OVERVIEW: What every clinician needs to know

Parasite name and classification

  • There are three major types of liver flukes pathogenic for humans: Clonorchis sinensis, various Opisthorchis species (viverrini, felineus) and Fasciola species (hepatica and gigantica). All flukes are trematodes, a subset of platyhelminthes (flatworms).

  • There are many species of intestinal flukes that infect humans, primarily in Asia. Of these, the major human pathogens discussed here will be Fasciolopis buski, Heterophyes heterophyesand Metagonimus yokogawai.

  • Eight lung flukes of the genus Paragonimusare known to be pathogenic in humans. Of these the most prevalent is P. westermanii , which is endemic to the Far East. Other less prevalent species are found in Asia, Africa, and South, Central and North America.

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What is the best treatment?

  • Praziquantel is the drug of choice for Clonorchis and Opisthorchis species. It is also the first-line therapy for all the intestinal flukes and Paragonimus infection.

    Praziquantel causes a spastic paralysis of the worms and alteration and disintegration of the worm tegument by incompletely understood mechanisms.

    Praziquantel is administered at 25mg/kg given orally three times a day for two days. The dose is the same for children. Reported cure rates are over 80%.

    Observed side effects include dizziness, sleepiness, headache, and diarrhea, but are generally transient.

    Praziquantel is FDA-approved but considered investigational for the treatment of intestinal flukes.

    For cerebral disease, a short course of corticosteroids may be given with praziquantel to minimize the inflammatory response to dying flukes.

  • Triclabendazole is the first-line therapy for F. hepaticainfection (fascioliasis). A single oral dose of 10mg/kg is administered. Two doses 12-24 hours apart may also be given for severe infections. Triclabendazole is not available in the US for human use but may be obtained from the CDC. Fasciolaserologic testing can be used to assess the response to therapy. Seroreversion (loss of detectable antibodies) usually is noted 6 to 12 months after cure.

  • Are there issues of anti-infective resistance?

    Clinically important resistance of liver flukes to praziquantel has not been observed but low cure rates for schistosomiasis have been reported, indicating the possibility of development of resistance in the future.

  • What alternative therapies are available?

    Opisthorchis and Clonorchis: Albendazole at 10mg/kg/day for 10 days may be used if praziquantel is not available or contraindicated but is not FDA approved for this indication. A single 400mg dose of tribendimine has also been highly effective in initial clinical trials against both C. sinensis and O. viverrini but is not yet clinically available in the US.

    Paragonimus may be also treated with triclabendazole, 10mg/kg as a single oral dose which may be repeated.

    For Fasciola infection, nitazoxanide may also be effective but is unproven. The adult dosage of nitazoxanide is 500mg po bid (twice a day) for 7 days, with food.

What are the clinical manifestations of infection with this organism?

  • Clonorchis and Opisthorchis

    Acute infection with C. sinensis and O. viverrini are usually asymptomatic. Shortly after infection with C. sinensis, urticaria, right upper quadrant abdominal pain and fever may develop. High-grade fever, arthralgia and lymphadenopathy as well as abdominal pain may occur after O. felineus infection. Chronic symptoms include abdominal pain and discomfort, weight loss and anorexia.

    Hepatomegaly and right upper quadrant tenderness may be observed both in the acute and chronic setting.

  • Fasciola

    Distinct syndromes are associated with the acute and chronic phases of infection:

    The acute phase may last for a few months and occurs within a few weeks of infection. Symptoms are associated with migration of the larval parasite through liver parenchyma (see life cycle below), and include abdominal pain, cough, urticaria and fever. Symptoms of chronic infection are subtle and similar to those seen with Clonorchis and Opisthorchis described above.

  • Intestinal Flukes

    Most infections are asymptomatic.

    Heavy infections may be associated with fever, weight loss, abdominal pain, diarrhea, anasarca and obstruction.

  • Lung flukes

    Predominant symptoms include chronic cough, hemoptysis and production of brown sputum.

    Chest pain and shortness of breath are common.

    Acute infection may be accompanied by abdominal pain, diarrhea and urticaria or remain asymptomatic.

    Extrapulmonary migration may result in symptoms dependent on the site of involvement. CNS involvement may result in headache, seizures, other neurological deficits or meningitis.

Do other diseases mimic its manifestations?

  • Symptoms caused by other causes of hepatic inflammation or mass lesions may mimic those of liver fluke infection, and include amebic and bacterial liver abscess, schistosomiasis, cholecystitis, cholangitis and acute hepatitis.

  • Pulmonary tuberculosis, other fungal and chronic bacterial pneumonias or malignancy may resemble Paragonimiasis radiologically.

  • Extrapulmonary involvement, especially by Paragonimus, may resemble central nervous system (CNS) tumor or other infections including brain abscess or neurocysticercosis.

What laboratory studies should you order and what should you expect to find?

  • Liver and intestinal flukes

    The most useful test for diagnosis of Clonorchis and Opisthorchis liver flukes is the detection of eggs in the stool by microscopic examination. Wet mount preparations are examined for the presence of characteristic eggs. Clonorchis eggs are oval, 27 to 35 µm by 11 to 20 µm and have an operculum or lid, at the smaller end of the oval egg. A small knob or hook is often seen projecting from the other end. Opisthorchis eggs are visually virtually identical.

    Adult worms may occasionally be identified from surgically or endoscopically obtained samples. Clonorchis and Opisthorchis species are approximately 5-25mm X 2-5mm whereas adult Fasciola worms are larger and approximately 30mm X 15mm. F. gigantica worms are larger, reaching a size of 75mm.

    Ultrasound examination of the biliary tract and gallbladder may occasionally visualize motile worms. Abdominal computed tomography (CT) scan frequently reveals small hypodense nodules and linear tracks within the liver parenchyma caused by migration of Fasciola hepatica. Characteristic magnetic resonance (MR) imaging findings in F. hepatica have also been reported and may add sensitivity.

    Peripheral eosinophilia is common, especially with acute fascioliasis and paragonimiasis. The pleural fluid in Paragonimiasis usually contains numerous eosinophils.

    Serological tests are useful for diagnosis of F. hepatica, especially in early stages of infection before egg shedding is detectable, but are not widely available. The CDC can provide information on serological testing, including testing available in the US outside the CDC.

    Diagnosis of intestinal flukes is made by clinical picture and microscopic detection of eggs in the stool although Fasciolopsis eggs are morphologically indistinguishable from those of F. hepatica whereas Heterophyes and Metagonimus eggs are similar to those of Clonorchis and Opisthorchis. Specific diagnosis is possible by identification of adult worms passed in the stool after treatment.

  • Lung flukes

    Detection of eggs in sputum and stool may be difficult and insensitive.

    EIA and Western blotting are highly sensitive and specific and may be obtained at the CDC. Levels of seropositivity decline with treatment and may be used to monitor therapy. Other Paragonimus species may be missed by the P. westermanii tests available.

    Chest XCXR and CT may show a wide variety of pulmonary abnormalities, including cystic lesions, nodules, infiltrates or pleural effusions. The radiological picture may suggest tuberculosis or malignancy.

What imaging studies will be helpful in making or excluding the diagnosis of infection with flukes?

  • In liver fluke infection, ultrasound and abdominal CT scan may be useful to assess the presence of complications requiring surgical intervention or antibiotic therapy.

  • MR imaging of the liver may also add sensitivity to the diagnosis of F. hepatica.

  • Pulmonary imaging is often highly suggestive although not specific for Paragonimus infection.

What complications can be associated with this parasitic infection, and are there additional treatments that can help to alleviate these complications?

  • Liver flukes

    Long-term complications associated with chronic infection with all liver flukes include right upper quadrant pain, loss of appetite and weight loss.

    In addition, complications associated with heavy worm burden, inflammation and obstruction include cholecystitis, cholangitis, hepatic abscess and pancreatitis.

    Cholangiocarcinoma is associated with chronic Opisthorchis and Clonorchis infection.

    Ectopic migration of F. hepatica larva during the initial acute phase may result in nodules and symptoms of inflammation in virtually any organ.

  • Intestinal flukes

    Ileus and obstruction may occur with heavy worm burdens. Rarely, embolization of eggs via the circulation has been reported to cause severe CNS complications.

  • Lung flukes

    Cerebral invasion by migrating larvae are the most common and serious extra-pulmonary manifestation of P. westermanii infection

What is the life cycle of the parasite, and how does the life cycle explain infection in humans?

  • Clonorchis and Opisthorchis species have a similar life cycle that requires three distinct hosts: a mammalian host, a snail and a fish or crustacean (see Figure 1). Adult worms resident in the biliary tree produce up to 2500 embryonated eggs per day that are shed in the stool. When these eggs reach fresh water, they are ingested by specific species of snails in which the eggs hatch and each egg releases a miracidium. The miracidia undergo several stages of maturation, initially becoming sporocysts that each release 20-50 rediae, that each release up to 50 cercariae. Thus each egg results in the release of approximately a thousand free-swimming cercariae. When the cercariae encounter an appropriate fish intermediate host, they invade the skin and encyst as metacercariae. These metacercariae remain viable for up to a year in the muscle of the fish. When consumed by humans, the metacercariae excyst and release larvae in the duodenum, where they rapidly travel via the ampulla of Vater to take up residence in the biliary tree and begin producing eggs. Mature worms may survive for decades.

Figure 1.

Life cycle of Clonorchis and Opisthorchis species. From DPDx, website for laboratory diagnosis of parasitic diseases of the Division of Parasitic Diseases, National Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA [http://www.dpd.cdc.gov/DPDx).

  • Fasciola hepatica has a life cycle similar to that of Clonorchis and Opisthorchis but does not have an intermediate fish host (see Figure 2). Adult worms that reside in the biliary tree of sheep and cattle produce unembryonated eggs that embryonate in water and release free-swimming miracidia that invade snails. Further development through the stages of sporocysts, rediae and cercariae occurs in the snail. Free-swimming cercariae encyst as metacercariae on aquatic plants such as watercress, which are consumed by cattle, sheep or humans. The metacercariae excyst in the duodenum and then invade the intestinal wall, migrate through the peritoneum and eat through the liver parenchyma until the reach the large biliary ducts where maturation into adult worms and oviposition occurs.

Figure 2.

Fasciola hepatica life cycle. From DPDx, website for laboratory diagnosis of parasitic diseases of the Division of Parasitic Diseases, National Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA [http://www.dpd.cdc.gov/DPDx).

  • Intestinal flukes reside in the small intestine of the mammalian host (see Figure 3 and Figure 4)). Eggs are passed in the stool and embryonate in fresh water. The eggs are either ingested by snails in the case of Fasciolopsis or miracidia are released and invade an intermediate snail host in the case of Heterophyes and Metagonimus. Cercariae released from the snail either invade fish and encyst (Heterophyes andMetagonimus) or encyst on water plants (Fasciolopsis) and are subsequently consumed by humans. The larva excyst and take up residence in the wall of the small intestine where they develop into adult egg-laying worms. Fasciolopsis adults are 20 to 75 mm by 8 to 20 mm, whereas Heterophyes and Metagonimus are much smaller (1.0 mm to 2.5 mm by 0.4 mm to 0.75 mm). Pigs also become infected with Fasciolopsis by consuming plants and serve as a definitive host whereas cats, dogs and birds that eat fish may harbor the other intestinal flukes.

Figure 3.

Fasciolopsis life cycle. From DPDx, website for laboratory diagnosis of parasitic diseases of the Division of Parasitic Diseases, National Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA [http://www.dpd.cdc.gov/DPDx

Figure 4.

Life cycle of minute intestinal flukes (Heterphyes and Metagonimus). From DPDx, website for laboratory diagnosis of parasitic diseases of the Division of Parasitic Diseases, National Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA [http://www.dpd.cdc.gov/DPDx

  • Lung flukes reside in cystic cavities in the human lung (see Figure 5). Eggs are either expectorated in sputum or passed in the stool. Upon reaching fresh water, eggs undergo embryonation and release free-living miracidia that find and invade a suitable snail host. Development through successive stages similar to those of liver flukes results in the release of cercariae that invade the second intermediate host, a crustacean of the crab or crayfish families, where they encyst to form metacercariae. Metacercariae are ingested by humans who eat inadequately cooked or pickled crustaceans. Excystation occurs in the duodenum and the larva migrate through the intestinal wall, peritoneum, and diaphragm, to ultimately reach the pulmonary parenchyma. In the lung, the larva encapsulates and develops into adult worms that begin oviposition in 65-90 days.

  • Where are these infections prevalent?

    C. sinensis is endemic in Asia including Korea, China, Taiwan, and Vietnam, with 15-20 million being infected, and 200 million at risk of infection. O. viverriniis found mainly in northeast Thailand, Laos, and Kampuchea. O. felineusis found mainly in Europe and Asia, including the former Soviet Union. At least ten million people are infected with Opisthorchis species in Laos and Thailand alone. Prevalence of infection in endemic areas may be as high as 25%.

    F. hepatica is found worldwide, particularly in Bolivia, Peru, Egypt, Iran, Portugal, and France and approximately 3 million individuals are infected.

    Intestinal flukes are found in Egypt, the Middle East, and Far East (Heterophyes), the Far East, as well as Siberia, Manchuria, the Balkan states, Israel, and Spain (Metagonimus), and Asia and the Indian subcontinent (Fasciolopsis).

    P. westermanii is found in Asia including China, the Philippines, Japan, Vietnam, South Korea, Taiwan, and Thailand. Other species are found in Africa and Central and South America. Several cases of infection with P. kellicottii have been described in the Midwestern US.

  • How is infection acquired?

    Consumption of raw or inadequately cooked fish is the primary risk factor for acquisition of Clonorchis and Opisthorchis infection in endemic areas. Occasional cases in the US occur due to consumption of imported fish.

    Fasciola infection occurs through consumption of fresh vegetation including watercress, parsley etc.

    Fasciolopsis infection occurs through consumption of fresh vegetation and the other intestinal flukes are found in uncooked fish.

    Pargonimus infection is acquired through the consumption of uncooked or pickled, crabs and crayfish.

  • Prevention

    Avoiding uncooked, pickled or smoked fish, crustaceans or raw vegetables in endemic areas is the only method to prevent infection. The following methods will kill the metacercariae in fish products: Cooking fish adequately (to an internal temperature of at least 145° F [~63° C]). Freezing at -4°F (-20°C) or below for 7 days (total time), or at -31°F (-35°C) or below until solid, and storing at -31°F (-35°C) or below for 15 hours, or at -31°F (-35°C) or below until solid and storing at -4°F (-20°C) or below for 24 hours.

    Various strategies to improve aquacultural practices and treatment of infected populations are underway but have met with limited success to date.

Figure 5.

Paragonimus life cycle. From DPDx, website for laboratory diagnosis of parasitic diseases of the Division of Parasitic Diseases, National Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA [http://www.dpd.cdc.gov/DPDx).

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Furst, TU, Duthaler, B, Sripa, J, Utzinger, JK. “Trematode infections: liver and lung flukes”. Infect Dis Clin North Am. vol. 26. 2012. pp. 399-419. (Describes the major liver and lung fluke infections, including epidemiology, life cycle, clinical presentation, diagnosis, and approaches to prevention, treatment, and control.)

Hong, ST, Fang, Y. “Clonorchis sinensis and clonorchiasis, an update”. Parasitol Int. vol. 61. 2012. pp. 17-24. (A comprehensive review of the epidemiology, biology, clinical manifestations and current research on Clonorchis infections.)

Liu, QF, Wei, WL, Yang, S, Zhang, X. “Paragonimiasis: an important food-borne zoonosis in China”. Trends Parasitol. vol. 24. 2008. pp. 318-323. (Comprehensive review that includes details of complications and extrapulmonary involvement seen Paragonimus infection.)

Mairiang, E, Mairiang, P. “Clinical manifestation of opisthorchiasis and treatment”. Acta Trop. vol. 88. 2003. pp. 221-227. (A detailed exposition of the problem of opisthorchiasis in Asia.)

Mas-Coma, S, Bargues, MD, Valero, MA. “Fascioliasis and other plant-borne trematode zoonoses”. Int J Parasitol. vol. 35. 2005. pp. 1255-1278. (A review of intestinal and hepatic flukes transmitted via plant food sources.)

Pozio, E, Armignacco, O, Ferri, F, Morales, MAG. “Opisthorchis felineus, an emerging infection in Italy and its implication for the European Union”. Acta Trop. vol. 126. 2013. pp. 54-62. (An interesting description of the unique clinical and epidemiologic aspects of O. felineus in Europe.)