Clonorchis, Opisthorchis, Fasciola, and Paragonimus Species

Description of the Pathogens

The adult Clonorchis worms are flat, elongated flukes, measuring 10–25 mm long and 3–5 mm wide. Adult Opisthorchis worms are smaller and measure 5–12 mm long and 1–3 mm wide. The flukes inhabit the biliary tract or pancreatic ducts ( Opisthorchis spp.), where they produce eggs that are passed into feces. Snails ingest these eggs, become infected, and release thousands of cercariae into water. The cercariae encyst (as metacercariae) in tissues of susceptible fish and shrimp.

More than 100 species of freshwater fish and several species of freshwater shrimp are susceptible to infection. When infected raw or undercooked fish or shrimp are ingested, the larvae excyst in the duodenum and migrate through the ampulla of Vater to the bile ducts, where they mature into adults in approximately 4 weeks. The adult flukes can live as long as 30 years.

Epidemiology

Infections occur where it is customary to eat raw fish dishes. Men are most affected in some areas, but in parts of China, children catch and eat small fish and become heavily infected. Clonorchis sinensis infects an estimated 15 million people in China. The fluke is endemic in East and Southeast Asia. ^, Pigs, cats, and dogs are reservoir hosts of C. sinensis . Infections may be related to imported fish in areas not known to have a transmission cycle.

Opisthorchis viverrini is endemic in Thailand, Cambodia, Vietnam, and Laos, especially along the Mekong River, and has recently been identified in Myanmar. It has reservoirs in dogs. Opisthorchis felineus is most common in cats and has been associated with ingestion of freshwater lake fish from Italy, other places in Eastern Europe, and Siberia. An estimated 10 million people are infected with O. viverrini, and approximately 1.6 million are infected with O. felineus. ^{, ,}

Clinical Manifestations

Adult flukes can be found in bile ducts, the pancreatic duct, and gallbladder. Infection produces inflammatory and hyperplastic changes in the epithelium of bile ducts, with sludging of bile. Eggs and flukes can serve as a nidus for formation of stones. The gallbladder and liver commonly become enlarged, but liver function usually is preserved, and in chronic infection portal cirrhosis can occur. ^{, ,}

Most infections are asymptomatic or produce only epigastric discomfort and are discovered only incidentally on routine screening examination of stool. In moderate to severe infection, an acute syndrome of fever, loss of appetite, diarrhea, right upper quadrant pain, hepatomegaly, and eosinophilia can occur approximately 2–4 weeks after ingestion of infected fish or shrimp. ^, Acute opisthorchiasis caused by O. felineus infection can present with fever, abdominal tenderness, hepatosplenomegaly, and eosinophilia up to 40% of white blood cell count; these symptoms occur early in infection, soon after exposure to a large dose of metacercaria. In endemic areas, the prevalence of infection increases with age and often plateaus in late adolescence or early adulthood, but symptoms may not occur until the third decade or later. Complications include pyogenic cholangitis, obstructive jaundice, gallstones, pancreatitis, and cholangiocarcinoma.

Laboratory Findings and Diagnostic Tests

In chronic disease, serum hepatic transaminase levels usually remain normal, but direct and indirect bilirubin and alkaline phosphatase values may be elevated. Definitive diagnosis is made through identification of eggs in stool or duodenal aspirates, or identification of adult worms extracted during surgery. To improve the chance of finding eggs, multiple examinations using a stool concentration technique may be necessary. Clonorchis and Opisthorchis eggs are small (∼30 × 15 μm) and yellowish brown, with an operculum that rests on a distinctive rim, and they often are difficult to distinguish from each other. ^,

Serologic tests have been developed but usually are not readily available outside of endemic areas and may not have optimal specificity. When available, a combination of serologic testing and morphologic examination improves diagnostic sensitivity. Molecular detection methods for fecal samples are under investigation. ^,

Cholangiography, ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) demonstrates hepatobiliary dilation, sludging, stones, and neoplasia. Adult flukes sometimes can be seen as shadows or filling defects in endoscopic retrograde cholangiography. M-mode (or motion mode) ultrasonography can show mobile worms in gallbladder ducts.

Treatment

Treatment consists of praziquantel in a dose of 25 mg/kg given 3 times per day for 2 consecutive days (>90% cure rate). ^, The safety of praziquantel has not been conclusively established in children aged <4 years, but many young children have been treated without reported adverse effects in mass prevention campaigns and in studies of schistosomiasis. Praziquantel is a US Food and Drug Administration (FDA) pregnancy category B medication. Animal studies have revealed no evidence of harm to the fetus, but there are no adequate studies in pregnant women. Side effects include malaise, headache, dizziness, abdominal discomfort, elevated temperature, and urticaria; these effects usually are mild, time limited, and do not require intervention.

Alternative therapy for C. sinensis infection is albendazole (10 mg/kg/day for 7 days). The safety of albendazole in children aged <6 years is not certain, but the World Health Organization (WHO) guidelines for mass prevention campaigns for soil transmitted helminths use albendazole in children aged ≥1 year. Many children aged <6 years have been treated in these campaigns, albeit at the reduced dose of 200 mg as opposed to the standard dose of 400 mg for older children. Tribendimidine trials have shown good efficacy in the treatment of C. sinensis and O. viverrini infections in Asia, although further investigation is needed.

After successful treatment, eggs usually disappear from the stool within a week. Biliary changes usually are reversible in children, but damage from longstanding infection in adults is slow to resolve and may not resolve. Secondary pyogenic cholangitis is treated with appropriate antimicrobial therapy.

Special Considerations

An increased incidence of cholangiocarcinoma is associated with C. sinensis and O. viverrini infections. ^{, ,} Conservative estimates suggest liver flukes are responsible for approximately 7000 new cases of cholangiocarcinoma per year. Pathologically, these tumors are primarily adenocarcinomas originating from the epithelial lining of bile ducts. Individuals living in Opisthorchis -endemic areas may have a 15-fold excessive risk of cholangiocarcinoma with heavy infection. N -nitrosamines in food may be an important cofactor in inducing the neoplasia.

Prevention

Thoroughly cooking freshwater fish and shrimp to 63°C (145°F) prevents infection; freezing to −20°C (−4°F) for 7 days also prevents infection. Travelers should be advised to avoid eating raw freshwater fish and shrimp. The practice of using human feces to enrich fish ponds should be avoided. Repeated mass treatment of populations with praziquantel every 6–12 months has been used for clonorchiasis control in China.