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Clonorchiasis: a key foodborne zoonosis in China

Zhao-Rong Lun, Robin B Gasser, De-Hua Lai, An-Xing Li, Xing-Quan Zhu, Xing-Bing Yu, and Yue-Yi Fang Lancet Infect Dis 2005; 5: 31–41 Z-RL, D-HL, and A-XL are at the The oriental liverfluke, Clonorchis sinensis, is of major socioeconomic importance in parts of Asia, including China, Center for Parasitic Organisms Japan, Korea, Taiwan, and Vietnam. The parasite is transmitted via snails to freshwater fish, and then to human and the Key Laboratory for Tropical Diseases Control of the beings and other piscivorous mammals, and causes substantial clinical or subclinical disease, known as clonorchiasis. Ministry of Education, School of There is considerable evidence for an aetiological relation between clonorchiasis and cholangiocarcinoma in human Life Sciences, and X-BY is at the beings. It is estimated that about 35 million people are infected globally, of whom approximately 15 million are in Parasitology Institute, School of China. Although very little information from China has been published in the English language, recent analyses of Medicine, Zhongshan (Sun Yat-Sen) University, epidemiological data sets suggest that clonorchiasis is having an increased human-health impact due to the greater Guangzhou, China; RBG is at the consumption of raw freshwater fish. To gain an improved insight into clonorchiasis in China, this review provides a Department of Veterinary background on the parasite and its life cycle, summarises key aspects regarding the pathogenesis, diagnosis, and Science, The University of treatment of clonorchiasis, describes the geographic distribution and prevalence of clonorchiasis, and makes some Melbourne, Victoria, Australia; X-QZ is at the Department of recommendations for future research and the control of this important disease. Parasitology, College of Veterinary Medicine, South China Parasites of the class Trematoda (phylum traditional delicacy. It is thus timely and appropriate to Agricultural University, Platyhelminthes: Digenea) are important eukaryotic review the Chinese literature on and human Guangzhou; and Y-YF is at the C sinsensis Parasitology Institute, Center for pathogens of vertebrates, particularly in Asian clonorchiasis, to gain a better insight into its Disease Control of Guangdong countries.1–3 For example, members of the family epidemiology and socioeconomic impact in China. The Province, Guangzhou. Opistorchidae, which includes the genera Opistorchis purpose of the present review is to provide background Correspondence to: and Clonorchis, are considered to be of major socio- information on the parasite and its life cycle, to Dr Zhao-Rong Lun, Center for economic importance in human beings and animals.2–6 summarise some key aspects regarding the Parasitic Organisms and the Key Laboratory for Tropical Diseases Clonorchis sinensis, the oriental or Chinese liverfluke, is pathogenesis, diagnosis, and treatment of clonorchiasis, Control of the Ministry of of major relevance because it is zoonotic—being to give an account of the state of knowledge of the Education, School of Life transmissible via food (fish) to people—and causes geographic distribution and prevalence of clonorchiasis Sciences, Zhongshan substantial subclinical or clinical disease, known as in China, and to conclude by making some suggestions (Sun Yat-Sen) University, Guangzhou 510275, China clonorchiasis. This parasite is endemic predominantly in for further research and recommendations for the [email protected] Asian countries or regions, such as China (including prevention and control of this important disease. or Dr Robin Gasser, Department Hong Kong and Taiwan), Japan, Korea, and Vietnam.2,3,7 of Veterinary Science, University Since 1991, no cases of clonorchiasis have been reported of Melbourne, 250 Princes Parasite and its life cycle Highway, Werribee Victoria 8 in Japan. The prevalence rates are estimated at 1·4% in Like most other Digenea, the adult of C sinensis is a 3030, Australia Korea9 and 5·3–28·4% in northern Vietnam.10–13 The dorso–ventrally flattened hermaphroditic worm, usually [email protected] parasite can also cause major problems, for example, in about 10–25 mm in length and 3–5 mm in width, with an people who travel to endemic regions, and in Asians anterior oral sucker, and a centrally located ventral sucker who immigrate from endemic to non-endemic countries and uterine pore.3,4 The life cycle of C sinensis involves who subsequently develop serious clinical disease. For piscivorous mammals—including human beings, dogs, instance, early studies described clinical clonorchiasis in and cats—as definitive hosts in which sexual Asian immigrants to North America, the prevalence reproduction takes place, snails (in which asexual rates being up to 26%.14–18 Although clonorchiasis may reproduction takes place), and freshwater fish not have a major impact in a non-endemic country, the (Cyprinidae) or shrimp as intermediate hosts (figure 1).3,4 correct diagnosis and treatment of the disease in In the definitive host, the adult worm lives mainly in immigrants from, or travellers to, endemic regions is of intrahepatic bile ducts and the gall bladder, and less paramount importance. frequently in the extrahepatic and pancreatic ducts. Each Based on a range of studies, it is currently estimated adult C sinensis can produce about 1000–4000 eggs per that about 35 million people are infected globally, of day for at least 6 months, depending on the mammalian whom 15 million are in China.19–38 While there is a host species. The ovoid eggs, which are operculate, each substantial body of published literature on clonorchiasis contain a fully formed larva known as a miracidium. The and its causative agent, and its epidemiology in Asia, eggs are released from the adult via the uterine pore into only a small number of articles from China has been the bile and the small intestine, and are subsequently published in the English language. Moreover, recent excreted via the faeces into the external environment, to analysis of epidemiological data obtained from eventually reach a body of freshwater (eg, ponds, governmental departments in China (sources available streams, or rivers). from the primary author) suggests that the prevalence of There, the eggs are ingested by a range of small snails clonorchiasis in human beings is increasing in various (order Mesogastropoda), which act as first intermediate parts of China, possibly due to the increased hosts (table 1). The miracidium hatches from the egg in consumption of raw freshwater fish, considered a the gastrointestinal tract of the snail and then http://infection.thelancet.com Vol 5 January 2005 For personal use. Only reproduce with permission from Elsevier Ltd. 31 中国科技论文在线______http://www.paper.edu.cn

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(or small intestine), and the juvenile flukes migrate (within about 30 min) via the hepatopancreatic ampulla 1 to the intrahepatic bile ducts. The juvenile flukes travel against the bile flow along the biliary tree and attach themselves to the bile-duct epithelium using their suckers. Approximately 4 weeks after ingestion of the A metacercariae, the adult worms start producing eggs. In 2 highly endemic areas, large numbers of flukes have been collected at autopsy from the bile ducts of human beings, with 500–1500 or more worms per person being common in severe cases. Concomitant infection of the pancreatic duct can occur, resulting in dilatation and fibrosis of this duct. Flukes can also be found in the gall 3,38 5 3 bladder, duodenum, and, occasionally, stomach. Adult flukes have been suggested to be able to survive in people for periods of 20–25 years.3,55

Human clonorchiasis Clonorchiasis is characterised histopathologically by a hyperplasia (and metaplasia) of the intrahepatic bile- C B duct epithelium (“adenomatous hyperplasia”), followed by periductal fibrosis in chronic cases.56 The severity of these changes is associated with the intensity of 4 infection, the duration of infection, the number of reinfections, and/or the susceptibility of the host.57,58 The clinical manifestations of clonorchiasis also tend to Figure 1: Life cycle of Clonorchis sinensis 3,45,59–63 In the definitive host (A), the sexually mature liverfluke (1) exists predominantly in the intrahepatic bile ducts and relate to the intensity of infection but are variable. gall bladder. Eggs (with miracidium) (2) are shed into the external environment via faeces. Miracidia in water (3) Most people infected with a small number of worms are ingested by small snails (B), the first intermediate host. Infected snails shed numerous motile cercariae (4) into (<100) usually have few clinical signs (abdominal the water, which seek the second intermediate host, fish (C). The cercariae encyst under the skin or in the discomfort, diarrhoea, and/or malaise). Some patients musculature, forming metacercariae (5). Ingestion of raw or undercooked infected fish results in infection of the definitive host. Modified from Piekarski39 (10–40%) can have peripheral eosinophilia with intermittent jaundice. People infected with a moderate transforms (within about 4 h) to a sporocyst in the number of worms (<1000) can present with similar or intestinal wall or in other organs to undergo asexual more pronounced clinical signs, including fever and/or reproduction. The rediae are produced within about 17 chills, anorexia, weight loss, colic, fatigue, and/or days. After 21–30 days, cercariae develop (5–50 per abdominal distension. Superimposed on these signs, redia). The cercaria has a long tail with a long dorsal and people infected with higher numbers (1000–25 000) of some shorter ventral fins, a finely spined tegument, worms can present with acute pain in the right upper seven pairs of penetration glands, 14 cystogenous quadrant. In the chronic phase of severe cases, portal glands, a pair of eye-spots, and large amounts of hepatomegaly, ascites, and hypertension can occur, as brownish pigment. Infected snails shed numerous, well as jaundice and/or diarrhoea.17,18,57,58,64 Since the motile cercariae into water, which seek the second parasite can survive for many years, the liver damage intermediate host, usually a cyprinoid freshwater fish. associated with heavy, chronic infection, and the The cercariae penetrate between the scales of the fish, stenosis caused by the epithelial hyperplasia and fibrosis and encyst as metacercariae under the skin or in the in the biliary ducts or cholelithiasis (linked to the musculature. In doing so, the cercariae lose their eye- degeneration and death of parasites) can lead to serious, spots and develop a sac-like excretory bladder filled with acute clinical signs that, in some cases, can be fatal.38,58,65 coarse, refractile granules. The metacercarial stage is Clinically, a range of hepatic and biliary diseases can usually ovoid (about 120 x 140 µm in size) and possesses present similarly to clonorchiasis. Differential diagnoses a relatively thin wall. Hundreds to thousands of of clonorchiasis include acute or chronic hepatitis of metacercariae may be harboured within a single fish, other aetiologies (eg, fascioliasis), cancer of the biliary depending on species and ecological circumstances, system, hepatocholedocholithiasis with recurrent thus being infective to the definitive host. pyogenic cholangitis, sclerosing cholangitis, and Caroli’s When the definitive host ingests raw or undercooked disease.66–68 Complications as a consequence of chronic (or even inadequately cured, dried, pickled, or salted) clonorchiasis can include pyogenic cholangitis, infected fish or shrimp, the metacercariae pass through cholelithiasis, cholecystitis, and/or pancreatitis.64,69,70 the gastric environment to then hatch in the duodenum Importantly, there is also considerable epidemiological,

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experimental, and histopathological evidence for a Province and references Family Species causative link between clonorchiasis and malignant Anhui3 Hydrobiidae cholangiocarcinoma in human beings,2,3,38,45,56,62,65 Alocinma longicornis, Parafossarulus striatulus (= P manchouricus) although the carcinogenic mechanism has not yet been Bithyniidae Bithynia fuchsianus proven. It is hypothesised that the mechanism is Melaniidae Semisulcospira cancellata multifactorial, linked to the hyperplasia/metaplasia of Fujian3 Hydrobiidae A longicornis, P striatulus Bithyniidae the bile duct epithelium being susceptible to exogenous B fuchsianus Melaniidae S cancellata and/or endogenous (eg, from the worm) chemical Thiaridae Melanoides tuberculata carcinogens.56 Clearly, this is an exciting area for future Guangdong3,21,40–42 Hydrobiidae A longicornis, P striatulus investigation. Bithyniidae B fuchsianus Melaniidae S cancellata Assimineidae Assiminea lutea Epidemiology Thiaridae M tuberculata Distribution and prevalence of human clonorchiasis Guangxi3,43,44 Hydrobiidae A longicornis, P striatulus Bithyniidae C sinensis was first discovered in the bile ducts of a B fuchsianus Thiaridae M tuberculata Chinese carpenter in Calcutta, India, in 1875, and the 3,24, 45,46 Heilongjiang Hydrobiidae P striatulus 3,40 first autochtonous case reported in China was in 1908. Melaniidae S cancellata However, there is archaeological evidence of human Henan3,47 Hydrobiidae A longicornis, P striatulus 3,48–50 clonorchiasis dating back to the Ming and Western Han Hubei Hydrobiidae A longicornis, P striatulus Bithyniidae dynasties. For instance, in 1956, archaeological studies B fuchsianus Melaniidae S cancellata found C sinensis eggs in desiccated faecal remains from a Hunan3,29 Hydrobiidae A longicornis, P striatulus mummy linked to the Ming dynasty (1368–1644),3,20,38 Bithyniidae B fuchsianus which indicates that human clonorchiasis was present in Melaniidae S cancellata Sichuan3,51–53 Hydrobiidae Guangdong about 500 years ago. Also, in 1975, A longicornis, P striatulus Bithyniidae B fuchsianus, B robustus archaeologists detected C sinensis eggs in the faecal Thiaridae M tuberculata remains from an ancient corpse buried during the West Shandong3,27,54 Hydrobiidae A longicornis, P striatulus, Han dynasty (206 BC–23 AD) in Hubei, China,3,71 Melaniidae S cancellata indicating that this disease has been present in this Table 1: Species of freshwater snail (order Mesogastropoda) presently recognised as key first province for more than 2000 years. More recently, intermediate hosts of Clonorchis sinensis in China human clonorchiasis has been reported mainly in southern China, particularly in the provinces of Guangdong and Guangxi, where more than 5 and 3·5 million people are estimated to be infected, respectively. The consumption by people of raw or undercooked Estimated prevalence (%) freshwater fish and crustaceans is thought to be the 0 main factor linked to this high prevalence. A high <0·04 prevalence of this disease is also found in Korean 0·04–0·4 (minority) communities in the northeastern provinces of Heilongjiang China, such as Heilongjiang, Jilin, and Liaoning.24,33,72–74 0·4–1·0

In China, human clonorchiasis has been reported for >1·0 Jiling most provinces, except Inner Mongolia, Ningxia, Qinghai, Tibet, and Xinjiang (figure 2).3,7,31 Table 2 Liaoling summarises epidemiological information on human clonorchiasis, based on a range of national and provincial studies carried out over multiple decades. Shangdong In the province of Guangdong, human clonorchiasis Jiangsu was detected in 62 of 95 counties or cities by epidemiological surveys carried out from 1973 to 2003, Sichuan Hubei and an analysis of the coprological examination results Chongqing showed that about 18% of all 862 393 people examined Jiangxi Hunan were infected with C sinensis.21,31,40–42,76–79,104 Some surveys also revealed that 78·5–85% of individuals were infected Guangdong Taiwan with the parasite in endemic areas, such as Guanyuan, Guangxi Dongyong, Sanshui, and Shunde, where the consumption of raw fish is very common.40,42,77,80 The Hainan streams extending from the Pearl and Han rivers are thought to be linked to the most important endemic areas for clonorchiasis in this province.21,40–42,78 Figure 2: Prevalence of human clonorchiasis in different regions of China http://infection.thelancet.com Vol 5 January 2005 For personal use. Only reproduce with permission from Elsevier Ltd. 33 中国科技论文在线______http://www.paper.edu.cn

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praziquantel treatment,90 which is the most worms ever Province and references Year(s) Number of Number infected Prevalence (%) people examined recorded for a human patient in China. Anhui75 1988–1999 54329 782 1·44 In Hunan province, based on the epidemiological Beijing75 1976–1978 811 520 14 636 1·8 survey conducted from 1971 to 1990, 20 counties and Gansu36 1987–1997 28 700 28 0·10 cities were confirmed to be endemic for clonorchiasis. 38,40,75–82 Guangdong 1973–2003 862 393 153 500 1·8–57·4 (17·8) 40 569 people were examined, and 3043 (7·5%), aged Guangxi7,22,33,75,83–86 1988–2003 215 920 45 157 13·1–74·7 (20·9) Heilongjiang24,45,72,87–91 1988–2002 94 483 15 916 1·2–85·3 (16·9) from 2 to 75 years, were found to harbour C sinensis. The Henan3,47,92–94 1964–1990 738 415 9104 0·08–28·4 (1·23) highest prevalence—85·2%—was found in Qiyang.29 Hubei45,75,95,96 1987–1991 78 666 630 0·09–2·3 (0·80) In the province of Hubei, the first epidemiological 29 Hunan 1971–1990 40 569 3036 2·1–85·2 (7·48) survey conducted in 1988 showed that human Jiangsu23,25,97 1987–2000 85 257 359 0·12–3·98 (0·42) Jilin28 1998 910 81 8·90 clonorchiasis was widespread (ie, present in 14 of 17 Liaoning30 1998 14 390 60 0·42 counties and cities), with a mean prevalence of more Shandong26,27,37,75 1960–2000 5 376 708 75 194 0·3–1·5 (1·40) than 10%.32,49,95,96 A subsequent study revealed an 51–53,75,98–102 Sichuan 1978–1997 228 109 10 521 0·38–20·9 (4·61) endemic focus of in the Yangxin county. Tianjin103 1987–1990 22 144 44 0·20 C sinensis Total 1960–2003 7 759 847 304 126 0·08–57·4 (3·8) There, 6865 people from 20 sites in the township of Panqiao were examined, and nearly 6% were found to Due to political movements and the cultural revolution that took place from 1954 to 1976, reports of human clonorchiasis harbour the parasite. Based on coprological from the endemic regions are not available. Therefore, these data are not entirely representative for China for the past 50 years, rather a collation of results, based on data for the past two decades. examinations, infected persons were mainly peasants and children, and men were found to excrete Table 2: The prevalence of human clonorchiasis, according to a range of national and provincial surveys in China, carried out from 1960–2003 significantly more C sinensis eggs in the faeces than women, who were usually asymptomatic.50 Coprological surveys done in other provinces In the province of Guangxi, 48 of 82 counties and cities indicate a relatively high prevalence of clonorchiasis. were shown to be endemic.33,83 San and co-workers44 In the provinces of Sichuan and Shandong, estimated that 3·5 million people were infected in this prevalences were estimated at 4·6% (of 228 109 people province, based on the calculation of the mean examined) and 1·4% (of 5 376 708 people examined), prevalence of patent infection (12%) in the human respectively.26–27,37,51–52,54,75,98–102 Although Jilin is considered population in endemic regions. Other studies reported to be endemic, there is a paucity of information for this that the mean prevalence of clonorchiasis in this province.28 province was about 21%, the highest prevalence—about There are a number of interesting epidemiological 75%—being in Mashan.22,34,43,83–85 In addition, results aspects to human clonorchiasis, which mainly relate to from a recent provincial survey of human parasites human behaviour. It is commonplace in some endemic revealed a mean prevalence of about 21% and 10% in regions in China, particularly in the province of southern and northern regions of this province, Guangdong and Guangxi (figure 3), for “lavatories” to be respectively.43,83 A comprehensive coprological survey built adjacent to fish ponds, so that human excrement conducted using the Kato–Katz method7 in selected containing C sinensis eggs ends up in the pond water. townships of Hengxian county demonstrated that faecal Such eggs represent the source of infection of samples from about 32% of 1552 people tested intermediate hosts. Obviously, eliminating such contained C sinensis eggs.34 Of the “positive” samples, lavatories represents an important step in preventing 11·6%, 33%, and 55·4% contained small (<1000), and controlling this disease in endemic areas, but may moderate (1000–9999), and large (>10 000) numbers of eggs, respectively, with a mean of 4845 eggs/g of faeces. Interestingly, the prevalence in men was twice that of women (approximately 42% versus 21%), and the numbers of eggs excreted by men were about three to five times greater, suggesting a higher intensity of infection in the latter sex.34 In the province of Heilongjiang, the prevalence of human clonorchiasis was 1·2% in 1988.24,74 However, in studies conducted from 1988 to 2002, 67 666 people from 21 different study sites were subjected to coprological examination. The mean prevalence was 9·5%, and the highest prevalence was about 85%,24,45,72,74,87–89 demonstrating that clonorchiasis is an important public-health problem also in this province. In a recent study in this province, a human patient Figure 3: Such “lavatories”, built at the banks of freshwater fish ponds, are eliminated nearly 10 000 adults of C sinensis after very common in the province of Guangdong, China

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not be enforceable in many under-privileged Guangdong, the prevalence of infected A longicornis is communities. Also, there is a difference in the greater than 27%,3,21 whereas it is about 15% in prevalence of human clonorchiasis between men and Guangxi,43,83 and 3% in Hubei.95 Infected B fuchsianus are women in some endemic regions (table 3), suggesting considered to be distributed mainly in the provinces of that women consume less raw freshwater fish compared Guangxi, Hubei, and Sichuan, and the prevalence of with men.34,35,38,43,44,84,105 This hypothesis is supported by infected snails in some endemic areas of Guangxi is epidemiological findings for the Guangxi province, about 8%.43,83 Infected P striatulus have been detected where, traditionally, women are indeed known to mainly in the provinces of Guangdong, Guangxi, consume less raw fish.44 Furthermore, there is evidence Heilongjiang, Hubei, Hunan, and Sichuan, the that human beings can become infected via the prevalence of infected snails being about 8% in many accidental ingestion of C sinensis metacercariae via their endemic areas of Guangxi,46,83 and 3% in both hands, contaminated as a consequence of not washing Heilongjiang and Hubei provinces.45,49 Also, after catching and handling freshwater fish.106 P anomalospiralis and P sinensis are considered to be important hosts in Hubei.49 Animal hosts and their relevance as reservoirs of Numerous species of cyprinoid freshwater fish infection (table 5) and crustaceans can act as second intermediate In addition to human beings, many mammals, such as hosts of C sinensis.3,38,75,115 Currently, 132 species of fish cats, dogs, foxes, pigs, rodents, and possibly any fish- (in at least 46 genera and belonging to about 11 families) eating mammal, can serve as definitive hosts for and three species of shrimp are recognised as hosts in C sinensis and thus represent reservoirs of infection.3,20 China.33,75 Of these, 71 fish species (in 36 genera) belong There is also evidence that rabbits, guineapigs, and to the family Cyprinidae. Species including hamsters are highly susceptible to this parasite in the Ctenopharyngodon idellus, Pseudorasbora parva, laboratory.3 Cats and dogs are considered the most Saurogobio dabryi, Cyprinus carpio, Carassius auratus, important animal hosts in the endemic regions of China Parabramis pekinesis, Abbottina sinensis, Gnathopogon (table 4). By contrast with many other countries, most timberbis, and Parapelecus argenteus are considered to be cats and dogs are not kept as pets in China, but usually the most important hosts.3,38,75 Young fish are considered roam freely in villages and cities, and thus have ready to be most susceptible to cercarial infection because of access to the remains of raw or undercooked fish in their thin skin and lack of previous exposure (ie, household waste.3,108,109 In most endemic regions studied immune status). Experimental studies have shown that to date, all cats examined at necropsy were shown to be the metacercariae isolated from fish flesh can survive in infected with C sinensis.3,80,95,110,111 The intensity of water for more than 1 week, suggesting that they may be infection has been reported to be as high as 600 worms able to contaminate other food stuffs.119 per cat,108 but is likely to be higher since there has been P parva is considered to be the most important second limited necropsy study of carnivorous animals. intermediate host in China, particularly in the provinces In China, eight main species of small freshwater snails of Anhui, Guangdong, Guangxi, Heilongjiang, Hubei, (order Mesogastropoda) are presently recognised as the Hunan, Shandong, Sichuan, and first intermediate hosts for C sinensis. They include Tianjin.3,45,48,49,51,53,112,116,120–122 This fish is a wild-caught Alocinma longicornis, Parafossarulus striatulus species and is not raised in aquaculture systems. In (P manchouricus), P sinensis (family Hydrobiidae), some endemic regions of these provinces, studies have Semisulcospira cancellata (family Melaniidae), Bithynia shown that all P parva examined at necropsy harboured fuchsianus, B robustus (family Bithyniidae), Melanoides metacercariae of C sinensis.3,38,116,120,121 The high intensity of tuberculata (family Thiaridae), and Assiminea lutea infection in this species46,121,123 is believed to relate to the (family Assimineidae) (table 1). Of these, A longicornis, synchrony of development and ecology of the P striatulus, and B fuchsianus are presently considered to intermediate hosts and the parasite, and the be of greatest importance. Infected A longicornis are susceptibility of the fish to C sinensis. The mean body mainly found in the provinces of Guangdong, Guangxi, weight of many small species of freshwater fish hosts Hubei, and Sichuan. For example, in parts of (eg, P parva and P argenteus) is in the range 0·5–1·5 g.

Province and Number of Number of Prevalence (%) Number of Number of Prevalence (%) references men examined infected men women examined infected women Guangdong76,77 7533 2693 35·75 8339 2459 29·49 Guangxi34,43,83–85 19 117 4246 22·21 13 931 1160 8·33 Heilongjiang87,88,90,91 6006 2224 37·06 3947 929 23·54 Hubei96 207 8 3·86 261 3 1·15 Sichuan51,52 27 588 2433 8·82 25 474 1869 7·34 Total 60 451 11 604 19·20 51 952 6420 12·36

Table 3: Prevalence of clonorchiasis in men and women in parts of China, based on a number of different national and provincial epidemiological surveys http://infection.thelancet.com Vol 5 January 2005 For personal use. Only reproduce with permission from Elsevier Ltd. 35 中国科技论文在线______http://www.paper.edu.cn

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The intensity of infection can range from about 50 to magnetic resonance imaging (MRI), tissue harmonic 1600 metacercariae/kg of flesh.3,45,48,112,116,123 imaging (THI), immunological approaches, and Larger fish, such as Cy carpio, Hypophthalmichthys serological techniques have also been used for diagnosis molitrix, and P pekinesis, are farmed in aquaculture in some endemic regions,38,60,63–65,75,97,125–127 but some are systems and thus usually have a lower mean intensity of less practical and more costly to do, and can be less metacercarial infection, which relates to their large body specific compared with the copro-diagnostic size and shorter cercarial exposure times. Thus, people approach.128–131 Ultrasound can be a useful diagnosic tool, who eat the smaller fish species are more likely to given its relatively high sensitivity in detecting receive a heavier infestation compared with those who “echogenic” fibrosis, biliary stones, and dilatation. eat larger species. For instance, Ct idellus is a larger fish However, since bile stones and sludge in clonorchiasis (which can weigh 2–5 kg and is commonly sold in can sometimes be “isoechoic” relative to the liver markets) and considered to be one of the key second parenchyma (ie, they have little to no contrast compared intermediate hosts, particularly in Guangdong and with surrounding tissue), pathological changes can be Guangxi. Other small freshwater fish, such as Oryzias overlooked. CT is used mainly for evaluating the lumen latipes, P parva, Phoxinus percnurus, Perccottus glenii,and diameter of the bile ducts, detecting fibrosis, Rhodeus sericeus, are important hosts in Heilongjiang.3 calcification, and epithelial hyperplasia.65,125,132,133 P argenteus infected with metacercariae have been However, the differentiation between existing chronic reported mainly in the provinces of Anhui and clonorchiasis and other infectious or non-infectious liver Hubei.48,112 Infected A sinensis have been reported in the diseases may not always be reliable by CT. Thus, CT provinces of Shandong and Sichuan, reaching a scanning should be considered as a complementary tool maximum prevalence of about 95%.27,52–53 Infected Ct for the diagnosis of this disease. MRI performs similarly idellus have been reported, and are considered to CT, and can be useful for detecting subtle cases of important in the provinces of Guangdong, Guangxi, cholangiocellular carcinoma, which may be associated Henan, Hubei, Hunan, and Sichuan,3,48,53,80,113,116,118,121 with with leukocytosis (>30 000) and eosinophilia (sometimes the highest prevalence of more than 80% being in >40%). THI is used to observe bile-duct wall trauma and Sanshui city, Guangdong.98 The intensity of infection stones.134 A variety of immunological and serological for this species of fish can be greater than 64 approaches, including intradermal testing, complement metacercariae/kg of flesh.48 Infected G timberbis have fixation and indirect haemagglutination, ELISA, and been reported in the provinces of Hunan and Sichuan, indirect fluorescence antibody tests have been used for with a prevalence of more than 67% recorded in diagnosis, with varying degrees of success.22,76,97 Liver endemic areas of the latter province.53 Infected P biopsy may also be helpful in some patients,3 but, pekinesis have been reported for the provinces of Anhui, obviously, carries additional risks. Guangdong, Guangxi, and Hubei.3,38,49,112 The prevalence recorded in some endemic areas of Guangdong was Provinces and references Species Prevalence (%) greater than 80%,80 the intensity of infection in some Anhui94 Dog 4·6 fish being as high as about 44 100 metacercariae/kg of Pig 2 Guangdong79,80,107 Cat 100 48 flesh. Importantly, Wang and colleagues reported that Dog 40–100 C sinensis metacercariae were found in all P parva Pig 25 (n=40) examined from water reservoirs in Tianjin,103,120 Cattle Few 43 raising awareness about the importance of this host Guangxi Cat 64 Dog 56·4 species as a major source of human clonorchiasis in Heilongjiang46,88,108 Cat 94 this non-endemic area. Dog 27–81 Pig and rat Few Henan3 Cat 59 Diagnosis and treatment Dog 41 Clonorchiasis should be suspected in any patients who Pig 22 have been living in, or have travelled to, an endemic Hubei48,96 Cat, dog, and pig 67–100 region, have consumed raw freshwater fish, and who Cattle and rat Few Hunan3,29 Dog 47 have developed clinical signs consistent with a biliary or Rat 14 hepatic disease. Diagnosis of patent infection has mainly Shandong3,27 Cat 56–70 been based on the microscopic detection of C sinensis Dog 16–65 eggs in the faeces. The eggs (27–35 µm x 12–20 µm in Pig 0·9–6 Sichuan51–53 Cat 45 size) have an operculum at the slender end and Dog 27 prominent shoulders, and the other (abopercular) end is Rat 10 broad and has a spine-like prominence.124 Microscopic Pig 5·7

demonstration of eggs in duodenal aspirates or gall is Table 4: Prevalence of Clonorchis sinensis in various species of animal in also possible but aspiration is invasive, risky, and labour China intensive. Ultrasound, computer tomography (CT),

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Province and references Species

Anhui3,112 Cambarus clarkii, Carassius auratus, Parabramis pekinesis, Parapelecus argenteus, Pseudorasbora parva, Rhodeus sinensis Guangdong3,21,41,42,80,113–115 Cirrhinus molitorella, Ctenopharyngoden idellus, Cyprinus carpio, Megalobrama hoffmanni, P parva, P pekinesis Guangxi43,44,83,84,116 C auratus, C idellus, C molitorella, Macropodus chinensis, P parva, P pekinesis, R sinensis, Rhodeus ocellatus Hainan117 C auratus, C carpio, C molitorella, Ephippus orbis, Tilapia mossambica Heilongjiang3,45,46,88,89 C auratus, Hemiculter leucisculus, Misgurnus anguillicaudatus, Oryzias latipes, P parva, Perccottus glenii, Phoxinus percnurus, Rhodeus sericeus, Saurogobio dabryi Henan3,92,93,118 C auratus, C idellus, P parva, S dabryi Hubei3,48–50 C auratus, C carpio, C idellus, C molitorella, Hypophthalmichthys molitrix, H nobilis, Hypseleotris swinhonis, P argenteus, P parva, P pekinesis, R sinensis Hunan29 C auratus, C carpio, C idellus, Gnathopogon timberbis, Leuciscus leuciscus, P parva, R sinensis, Silurus asotus Shandong3,26,27,37,54 Abbottina sinensis, P parva Sichuan51–53 A sinensis, Aphyocypris chinensis, C idellus, G timberbis, H leucisculus, H molitrix, H swinhonis, Hemibarbus maculates, Macropodus opercularis, O latipes, P parva, R sinensis, Rhodeus ocellatus, S dabryi, Sarcocheilichthys nigripinnis, Silurus meridionalis, Sinilabeo rendahli, Siniperca chuatsi, Squalidus argentatus

Table 5: Species of freshwater fish (family Cyprinidae) recognised as key second intermediate hosts of Clonorchis sinensis in China

Although a range of compounds has been tested for and transmission. Moreover, there is substantial their efficacy against C sinensis,58 the most common evidence for a relationship between clonorchiasis and chemotherapeutic compound used in China against cholangiocarcinoma in humans,56 and future research human clinical clonorchiasis has been should focus on establishing the prevalence of this praziquantel.65,135,136 Administered at a total dose of cancer in infected people, and on determining the 37·5–45 mg, 60–75 mg, or 75–90 mg per kg of body mechanism of the carcinogenesis. Although high weight (divided into two doses a day for 2 days, prevalence in human beings in southern parts of China depending on the intensity of infection), the cure rates may, to some extent, reflect an increased awareness of reported are about 98–100%.65,135,136 Other compounds, clonorchiasis in some regions, this is less likely for such as albendazole and Chinese traditional medicines, isolated, impoverished communities. Irrespective of have also been used for the treatment of this disease.7,75,137 these points, measures are urgently required to control For instance, albendazole administered at a dose of and prevent human clonorchiasis to increase the health 56–84 mg/kg per day for 7 days has been shown to status and quality of life in endemic communities. achieve a cure rate of up to 90–100%.7,40 Surgical removal The control of clonorchiasis is focused predominantly of parasites and infected tissue has also been employed on a reduction or elimination of the transmission of the in selected cases,61,63 but this carries a high degree of risk, disease. In theory, the means of control in endemic is costly, and only applicable in extreme circumstances. regions can include: a reduction of the sources of infection, particularly human beings, through effective Considerations and recommendations for treatment; the protection of fish ponds and aquaculture prevention and control systems from contamination with faeces from people Of the 570 million people in endemic areas of China, it and other definitive hosts; the treatment or sterilisation is estimated that 10 million are infected with C sinensis. of faeces; the control of snail host populations; and the There is evidence that the prevalence of this disease in implementation of education campaigns. Therefore, in people has been increasing over the past decade, mainly principle, the prevention and control of clonorchiasis is as a consequence of an increased consumption of raw relatively simple. Since infection of the definitive host is freshwater fish and shrimp. For example, according to only contracted through the ingestion of flesh from the the second survey of intestinal parasites of human second intermediate hosts, the most practical measure beings in the province of Guangdong conducted in 1998, for preventing and controlling human infection is to the mean prevalence of patent C sinensis infection was eliminate the consumption of raw, undercooked, or 128% higher than that of the first survey conducted a freshly pickled fish and shrimp flesh. However, this decade earlier.41,42 Whereas much is known about the strategy may be difficult to implement in some endemic distribution and prevalence of clonorchiasis of humans, regions because of the ancient tradition of eating raw little is known about the prevalence in piscivorous fish. For instance, in south China (including Hong reservoir hosts, such as dogs and cats. Also, there are Kong) and parts of east Asia, various species of carp, still major gaps in the fundamental knowledge and particularly Ct idellus (grass carp), eaten raw as a “sushi” understanding of the specific transmission patterns and or as a “yusheng zhou”—fish congee, dipping of raw fish ecology of C sinensis in different communities, the in hot rice soup—are considered delicacies. Thus, only genetic make-up of the parasite within and among adequate cooking will render such fish safe for human different populations in China, and aspects of human consumption. Nonetheless, together with education and animal behaviour (eg, contamination of fish ponds awareness programmes focused particularly on teaching and aquaculture practices) associated with the life cycle young children about the parasite, its life cycle, and the http://infection.thelancet.com Vol 5 January 2005 For personal use. Only reproduce with permission from Elsevier Ltd. 37 中国科技论文在线______http://www.paper.edu.cn

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disease will have important implications for its Search strategy and selection criteria prevention, diagnosis, and treatment in people travelling Literature searches were conducted predominantly using the to endemic areas. following databases: CNKI (http://www.cnki.com.cn; Conflicts of interest http://www.chinajournal.net.cn); Wanfang Data We declare that we have no conflicts of interest. (http://www.wanfang.calis.edu.cn); and PubMed. Relevant Acknowledgments articles or book chapters in Chinese or English were We thank David Rollinson for constructive comments on the considered, and epidemiological data sets were obtained manuscript. The references published in the Chinese language and cited in this article are available from the corresponding author. The from governmental departments in China. Search terms authors thank X H Liao, X Z Yang, D Z Wu, X G Chen, and M Q Xie for included were “Clonorchis sinensis”, “clonorchiasis”, their critical comments on the draft manuscript. This work was “ganxichong, huazhigaoxichong”, and “cholangiocarcinoma”. supported in part by grants from the National Science Foundation of China (NSFC number 30170124), Natural Science Foundation of Guangdong (NSFGD number 036606), and the Scholar Funds of Zhongshan (Sun Yat-Sen) University (number 3253280). disease it causes, prevention and control could be References successful. Targeting children may have the advantage 1 Chen M, Lu Y, Hua X, Mott KE. Progress in assessment of that they are less entrenched than adults in their morbidity due to Clonorchis sinensis infection: a review of recent customs and eating habits. Chemotherapy of infected literature. Trop Dis Bull 1994; 91: R7–65. 2 Park GM, Yong TS. Geographical variation of the live fluke, individuals is another complementary approach, Clonorchis sinensis, from Korea and China based on the karyotypes, although the treatment of infected animals’ hosts is zymodeme and DNA sequences. 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