Liver flukes: Fascioliasis

INTRODUCTION — Fascioliasis is a trematode flatworm infection caused by Fasciola hepatica or Fasciola gigantica [1]. F. hepatica has a worldwide distribution; F. gigantica occurs predominantly in the tropics. Both parasites are hermaphroditic, have similar life cycles, and cause similar clinical manifestations in humans. The organism causes "liver rot" among sheep and cattle, which are the definitive hosts; humans are incidental hosts.

FASCIOLA HEPATICA

Epidemiology — F. hepatica occurs globally, mainly in sheep-rearing areas of temperate climates. Infection is endemic in Central and South America (especially Bolivia and Peru), Europe (especially Portugal, France, Spain, and Turkey), Asia (especially China, Vietnam, Taiwan, Korea, and Thailand), Africa, and the Middle East [2]. It is estimated that 50 percent of the world's infection burden of fascioliasis occurs in the Andean Plateau [3,4]. Sporadic cases have also been reported in the United States [5], Australia [6], and elsewhere [1]. An estimated 2.4 to 17 million people are infected in more than 51 countries [7]; 180 million are at risk worldwide [8]. Children are commonly infected.

Sheep and cattle are the most important definitive hosts of F. hepatica; goats, buffalo, horses, donkeys, camels, hogs, deer, and rabbits can also be infected. By infecting livestock, fascioliasis causes significant problems to industry and farmers. Snails are intermediate hosts. Humans are incidental hosts and most often acquire infection by eating watercress or water chestnuts grown in sheep-raising areas. Infection may also be transmitted by other freshwater plants, including water lettuce, mint, alfalfa, and parsley. Humans can also acquire infection by drinking contaminated water containing viable metacercariae [9]; outbreaks have been described [10]. The incidence of animal and human infection rises during wet years because of an increased number of snails and longer survival of encysted cercariae [11].

In some areas, endemicity is almost 100 percent. In endemic regions, very young children and women are most likely to be infected. There is a high incidence of coinfection with other parasites, especially echinococcosis. The geographic distribution of infection and transmission risks are expanding due to human and livestock migration, climate change, and man-made modifications of the environment [12,13]. 

Life cycle — The life cycle of fascioliasis begins with release of unembryonated eggs into the biliary ducts, which are then passed in the stool of herbivores (definitive hosts) or humans (incidental hosts) (figure 1). Eggs become embryonated in water and release miracidia, which invade a snail (intermediate host), where the parasites undergo several developmental stages (sporocysts, rediae, and cercariae). The cercariae are released and encyst as metacercariae on aquatic vegetation.

Sheep, cattle, or humans acquire infection by eating vegetation containing metacercariae. After ingestion, the metacercariae excyst in the duodenum and migrate through the intestinal wall, peritoneal cavity, and liver parenchyma into the biliary ducts, where they develop into adults; in humans, this takes three to four months. The adult flukes reside in the large biliary ducts of the mammalian host.

Migrating metacercariae cause liver parenchymal destruction, since tracks undergo necrosis and fibrosis. In addition, adult flukes can partially obstruct the bile ducts, causing thickening, dilatation, and fibrosis of the proximal biliary tree [14]. The amount of liver damage is correlated with the parasite load; the number of adult flukes that reach the biliary tree and develop to sexual maturity is usually small. The life span of adult F. hepatica flukes within humans is estimated to be 9 to 13 years.

Clinical manifestations — Many infections are mild; morbidity increases with fluke burden [15]. Forms of infection include the acute (liver) phase, chronic (biliary) phase, ectopic fascioliasis, and pharyngeal fascioliasis.

Acute (liver) phase — Acute symptoms usually begin within 6 to 12 weeks of metacercariae ingestion. The early phase of migration through the liver is often associated with fever, right upper quadrant pain, and hepatomegaly. Jaundice is occasionally observed (table 1). Other symptoms include anorexia, nausea, vomiting, weight loss, myalgia, cough, and urticaria. Marked peripheral eosinophilia is almost always present. The acute phase can be complicated by hemobilia or subcapsular hematomas of the liver [9]. In most cases, acute symptoms generally resolve after about six weeks, although, in very heavy infections, extensive liver parenchymal necrosis can result.

Extrahepatic symptoms may also occur during the acute phase, likely related to an immunologic or allergic mechanism [11]. A Loeffler-like syndrome or right-sided pleural effusion containing many eosinophils may be observed [2,16]. The urticaria may be associated with pruritus and dermatographia [17]. Pericarditis, cardiac conduction abnormalities, meningeal symptoms, focal neurologic changes, or seizures have also been described but are uncommon.

Chronic (biliary) phase — The chronic phase usually begins about six months after infection and may last 10 years or more [18]. This phase is usually asymptomatic, although epigastric and right upper quadrant pain, diarrhea, nausea, vomiting, wasting, hepatomegaly, and jaundice can occur. Common bile duct obstruction can develop, and chronic infection can lead to biliary colic, cholangitis, cholelithiasis, and obstructive jaundice. Secondary pancreatitis has been reported in up to 30 percent of cases [19,20]. Parasite eggs or adult worms may serve as a nidus for stone formation, leading to intra- or extrahepatic biliary lithiasis. Prolonged and/or heavy infection can also result in sclerosing cholangitis and biliary cirrhosis. Peripheral eosinophilia may or may not be present in the biliary phase.

Ectopic fascioliasis — Extrahepatic involvement may occur; it is unknown whether the parasites migrate to ectopic sites hematogenously or through soft tissues. Ectopic fascioliasis results in eosinophilic and mononuclear infiltration with secondary tissue damage. The most common ectopic site is the subcutaneous tissue of the abdominal wall. The lungs, heart, brain, muscle, genitourinary tract, skin, and the eye may also be affected [21-23]. Tender, migrating, erythematous, itchy nodules (1 to 6 cm in diameter) can develop; in some cases, these may result in localized abscesses. Generalized lymphadenopathy may also develop [14]. Cerebral manifestations include space occupying lesions, cerebral infarction, and hemorrhage (intracerebral, subdural, or subarachnoid) [24].

Pharyngeal fascioliasis — Pharyngeal fascioliasis is a form of fascioliasis that occurs in the Middle East; it is acquired by consumption of raw liver of an infected animal [25]. The living fluke can attach to the upper respiratory or digestive tract, causing an allergic pharyngitis with edema and congestion; suffocation may result.

This condition is also known as ‘Halzoun syndrome.’ The syndrome was first described in Lebanon in 1905 and initially attributed to Fasciola hepatica; subsequent publications have also attributed it to other pathogens including Dicrocoelium dendriticum and Linguatula serrata [26].

Diagnosis

Clinical approach — The diagnosis of fascioliasis should be considered in patients with abdominal pain and hepatomegaly accompanied by peripheral eosinophilia. A careful dietary history should be obtained, including a history of watercress ingestion or consumption of raw vegetables washed in potentially contaminated water [27].

The diagnosis can be established by identifying eggs in stool, duodenal aspirates, or bile specimens. Alternative approaches to diagnosis include identification of adult worms in endoscopic or surgical specimens or serology. Imaging can be an adjunctive diagnostic tool. Additional diagnostic clues include anemia, abnormal liver function tests, elevated erythrocyte sedimentation rate, and hypergammaglobulinemia.

Diagnosis of fascioliasis should prompt evaluation of family members. (See 'Follow-up' below.)

There is often a delay in diagnosis of fascioliasis. In one review of patients with fascioliasis in developed countries, symptoms related to acute infection preceded the diagnosis for ≥1 month in 73 percent of cases [20]. In another review with patients with biliary-phase fascioliasis, the delay was even longer (symptoms for 1 to 208 weeks; mean 64 weeks).

Microscopy — The diagnosis can be established by identifying eggs in stool, duodenal aspirates, or bile specimens. However, eggs are not detectable in stool during the acute phase of infection or in the setting of ectopic fascioliasis. (See 'Acute (liver) phase' above and 'Ectopic fascioliasis' above.)

Eggs of F. hepatica are oval, yellow-brown, and measure 130 to 150 micrometers long by 60 to 90 micrometers wide (picture 1). It can be difficult to distinguish between the eggs of F. hepatica, F. gigantica, and the intestinal fluke Fasciolopsis buski. Specimen concentration facilitates egg identification. Examination of multiple specimens may be needed because egg excretion may be intermittent; negative stool examinations do not exclude the diagnosis.

Since stool examination may be negative during the acute phase or in the setting of ectopic fascioliasis, in such cases, the diagnosis may require serology or examination of surgical specimens following removal of the parasite [28].

Liver biopsy rarely demonstrates eggs or adult flukes [29]. Histopathologic changes that may suggest fascioliasis include Charcot-Leyden crystals, eosinophils, and multiple calcific foci [30].

Endoscopy or surgery — The diagnosis may be made during surgery or endoscopy for biliary obstruction when adult flukes are found in the biliary tree. On endoscopic retrograde cholangiopancreatography (ERCP), adult flukes may appear as small, radiolucent linear, elliptical, or crescent-like shadows, with jagged, irregular margins in the gallbladder or dilated bile ducts [31,32]. Laparoscopy may also demonstrate nodules in the liver capsule.

The adult F. hepatica flukes are large, flat, brown, and leaf shaped, measuring approximately 30 mm in length by 15 mm wide (picture 2). The broad anterior portion is covered with scale-like spines.

Serology — Serology usually becomes positive during the early phase of migration through the liver; therefore, it is useful for diagnosing early symptoms prior to the appearance of eggs in the stool. It is also useful in ectopic disease, when eggs are not detectable in the stool.

Serologic tests include indirect hemagglutination, complement fixation, counterimmunoelectrophoresis, immunofluorescence assays, and enzyme-linked immunosorbent assay (ELISA). In general, these tests have good sensitivity, but many have suboptimal specificity and cross-react with other parasitic infections.

ELISA-based assays, especially ones that use genus-specific antigens, have largely replaced other techniques because they are sensitive, rapid, and quantitative [33-35]. A variety of different antigens, such as Fas2, CL1, SAP2, and FhSAP2, have been used. For example, in a study among 634 Peruvian children with fascioliasis, the Fas2-ELISA (cathepsin L1-based antibody) had high sensitivity and specificity (92 and 84 percent, respectively) [36]. In another study, an ELISA employing a recombinant form of the F. hepatica cathepsin L1 as the antigen showed 99.9 percent sensitivity and 99.9 percent specificity [37].

Many antigens have been evaluated in in-house assays; the United States Centers for Disease Control and Prevention (CDC) recommends enzyme immunoassays (EIA) with excretory-secretory (ES) antigens combined with confirmation of positive results by immunoblot [38]. The CDC immunoblot assay is based on a recombinant F. hepatica antigen (FhSAP2) and has a reported sensitivity and specificity of 94 and 98 percent, respectively [39]. Specific antibodies to Fasciola may be detectable two to four weeks following infection (which is five to seven weeks before eggs appear in stool). Successful treatment often correlates with a decline in ELISA titers, although antibodies may be detectable for years after infection [40].

An ELISA antigen capture technique that detects circulating antigens is available and has a reported sensitivity and specificity of 100 and 98 percent, respectively [41]. Antigen levels correlate with burden of infection [42]. In addition, the assay is diagnostic prior to the appearance of eggs in the stool so is particularly useful for diagnosis during acute infection. The assay becomes negative in approximately 65 percent of patients one month after successful therapy [43,44]. Tests that detect antigens in stool have also been developed but are not commercially available [45].

Molecular testing — Real-time polymerase chain reaction (PCR) on stool is emerging as an alternative diagnostic technique with high sensitivity, but is not yet commercially available [46-48]. PCR on the aspirate from a liver abscess has also been used for diagnosis [49]. Molecular testing of environmental water samples has also been described [50].

Imaging — Useful radiographic tools for fascioliasis include computed tomography (CT), ultrasonography, cholangiography, ERCP, and magnetic resonance imaging (MRI) (image 1) [51]. A review of radiographic findings in fascioliasis noted that multiple small (up to 25 mm in diameter) nodular and branching lesions were the most common findings; these frequently occur in the subcapsular area of the liver parenchyma. They most often appear hypoechoic on ultrasonography, hypodense on CT, and T2 hyper- and T1 hypointense on MRI [52]. Peripheral enhancement on postcontrast images is characteristic [53]. Necrotic areas may be seen especially in larger lesions [54].

CT scanning of the liver may demonstrate characteristic hypodense nodules or tortuous tracks due to migration of the parasite through the liver [2]. Thickening of the liver capsule, subcapsular hematoma, or parenchymal calcifications may also be detected [55].

Ultrasonography, cholangiography, and ERCP are useful in the biliary stage of infection. These techniques may demonstrate mobile leaf-like flukes in the bile ducts and gallbladder, often associated with stones [56]. Irregular thickening of the common bile duct wall may be observed [57]. Peri-portal lymphadenopathy and hepatomegaly and/or splenomegaly may be seen, especially in acute fascioliasis [54].

Differential diagnosis — The differential diagnosis of fascioliasis varies according to the stage of infection.

In the acute phase (fever, right upper quadrant pain, and eosinophilia as well as extrahepatic symptoms including a Loeffler-like syndrome), the differential diagnosis includes:

●Toxocariasis – Toxocariasis (also called visceral larva migrans) refers to human infection caused by roundworms that are not natural human parasites; larvae migrate through the liver and lungs, resulting in hepatitis and/or pneumonitis. The diagnosis can be confirmed by ELISA antibody assay. (See "Toxocariasis: Visceral and ocular larva migrans".)

●Acute schistosomiasis – Schistosomiasis is caused by infection with parasitic blood flukes; clinical manifestations of acute infection include sudden onset of fever, urticaria and angioedema, chills, myalgias, arthralgias, dry cough, diarrhea, abdominal pain, and headache. Among returned travelers, the diagnosis is established via serology; in endemic areas, microscopy can be used to determine the infecting species and the burden of infection, although it is less helpful in the setting of early infection. (See "Schistosomiasis: Epidemiology and clinical manifestations" and "Schistosomiasis: Diagnosis".)

●Ascariasis – Ascariasis is a roundworm infection; clinical manifestations in sensitized individuals include transient respiratory symptoms during larval migration through the lungs; the pneumonitis is known as Loeffler syndrome. The diagnosis of ascariasis is usually established via stool microscopy. (See "Ascariasis".)

●Strongyloidiasis – Strongyloidiasis is a roundworm infection associated with transpulmonary migration of larvae, which can produce dry cough, throat irritation, dyspnea, wheezing, and hemoptysis. A Loeffler-like syndrome with eosinophilia is rarely observed. The diagnosis is usually made by detecting rhabditiform larvae in concentrated stool or via serologic methods. (See "Strongyloidiasis".)

In the setting of multiple liver lesions, the differential diagnosis includes the following conditions. F. hepatica infection may be able to be distinguished from these alternative conditions based on its radiographic appearance (multiple branching lesions).

●Malignancy (primary or secondary) – Patients with hepatocellular carcinoma may have manifestations of cirrhosis and/or hepatic decompensation; patients with metastatic tumors may have findings related to the underlying malignancy (eg, rectal bleeding in a patient with colon cancer). The evaluation includes radiography and laboratory testing. (See "Approach to the adult patient with an incidental solid liver lesion".)

●Pyogenic abscess – Clinical manifestations of pyogenic liver abscess include fever and abdominal pain. Other common symptoms include nausea, vomiting, anorexia, weight loss, and malaise. The diagnosis is confirmed radiographically followed by aspiration and culture of abscess material. (See "Pyogenic liver abscess".)

●Amebic liver abscess – Clinical manifestations of amebic liver abscess include right upper quadrant pain and fever. The diagnosis is generally established by radiographic imaging and confirmed with serologic or antigenic testing, perhaps supplemented with stool microscopy or antigenic testing of stool, with or without evaluation for the parasite in liver abscess fluid. (See "Extraintestinal Entamoeba histolytica amebiasis", section on 'Amebic liver abscess'.)

●Echinococcosis – Echinococcosis may cause a liver lesion; radiographic findings include membranes, mixed echogenicity, hydatid sand, and/or daughter cysts with characteristic internal septation. This appearance differs from the hypoechoic branching lesions seen with fascioliasis. (See "Echinococcosis: Clinical manifestations and diagnosis".)

In the biliary phase, the differential diagnoses includes other infectious and noninfectious causes of biliary obstruction:

●Biliary ascariasis, opisthorchiasis, and clonorchiasis – The specific diagnosis can be established via microscopy or endoscopic retrograde cholangiopancreatography. (See related topics.)

●Cholelithiasis, cholangitis, cholecystitis, and cholangiocarcinoma – Patients may present with right upper quadrant pain with elevated liver enzymes in a primarily cholestatic pattern, but with fascioliasis liver lesions may also be seen as a mobile leaf-like fluke in the bile ducts. (See related topics).

Treatment

Clinical approach — Treatment of fascioliasis consists of anthelminthic therapy. Additional intervention may be needed depending on the nature of the clinical presentation.

Anthelminthic therapy — The treatment of choice is triclabendazole [58,59]; bithionol and nitazoxanide are alternative choices [59].

Triclabendazole — Triclabendazole is an imidazole derivative. It is effective against all stages of fascioliasis with a cure rate of >90 percent [18,60]. Dosing consists of 10 mg/kg orally for one or two days. The drug is relatively well tolerated; absorption is improved by postprandial administration, preferably following a fatty meal. The US Food and Drug Administration has approved a recommendation of a total dose of 20 mg/kg (two 10 mg/kg doses given 12 hours apart) for treatment of patients aged 6 years or more [38,59]. Triclabendazole has been administered in children <6 years of age despite limited safety and efficacy data [61].

A review of triclabendazole reported efficacy data in observational studies [62]. Early efficacy reports came from open-label, uncontrolled studies using an efficacy endpoint of parasitologic cure, based on the absence of Fasciola spp eggs in stool samples at day 60. Overall cure rates (using triclabendazole 10 mg/kg as a single dose or split into two 5 mg/kg doses) ranged from 64 to 100 percent; however participant numbers in each individual study were small (30 or fewer). Subsequent cases series confirmed cure rates of 70 to 80 percent (with single-dose triclabendazole) in acute and chronic stages of fascioliasis, and cure rates of 75 to 100 percent (with total dose 20 mg/kg triclabendazole; 10 mg/kg doses given on consecutive days) [63-68]. Juvenile parasites migrating through the liver seem to have reduced susceptibility to triclabendazole compared with mature parasites [69].

In one study including 90 Bolivian children treated with a two-dose triclabendazole regimen, cure rates were 78 percent after one treatment and 98 percent after two treatments; egg reduction rates ranged between 74 to 90 percent after one treatment and 84 to 99 percent after two treatments. The proportion of high-intensity infections (≥400 eggs) decreased from 8 to 1 percent after one treatment and to 0 percent after two treatments [65].

Cases of triclabendazole resistance in livestock have been described [70,71]. The mechanism of resistance of triclabendazole to Fasciola is unknown [72]. Human treatment failures have been reported and may be due to resistance [61,73-76], although some studies have shown cure following repeated triclabendazole doses [77].

Triclabendazole prolongs the QTc interval. The primary treatment complication consists of biliary obstruction by dead parasites, which may occur three to seven days following treatment and may require removal by ERCP [78,79].

Alternative agents — There are no well-established alternative agents to triclabendazole for treatment of fascioliasis [80], although limited evidence for nitazoxanide based on observational data and one trial of 65 Peruvian patients with fascioliasis [81,82] suggests that this can be considered. Nitazoxanide was well tolerated, and cure was achieved in 40 percent of children and 60 percent of adults compared with 6 percent in the placebo group (p<0.05). Dosing consisted of 500 mg twice daily for seven days. Bithionol has been used but is no longer available.

In general, F. hepatica responds poorly to praziquantel. Mebendazole and albendazole are not effective. Artesunate is also not effective [66,83]; in one randomized trial comparing triclabendazole and artesunate, triclabendazole had greater efficacy in terms of resolution of symptoms (92 versus 76 percent), eosinophilia (42 versus 16 percent), and ultrasound findings (70 versus 66 percent) [83].

Additional interventions — Biliary decompression (endoscopic, percutaneous, or surgical) may be warranted in some circumstances; indications may include biliary duct stones and/or cholangitis [56,57]. Worms may be extracted after creation of a small sphincterotomy (image 2). Bile should be sent to evaluate for eggs and adult worms.

Issues related to management of complications (such as biliary obstruction, stone formation, cholangitis, cholecystitis, liver abscess, pancreatitis, hepatitis, and cirrhosis) are discussed separately. (See related topics.)

Follow-up — Follow-up after therapy should include monitoring for resolution of eosinophilia, clearance of eggs in stool, and a decrease in serology titers. It is reasonable to repeat all tests that were initially positive at three months. Resolution of biliary tract findings on ultrasound after therapy may also be helpful [84].

In one case series including 24 asymptomatic individuals with positive stool tests for eggs who were treated with triclabendazole, a negative follow-up stool examination was reported in 79 percent after a single dose; 12 months after therapy, serologic tests were negative in more than 90 percent of the patients who were cured [34].

Diagnosis of fascioliasis should prompt screening of family members with serology (stool microscopy is not generally helpful since eggs are often absent early in infection). In one study of 326 adults in Peru, adults with fascioliasis were four times more likely to live with an infected child [85]. Asymptomatic individuals should be treated to avoid the risk of future complications.

Prevention — Infection can be prevented by avoiding ingestion of raw freshwater plants in endemic areas. Elimination of the snail intermediate hosts has also been attempted by molluscicide application and pasture drainage but, in general, is not practical.

Vaccine studies in animal models have shown reduction in worm burdens and egg production of approximately 70 percent; no vaccines are available for human use [86].

FASCIOLA GIGANTICA — F. gigantica is closely related to F. hepatica. It infects domestic livestock in warm tropical and subtropical areas in Africa, the Western Pacific, Hawaii, and Southeast Asia [4]. Herbivorous mammals are the definitive hosts and snails (genus Lymnaea) are the intermediate hosts; humans are incidental hosts.

F. gigantica has a similar life cycle and pathology to F. hepatica and also causes similar clinical manifestations in the acute (liver) phase, in the chronic (biliary) phase, and in ectopic sites. The eggs (190 by 90 microns) and the adult flukes (up to 7.5 cm in length) are larger than F. hepatica.

Diagnosis of F. gigantica can be challenging. Eggs are often not detected in the stool and serodiagnosis is often inconclusive. Reports have suggested that specific antigens of F. gigantica can be detected by indirect enzyme-linked immunosorbent assay or immunoblot with good sensitivity and specificity [87,88]. Immunochromatographic tests for serodiagnosis have been developed using antigens from adult F. gigantica excretory-secretory product and recombinant F. gigantica cathepsin L, with the former showing superior sensitivity and specificity (100 and 99 percent, respectively) among a small number of patients [89]. A polymerase chain reaction-restriction fragment length polymorphism assay has been used to distinguish between F. hepatica and F. gigantica but is not widely available [90]. Until diagnostic techniques improve, recovery of adult flukes in the appropriate epidemiologic setting can be used to exclude or confirm the diagnosis.

Treatment and preventive measures are the same as for F. hepatica.

SUMMARY AND RECOMMENDATIONS

●Fascioliasis is a trematode flatworm infection caused by Fasciola hepatica or Fasciola gigantica. F. hepatica has a worldwide distribution; F. gigantica occurs predominantly in the tropics. (See 'Introduction' above.)

●Herbivorous mammals are the definitive hosts, snails are intermediate hosts, and humans are incidental hosts (figure 1). Sheep, cattle, or humans acquire infection by eating aquatic vegetation containing metacercariae, which excyst in the duodenum and migrate through the intestinal wall, peritoneal cavity, and liver parenchyma into the biliary ducts, where they develop into adults. (See 'Life cycle' above.)

●Many infections are mild; morbidity increases with fluke burden. The acute (liver) phase of migration is often associated with fever, right upper quadrant pain, and hepatomegaly. Jaundice is occasionally observed. Other symptoms include anorexia, nausea, vomiting, myalgia, cough, and urticaria. Marked peripheral eosinophilia is frequently present. (See 'Acute (liver) phase' above.)

●The chronic (biliary) phase usually begins about six months after infection and may last 10 years or more. This phase is usually asymptomatic, although epigastric and right upper quadrant pain, diarrhea, nausea, vomiting, wasting, hepatomegaly, and jaundice can occur. Common bile duct obstruction can develop, and chronic infection can lead to biliary colic, cholangitis, cholelithiasis, pancreatitis, and obstructive jaundice. (See 'Chronic (biliary) phase' above.)

●The diagnosis can be established by identifying eggs in stool, duodenal aspirates, or bile specimens (picture 1). Alternative approaches to diagnosis include identification of adult worms in endoscopic or surgical specimens or serology. Imaging can be a helpful adjunctive diagnostic tool. Additional diagnostic clues include eosinophilia, abnormal liver function tests, and anemia. (See 'Diagnosis' above.)

●We suggest triclabendazole for treatment of fascioliasis (Grade 2C). Dosing is outlined above. Management of ascending cholangitis requires antibiotics and surgery. Biliary obstruction may require endoscopic retrograde cholangiopancreatography and direct removal of the parasites if possible. (See 'Treatment' above.)