Intestinal Flukes

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Background

Numerous trematodes cause disease in humans. Flukes that cause schistosomiasis, paragonimiasis, fascioliasis, clonorchiasis, and opisthorchiasis are included in the World Health Organization (WHO) list of neglected tropical diseases (NTD) to which interventions for poor and marginalized populations are prioritized given the significant health burden.[1] Although this article focuses on intestinal trematodes, a limited discussion on liver flukes (Clonorchis sinensis, Opisthorchis viverrini, Fasciola hepatica, Fasciola gigantica) is provided given the similarity in the mode of acquisition (foodborne) and the challenge in terms of diagnostic differentiation with the intestinal flukes.

Intestinal trematodes can be classified into at least 14 families (with their corresponding sources of infection found below), as follows:[2]

Intestinal trematodes are flat hermaphroditic worms that vary in length from a few millimeters to many centimeters (see the image below). Of the approximately 70 species known to colonize the human intestine, only a few species are known to cause actual infection. Globally, it is likely that more than the estimated 40-50 million people are infected with intestinal trematodes, primarily infected via the foodborne route. Populations in Southeast Asia appear to be most vulnerable. An exhaustive 2009 review of these infections in this region provides detailed information on the large number of species infecting humans, their pathogenicity, diagnostic issues, and treatments.[3]

In 2012, the various manifestations, methods of diagnosis, and management of foodborne trematodiasis, which include the intestinal flukes, were detailed in the British Medical Journal[4] and the European Journal of Microbiology and Infectious Diseases[5] . In the former, the species of intestinal flukes considered to be of public importance include the following:



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Adult fluke of Fasciolopsis buski. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta....

The most common human intestinal trematode was said to be F buski, which causes fasciolopsiasis,[6] and should be differentiated from F hepatica and F gigantica, which are liver flukes that cause fascioliasis. Conversely, the genus Echinostoma is the largest, with about 500 species of echinostomatid flukes. About 20 species belonging to 10 genera have been reported to cause human disease.[7] The genus Echinostoma is considered the largest, which includes Echinostomahortense, Echinostomaangustitestis, Echinostomacinetorchis, Echinostomaechinatum, Echinostoma ilocanum, Echinostomamacrorchis, and Echinostomarevolutum. E ilocanum was said to be the most common cause of infection in humans.[8]

Heterophyes heterophyes, Metagonimus yokogawai, and Gymnophalloides species are less-common causes of human intestinal fluke infection.

Other intestinal flukes that rarely cause human intestinal infection include Gastrodiscoides hominis, Phaneropsolus bonnei, and Prosthodendrium molenkampi. Intestinal flukes have likely infected humans for hundreds of years, if not longer. Evidence of G seoi infection has been traced back to the 17th century based on discovery of G seoi eggs in a Korean mummy.[9]

See Common Intestinal Parasites, a Critical Images slideshow, to help make an accurate diagnosis.

Pathophysiology

Intestinal flukes cause inflammation, ulceration, and mucous secretion at the site of attachment. Severe infections may also cause intestinal obstruction or malabsorption, leading to hypoalbuminemia, protein-losing enteropathy, and impaired vitamin B-12 absorption. Foodborne illness has been associated with the ingestion of many different types of potentially infected foods, such as different types of both freshwater and brackish-water fish and snails, reptiles (amphibians and certain snakes), aquatic plants, and insects.[3]

Fasciolopsis buski

F buski, which causes fasciolopsiasis, attaches to the duodenal and jejunal mucosa; however, in severe infections, it may attach to the ileum or colon.

In London, Busk first described F buski in 1843 after finding it in the duodenum of a sailor. In 1925, Barlow first determined its life cycle in humans. A well-known illustrative life cycle schematic is shown below.



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Life cycle of Fasciolopsis buski. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta,....

The immature eggs (see the images below) are discharged from human feces and reach fresh water, hatching after 3-7 weeks and forming miracidia.



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The life cycle of Fasciolopsis. Immature eggs are discharged into the intestine and stool and become embryonated in water. The eggs then release mirac....



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Egg of Fasciolopsis buski. Images reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Upon contact with host snails, the miracidia penetrate the soft tissues and form sporocysts, first- and second-generation rediae, and, lastly, cercariae. The cercariae encyst on various plants such as water caltrop, water chestnut, lotus (on the roots), water bamboo, and other aquatic vegetables. Humans are infected by consuming these raw vegetables.

In the human duodenum, the metacercariae attach to the walls and become adult worms in approximately 3 months. The adult worm (see image below) causes traumatic, toxic, and obstructive damage to the intestinal mucosa. Deep inflammatory ulcerations develop at the site of attachment. Large numbers of worms provoke excess mucous discharge and can obstruct the lumen. The adult worm metabolites can also cause intoxication and sensitization when absorbed via the lumen. A recent case report provides evidence of heavy infestation as a risk factor for intestinal perforation.[10]



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Adult fluke of Fasciolopsis buski. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta....

Echinostoma species

In 1907, in Manila, Garrison first noted the genus Echinostoma, which is reported to have 12 species that may cause disease in humans. The most common species is E ilocanum, which has a characteristic horseshoe-shaped collar of 1-2 rows of straight spines that surround the dorsal and lateral sides of the oral sucker. E ilocanum flukes are small and elongated, measuring 5-15 mm in length and 1-2 mm in width. The most well-studied human-infecting species is E hortense.[11]

The adult worm, attached to the intestinal wall of humans, produces eggs that are passed in the feces. The eggs reach water, and miracidia develop and penetrate the first intermediate hosts—snails. During the course of 6-7 weeks inside the host snails, they develop into sporocysts, mother rediae, daughter rediae, and cercariae.

The cercariae leave the snails to encyst in the second intermediate hosts, which can be freshwater snails, fish, tadpoles, or vegetables. Humans are infected by ingesting raw or undercooked second intermediate hosts. Although not directly applicable to the human host, data in rodents suggest that, depending on trematode species, host species, and strain, primary expulsion of the fluke may occur.[12, 13] Inside human hosts, the flukes then attach to the small intestinal mucosa and, depending on the severity of infection, can produce shallow ulcers with mild inflammation and/or local necrosis. Mild infections do not cause symptoms, but heavy infections produce diarrhea, flatulence, and intestinal colic similar to fasciolopsiasis.

Disease manifestations in humans likely result from two pathogenetic mechanisms, including fluke-induced mechanical irritation and/or the related allergic reaction to various toxic metabolites.[11] Humoral responses to echinostomal infections may include elevated serum and gut-associated immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels, as demonstrated by studies involving Echinostoma caproni.[14]

The intestinal epithelium appears to provide an important mechanism in mucosal defense. Its rapid epithelial cell turnover seems to facilitate the rejection of intestinal helminths. In rats, it has been shown that E caproni infection stimulates the augmented renewal of the intestinal epithelium, preventing the parasite from establishing itself in the host, resulting in clearance of the helminth.[15]



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Various animals may be definitive hosts for different Echinostoma species, such as aquatic birds, carnivores, rodents, and humans. Unembryonated eggs ....

Heterophyes heterophyes

H heterophyes is the most common of the 10 species that compose the genus Heterophyes. H heterophyes is a small fluke, measuring 1-1.8 mm in length and 0.3-0.7 mm in width, with a broadly rounded posterior end. The oral sucker is subterminal and is one third the size of the ventral sucker.

H heterophyes are observed in the human intestine, jejunum, and ileum. The illustrative life cycle schematic for H heterophyes is shown below. These worms produce eggs, which are excreted in the feces and into the water. The first intermediate hosts, the snails, ingest the eggs. In the snails, the eggs hatch and undergo their developmental cycle, forming cercariae, which emerge from the snails and encyst on the second intermediate hosts—brackish or freshwater fish. In the second intermediate hosts, the cercariae are transformed into metacercariae, which infect humans upon ingestion of raw or undercooked fish. See the image below.



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The life cycle of Heterophyes. The adult parasites release embryonated eggs (each with a fully developed miracidium), which are then passed in the hos....

In humans, the flukes attach to the small bowel and cause shallow ulcers, mild inflammation, and/or superficial necrosis. Clinical presentation includes diarrhea, dyspepsia, and intestinal colic. Because of their small size, the eggs, and sometimes the adult flukes, enter blood vessels and embolize to the brain, producing symptoms similar to cerebral hemorrhage. Eggs may also enter the mesenteric lymphatics and travel to the heart, causing myocarditis, chronic congestive heart failure, and death.

Metagonimus yokogawai

M yokogawai, which is closely related to H heterophyes, is another important parasite. M yokogawai measures 1-2.5 mm in length and 0.4-0.75 mm in width. The ventral sucker is located to the right of the midline.

M yokogawai has a life cycle similar to that of H heterophyes, in which the adult worm in the human intestine produces eggs that are excreted in the feces. The illustrative life cycle schematic for M yokogawai is shown below. The eggs enter the water and infect the first intermediate hosts, the snails, where the eggs undergo their developmental cycle and become cercariae. Cercariae infect the second intermediate hosts, freshwater fish, and become metacercariae. Metacercariae infect humans after ingestion of raw or undercooked fish. The flukes then invade the mucosa of the small intestines, causing inflammation and ulcerations. Flukes eventually become encapsulated.

See the image below.



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Life cycle of Metagonimus. The adult parasites release fully embryonated eggs (each with a fully developed miracidium), which are then passed in the h....

As in infection with H heterophyes, M yokogawai occasionally embolize to other organs. Patients infected with M yokogawai present with mucous, diarrhea, and vague abdominal symptoms. Prognosis is usually good, except in cases of embolization. Fortunately, health studies performed in 2006 indicate that M yokogawai species and infections have become less endemic in certain regions.[16]

Epidemiology

Frequency

United States

Infection with intestinal flukes affects only immigrants from endemic areas.

International

Intestinal flukes are endemic in the Far East and Southeast Asia. Table 1 shows the geographic distribution and source of most commonly reported intestinal trematodes. The list of countries where human trematode infections have been reported is long, with several studies indicating variable incidence rates.[17, 18, 19, 3, 20, 21, 22, 8, 23, 24, 25]

Table 1. Common Intestinal Trematode Infections



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Multiple families of trematodes cause intestinal infections, and most of them are found in Asia. The Brachylaimidae family can be found in Oceania. The families found in Africa include Echinostomatidae, Gastrodiscidae, Heterophyidae, and Paramphistomidae. Those that have been reported in Europe include Echinostomatidae, Gastrodiscidae, Heterophyidae, and Nanophyetidae. A minority are present in the Americas, particularly Heterophyidae and Paramphistomidae.[2]

The largest human outbreaks of Fasciola species infection have occurred in the Gilan Province of Iran, affecting more than 15,000 people.[26]

Bihar, East India, was recently found to be endemic for fasciolopsiasis, especially since this area is generally poor, with both villagers and local medical practitioners lacking awareness about the parasite.[27]

China, Japan, and South Korea are considered high prevalence areas for human E hortense infections. This is especially true in Koje-myon, Kochang-gun, Kyongsangnam-do Province of South Korea, where prevalence has been reported to be up to 9.5%.[28]

In Xieng Khouang Province, Lao PDR (a country close to Myanmar), Cambodia, China, Thailand, and Vietnam, the rate of positivity for small trematode eggs was 4.4%, including O viverrini, heterophyids, and lecithodendriids.[29]

In 2017, Tanzania reported their first case of E ilocanum infection after ingestion of raw fish (Tanganyika perch and Emperor Cichlid ”yellow belly”) caught from Lake Tanganyika by a group of travelers.[30]

Parasitism with heterophyids are mostly due to Heterophyes and Metagonimus. An extensive review by Hung et al showed a worldwide distribution of heterophyid species, with most human infections reported in Egypt and East Asia.[31]

In Boseong River, Gokseong-gun, South Korea, it has been shown that the eggs of M yokogawai and other Metagonimus species could be found in 24.3% of residents.[32]

In Tabiz, Iran, vegetable contamination (tarragon, mint) with heterophyid eggs has been reported, providing other potential sources of infection with these parasites.[33]

G seoi is endemic to Shinan-gun, Jeollanam-do, Korea, based on surveillance of oysters in 1996.[34] A 2017 report showed that 100% of oysters sampled from Shinan-gun were infected with G seoi metacercaria.[35]

Mortality/Morbidity

Death from infection is rare and usually occurs only in persons with a heavy worm burden who present with severe cachexia and prostration. Other intercurrent infection may also cause death. In cases of infection with H heterophyes or M yokogawai, death may occur after embolization of the eggs to the heart or brain. Embolization to the brain and spinal cord can also cause focal neurologic disease.

Race

Intestinal flukes are endemic in Asia and in some parts of North Africa, affecting groups who live in these areas.

Sex

Intestinal flukes have no predilection for either sex.

Age

Intestinal flukes can affect both children and adults, but children are affected more severely. These intestinal infections are important public health problems, particularly among school children in developing countries.[36]

Prognosis

Light infections may resolve spontaneously within one year, even without treatment. The prognosis may be grave in patients with heavy infection.

Immunocompromised hosts may be at an increased risk of complications. For example, G seoi worms were found to penetrate into colonic lymphoid tissue in a patient with colon cancer.[37]

Patient Education

Health education is essential. Instruct patients on proper food preparation to avoid infection with intestinal flukes. Proper washing and thorough cooking of vegetables or fish are essential to prevent egg ingestion. Thoroughly cooking fish and mollusks is always recommended.

Educational interventions that emphasize avoidance of fecal contamination of water where fish and aquatic plants thrive are recommended to prevent intestinal trematode infections.

History

Humans become infected with intestinal flukes by consuming contaminated food and water that consists of or contains the second intermediate hosts (eg, vegetation, snails, fish).

Most infected persons are asymptomatic and exhibit no physical signs.

Individuals with moderate infection present with occasional loose stools, some weight loss, malaise, and, occasionally, generalized abdominal pain.

In severe infection, diarrhea may alternate with constipation. Hunger pangs may be one of the first symptoms to appear, usually occurring near the end of the incubation period. Minimal bleeding at the site of attachment may manifest as bloody diarrhea. As the infection progresses and the worm burden increases, intoxication results from the absorption of worm metabolites by the host.[38] The patient then experiences toxic and allergic symptoms such as edema of the face, abdominal wall, and lower limbs. Patients may report increased abdominal girth and abdominal pain. Anorexia, nausea, and vomiting are also common. The diarrhea persists, becoming greenish-yellow and exceptionally malodorous.

Heavy F buski infection may cause intestinal obstruction. On the other hand, eggs of H heterophyes may embolize, causing myocarditis, heart failure, and intracerebral hemorrhage. Eggs lodged in the spinal cord may manifest as motor and sensory deficits at the level of the lesion.[38]

Mild to moderate infections with the liver flukes C sinensis and O viverrini may also manifest as symptoms similar to those of intestinal flukes. However, distinction between these parasites is important, as these liver flukes are known to be associated with the development of cholangiocarcinoma.[39]

Physical

In mild infections, patients are asymptomatic on physical examination.

In severe infections, patients are asthenic, with gray and harsh skin and edema of the face and lower extremities.

Causes

Intestinal flukes are endemic in areas that contain abundant snail hosts (eg, China, Vietnam, India, other parts of Asia).

Table 2. Commonly Associated Exposures and Clinical Features of Certain Intestinal Trematodes*



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See Table

Laboratory Studies

Stool examination to visualize the ova or adult worms is the diagnostic method of choice.

The eggs of heterophyid species are smaller than eggs of other intestinal flukes. Modified Kato thick method has a higher sensitivity than formalin-ether/ethyl acetate concentration technique (31% vs 13.6%) in detecting heterophyid eggs.[38] Heterophyid species are difficult to distinguish and may also be confused with Clonorchis and Opisthorchis eggs. In areas endemic for liver flukes, heterophyid eggs have been referred to as "opisthorchid-like eggs."

Other laboratory findings include anemia and eosinophilia.

Serologic tests have limited application; however, for certain combinations of pathogens and their available diagnostic testing, serodiagnosis may be helpful, as in the case of F buski infections.[41]

Chronic fascioliasis is generally evaluated with fecal egg counting after concentration of the eggs in the stool sample via a zinc sulphate floatation method. However, using the sedimentation technique to concentrate the eggs is said to improve sensitivity. A F hepatica coproantigen enzyme-linked immunoassay (ELISA) has been introduced and studied in cattle and sheep. It more accurately reflects the presence of flukes in the host bile ducts in late prepatent infections and clearance of the flukes after treatment.[42] It can probably be used in humans in the future.

Urine assay, particularly of O viverrini excretory-secretory (ES) antigens in urine, has been used to detect O viverrini in Thailand. It was found easier to use and more sensitive than the traditional ethyl-acetate concentration technique.[43]

Diagnosing O viverrini infection via conventional stool examination is difficult, both because the infection may decrease in intensity after repeated treatments under control programs in endemic areas and because of the presence of coinfections with intestinal flukes. Thus, one study has examined a coproantigen sandwich ELISA using recombinant O viverrini cathepsin F (rOv-CF) that uses chicken immunoglobulin Y (IgY) raised against rOv-CF in combination with rabbit immunoglobulin G (IgG) antibody to the somatic O viverrini antigens. This test showed a sensitivity and specificity of 93.3% and 76.7%, respectively, in the detection of opisthorchiasis. The investigators found that it had a positive predictive value (PPV) and negative predictive value (NPV) of 66.7% and 95.2%, respectively, making it a promising test in endemic areas.[44]

The current criterion standard of diagnosis is the formalin ethyl-acetate concentration technique (FECT), performed with fecal samples. However, this test has difficulty detecting light O viverrini infections since the eggs may be confused with eggs of other minute intestinal flukes in stool.[43]

Other Tests

Merthiolate, iodine, formalin method

The merthiolate, iodine, formalin (MIF) method is used to detect intestinal fluke parasites.

The MIF method was established early as a versatile and accurate technique for identifying intestinal protozoa in stool and fecal samples.[45] The technique simultaneously preserves and stains stool specimens, which can then be examined with direct smear techniques.[46]

Following the development of a concentrated MIF technique, the sensitivity of positively identifying F buski, Heterophyes species, and Echinostoma species in stool specimens was increased.[47] This newly concentrated MIF technique involves the application of a concentration step to the stool specimen before preservation in MIF solution.

Polymerase chain reaction

Various polymerase chain reaction (PCR) methods have shown potential in detecting intestinal fluke parasites. These methods take advantage of the different types of DNA nucleotide sequence variations demonstrated by the different species of parasites within a particular genus.[48]

In Thailand, Lamanignao et al developed a PCR-based technique to detect and discriminate between O viverrini and Haplorchis taichui. O viverrini and heterophyids have similar egg morphology, so an experienced microscopist is usually required for distinction. Both parasites have similar intermediate and definite hosts and may exist as coinfections.[49] More importantly, chronic O viverrini infection is associated with the development of cholangiocarcinoma.[50] Although both can be treated with praziquantel, Opisthorchis infection requires two days of treatment.

Likewise, the difficulty of diagnosing parasitic pathogens led Won et al to develop a multiplex qPCR to detect the presence of eight major intestinal parasites known to cause gastroenteritis in the Korean population. This includes three trematodes (C sinensis, M yokogawai, G seoi). Analysis included 123 stool samples, with the multiplex qPCR exhibiting 100% sensitivity (95% CI; 80.5-100) and 100% specificity (95% CI; 96.58-100).[51]

Polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP)[17] and simple sequence repeat anchored PCR[52] have been reported to be useful in distinguishing among species of the Metagonimus genus (including M yokogawai). These methodologies are based on differences in restriction fragment length polymorphisms and simple sequence repeats among the species. Information derived from RFLP involving specific sites in ribosomal RNA and mitochondrial cytochrome oxidase I (mtCOI) genes may help to differentiate M yokogawai from other Metagonimus species.[53]

Six species of the genus Heterophyidae were reported to be distinguished with PCR assays developed based on variations in rDNA polymorphisms among the species.[54]

Medical Care

Praziquantel 10-20 mg/kg as a single dose or 25 mg/kg 3 times a day is the recommended treatment for intestinal flukes (including F buski infection). It should be taken with liquids during a meal.[4] Praziquantel is the drug of choice for most intestinal fluke infections, although niclosamide has been reported to have some in vitro efficacy.[55]

Praziquantel is a pyrazinoisoquinoline anthelmintic that was discovered in 1972 by Bayer Germany. Although widely used, praziquantel exhibits low and erratic bioavailability because of its poor water solubility. Nanostructured lipid carriers (NLC), second-generation solid lipid nanoparticles, were developed in the 1990s to improve the bioavailability of poorly water-soluble drugs.[56]

After 4 weeks, if the repeat stool examination result is again positive, retreatment with praziquantel is indicated.[41]

Artesunate has been used in vitro and in vivo for Echinostoma and Heterophyes infections, with promising results as alternative therapy. Although the exact mechanism of action for artesunate is still unknown, studies have demonstrated that parasites exposed to artesunate had slowed movement, tegument damage, and death at higher drug concentration and longer exposure time (72 hours).[57, 58]

The CDC recommends a 2-dose regimen of triclabendazole as the drug of choice for fascioliasis (liver fluke infection with F hepatica or F gigantica). Triclabendazole was approved by the FDA in 2019 after being available from the CDC for many years.[59]

Based on limited data from the CDC, nitazoxanide might be effective in some patients. Bithionol, a halogenated phenol previously used as a first-line agent for the treatment of fascioliasis in the United States, is no longer available. Praziquantel, which is active against most trematodes (flukes), is typically not active against Fasciola parasites. Therefore, the CDC does not recommend praziquantel therapy for fascioliasis.[60]

For Opisthorchis infections, praziquantel 25 mg/kg 3 times a day for 2 days taken with liquids during a meal is the recommended treatment.[4] An open-label phase II trial found that tribendimidine had similar tolerability and efficacy to praziquantel against O viverrini.[61] In contrast, mefloquine, artesunate, and mefloquine-artesunate were not effective in the same trial and were associated with vertigo, nausea, vomiting, and anxiety. Further large-scale clinical trials are needed to identify the best role of tribendimidine; future data may support this drug as yet another potential treatment option.

For Clonorchis infections, praziquantel 25 mg/kg 3 times a day for 2 days taken with liquids during a meal is also the recommended treatment, although albendazole 10 mg/kg as a single dose for 7 days may also be used.[4]

The WHO states that all confirmed cases of fascioliasis, opisthorchiasis and clonorchiasis should be treated, as well as all suspected cases in endemic areas.[62]

Diet

Proper cleaning and processing of raw vegetables by immersing in boiling water for a few seconds, followed by peeling and washing in clean water is important in preventing infection with intestinal flukes, especially in endemic areas.

The importance of thoroughly cooking contaminated vegetables cannot be overemphasized.

Do not eat raw or undercooked fish.

The diet in infected individuals should contain adequate protein.

Activity

The patient should be on bed rest.

Prevention

Eliminating the intermediate host snail is the key to controlling infection with intestinal flukes.

Proper cleaning and processing of raw vegetables by immersing in boiling water for a few seconds, followed by peeling and washing in clean water, is important in preventing infection with intestinal flukes, especially in endemic areas.

Night soil (human excreta) and pig excreta should not be used as fertilizers.

Metacercariae are not necessarily inhibited or destroyed by interventions such as smoking or freezing; and the practice of fish pickling is ineffective. Irradiation practices may be of benefit in managing the burden of metacercariae in the process of food preparation.

Many strategies to control opisthorchiasis have been used in Thailand. The strategies include mass drug administration and education to decrease the consumption of raw fish. Over the last decade, these methods have changed the epidemiology of O viverrini infection in Thailand. In the past, O viverrini infections were characterized as heavy infections that were concentrated in particular villages. Now, because of these strategies, O viverrini infections have become "lighter" but more widespread in terms of geographic distribution.[63]

Parasitic helminths reside in immunologically exposed extracellular locations within their hosts, yet they are capable of surviving for extended periods. To enable this survival, these parasites have developed complex and multifaceted mechanisms to subvert or suppress host immunity. There are studies on the immunomodulation by helminth parasites of ruminants and the parasite-derived molecules involved in driving this modulation. Such immunomodulatory molecules have considerable promise as vaccine targets.[64]

Triclabendazole 10 mg/kg as a single dose is the preventive chemotherapy for fascioliasis and is recommended in subdistricts, villages, or communities with clustering of cases. The WHO recommends that all school-aged children (aged 5-14 years) or all residents should be given the preventive chemotherapy every 12 months.[62]

Praziquantel 40 mg/kg as a single dose is the preventive chemotherapy for clonorchiasis and opisthorchiasis and is recommended in all people residing in areas where the prevalence of infection is 20% and above. Among people who live in areas with less than 20% prevalence, the recommendation is to administer preventive chemotherapy (1) to everyone every 24 months or (2) every 12 months to those who eat raw fish.[62]

Further Inpatient Care

Antispasmodics may relieve abdominal pain.

Iron supplements may be used to treat anemia, which may require transfusions in severe cases.

Vitamin C (ascorbic acid) may be administered to facilitate iron absorption.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to eradicate the infection.

Praziquantel (Biltricide)

Clinical Context:  DOC in most infections and active against all schistosomal species. Increases cell membrane permeability in susceptible worms, resulting in loss of intracellular calcium, massive contractions, and paralysis of their musculature. In addition, produces vacuolization and disintegration of schistosome tegument. This is followed by attachment of phagocytes to the parasites and death. Patients should swallow tabs whole with liquid during meals. Keeping tabs in the mouth may result in a bitter taste, which can produce nausea or vomiting.

Albendazole (Albenza)

Clinical Context:  Decreases ATP production in worms, causing energy depletion, immobilization, and finally, death.

Triclabendazole (Egaten)

Clinical Context:  Triclabendazole is an anthelmintic agent. The mechanism by which triclabendazole exhibits its effect against Fasciola species is not fully elucidated. Studies in vitro and/or in infected animals suggest that triclabendazole and its active metabolites (sulfoxide and sulfone) are absorbed by the tegument of the immature and mature worms, leading to a decrease of the resting membrane potential and inhibition of tubulin function, as well as protein and enzyme synthesis. It is indicated for the treatment of fascioliasis in patients aged 6 years or older.

Nitazoxanide (Alinia)

Clinical Context:  Limited data suggest nitazoxanide might be effective therapy in some patients with fascioliasis. Interferes with pyruvate:ferredoxin oxidoreductase (PFOR), essential to anaerobic energy metabolism.

Class Summary

The biochemical pathways in parasites are different enough from those of the human host to allow selective interference with chemotherapeutic agents in relatively small doses.

Author

Joseph Adrian L Buensalido, MD, Clinical Associate Professor, Division of Infectious Diseases, Department of Medicine, Philippine General Hospital, University of the Philippines Manila College of Medicine; Specialist in Infectious Diseases, Private Practice

Disclosure: Nothing to disclose.

Coauthor(s)

Anna Flor G Malundo, MD, FPCP, Medical Specialist in STD/AIDS Guidance, Intervention and Prevention (SAGIP) Clinic, Section of Infectious Diseases, Department of Medicine, Philippine General Hospital, University of the Philippines Manila College of Medicine, Philippines

Disclosure: Nothing to disclose.

Marja Arcangel Bernardo-Buensalido, MD, Infectious Diseases Specialist, Section of Infectious Diseases, Department of Medicine, University of the Philippines-Philippine General Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

Asim A Jani, MD, MPH, FACP, Clinician-Educator and Epidemiologist, Consultant and Senior Physician, Florida Department of Health; Diplomate, Infectious Diseases, Internal Medicine and Preventive Medicine

Disclosure: Nothing to disclose.

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Disclosure: Nothing to disclose.

Chi Hiong U Go, MD, Assistant Professor, Department of Internal Medicine, Texas Tech University Health Science Center at Odessa

Disclosure: Nothing to disclose.

Paul Chen, University of Texas Southwestern Medical School

Disclosure: Nothing to disclose.

Thomas E Herchline, MD, Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Consultant, Public Health, Dayton and Montgomery County (Ohio) Tuberculosis Clinic

Disclosure: Nothing to disclose.

Acknowledgements

The author would like to acknowledge Paul Chen, BS, ScM (2008) in Genetic Epidemiology, Johns Hopkins University Bloomberg School of Public Health, whose contributions and insights were invaluable for the revision of this article.

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Adult fluke of Fasciolopsis buski. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Life cycle of Fasciolopsis buski. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

The life cycle of Fasciolopsis. Immature eggs are discharged into the intestine and stool and become embryonated in water. The eggs then release miracidia, which invade a suitable snail intermediate host, in which the parasites undergo several developmental stages (sporocysts, rediae, cercariae). The cercariae are released from the snail and encyst as metacercariae on aquatic plants, which are eaten by mammalian hosts (humans and pigs), who become infected. After ingestion, the metacercariae excyst in the duodenum and attach to the intestinal wall, where they develop into adult flukes (20-75 mm X 8-20 mm) in approximately 3 months and attach to the intestinal wall of the mammalian hosts. The adults have a life span of about one year. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Egg of Fasciolopsis buski. Images reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Adult fluke of Fasciolopsis buski. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Various animals may be definitive hosts for different Echinostoma species, such as aquatic birds, carnivores, rodents, and humans. Unembryonated eggs are passed in stool (1), and development occurs in the water (2). The miracidium takes an average of 10 days to mature and then hatches (3), penetrating the first intermediate host, a snail (4). Snails, in general, serve as the first intermediate host. The intramolluscan stages are as follows: sporocyst (4a); rediae (4b); and cercariae (4c). Cercariae may then encyst as metacercariae in the same first intermediate host or leave to penetrate a new second intermediate host (5). Several animals may become the second intermediate host, such as other snails, bivalves, fish, and tadpoles. The definitive host gets infected after eating infected second intermediate hosts (6). The metacercariae excyst in the duodenum (7). Adults then live in the small intestine (8). Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

The life cycle of Heterophyes. The adult parasites release embryonated eggs (each with a fully developed miracidium), which are then passed in the host's feces. After ingestion by a suitable snail (first intermediate host), the eggs hatch and release miracidia, which penetrate the snail's intestine. Snails of the genera Cerithidea and Pirenella are important hosts in Asia and the Middle East, respectively. The miracidia undergo several developmental stages in the snail (sporocysts, rediae, cercariae). Many cercariae are produced from each redia. The cercariae are released from the snail and encyst as metacercariae in the tissues of a suitable freshwater or brackish-water fish (second intermediate host). The definitive host becomes infected by ingesting undercooked or salted fish that contains metacercariae. After ingestion, the metacercariae excyst, attach to the mucosa of the small intestine, and mature into adults (measuring 1-1.7 mm X 0.3-0.4 mm). Heterophyes heterophyes infects humans, various fish-eating mammals (eg, cats, dogs), and birds. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Life cycle of Metagonimus. The adult parasites release fully embryonated eggs (each with a fully developed miracidium), which are then passed in the host's feces. After ingestion by a suitable snail (first intermediate host), the eggs hatch and release miracidia, which penetrate the snail's intestine. Snails of the genus Semisulcospira are the most common intermediate host for Metagonimus yokogawai. The miracidia undergo several developmental stages in the snail (sporocysts, rediae, cercariae). Many cercariae are produced from each redia. The cercariae are released from the snail and encyst as metacercariae in the tissues of a suitable freshwater or brackish-water fish (second intermediate host). The definitive host becomes infected by ingesting undercooked or salted fish that contains metacercariae. After ingestion, the metacercariae excyst, attach to the mucosa of the small intestine, and mature into adults (measuring 1-2.5 mm X 0.4-0.75 mm). M yokogawai infects humans, fish-eating mammals (eg, cats, dogs), and birds. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Life cycle of Fasciolopsis buski. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

The life cycle of Fasciolopsis. Immature eggs are discharged into the intestine and stool and become embryonated in water. The eggs then release miracidia, which invade a suitable snail intermediate host, in which the parasites undergo several developmental stages (sporocysts, rediae, cercariae). The cercariae are released from the snail and encyst as metacercariae on aquatic plants, which are eaten by mammalian hosts (humans and pigs), who become infected. After ingestion, the metacercariae excyst in the duodenum and attach to the intestinal wall, where they develop into adult flukes (20-75 mm X 8-20 mm) in approximately 3 months and attach to the intestinal wall of the mammalian hosts. The adults have a life span of about one year. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Egg of Fasciolopsis buski. Images reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Adult fluke of Fasciolopsis buski. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

The life cycle of Heterophyes. The adult parasites release embryonated eggs (each with a fully developed miracidium), which are then passed in the host's feces. After ingestion by a suitable snail (first intermediate host), the eggs hatch and release miracidia, which penetrate the snail's intestine. Snails of the genera Cerithidea and Pirenella are important hosts in Asia and the Middle East, respectively. The miracidia undergo several developmental stages in the snail (sporocysts, rediae, cercariae). Many cercariae are produced from each redia. The cercariae are released from the snail and encyst as metacercariae in the tissues of a suitable freshwater or brackish-water fish (second intermediate host). The definitive host becomes infected by ingesting undercooked or salted fish that contains metacercariae. After ingestion, the metacercariae excyst, attach to the mucosa of the small intestine, and mature into adults (measuring 1-1.7 mm X 0.3-0.4 mm). Heterophyes heterophyes infects humans, various fish-eating mammals (eg, cats, dogs), and birds. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Life cycle of Metagonimus. The adult parasites release fully embryonated eggs (each with a fully developed miracidium), which are then passed in the host's feces. After ingestion by a suitable snail (first intermediate host), the eggs hatch and release miracidia, which penetrate the snail's intestine. Snails of the genus Semisulcospira are the most common intermediate host for Metagonimus yokogawai. The miracidia undergo several developmental stages in the snail (sporocysts, rediae, cercariae). Many cercariae are produced from each redia. The cercariae are released from the snail and encyst as metacercariae in the tissues of a suitable freshwater or brackish-water fish (second intermediate host). The definitive host becomes infected by ingesting undercooked or salted fish that contains metacercariae. After ingestion, the metacercariae excyst, attach to the mucosa of the small intestine, and mature into adults (measuring 1-2.5 mm X 0.4-0.75 mm). M yokogawai infects humans, fish-eating mammals (eg, cats, dogs), and birds. Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Various animals may be definitive hosts for different Echinostoma species, such as aquatic birds, carnivores, rodents, and humans. Unembryonated eggs are passed in stool (1), and development occurs in the water (2). The miracidium takes an average of 10 days to mature and then hatches (3), penetrating the first intermediate host, a snail (4). Snails, in general, serve as the first intermediate host. The intramolluscan stages are as follows: sporocyst (4a); rediae (4b); and cercariae (4c). Cercariae may then encyst as metacercariae in the same first intermediate host or leave to penetrate a new second intermediate host (5). Several animals may become the second intermediate host, such as other snails, bivalves, fish, and tadpoles. The definitive host gets infected after eating infected second intermediate hosts (6). The metacercariae excyst in the duodenum (7). Adults then live in the small intestine (8). Image reproduced from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA.

Magnified image of Echinostoma spp. egg. Echinostoma eggs resemble F busk and Fasciola eggs, with the latter two only bigger in size. Specimen slides courtesy of the University of the Philippines - College of Public Health, Department of Parasitology.

Low power magnification (arrow) of a Heterophyid egg. Specimen slides courtesy of the University of the Philippines - College of Public Health, Department of Parasitology.

Magnified view of a Heterophyid egg. Specimen slides courtesy of the University of the Philippines - College of Public Health, Department of Parasitology.

Infection

Source*

Geographic Distribution**

FasciolopsiasisFreshwater plants (water caltrop, water chestnut)Asia and Indian subcontinent, especially in areas where humans raise pigs and consume freshwater plants (as of December 8, 2017)
EchinostomiasisTadpoles, freshwater snails, fish, frogsWorldwide, but human cases seen most frequently in Southeast Asia and in areas where undercooked or raw freshwater snails, clams, and fish are eaten (as of December 27, 2017)
HeterophyiasisFishEgypt, Middle East, Far East (as of January 3, 2018)
MetagonimiasisFish (cyprinid)Far East, Siberia, Manchuria, the Balkan states, Israel, Spain (as of December 29, 2017)
* Adapted with permission from Tribble D, Wagner KF. Trematode infections. Infectious Disease Practice. 1996; 20:69-73.



** Updated data from the Centers for Disease Control and Prevention (DPDx Laboratory Identification of Parasites of Public Health Concern. Available: http://www.cdc.gov/dpdx/)



Infection Source Clinical Features
Alaria americana Undercooked frog legsDisseminated fatal thoracic, gastrointestinal, retroperitoneal, and CNS manifestations; intraocular infections
Echinostomiasis (16 species)Freshwater fish, aquatic plants, clams, snails, mollusks, contact with aquatic birdsMay be asymptomatic; mild abdominal pain, bloating, dyspepsia, diarrhea, eosinophilia
Fibricola speciesTadpolesAbdominal pain, diarrhea, fever, eosinophilia
Fasciolopsis speciesWater chestnut, water calthrop, water bamboo, water morning glory lotus and water hyacinthMay be symptomatic; may be subclinical; gastritis, nausea, diarrhea, eosinophilia; generalized edema in persons with heavy infection burden
Gastrodiscoides speciesVegetables, aquatic plantsOften asymptomatic; may manifest as abdominal pain and diarrhea in severe cases
Watsonius watsoni Water bambooSevere diarrhea
Fischoederius elongates Aquatic plantsEpigastric pain and vomiting
Heterophyes speciesMullets, fish; brackish waterMay be asymptomatic; intestinal mucosal disease, ulcer-related abdominal pain, dyspepsia, nausea, vomiting, diarrhea, weight loss
Gymnophalloides seoi OystersFever, abdominal pain, anorexia, weight loss, diarrhea, pancreatitis
Carneophallus brevicaeca ShrimpFatal when infection involves CNS and heart
Brachylaima ruminae Poultry, ratsAbdominal pain, diarrhea
Metagonimiasis speciesFish (ayu, golden carp)May be asymptomatic; intestinal mucosal disease, ulcer-related abdominal pain, dyspepsia, nausea, vomiting, diarrhea, weight loss
Nanophyetus salmincola Undercooked fish (eg, salmon, trout, steelhead)May be symptomatic; mild diarrhea, abdominal pain
*Adapted from Berger SA, Marr JS. Human Parasitic Diseases Sourcebook. 1st ed. Sudbury, MA: Jones and Bartlett; 2006.