korea in 2012,9 then six cases with four deaths were reported in 2013.65 In Japan, 11 cases and seven deaths were reported by April, 2013, and the apparently increasing numbers of cases seem to be contracted locally rather than imported from China.66 In the USA, the disease was first noticed in 2009, when two farmers in northwestern Missouri were admitted to hospitals with high fever, fatigue, diarrhoea, thrombocytopenia, and leucopenia; both had been bitten by ticks 5–7 days before the onset of illness.11 The overall mortality of SFTSV infection in China is about 7·3% (2391 cases and 174 deaths), ranging from 6·3% to 30·0% in various studies.1,61,71–76 The major at-risk group is farmers in endemic areas; almost 97% of the patients in China are farmers living in wooded and hilly areas and working in the fields; many have reported tick bites 7–9 days before illness.1 The incubation period is generally 7–14 days, with an average of 9 days. SFTS cases are distributed mainly in individuals of age (35–80 years) exposed to tick populations. The disease occurs mainly in April and May during the tea-picking season in Henan.1 Rural activities, such as camping and hiking, are also a potential risk factor for tick exposure.6 SFTS mostly arises as sporadic cases in the spring and summer. Direct contact with infected blood or bloody secretions can cause infection, and a few clusters of cases have been reported, which suggests human-to-human transmission of the disease.67–69 Hospital health-care workers, relatives of patients, and accompanying individuals are the second most affected population, through caring for patients with bloody secretions. Although there is no evidence that the virus causes disease in animals, blood from subclinically infected animals could be a source of infection.60,70 Therefore, veterinarians and abattoir workers are also at risk.77
Ecology Vectors As a newly discovered phlebovirus, SFTSV is thought to be an arbovirus, which suggests that it can be transmitted by various vectors. In China, SFTSV has been detected in the tick H longicornis (prevalence of 2·1–5·4%), collected from domestic animals in the areas where patients with SFTS lived; the RNA sequences of these isolated viruses are very closely related to those of SFTSV isolates from the patients.2,7,78,79 SFTSV has also been detected in Boophilus microplus from both endemic
No cases reported Cases reported
Heilongjiang
Jilin
Inner Mongolia
Ningxia
Xinjiang
Liaoning Beijing Tianjin Hebei Shanxi Shandong
Qinghai Gansu Shaanxi
Tibet
Anhui
Hubei
Sichuan
Jiangsu
Henan
Jiangxi Chongqing
Guizhou
Hunan
Yunnan Guangxi
Shanghai Zhejiang
Fujian
Guangdong
Taiwan
Hong Kong Macau Hainan
Figure 1: Geographical distribution of SFTS cases in mainland China in 2012 Red triangle=first SFTS case in Dingyuan county, Chuzhou city, Anhui province, in September, 2006. SFTS=severe fever with thrombocytopenia syndrome.
and non-endemic regions, but the prevalence in this tick (0·6%) is lower than that in H longicornis (4·9%). The higher prevalence in H longicornis in endemic regions than in non-endemic regions suggests that it is the major vector of SFTSV.7 H longicornis and B microplus are widely distributed in China and other countries, so SFTSV surveillance in these ticks is necessary.80 Gamasid and chigger mites collected from striped field mice (Apodemus agrarius) and goats in endemic regions were also found to carry SFTSV, so are also potential vectors.81 In the USA, Heartland virus was detected11 and isolated from questing nymphs of Amblyomma americanum collected from a patient’s farm and a nearby conservation area; these findings imply that the tick nymphs become infected by feeding on viraemic hosts and the virus is transmitted to people by host-seeking nymphs during the spring and summer. Thus, A americanum is thought to be the vector for Heartland virus.82 SFTSV and Heartland virus have not been detected in mosquitoes;2,82 phlebotomine sandflies have not yet been investigated.63
Vertebrate reservoir hosts SFTSV is thought to circulate in an enzootic tick– vertebrate–tick cycle. Although no evidence that the virus causes disease in animals is available, the seroprevalence of SFTSV by nucleoprotein-based double-antigen sandwich ELISA has been surveyed in domestic animals. In Shangdong province, the seroprevalence was 75–95% in goats, 57% in cattle,
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52% in dogs, and 36% in chickens.60–62,83 In Jiangsu province, 1% of chickens, 5% of pigs, 6% of dogs, 32% of cattle, and 57% of goats were seropositive.84 In Hubei province, 55% of dogs, 67% of goats, and 80% of cattle were seropositive.85 Viral RNA, typically at low levels, was detected in only a small proportion of the animals studied (1·7–5·3%).63 These findings suggest that the domestic animals could act as amplifying hosts of SFTSV, which play an important part in the spread of SFTSV by feeding the ticks. In addition to domestic animals, many wild animals, such as deer, hedgehogs, weasels, brushtail possums, and some bird species, are regular hosts of ticks. SFTSV infection has been found in rodents, with infection rates of 7% in A agrarius and 8% in Mus musculus and Rattus norvegicus.86 In Minnesota, USA, antibodies to SFTSV nucleoprotein were detected in 11% of goats, 13% of sheep, 16% of cattle, 12% of white-tailed deer, and 18% of elk; thus, both domestic and captive farmed animals in that area are exposed to SFTSV or Heartland virus.87
Clinical features The disease is characterised by abrupt onset of fever and respiratory tract or gastrointestinal symptoms, followed by a progressive decline in platelets and white blood cells. The typical course of infection has four distinct periods: incubation, fever, multiple organ failure, and convalescence (figure 2). The incubation stage after tick bite is generally 5–14 days.6,81 The incubation time can be affected by several factors, including viral dose and route Platelets White blood cells Aspartate amino transferase Lactate dehydrogenase Fever Headache Fatigue Myalgia Diarrhoea
Lymphadenopathy Haemorrhagic signs MOF DIC
Death
0
11
14
20
Time (days) Incubation 5–14 days
Fever stage 5–11 days
MOF stage 7–14 days
Figure 2: Clinical and laboratory course of SFTS MOF=multiple organ failure. DIC=disseminated intravascular coagulation.
4
Convalescence 11–19 days
of infection. The mean time from contact with or exposure to blood or bloody secretions of infected patients to onset is about 10 days (range 7–12).67,88 The fever stage is characterised by influenza-like symptoms, such as the sudden onset of fever (temperature 38–41°C) lasting for 5–11 days, headache, fatigue, myalgia, and gastrointestinal symptoms, such as lack of appetite, nausea, vomiting, and diarrhoea (table), which is accompanied by thrombocytopenia, leucocytopenia, and lymphadenopathy.81 A high viral load can be detected at this stage; it is an important marker for clinical diagnosis.81,94 The next stage is characterised by progressive worsening of multiple organ failure in fatal cases or a self-limiting process in survivors. Multiple organ failure develops rapidly, first in the liver and heart, then the lungs and kidneys, which can overlap with the fever stage; it occurs in most cases about 5 days after the onset of illness and persists 7–14 days.81 In this phase, the serum viral load gradually falls in survivors but remains high in patients who die. The concentrations of important biomarkers for this stage (including aspartate aminotransferase, creatine kinase, lactate dehydrogenase, and creatine kinase MB fraction) are significantly higher in fatal cases than in survivors.81,95 The clinical symptoms include haemorrhagic and neurological symptoms, disseminated intravascular coagulation, multiple organ failure, and sustained thrombocytopenia, which are major risk factors for death. This phase of SFTS is important, since patients who survive this period recover from the disease.81,96 The average period from onset of illness to death is 9 days.76 Most (85%) patients have a good outcome, but outcome is more likely to be poor in those with a history of underlying diseases, or neuropsychiatric symptoms, bleeding tendency, or hyponatraemia, and in elderly patients.6 The convalescence stage begins in survivors about 11–19 days after disease onset. Clinical symptoms begin to resolve, and laboratory measurements gradually revert to normal.81 Thrombocytopenia (
Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis Quan Liu, Biao He, Si-Yang Huang, Feng Wei, Xing-Quan Zhu
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging haemorrhagic fever that was first described in rural areas of China. The causative agent, SFTS virus (SFTSV), is a novel phlebovirus in the Bunyaviridae family. Since the first report in 2010, SFTS has been found in 11 provinces of China, with about 2500 reported cases, and an average case-fatality rate of 7·3%. The disease was also reported in Japan and Korea in 2012; Heartland virus, another phlebovirus genetically closely related to SFTSV, was isolated from two patients in the USA. The disease has become a substantial risk to public health, not only in China, but also in other parts of the world. The virus could undergo rapid evolution by gene mutation, reassortment, and homologous recombination in tick vectors and vertebrate reservoir hosts. No specific treatment of SFTS is available, and avoiding tick bites is an important measure to prevent the infection and transmission of SFTSV. This Review provides information on the molecular characteristics and ecology of this emerging tick-borne virus and describes the epidemiology, clinical signs, pathogenesis, diagnosis, treatment, and prevention of human infection with SFTSV.
Introduction In May, 2007, three patients with high fever, gastrointestinal bleeding, abdominal pain, bloating, nausea, vomiting, and high concentrations of aminotransferases were diagnosed as having acute gastroenteritis in a local hospital in Xinyang, Henan province, China. A relative of one patient reported the disease to the Henan Centre for Disease Control and Prevention; a special investigation by the centre showed the clinical characteristics of acute onset with fever, low counts of white blood cells and platelets, high concentrations of alanine and aspartate aminotransferases, and proteinuria. On the basis of these features, the centre ruled out gastrointestinal disorders and started to search for similar cases. 79 cases, with ten deaths (a case-fatality rate of 12·7%), were found in Henan in 2007.1 At that time, there were outbreaks of Tsutsugamushi (scrub typhus), caused by Orientia tsutsugamushi, in this area2,3 and human granulocytic anaplasmosis, caused by Anaplasma phagocytophilum, in neighbouring Anhui province.4,5 These diseases have similar clinical features. Rickettsial diseases, such as human granulocytic anaplasmosis, Tsutsugamushi, and human monocytic ehrlichiosis, caused by Ehrlichia chaffeensis, were thus regarded as possible causes of the Henan outbreak. However, only six (3%) of 206 suspected cases were confirmed as A phagocytophilum infection, and no pathogen was isolated in the 3 years from 2007.1 Patients with severe fever with thrombocytopenia syndrome (SFTS) were also reported in the provinces of Shandong, Jiangsu, Hubei, Anhui, and Liaoning.6 In 2010, a novel bunyavirus, designated as SFTS virus (SFTSV) or Huaiyangshan virus,7 was isolated from patients with SFTS. It was regarded as the causative agent of the lifethreatening illness associated with fever and thrombocytopenia in China.1,2 In 2012, the disease was also described in Japan8 and Korea,9,10 and another phlebovirus, named Heartland virus, was reported as the cause of two cases of severe
febrile illness with thrombocytopenia in Missouri, USA.11 Heartland virus is genetically closely related to SFTSV. The disease was traced back to 2009 for the USA, and the summer of 2012 for Japan and Korea, and no evidence was found that the patients had travelled to China. These viruses might have different origins, but cause similar or even identical symptoms and clinical outcomes. The newly emerged SFTSV actually originated in China about 50–150 years ago.12 Perhaps this pathogen has also been present in Japan and Korea, and Heartland virus in the USA, for a long time. In this review, we discuss the molecular characteristics and ecology of SFTSV and describe the epidemiology, clinical signs, pathogenesis, diagnosis, treatment, and prevention of this emergent tick-borne zoonosis.
Lancet Infect Dis 2014 Published Online May 16, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70718-2 State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China (Q Liu PhD, S-Y Huang PhD, Prof X-Q Zhu PhD); Military Veterinary Institute, Academy of Military Medical Sciences, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun, China (Q Liu, B He PhD); and College of Life Science, Jilin Agricultural University, Changchun, China (F Wei PhD) Correspondence to: Prof Xing-Quan Zhu, State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province 730046, China [email protected]
Causative agent Classification SFTSV is a phlebovirus of the family Bunyaviridae. Bunyaviridae includes the largest group of RNA viruses, with more than 350 viruses classified in five genera: the orthobunyaviruses (eg, Bunyamwera,13 Schmallenberg,14 Oropouche,15 and La Crosse16 viruses), the nairoviruses (eg, Crimean-Congo haemorrhagic fever virus and Nairobi sheep disease virus17,18), the tospoviruses (eg, tomato spotted wilt virus19), the phleboviruses (eg, Rift Valley fever,20 Candiru,21 sandfly fever Naples,22 Punta Toro,22 sandfly fever Sicilian,23 and Toscana24 viruses), and the hantaviruses (eg, Hantaan and Sin Nombre viruses25,26). Except for the rodent-borne hantaviruses, the Bunyaviridae are transmitted by arthropod vectors.27 Bunyaviruses can infect various animals and plants,25 and many viruses of this family have caused febrile infections in people, with encephalitis and haemorrhagic fevers. They are regarded as emerging pathogens of public health importance, owing to the increased incidence of late in new hosts and geographical locations.28–30 The phleboviruses are about 70 antigenically distinct serotypes, classed in two groups. The phlebotomus fever
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group are transmitted by phlebotominae sandflies or mosquitoes, and the Uukuniemi group by ticks.31 Genetically, SFTSV is grouped in the phlebovirus branch, but it differs from other known phleboviruses and probably is a third distinct group within the genus.1,2 Although SFTSV and Heartland virus have limited sequence similarity to other members of the Uukuniemi group, they were assigned to that group because they lack the small non-structural protein on their M segment, have certain serological characteristics, and have ticks as the common arthropod vector.32–34 Matsuno and colleagues34 have identified a new species of phlebovirus, the Bhanja group, which includes Bhanja, Forecariah, and Palma viruses.32 SFTSV and Heartland virus are more closely related to the Bhanja group than to the Uukuniemi group.34
Genome and structure SFTSV particles are spherical, measure 80–100 nm in diameter, and have a unit membrane envelope, from which protrude polypeptide spikes 5–10 nm long.2 The genome consists of three negative-stranded RNA segments: small, medium, and large. The small RNA segment has 1744 nucleotides and encodes the nucleoprotein and a non-structural protein by the ambisense strategy. The non-translated regions at the 3ʹ and 5ʹ termini are highly conserved, and show extensive nucleotide complementarity, forming a panhandle-like structure.1,2 The nucleoprotein encapsidates and packages genomic RNA into ribonucleoprotein complexes to protect it from degradation by exogenous nucleases or immune systems in the host cell.35 Despite the similar functions of nucleoprotein, the crystal structure of SFTSV nucleoprotein processes a stable hexameric ring to facilitate viral RNA encapsidation, a crucial step in replication of the virus. The four residues, A8, F11, A25, and L28, are essential for its oligomerisation, which differs substantially from that of other members of the Bunyaviridae.36–38 In addition, nucleoprotein has an active role in RNA transcription and replication and virion assembly.39,40 Both the nucleoprotein and the non-structural protein of SFTSV inhibit the antiviral immune response in host cells by suppressing the activation of interferon β and nuclear factor κB signalling.41–44 The medium RNA segment is 3378 nucleotides long and contains a single open reading frame encoding 1073 aminoacids for the precursor of the glycoprotein, which has crucial roles in virus assembly, formation of the virus particle, and attachment to new target cells.27 The glycoprotein binds to non-muscle myosin heavy chain IIA of cell surface protein, contributing to the efficiency of early infection by SFTSV.45 The large RNA segment is 6368 nucleotides long, and encodes 2084 aminoacids of the large protein, the viral RNA-dependent RNA polymerase, which brings about replication and transcription of the viral RNA.27 The 2
influenza-like endonuclease domain within its N-terminal is essential for viral cap-dependent transcription.46
Genetic diversity Despite more than 90% sequence similarity of SFTSV isolates irrespective of their broad geographical distribution, they are grouped into five sublineages A–E. Those isolated from animals (dogs, cats, goats, buffalo, and cattle) are in lineage A and do not show a geographical clustering pattern,12 which is distinct from other zoonotic viruses, such as rabies virus and hantavirus.47,48 Heartland virus and SFTSV share a common ancestor among viruses in the Bhanja group.12,34 The molecular mechanism of genetic diversity of SFTSV has not been completely elucidated, but several studies have shown that the virus can undergo rapid evolution by gene mutation, natural reassortment, and homologous recombination.12 Because its RNA-dependent RNA polymerase has no proof-reading function, SFTSV has a high mutation rate (about 10–⁴ substitutions per site each year) during its replication, the basis of its genetic diversity.12 Reassortment is a very efficient evolutionary force in segmented-genome viruses, which is associated with high pathogenicity and transmissibility among vectors and hosts and even results in new outbreaks.49 Phylogenetic evidence for natural reassortment has been reported in members of the genus phlebovirus, such as Rift Valley fever and Candiru viruses.12,21,50 Ding and colleagues51 have identified two SFTSV strains with reassortment in the small segment, which suggests that this process is the force to drive rapid change in SFTSV. Although homologous recombination is thought to be rare in negative-strand RNA viruses, it has been found in the medium segment of SFTSV52 and in other negative-sense RNA viruses, such as influenza,53–55 Ebola,56 and hantaviruses,57,58 which suggests that intragenic recombination has a role in the rapid evolution of the virus. The tick vector of SFTSV, Haemaphysalis longicornis, and the vertebrate reservoir hosts could provide the place of the coinfection by homologous recombination and natural reassortment for the virus.
Epidemiology SFTS was first reported in rural regions in Henan and Hubei provinces of central China between March and July, 2009.6 However, the first case occurred in Dingyuan County, Chuzhou, Anhui province, in September, 2006.59 From June, 2009, to September, 2010, 171 patients were identified as having SFTSV infection in Henan, Hubei, Shandong, Liaoning, Anhui, and Jiangsu provinces.1 By the end of 2012, the disease had been found in 11 provinces: Henan, Hubei, Anhui, Shandong, Jiangsu, Zhejiang, Jiangxi, Guangxi, Yunnan, Shaanxi, and Liaoning (figure 1). During 2011–12, 2047 cases occurred in China (with 129 deaths), mainly distributed in 206 counties of eastern and central China. The highest numbers of
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reported cases were in Henan (48% of the total), Hubei (22%), and Shandong (16%). Serosurveillance showed that 1·0–3·8% of the examined population in hilly areas had SFTSV antibodies, which suggests that SFTSV has circulated widely in China and that a very small proportion of infected individuals develop disease.60–72 The incidence of SFTS ranged from 0·03 per 1000 in Hubei province to 0·05 per 1000 in Shandong province.63 The first case of SFTS outside China was in North Korea in 2009.10 A fatal case was identified in South Korea in 2012,9 then six cases with four deaths were reported in 2013.65 In Japan, 11 cases and seven deaths were reported by April, 2013, and the apparently increasing numbers of cases seem to be contracted locally rather than imported from China.66 In the USA, the disease was first noticed in 2009, when two farmers in northwestern Missouri were admitted to hospitals with high fever, fatigue, diarrhoea, thrombocytopenia, and leucopenia; both had been bitten by ticks 5–7 days before the onset of illness.11 The overall mortality of SFTSV infection in China is about 7·3% (2391 cases and 174 deaths), ranging from 6·3% to 30·0% in various studies.1,61,71–76 The major at-risk group is farmers in endemic areas; almost 97% of the patients in China are farmers living in wooded and hilly areas and working in the fields; many have reported tick bites 7–9 days before illness.1 The incubation period is generally 7–14 days, with an average of 9 days. SFTS cases are distributed mainly in individuals of age (35–80 years) exposed to tick populations. The disease occurs mainly in April and May during the tea-picking season in Henan.1 Rural activities, such as camping and hiking, are also a potential risk factor for tick exposure.6 SFTS mostly arises as sporadic cases in the spring and summer. Direct contact with infected blood or bloody secretions can cause infection, and a few clusters of cases have been reported, which suggests human-to-human transmission of the disease.67–69 Hospital health-care workers, relatives of patients, and accompanying individuals are the second most affected population, through caring for patients with bloody secretions. Although there is no evidence that the virus causes disease in animals, blood from subclinically infected animals could be a source of infection.60,70 Therefore, veterinarians and abattoir workers are also at risk.77
Ecology Vectors As a newly discovered phlebovirus, SFTSV is thought to be an arbovirus, which suggests that it can be transmitted by various vectors. In China, SFTSV has been detected in the tick H longicornis (prevalence of 2·1–5·4%), collected from domestic animals in the areas where patients with SFTS lived; the RNA sequences of these isolated viruses are very closely related to those of SFTSV isolates from the patients.2,7,78,79 SFTSV has also been detected in Boophilus microplus from both endemic
No cases reported Cases reported
Heilongjiang
Jilin
Inner Mongolia
Ningxia
Xinjiang
Liaoning Beijing Tianjin Hebei Shanxi Shandong
Qinghai Gansu Shaanxi
Tibet
Anhui
Hubei
Sichuan
Jiangsu
Henan
Jiangxi Chongqing
Guizhou
Hunan
Yunnan Guangxi
Shanghai Zhejiang
Fujian
Guangdong
Taiwan
Hong Kong Macau Hainan
Figure 1: Geographical distribution of SFTS cases in mainland China in 2012 Red triangle=first SFTS case in Dingyuan county, Chuzhou city, Anhui province, in September, 2006. SFTS=severe fever with thrombocytopenia syndrome.
and non-endemic regions, but the prevalence in this tick (0·6%) is lower than that in H longicornis (4·9%). The higher prevalence in H longicornis in endemic regions than in non-endemic regions suggests that it is the major vector of SFTSV.7 H longicornis and B microplus are widely distributed in China and other countries, so SFTSV surveillance in these ticks is necessary.80 Gamasid and chigger mites collected from striped field mice (Apodemus agrarius) and goats in endemic regions were also found to carry SFTSV, so are also potential vectors.81 In the USA, Heartland virus was detected11 and isolated from questing nymphs of Amblyomma americanum collected from a patient’s farm and a nearby conservation area; these findings imply that the tick nymphs become infected by feeding on viraemic hosts and the virus is transmitted to people by host-seeking nymphs during the spring and summer. Thus, A americanum is thought to be the vector for Heartland virus.82 SFTSV and Heartland virus have not been detected in mosquitoes;2,82 phlebotomine sandflies have not yet been investigated.63
Vertebrate reservoir hosts SFTSV is thought to circulate in an enzootic tick– vertebrate–tick cycle. Although no evidence that the virus causes disease in animals is available, the seroprevalence of SFTSV by nucleoprotein-based double-antigen sandwich ELISA has been surveyed in domestic animals. In Shangdong province, the seroprevalence was 75–95% in goats, 57% in cattle,
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52% in dogs, and 36% in chickens.60–62,83 In Jiangsu province, 1% of chickens, 5% of pigs, 6% of dogs, 32% of cattle, and 57% of goats were seropositive.84 In Hubei province, 55% of dogs, 67% of goats, and 80% of cattle were seropositive.85 Viral RNA, typically at low levels, was detected in only a small proportion of the animals studied (1·7–5·3%).63 These findings suggest that the domestic animals could act as amplifying hosts of SFTSV, which play an important part in the spread of SFTSV by feeding the ticks. In addition to domestic animals, many wild animals, such as deer, hedgehogs, weasels, brushtail possums, and some bird species, are regular hosts of ticks. SFTSV infection has been found in rodents, with infection rates of 7% in A agrarius and 8% in Mus musculus and Rattus norvegicus.86 In Minnesota, USA, antibodies to SFTSV nucleoprotein were detected in 11% of goats, 13% of sheep, 16% of cattle, 12% of white-tailed deer, and 18% of elk; thus, both domestic and captive farmed animals in that area are exposed to SFTSV or Heartland virus.87
Clinical features The disease is characterised by abrupt onset of fever and respiratory tract or gastrointestinal symptoms, followed by a progressive decline in platelets and white blood cells. The typical course of infection has four distinct periods: incubation, fever, multiple organ failure, and convalescence (figure 2). The incubation stage after tick bite is generally 5–14 days.6,81 The incubation time can be affected by several factors, including viral dose and route Platelets White blood cells Aspartate amino transferase Lactate dehydrogenase Fever Headache Fatigue Myalgia Diarrhoea
Lymphadenopathy Haemorrhagic signs MOF DIC
Death
0
11
14
20
Time (days) Incubation 5–14 days
Fever stage 5–11 days
MOF stage 7–14 days
Figure 2: Clinical and laboratory course of SFTS MOF=multiple organ failure. DIC=disseminated intravascular coagulation.
4
Convalescence 11–19 days
of infection. The mean time from contact with or exposure to blood or bloody secretions of infected patients to onset is about 10 days (range 7–12).67,88 The fever stage is characterised by influenza-like symptoms, such as the sudden onset of fever (temperature 38–41°C) lasting for 5–11 days, headache, fatigue, myalgia, and gastrointestinal symptoms, such as lack of appetite, nausea, vomiting, and diarrhoea (table), which is accompanied by thrombocytopenia, leucocytopenia, and lymphadenopathy.81 A high viral load can be detected at this stage; it is an important marker for clinical diagnosis.81,94 The next stage is characterised by progressive worsening of multiple organ failure in fatal cases or a self-limiting process in survivors. Multiple organ failure develops rapidly, first in the liver and heart, then the lungs and kidneys, which can overlap with the fever stage; it occurs in most cases about 5 days after the onset of illness and persists 7–14 days.81 In this phase, the serum viral load gradually falls in survivors but remains high in patients who die. The concentrations of important biomarkers for this stage (including aspartate aminotransferase, creatine kinase, lactate dehydrogenase, and creatine kinase MB fraction) are significantly higher in fatal cases than in survivors.81,95 The clinical symptoms include haemorrhagic and neurological symptoms, disseminated intravascular coagulation, multiple organ failure, and sustained thrombocytopenia, which are major risk factors for death. This phase of SFTS is important, since patients who survive this period recover from the disease.81,96 The average period from onset of illness to death is 9 days.76 Most (85%) patients have a good outcome, but outcome is more likely to be poor in those with a history of underlying diseases, or neuropsychiatric symptoms, bleeding tendency, or hyponatraemia, and in elderly patients.6 The convalescence stage begins in survivors about 11–19 days after disease onset. Clinical symptoms begin to resolve, and laboratory measurements gradually revert to normal.81 Thrombocytopenia (
