Emerging tick-borne infections in mainland China: an increasing public health threat

Summary

Since the beginning of the 1980s, 33 emerging tick-borne agents have been identified in mainland China, including eight species of spotted fever group rickettsiae, seven species in the family Anaplasmataceae, six genospecies in the complex Borrelia burgdorferi sensu lato, 11 species of Babesia, and the virus causing severe fever with thrombocytopenia syndrome. In this Review we have mapped the geographical distributions of human cases of infection. 15 of the 33 emerging tick-borne agents have been reported to cause human disease, and their clinical characteristics have been described. The non-specific clinical manifestations caused by tick-borne pathogens present a major diagnostic challenge and most physicians are unfamiliar with the many tick-borne diseases that present with non-specific symptoms in the early stages of the illness. Advances in and application of modern molecular techniques should help with identification of emerging tick-borne pathogens and improve laboratory diagnosis of human infections. We expect that more novel tick-borne infections in ticks and animals will be identified and additional emerging tick-borne diseases in human beings will be discovered.

Introduction

Ticks were the first arthropods to be recognised as vectors that can transmit pathogens to human beings and are second only to mosquitoes as vectors of infectious diseases in the world.¹ Tick-borne infections are zoonoses with pathogens maintained in natural cycles involving tick vectors and animal hosts. Human beings are occasional hosts for ticks and are usually viewed as dead-end hosts that have no role in maintaining tick-borne agents in nature.² Different tick species favour distinct biotopes or environments, which define their geographical distribution and, consequently, the areas of risk for human tick-borne infections. In the past three decades, tick-borne pathogens have emerged worldwide and become a great threat to human health.1, 3

China is the largest developing country in the world and has made tremendous progress in the control and prevention of infectious diseases; however, emerging infectious diseases are the new challenge now facing China.⁴ Although outbreaks of severe acute respiratory syndrome and H5N1 and H7N9 avian influenza virus infections have attracted great attention, emerging tick-borne diseases have generally been neglected by primary health-care providers and clinicians. Although an increasing number of tick-borne infections have been reported in mainland China, no comprehensive review of this substantial public health problem has been undertaken. We will provide an overview of the type and distribution of emerging tick-borne infections in tick vectors, animal hosts, and human beings. We will describe the clinical characteristics of human tick-borne diseases, and discuss possible factors contributing to their emergence.

Emergence of tick-borne infections in mainland China

Since 1982, 33 emerging tick-associated agents have been identified in mainland China, including eight species of spotted fever group rickettsiae (SFGR);5, 6, 7, 8, 9, 10, 11 three species of Ehrlichia,12, 13, 14 three species of Anaplasma,15, 16, 17 and Candidatus Neoehrlichia mikurensis¹⁸ in the family Anaplasmataceae; six genospecies in the complex Borrelia burgdorferi sensu lato;19, 20, 21, 22, 23 11 species of Babesia;24, 25, 26, 27, 28, 29, 30, 31, 32, 33 and severe fever with thrombocytopenia syndrome virus (SFTSV).³⁴ The location and year in which each emerging tick-borne agent was first identified are shown in the appendix. Most (19 of 33) were initially detected in ticks; however, six were identified in domestic animals (sheep, goat, buffalo, and dog), two in wild animals (Chinese white-bellied rat and Chinese hare), and six in people. Detailed information regarding the identification of these emerging tick-borne infections is summarised in table 1 .

Table 1.

First identification and origin of emerging tick-borne infections in mainland China since 1982

		First identified origin*	First identified province (year)†	Reference (subsequent investigations)
Spotted fever group rickettsiae
	Rickettsia heilongjiangiensis	Dermacentor silvarum	Heilongjiang (1982)	5 (6,8,35–45)
	Rickettsia sibirica sp BJ-90	Dermacentor sinicus	Beijing (1990)	7 (46)
	Rickettsia sibirica sp mongolotimonae	Hyalomm asiaticum kozlovi	Inner Mongolia (1991)	7
	Rickettsia monacensis	Ixodes persulcatus	Henan, Anhui, and Hubei provinces (2006)	8 (44,47)
	Rickettsia raoultii	D silvarum	Xinjiang (2011)	9 (48–50)
	Rickettsia slovaca	D silvarum	Xinjiang (2011)	9 (50,51)
	Candidatus Rickettsia hebeiii	Haemaphysalis longicornis	Hebei (2011)	10 (52)
	Candidatus Rickettsia tarasevichiae	Man (I persulctus)	Heilongjiang (2012)	11
Anaplasmataceae
	Ehrlichia chaffeensis	Amblyomma testudinarium	Yunan (1996)	12 (32,36,53–62)
	Ehrlichia canis	Rhipicephalus sanguineus sensu stricto	Guangdong (1997)	13 (16,57,63)
	Ehrlichia sp Tibet	Rhipicephalus microplus	Tibet (2000)	14
	Anaplasma phagocytophilum	I persulcatus	Heilongjiang (1997)	15 (36,51,53–55,62–75)
	Anaplasma platys	Dog	Guangdong (1998)	16 (63)
	Anaplasma capra‡	Goat	Heilongjiang (2014)	17
	Candidatus Neoehrlichia mikurensis	Man (I persulctus)	Heilongjiang (2010)	18 (76,77)
Borrelia burgdorferi sensu lato
	Borrelia garinii	Man (I persulcatus)	Heilongjiang (1986)	19 (21,23,36,54,78–91)
	Borrelia valaisiana	Ixodes granulatus (Apodemus agrarius)	Zhejiang (1997)	20 (86,92)
	Borrelia sinica	Niviventer confucianus	Chongqing (1997)	20
	Borrelia afzelii	Man	Heilongjiang (2000)	21 (36,78,79,81,83–85,90)
	Borrelia valaisiana-related genospecies	I granulatus, H longicornis (A agrarius)	Guizhou (2006)	22 (78,83,86,88)
	Borrelia burgdorferi sensu stricto	Caprolagus sinensis	Hunan (2010)	23 (92)
Babesia spp
	Babesia ovis	Sheep	Sichuan (1982)	24 (93)
	Babesia major	H longicornis (cattle)	Henan (1988)	25 (94)
	Babesia ovata	Cattle	Henan (1990)	26 (95)
	Babesia orientalis	Buffalo	Hubei (1997)	27 (96,97)
	Babesia motasi	Sheep	Gansu (1997)	28 (98,99)
	Babesia caballi	D silvarum, Dermacentor nuttalli	Gansu (1998)	29 (100–102)
	Babesia sp Kashi	Hyalomma anatolicum	Xinjiang (2005)	30 (103)
	Babesia sp Xinjiang	R sanguineus sensu stricto, H anatolicum	Xinjiang (2007)	31 (103)
	Babesia microti	I persulcatus, Haemaphysalis concinna	Heilongjiang (2007)	32 (36,104–107)
	Babesia divergens	I persulcatus, H concinna, Haemaphysalis japonica (A agrarius)	Heilongjiang (2007)	32 (36,108)
	Babesia venatorum‡	Man	Xinjiang (2012)	33 (109)
SFTSV		Man	Henan (2009)	34 (110–118)

SFTSV=severe fever with thrombocytopenia syndrome virus.

^*First identified origin of each emerging tick-associated agent, including man, domestic animal, rodent, and tick. The agent that was simultaneously identified from other hosts or ticks is shown in parentheses.

^†Provinces include autonomous regions and metropolis.

^‡Not been formally described in taxonomic papers.

Among the 33 newly recognised tick-associated agents, 15 have been reported to cause human infection, including: four species of SFGR;11, 35, 46, 48 an Ehrlichia species,⁵³ two Anaplasma species,17, 53 and Candidatus N mikurensis;¹⁸ three genospecies of B burgdorferi sensu lato;19, 21, 78 three species of Babesia;33, 104, 108 and SFTSV (table 2 ).³⁴ Six of the tick-borne pathogens were first identified in febrile patients (Candidatus Rickettsia tarasevichiae, Candidatus N mikurensis, Borrelia garinii, Borrelia afzelii, Babesia venatorum [not yet formally described], and SFTSV) and then shown to be associated with ticks (table 1). The other nine human pathogens were initially detected in ticks or animals and subsequently shown to infect human beings (Rickettsia heilongjiangiensis, Rickettsia sibirica sp BJ-90, Rickettsia raoultii, Ehrlichia chaffeensis, Anaplasma phagocytophilum, Anaplasma capra, Borrelia valaisiana-related genospecies, Babesia microti, and Babesia divergens). Among these 15 emerging tick-borne diseases, severe fever with thrombocytopenia syndrome (SFTS) was first identified in mainland China³⁴ and subsequently reported in South Korea and Japan.134, 135 A disease similar to SFTS has been reported in the USA.¹³⁶ Human infections with R sibirica sp BJ-90, Candidatus R tarasevichiae, A capra, and B valaisiana-related genospecies have been exclusively diagnosed in mainland China.11, 17, 46, 78 Human infections of Candidatus N mikurensis, Ba venatorum, and R raoultii, which have been detected in China, were first identified in Europe.18, 33, 48 Five tick-borne pathogens have been detected in ticks or reservoir hosts, or both, but have not yet been reported to cause infection in human beings in China. They include Rickettsia monacensis, Rickettsia slovaca, Rickettsia sibirica sp mongolotimonae, B valaisiana, and B burgdorferi sensu stricto.137, 138, 139, 140, 141 Additionally, a Rickettsia species (Candidatus Rickettsia hebeiii), two Ehrlichia species (Ehrlichia canis and Ehrlichia sp Tibet), an Anaplasma species (Anaplasma platys), a genospecies of B burgdorferi sensu lato (Borrelia sinica), and eight Babesia species (Babesia ovis, Babesia ovata, Babesia orientalis, Babesia major, Babesia motasi, Babesia caballi, Babesia sp Kashi, and Babesia sp Xinjiang) have been identified in ticks or animals, but their pathogenicity to human beings is unknown.

Table 2.

Emerging tick-borne diseases of human beings reported in mainland China as of May 31, 2015

	Pathogen	Number of patients	Diagnostic methods*(reference)
Rickettsiosis	Rickettsia heilongjiangiensis	34	A and B (35), B and C (43), A and C (45)
Rickettsiosis	Rickettsia sibirica sp BJ-90	1	A and B (46)
Rickettsiosis	Rickettsia raoultii	2	A and B (48)
Rickettsiosis	Candidatus Rickettsia tarasevichiae	5	B (11)
Rickettsiosis	Uncharacterised Rickettsia spp	37	C (119–121), B (122), A and C (123), E (124)
Human monocytic ehrlichiosis	Ehrlichia chaffeensis	12	B (53,55)
Human granulocytic anaplasmosis	Anaplasma phagocytophilum	104	B (53,55,74,75), A, B, and C (73), A and B (64), E (71)
Human infection with Anaplasma capra†	A capra†	28	A, B, and C (17)
Human infection with Candidatus Neoehrlichia mikurensis	Candidatus N mikurensis	7	B (18)
Lyme disease	Borrelia garinii	30	B (21,23,78,90,91)
Lyme disease	Borrelia afzelii	8	B (21,23,78,90), C (125)
Lyme disease	Borrelia valaisiana-related genospecies	1	B (78)
Lyme disease	Uncharacterised Borrelia burgdorferi sensu lato	2691	A (126–130), E (131)
Babesiosis	Babesia divergens	2	B (108)
Babesiosis	Babesia microti	11	B and D (104,107)
Babesiosis	Babesia venatorum†	49	A, B, and C (33), B, C, and D (109)
Babesiosis	Uncharacterised Babesia spp	3	D (132,133)
SFTS	SFTSV	2543	A, B, and C (34,117), A or B or C (113,118), A or B (114), B and C (115), B (116)

SFTS=severe fever with thrombocytopenia syndrome. SFTSV=severe fever with thrombocytopenia syndrome virus.

^*Diagnostic methods: (A) a four-fold increase in titre of specific antibodies in blood sera collected from the acute and convalescent stages of illness, or a seroconversion of specific antibodies; (B) molecular detection and sequence determination; (C) isolation of pathogens from clinical samples; (D) light or electronic micrograph identification for thin blood smear; and (E) methods were not provided.

^†Not been formally described in taxonomic papers.

Emerging SFGR infections

Eight novel species of SFGR have been recorded in mainland China since 1982 (table 1).5, 6, 7, 8, 9, 10, 11 These species are mainly distributed in northern China (north of 36° north latitude).

Tick and animal infections

The eight emerging species and uncharacterised species of SFGR have been shown to be associated with 16 tick species (figure 1 ). R heilongjiangiensis has been proven to infect a range of tick species, three rodent species, and goats (appendix). In northeastern China, R heilongjiangiensis was detected in nine tick species and two rodent species from Heilongjiang Province,36, 37, 38 and in Haemaphysalis spp ticks from Jilin Province.³⁸ In Inner Mongolia, R heilongjiangiensis has been reported in Haemaphysalis verticalis, Detmacentor niveus, Hyalomma asiaticum kozlovi, Rhipicephalus pumilio, and Detmacentor nuttalli ticks.³⁹ In northwestern China, R heilongjiangiensis has been detected in Dermacentor silvarum ticks from Qinghai Province.⁴⁰ In southern China, R heilongjiangiensis has been detected in Haemaphysalis longicornis ticks from Guangdong Province,⁴¹ in goats from Yunnan Province,⁴² and in chestnut white-bellied rats from Hainan Province.⁴³ In central and eastern China, R heilongjiangiensis was identified in Haemaphysalis flava ticks from Henan, Anhui, and Hubei provinces,⁸ and in H longicornis from Zhejiang Province.⁴⁴ R sibirica sp BJ-90 was detected in Dermacentor sinicus ticks from a Beijing suburb.⁷ R raoultii was detected in Dermacentor species ticks, including D silvarum and Dermacentor marginatus, in western China,9, 49 in H verticalis collected from Inner Mongolia, in D silvarum from Heilongjiang Province, and in H longicornis from Liaoning Province.48, 39, 50, 51 Four species, including R sibirica sp mongolotimonae, R monacensis, R slovaca, and Candidatus R hebeiii, have not been proven to infect human beings. Data regarding infected ticks and animal hosts are shown in figure 1 and the appendix.7, 8, 9, 10, 47, 52, 54, 119, 142, 143, 144, 145, 146, 147

Figure 1.

Matrix of emerging tick-associated agents and tick species in mainland China

*Not yet formally described. SFTSV=severe fever with thrombocytopenia syndrome virus.

Human infections

Four species of emerging SFGR have been reported to infect human beings, including R heilongjiangiensis, Candidatus R tarasevichiae, R sibirica sp BJ-90, and R raoultii (table 2; figure 2 ). Of 34 people infected with R heilongjiangiensis, 19 were diagnosed in forested areas of northeastern China in the 1990s.35, 45 The other 15 cases of infection were reported on the island of Hainan Province in 2008.⁴³ In 2012, we undertook an active surveillance for human SFGR infections at the Mudanjiang Forestry Central Hospital of Heilongjiang Province in northeastern China, and eight cases of SFGR infection (including five infected by Candidatus R tarasevichiae, one by R sibirica sp BJ-90, and two by R raoultii) were identified by molecular detection and sequence determination. The presence of antibody against SFGR antigen in serum samples detected by immunofluorescence assay lent support to the diagnosis of SFGR.46, 48 Additionally, 37 patients were reported to have been infected with uncharacterised species of SFGR, including one in Inner Mongolia, one in Xinjiang Autonomous Region, 29 in Hainan Province, and six in Heilongjiang Province (figure 2).119, 120, 121, 122, 123, 124 The clinical manifestations of SFGR infections mainly include fever, eschar, headache, malaise, asthenia, anorexia, nausea, and lymphadenopathy. A few patients had rash and neurological manifestations such as coma, neck stiffness, and Kernig's sign.11, 35, 43, 45, 46, 48, 119, 120, 121, 122, 123, 124 Detailed information about the clinical and laboratory characteristics of patients infected with each of the emerging SFGR species are summarised in the appendix.

Figure 2.

Geographical distribution of emerging tick-borne diseases in mainland China

Human cases of SFGR infections are shown in blue; patients infected with agents in the family Anaplasmataceae in green; patients infected with agents in the complex Borrelia burgdorferi sensu lato in purple; and patients infected with agents in the genus Babesia in black. SFGR=spotted fever group rickettsiae. *Not yet formally described.

Emerging infections with agents in the family Anaplasmataceae

Seven species in the family Anaplasmataceae have been identified in mainland China, including E chaffeensis, E canis, Ehrlichia sp Tibet, A phagocytophilum, A capra, A platys, and Candidatus N mikurensis (table 1).

Tick and animal infections

The seven emerging agents in the family Anaplasmataceae are known to be associated with 17 tick species (figure 1). E chaffeensis was first detected in Amblyomma testudinarium ticks from Yunnan Province in 1996.¹² Several surveys report that it infects various tick species, and is widely dispersed in mainland China.31, 54, 55, 56, 57, 58 Furthermore, E chaffeensis was detected in dogs from Shandong Province, in long-tailed ground squirrels (Citellus undulates Pallas) and gerbils from Xinjiang Autonomous Region, in the striped field mouse (Apodemus agrarius) from Heilongjiang Province, and in rodents (Rattus norvegicus, Rattus losea, Rattus flavipectus, Rattus niviventer, Mus musculus, Niviventer confucianus, and Rattus edwardsi) and hares (Lepus sinensis) from Fujian and Zhejiang provinces (appendix).36, 55, 59, 60, 61, 62 A phagocytophilum was first detected in Ixodes persulcatus from Heilongjiang Province in 1997,¹⁵ and is now the most widely encountered species in the family Anaplasmataceae over broad areas where multifarious tick species are vectors (figure 1). Additionally, A phagocytophilum infects domestic and wild animals, including cattle, sheep, goats, horses, dogs, hare, yaks, and 24 species of rodents (appendix).36, 51, 54, 55, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72 A capra was first recognised in goats (Capra aegagrus hircus) and provisionally named by our group, but has since been detected in I persulcatus ticks in Heilongjiang Province.¹⁷ Although Candidatus N mikurensis was initially identified in I persulcatus and Haemaphysalis concinna ticks,¹⁸ it was subsequently detected in D silvarum, H longicornis, and various rodents from many areas of mainland China.18, 76, 77 Three other species, including E canis, Ehrlichia sp Tibet, and A platys, have not been proven to infect human beings. Data regarding infected ticks and animal hosts are shown in figure 1 and the appendix.13, 14, 16, 57, 63

Human infections

Four species of Anaplasmataceae have been identified to cause human infections in mainland China: E chaffeensis, A phagocytophilum, A capra, and Candidatus N mikurensis. The first human case of monocytic ehrlichiosis was diagnosed in a forested area of Inner Mongolia in 1999.⁵³ Of the 12 human cases of monocytic ehrlichiosis reported, four were recorded in Inner Mongolia, two in Beijing, two in Tianjin, and four in Shandong Province (figure 2).53, 55 A cluster of ten cases of human granulocytic anaplasmosis caused by nosocomial transmission was identified in Anhui Province in 2006.⁷³ An additional 94 cases of human granulocytic anaplasmosis have been reported, including 33 in Beijing, six in Tianjin, 41 in Shandong Province, one in Anhui Province, and four to five each in Henan and Hubei provinces and Inner Mongolia (figure 2).53, 55, 64, 74, 75 In 2015, 28 patients were reported to be infected with A capra in Heilongjiang Province.¹⁷ Seven cases of Candidatus N mikurensis infection were identified from 622 febrile patients in the same location in 2010.¹⁸ Patients with infections caused by species from the Anaplasmataceae family showed undifferentiated clinical manifestations, mainly including fever, malaise, myalgia, arthralgia, and gastrointestinal symptoms (diarrhoea, nausea, vomiting, and anorexia). Laboratory abnormalities included leucopenia, thrombocytopenia, and raised hepatic aminopherase, lactate dehydrogenase, and blood urea nitrogen (appendix).17, 18, 53, 55, 64, 73, 74, 75

Emerging infections with B burgdorferi sensu lato

B burgdorferi sensu lato was first detected in human beings and I persulcatus in China (Heilongjiang Province) in 1986.¹⁹ This isolate was later classified as B garinii by molecular biological methods in our laboratory. Five other genospecies were subsequently identified, including B valaisiana, B sinica, B afzelii, B valaisiana-related genospecies, and B burgdorferi sensu stricto (table 1).

Tick and animal infections

Over a wide geographical distribution of 25 provinces in mainland China, 26 tick species have been shown to carry B burgdorferi sensu lato (figure 1). B garinii is the most common genospecies and has been identified in many tick species (figure 1).54, 79, 80, 81, 82, 83, 84, 85, 86 B garinii has been detected in rodents from many endemic areas,23, 36, 79, 85, 87, 88 in dogs from Yunnan Province, in sheep keds (Melophagus ovinus) from Tibet, and in hares from Gansu Province (appendix).⁸⁹ B afzelii is the second most common genospecies, and has been identified in the same ticks and rodents as B garinii with a similar distribution.36, 79, 81, 83, 84, 85 B valaisiana-related genospecies (a genetically related but distinct genospecies of B valaisiana) was detected in Ixodes granulatus and H longicornis from Guizhou Province, and in rodents from Guizhou and Zhejiang provinces.22, 83 Three other genospecies that have not been reported to infect human beings include B valaisiana, B sinica, and B burgdorferi sensu stricto. Data regarding infected ticks and animal hosts are shown in figure 1 and the appendix.20, 23, 86, 92, 148, 149, 150, 151, 152, 153, 154, 155, 156

Human infections

After the identification of B burgdorferi sensu lato in ticks and animals, human cases of B burgdorferi sensu lato infection have been reported frequently in almost all provinces in mainland China, except for Tibet and Shanghai metropolis (figure 2). B garinii, B afzelii, and B valaisiana-related genospecies have been reported to cause human infections (table 2).19, 21, 23, 78, 90, 91, 125 The genospecies causing thousands of cases of Lyme disease in mainland China have not been characterised.126, 127, 128, 129, 130, 131 All the uncharacterised human cases in figure 2 were classified as B burgdorferi sensu lato infections irrespective of their actual genospecies. Infections with different genospecies of B burgdorferi sensu lato might result in slightly different clinical manifestations, including erythema migrans, arthritis or arthralgia, fever, headache, and fatigue.19, 21, 23, 78, 90, 91, 125, 126, 127, 128, 129, 130, 131 Generally, clinical manifestations in mainland China are mild compared with those in USA and Europe.⁷⁸

Emerging Babesia species infections

Since 1982, 11 Babesia species have been discovered in mainland China, including Ba ovis, Ba major, Ba ovata, Ba orientalis, Ba motasi, Ba caballi, Babesia sp Kashi, Babesia sp Xinjiang, Ba microti, Ba divergens, and Ba venatorum (table 1).

Tick and animal infections

The transmission of babesia is associated with 13 tick species (figure 1). Ba microti, Ba divergens, and Ba venatorum have been proven to infect human beings. Ba microti was identified in I persulcatus and H concinna ticks and in striped field mice and reed voles (Microtus fortis) from forested areas of Heilongjiang Province, in H longicornis ticks and dogs from Henan Province, and in rodents from Fujian, Zhejiang, Henan, and Heilongjiang provinces.32, 36, 58, 105, 106 Ba divergens was detected in I persulcatus, H concinna, and Haemaphysalis japonica ticks and striped field mice in several areas of Heilongjiang Province.32, 36 Ba venatorum was reported in I persulcatus ticks from forested areas of northeastern China.¹⁰⁹ Other species of Babesia that have not been shown to infect human beings include Ba ovis, Ba major, Ba ovata, Ba orientalis, Ba motasi, Ba caballi, Babesia sp Kashi, and Babesia sp Xinjiang. Data regarding their infected ticks and animals are shown in figure 1 and the appendix.24, 25, 26, 27, 28, 29, 30, 31, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103

Human infections

Ba microti, Ba divergens, and Ba venatorum have been reported to cause human infections in mainland China (figure 2). A patient was diagnosed with Ba microti infection by peripheral blood and bone marrow smears and PCR assay in Zhejiang Province in 2011.¹⁰⁴ By use of PCR, Ba microti infections were identified in an additional ten patients among 449 febrile patients with malaria-like symptoms in Yunnan Province during 2012–13.¹⁰⁷ One patient was co-infected with Plasmodium vivax and another was co-infected with Plasmodium falciparum. Two cases of Ba divergens infection were detected from 377 patients with anaemia in Shandong Province in 2009.¹⁰⁸ A case of babesiosis caused by Ba venatorum was reported in a child from Xinjiang Autonomous Region.³³ Between 2011 and 2014, 48 cases of Ba venatorum infection were reported through our active surveillance at a sentinel hospital in forested areas of northeastern China. Among them, 32 were confirmed cases, and 16 were probable cases.¹⁰⁹ These infections were the first report of endemic human Ba venatorum disease anywhere in the world. Additionally, two cases of babesiosis caused by uncharacterised Babesia species were reported in Yunnan Province of southwestern China in 1982 and one in 2008 (figure 2).132, 133 Clinical manifestations for patients with Babesia species infections included fever, fatigue, anaemia, chills, and high levels of hepatic aminopherase and C-reactive protein.33, 108, 104, 109, 107, 132, 133 Detailed information about the clinical manifestations of each of these species of Babesia infections is summarised in the appendix.

Emerging SFTSV infections

SFTSV is a novel member of the genus Phlebovirus in the Bunyaviridae family, and was first identified in China. The identification of SFTSV infections was made possible by enhanced active surveillance in selected provinces of China.³⁴ Since a systematic review on the epidemiology, clinical signs, pathogenesis, diagnosis, treatment, and prevention of human infection with SFTSV has been published,¹⁵⁷ we provide only a brief description and some new information about the infection.

Tick and animal infections

SFTSV have been reported to infect H longicornis and Rhipicephalus microplus ticks, with a higher prevalence of infection in H longicornis (4–9%) compared with in R microplus (0–6%).34, 110 Various animals, including goats, cattle, dogs, pigs, rodents, chickens, geese, and hedgehogs, might be infected by this pathogen.110, 111 Studies in Shandong, Jiangsu, and Hubei provinces showed that goats and cattle had the highest seropositive rate. Furthermore, big animals usually had higher seropositive rates than small animals.111, 112

Human infections

As of 2013, 2543 human SFTS infections have been reported to the China Center For Disease Control And Prevention, including 154 deaths.34, 113, 114, 115, 116, 117, 118 Incidence hotspots are located in Henan, Hubei, Anhui, and Shandong provinces of middle-eastern China, in addition to Liaoning Province of northeastern China (appendix). Clinical manifestations in patients with SFTS are non-specific with major symptoms including respiratory tract symptoms, sudden onset of fever up to 38–41°C, headache, fatigue, myalgia, and gastrointestinal symptoms (loss of appetite, nausea, vomiting, and diarrhoea). Multiple organ failure develops rapidly in most patients (with raised concentrations of serum alanine aminotransferase, aspartate aminotransferase, creatine kinase, and lactate dehydrogenase; and proteinuria and haematuria), and is usually accompanied by thrombocytopenia, leucocytopenia, and lymphadenopathy.34, 117

Factors contributing to the emergence of tick-borne infections

Beyond doubt, advances in and application of molecular technologies have resulted in the discovery of novel agents and helped to identify human infections caused by agents previously detected in ticks. Thus, to some extent, the emergence of tick-borne infections has resulted from the discovery of novel pathogens through the use of more sensitive and reliable detection methods. However, various biological factors, such as tick and host population dynamics, which have caused an increase in the transmission and dissemination of tick-borne zoonotic diseases, are probably the main reasons for the emergence of these infections.³

Changes in land use have affected the emergence of tick-borne zoonotic diseases by altering the interactions and abundance of ticks, wild and domestic hosts, and human exposure to pathogens.¹⁵⁸ An example is the emergence of Lyme disease in northeastern USA. Reforestation of this region during the 20th century is thought to have increased the population of white-tailed deer, which greatly amplified the number of Ixodes scapularis. Consequentially, vector tick densities grew and expanded, contributing substantially to the emergence of Lyme disease in the USA.¹⁵⁹ Fragmentation of forests in eastern regions of Canada and the USA might have increased the relative abundance of small mammals because of a reduction in predator communities, leading to an increase in B burgdorferi sensu lato infection rates in I scapularis nymphs. Ultimately, people in these areas were confronted with a higher risk of Lyme disease.160, 161

Since the mid-1990s, the Chinese central government has initiated the Greening Program to regain forests and grasslands from former agricultural lands.¹⁶² Reforestation and grass replanting with high-quality vegetative cover could have increased the abundance and diversity of ticks and animal hosts, and favoured the re-establishment of pre-existing tick vector enzootic cycles in these areas. One example described in our study was in the most severely endemic region of SFTS. Our findings showed that the incidence of SFTS is significantly associated with vegetation-rich lands. A 10% increase in shrub, forest, and rain-fed cropland areas resulted in increased human SFTS incidence rates of 51%, 51%, and 90%, respectively.¹⁶³

Additionally, urbanisation has affected the emergence and increasing incidence of tick-borne diseases. Studies in Europe suggest that encroachment into forested and uncultivated areas, and protection of existing green spaces in the process of urbanisation, have created opportunities for ticks to survive in urban and especially suburban environments. The presence of many pets and domestic animals, which can serve as tick hosts and pathogen reservoirs, might help tick transmission of various human and animal pathogens.164, 165 In the past three decades, China has gone through the most rapid urbanisation in its history. This rapid urbanisation, followed by widespread rural-to-urban migration of the human population, intensive long-distance trade, and explosive short-term travel for shopping, has led to substantial health risks including air pollution, occupational and traffic hazards, and altered diets and activity.¹⁶⁶ All of these changes in human activity, together with increased contact between human beings and their pets and nature, have probably contributed to the increasing abundance of tick exposure, as reported in other developed countries.¹⁶⁴ Further investigation is needed to show the relation between emerging tick-borne diseases and urbanisation in mainland China.

The effect of worldwide climate change on the emergence of most vector-borne zoonotic diseases (including tick-borne diseases) is thought to be less important than changes in land use, animal host communities, human living conditions, and societal factors.³ Although the effects of climate on transmission of infectious diseases are thought to be non-linear and act in opposing directions in different climate regions, the seasonal dynamics of tick vectors are largely defined by climate conditions, which might further affect the seasonal pattern of tick-borne diseases. An increase in winter temperatures is known to cause the northward extension and increased abundance of Ixodes ricinus, which subsequently raises the risk of tick-borne disease dissemination.167, 168, 169 Although this topic is still under debate, climatic change could have a role in the emergence of tick-borne diseases in China. Further studies are needed to better elucidate this issue.

Perspectives

Ticks are thought to be second only to mosquitoes as worldwide vectors of human infectious diseases.¹⁷⁰ Up to now, more than 120 tick species have been identified in China, including over 100 species in the Ixodidae (so-called hard tick) family and 19 species in the Argasidae (soft tick) family.¹⁷¹ They transmit several pathogens when feeding on a range of animals, including human beings as accidental hosts. About 30 tick species are reported to feed on human beings.172, 173 The diverse geographical distribution and abundance of ticks are dependent on optimum environmental conditions and biotopes for each tick species, which define the risk areas for corresponding tick-borne zoonoses.³ In addition to the emerging tick-borne infections, previously documented and well established tick-borne diseases are a continuing threat to human health, including tick-borne encephalitis in northeastern China, Crimean-Congo haemorrhagic fever in northwestern China, tularaemia and north-Asia tick-borne spotted fever in northern China, and Q fever, which is widely distributed throughout China.174, 175, 176, 177, 178, 179, 180, 181, 182, 183

The non-specific clinical manifestations caused by tick-borne pathogens, such as SFGR, Anaplasma species, B burgdorferi sensu lato, Babesia species, and SFTSV, present a major diagnostic challenge. Most physicians are unfamiliar with the many tick-borne diseases that present with non-specific symptoms in the early stages of the illness. The wide distributions of the 33 emerging tick-associated agents and their tick vectors, in addition to the diversity of tick species throughout mainland China, imply that reported cases of infection might be only the tip of the iceberg in regard to the actual number of tick-borne diseases. To develop a reasonable differential diagnosis and identify a specific pathogen, laboratory diagnostic methods that are rapid, convenient, and practical are urgently needed for these emerging tick-borne diseases. Although great progress has been made in mainland China in the detection and identification of various tick-borne pathogens and diagnosis of the infections they cause, the necessary technologies are still unavailable in most general hospitals. Unfortunately, the importance of tick-borne diseases to human and animal health has not been sufficiently recognised as a result of inaccessibility to laboratory tests for aetiological diagnosis and inadequate surveillance activities.

In China, 18 tick-borne agents have been detected in ticks or animals, including four Rickettsia species, two Ehrlichia species, an Anaplasma species, three genospecies of B burgdorferi sensu lato, and eight Babesia species; however, the full effect of their pathogenicity to human beings is still to be established. Despite increasing knowledge about their geographical distribution, the natural cycle of these agents and the natural history of their infection in tick vectors and animal hosts have yet to be elucidated. Identifying human infections after potentially pathogenic agents are identified in ticks could take many years, in part because the microbial loads are much lower in human blood than in arthropods.¹⁸⁴ For example, R sibirica sp BJ-90 was first identified in D sinicus ticks in China in 1990,⁷ but was not discovered to infect human beings until 22 years later.⁴⁶ Similarly, A phagocytophilum was initially detected in China in 1997;¹⁵ however, nosocomial transmission of human granulocytic anaplasmosis was not recognised until 10 years later.⁷³ As such, the 18 tick-associated agents that have been recognised in China in either ticks or animals represent potential candidates for new tick-borne human diseases. Likewise, a search for potential new pathogens in ticks is essential for the discovery of emerging tick-borne diseases in human beings.

Conclusion

33 tick species belonging to six genuses have been reported to be naturally infected with the emerging pathogenic agents described in this Review (figure 1). Except for eight species (Dermacentor abaensis, Dermacentor daghestanicus, Haemaphysalis bispinosa, H flava, Haemaphysalis sinensis, Haemaphysalis yeni, Ixodes myospalacis, and Rhipicephalus turanicus), most species carry two or more agents. Conversely, some emerging agents such as R heilongjiangensis, E chaffeensis, A phagocytophilum, and B garinii can infect several tick species. Additionally, tick-borne pathogens that infect domestic animals might eventually cause human disease. A representative example is B divergens, which has long been recognised to cause cattle babesiosis in Europe, and was subsequently identified as a human pathogen.¹⁸⁵ In China, a wide range of emerging tick-borne agents are known to infect various domestic animals (appendix), and their potential capability to infect humans warrants great attention and further investigation. With the continued emergence of tick-borne diseases in mainland China, improving our understanding of the existence and health burden of these diseases is essential for China and for the rest of the world.

Search strategy and selection criteria

We searched PubMed and ISI Web of Science for articles published in English, and WanFang database, China National Knowledge Infrastructure, and Chinese Scientific Journal Database for articles published in Chinese between Jan 1, 1980, and May 31, 2015. We used the following search terms: “tick-borne disease”, “tick-borne zoonosis”, “tick-borne zoonotic disease”, “tick-associated agent”, “tick-associated microbe”, and “China”, in combination with each of the five genera of tick-borne agents. We did a secondary manual search of the references cited in these articles to find relevant articles. We investigated all the articles related to detection, identification, or infections of these five genera of tick-borne microbes in human beings, ticks, and animals. We contacted the corresponding authors for detailed information such as the time of discovery, location, and origin of tick-borne agents if any of this information was missing in the articles.

Contributors

L-QF, SL, XFY, GCG, PJK, and W-CC initiated the original ideas for the review. KL, X-LL, H-WY, RXS, YS, and W-JC contributed to the literature search and extracted data. KL, X-LL, H-WY, YY, SL, S-QZ, M-JM, HL, J-FJ, and WL assessed the data. L-QF, KL, X-LL, H-WY, R-XS, YS, W-JC, and W-CC created the figures. L-QF, GCG, and W-CC wrote the draft, and all authors contributed to the review and revision of the paper.

Declaration of interests

We declare no competing interests.