Fascioliasis

Fascioliasis is a waterborne and foodborne zoonotic disease caused by two parasites of class Trematoda, genus Fasciola; namely Fasciola hepatica and Fasciola gigantica.[1] Humans are incidental hosts and become infected by ingesting contaminated watercress or water. The illness occurs worldwide, particularly in regions with intensive sheep or cattle production. Incidence of human infection has increased over the past 20 years.[2, 3, 4]

Sheep, cattle and goats are the definitive hosts. Other alternate herbivore hosts are horses, pigs, buffaloes, donkeys, and pigs. The adult worms reside in the biliary passages of these hosts and are shed in their stools.[5]

In humans, maturation from metacercariae into adult flukes takes approximately 3 to 4 months. The adult flukes (F hepatica: up to 30 mm by 13 mm; F gigantica: up to 75 mm) reside in the large biliary ducts of the mammalian host. F hepatica infects various animal species, mostly herbivores (plant-eating animals).

The major risk factor is consumption of contaminated water plants or water. Many patients report consuming watercress.[6] Consumption of raw liver from infected sheep, goats, or cows is also a reported cause.

A study that applied a questionnaire and took fecal samples from 270 children in Peru reported that the risk factors for F hepatica were raising cattle, consumption of radishes, and chewing grass and that the prevalence in Baños del Inca district in Cajamarca, Peru was 6.30%.[7]

United States statistics

F hepatica infection is the only form of fascioliasis reported in the United States and only few such cases are acquired within, mainly reported from Hawaiian Islands, California, and Florida.[8, 9]  A large majority of the cases of fascioliasis are imported by travelers from Mexico, Puerto Rico, Haiti, Egypt, Thailand, Yemen, Peru, Portugal, Cape Verde, Ethiopia, Ireland, and Dominican Republic.[9]  A few cases of fascioliasis were found in refugees from Southeast Asia living in the United States.[10]

Owing to the endemic prevalence of lymnaeid snails in the United States, domestically acquired cases of fascioliasis are expected to be increasingly reported in the future.[9]

International statistics

Up to 17 million cases have been estimated to be affected with fascioliasis worldwide.[11, 12]  F hepatica typically occurs worldwide in temperate regions, except Oceania. F gigantica causes outbreaks in tropical areas of Southern Asia,[13] Southeast Asia, and Africa. Infection is most prevalent in regions with intensive sheep and cattle production. Miracidia require temperate water to develop and hatch.

A meta-analysis found that the regions of the world with the highest prevalence are South America (9.0%) and Africa (4.8%). The estimated global prevalence of fascioliasis is 4.5%.[14]

Disease prevalence is particularly high in specific regions of Bolivia (65-92%), Ecuador (24-53%), Egypt (2-17%), and Peru (10%).[15, 16] As many as 68% of Bolivian children in hyperendemic areas have evidence of infection, as do 11% of Ethiopians who emigrated to Israel. An epidemic of fascioliasis in Iran was estimated to affect 10,000 people.[17]

In a study of approximately 3000 Egyptian children, 3% were infected. Many were severely anemic. Among individuals who presented with fever of unknown origin to an Egyptian hospital, 4% had F hepatica. F hepatica caused disease that formerly occurred in scattered endemic foci along the Nile River and has now spread throughout the Nile Valley.

Travelers to and immigrants from regions of high endemicity are most frequently affected, as illustrated by a survey of imported cases in the United Kingdom.[18]

A distinct syndrome of fascioliasis, termed halzoun in Lebanon and marrerra in the Sudan, can result from consuming raw livers of infected sheep, goats, or cows. The living fluke adheres to the posterior pharyngeal wall, causing severe pharyngitis and laryngeal edema. Similarly, disease can follow consumption of sashimi of bovine liver served in "Yakitori" bars in Japan, if the liver is contaminated with juvenile worms.

Race-, sex-, and age-related demographics

Race

Fascioliasis infection has no apparent racial predilection.

Sex

Approximately 60% of infections occur in males, which may reflect occupational, dietary, or recreational exposures.

Age

Although most reported patients are adults, fascioliasis appears to equally affect people of all ages. Some geographic difference is observed in the age-related incidence of the disease; for example, it is rarely reported in children in Turkey. In contrast, a study by Ahmad et al, which was conducted in Upper Egypt, found a high prevalence of fascioliasis among elementary school–aged children.[19]

Prognosis is excellent with adequate therapy. However, because of the large numbers of people infected worldwide, fascioliasis causes considerable morbidity. In children, fascioliasis is often associated with severe anemia, although it is seldom fatal.

Complications

Severe anemia and, less commonly, pancreatitis, occur in children more frequently than in adults.

Rare complications include ectopic foci of infection, hemoperitoneum, subcapsular hematoma,[20]  hepatic mass, cholecystitis, ascending cholangitis, biliary obstruction,[21] hemobilia from ulceration of the biliary epithelium, gallstones, and sclerosing cholangitis.

Advise patients to avoid high-risk behaviors (ie, consumption of contaminated water plants, water, raw liver).

Approximately 15% of the infected patients are symptomatic; the majority are asymptomatic.[12]

The clinical course of fascioliasis can be divided into four phases.[22]

1. Incubation period: The period from ingestion of metacercariae to appearance of first symptom. This period can range from a few days to a few months.

2. Acute phase: The period of migration of larvae from the peritoneal cavity to the biliary tree and liver. This period ranges from 2-4 months. Localized or generalized allergic and toxic reactions mark this phase characterized by fever, generalized or right upper quadrant pain, hepatomegaly, loss of appetite, flatulence, nausea and diarrhea, cough, shortness of breath, chest pain, and urticaria.

3. Latent phase: This asymptomatic phase involves the period of maturation of the parasite and beginning of oviposition. This period can range from months to years. It is marked by eosinophilia and rarely do relapses of GI symptoms of the acute phase occur in this phase.

4. Chronic phase: This phase is marked by inflammation, hyperplasia and thickening of the bile ducts and gall bladder, leading to obstruction. The symptoms of this phase such as biliary colic, nausea, intolerance to fatty food, right upper quadrant pain, epigastric pain, obstructive jaundice, and pruritus, are the result of a blockade in the biliary tract and inflammation in the gall bladder. Biliary lithiasis is another manifestation of the chronic phase.

Ectopic fascioliasis can occur due to migration of the larvae to sites other than liver. Commonly involved organs are GI tract, abdominal wall subcutaneous tissue, pancreas, spleen, heart, lungs, and skeletal muscles. Neurofascioliasis and ophthalmofascioliasis has also been reported.[23]

Patients may present with painful or pruritic subcutaneous nodules, although this condition is rare. Halzoun/marrerra manifests with severe pharyngitis, dysphagia, foreign body sensation, and/or airway obstruction.

Physical examination typically reveals no specific signs of infection.

Abdominal tenderness may be general or may be localized to the right hypochondrium, right upper quadrant, gall bladder, mid epigastrium, or left upper quadrant.

Tender or non-tender hepatomegaly may occur.

Patients often have fever, pallor, and/or evidence of weight loss.

Less often, patients present with urticaria, wheezing, subcutaneous nodules as large as 6 cm in diameter, or other manifestations of ectopic larval migration to the skin, lungs, heart, brain, eye, intestine, and genitourinary tract.

Patients with halzoun/marrerra may have severe pharyngitis and/or laryngeal edema.

CBC count

Leukocytosis may occur. In developed countries, finding of eosinophilia and history of ingestion of watercress or freshwater plants in a symptomatic individual can be a good guide for further testing for fascioliasis. Eosinophilia is not specific for fascioliasis, as it can occur in many other parasitic infections, especially in endemic areas. Cases without eosinophilia have been reported both in acute and biliary phase.[5]

Eosinophilia may wax and wane during the chronic stage of infection. Among Egyptian children with acute fascioliasis, 14-82% had peripheral eosinophilia.[24]

Erythrocyte sedimentation rate

About one half of affected patients have an elevated erythrocyte sedimentation rate.

Immunoglobulin levels

These may be elevated, particularly immunoglobulins G and E.

Liver function tests

Elevated levels of gamma-glutamyl transpeptidase, alkaline phosphatase, and bilirubin may suggest cholestatic liver injury.

Although rare, elevated transaminase levels suggest hepatocellular injury.

Stool examination for ova and parasites

Detection of fasciolid eggs in the stools of the infected patients is the most definitive test for diagnosis. This test has some limitations as it can be falsely negative in the acute phase of disease and has low sensitivity in the later phases as well.[22] The small number of eggs in stool requires multiple specimens. The eggs measure 130-150 X 60-90 μm and can be confused with Fasciolopsis buski eggs. The FLOTAC technique may have superior sensitivity to standard sedimentation stool examinations.[25]

ELISA for Fasciola coproantigens may be performed on stool specimens.[26]

Flukes that measure 30 X 15 mm almost never appear in stool; the rare exceptions follow successful treatment.

Antibody detection

Antibody detection is useful during the acute phase of infection as the acute manifestations of human fascioliasis may precede the appearance of eggs in the stool by several weeks. Immunodiagnostic tests may be useful for confirmation of chronic fascioliasis when egg production is low or sporadic.

Immunodiagnostic tests for human Fasciola hepatica infection are as follows:[27] : enzyme immunoassays (EIA) with excretory-secretory (ES) antigens combined with confirmation of positive test by immunoblot. Specific antibodies to Fasciola may be detectable 2-4 weeks after infection (5-7 weeks before eggs appear in stool). Sensitivity for the FAST-ELISA format of EIA was 95%, sensitivity for immunoblot using 12-, 17-, and 63-kDa antigens appeared to be 100%. Antibody levels decrease to normal 6-12 months after treatment and can be used to predict the success of therapy.

Polymerase chain reaction (PCR) assays

PCR assays have been developed for the rapid diagnosis of fascioliasis.[28, 29]

Chest radiography

In patients with pulmonary symptoms, parenchymal infiltrates are rarely visible. A right-sided pleural effusion is also rare.

Ultrasonography

Ultrasonography may reveal hypodense/hypoechoic lesions in the liver that correspond to the burrow tracks of the larvae. Ultrasonography may reveal the adult fluke in a bile duct or the gallbladder. Ultrasonography rarely reveals scant ascites.

CT scanning

CT scanning may reveal multiple lesions that measure 1-10 mm or tunnels in the liver parenchyma.[30, 31] A radiating pattern of tunnels is diagnostic. CT scanning may also reveal an adult fluke in a bile duct or the gallbladder.

Findings of the ultrasound and CT scan can sometimes be confused with alternate diagnosis such as malignancy and stones.[5]

MRI

MRI may suggest granulomata of the liver parenchyma and may provide findings similar to CT scanning.

Cholangiography

Endoscopic retrograde cholangiopancreatography (ERCP) is considered the gold standard technique of imaging of the biliary tract in patients with the chronic phase of infection. It also aids in management of the fascioliasis with ERCP guided sphincterotomy and removal of adult flukes in chronic cases with obstructions of bile duct.[5]

US-guided gallbladder aspiration

This can reveal eggs in the bile, even when stool examination test results are negative.

Technetium-99 scanning

This imaging study reveals multiple intrahepatic defects in approximately 50% of cases.

Bone marrow aspiration, performed only as part of the diagnostic evaluation for other conditions, can reveal increased bone marrow eosinophils.

Duodenal aspiration may reveal eggs.

Liver biopsy findings include the following:

• Liver biopsy can reveal microabscesses and tunnels of parenchymal necrosis, surrounded by inflammatory infiltrates containing abundant eosinophils.

• Older lesions may be fibrotic.

Laparoscopy often reveals multiple gray-white and yellow nodules, 2-20 mm in diameter, and short vermiform cords on the liver surface. Rarely, these nodules may occur throughout the peritoneal cavity and intestine wall.

Exploratory laparotomy may reveal identical findings as laparoscopy; flukes are often present in the bile duct or gallbladder.

Upper GI endoscopy is associated with the following:

• Endoscopy can reveal a filling defect in the bile duct.

• Endoscopic removal of the fluke is possible.

• Administration of intravenous cholecystokinin can promote egg release, which can be sampled endoscopically for diagnosis.

Thoracentesis for pleural effusion may reveal increased eosinophils in pleural fluid.

Flukes can be found during autopsy or in surgical specimens. Multiple subcapsular cavities (5-10 mm in diameter) may be present, filled with necrotic material from which necrotic tracks radiate and surrounded by inflammatory infiltrates that contain large numbers of eosinophils.

Fibrosis may characterize older lesions. Tissues taken from ectopic sites of larval migration may demonstrate granulomatous nodules or small abscesses.

Triclabendazole, a benzimidazole derivative, has become the drug of choice for the treatment of fascioliasis.[22] It is recommended by the World Health Organization (WHO). Although available from the Centers for Disease Control and Prevention (CDC) for many years, triclabendazole was approved in the United States for fascioliasis in patients aged 6 years or older in February 2019. It is given as a 2-dose regimen of 10 mg/kg/dose separated by 12 hours. A study of 24 subjects in Chile revealed cure rates of 79.2% with one dose and 100% with 2 doses.[32] Another study comparing a group of 68 patients treated with one dose to a second group of 66 patients treated with two doses showed better cure rates of 93.9% in second group as compared with 79.4% in the first group.[33] A study of 90 pediatric subjects treated with triclabendazole in Bolivia reported no serious adverse effects and reduction of high intensity infections (>400 eggs per gm of stool) from 7.8% to 0% with two doses.[33] Resistance to triclabendazole in livestock is well known and now has been reported in human subjects as well.[34]

Nitazoxanide is a good alternative to triclabendazole, especially in the chronic stage of infection. It is given as 500 mg twice a day for 7 days in adults.[35, 36, 37] A pediatric study done in Mexico showed cure efficacy of 94% after one course and 100% after repeating the course.[38]

Bithionol, a halogenated phenol previously used as a first-line agent for the treatment of fascioliasis in United States, is no longer available.[37] Praziquantel, previously used as an alternative drug, is no longer recommended due to poor efficacy against Fasciola species. Other drugs that were used previously and are no longer recommended due to toxicity include emetine, dehydroemetine, metronidazole, albendazole, niclofolan, chloroquine, hexachloro-para-xylol, artesunate, and artemether.[22]

Fascioliasis complicated by ascending cholangitis requires treatment with appropriate antibacterial antibiotics.

The condition of the patient with fascioliasis determines inpatient care versus outpatient care. Transfer is necessary only when specialized services or care (see Consultations) are unavailable.

Patients with ascending cholangitis may require surgery.

An infectious diseases specialist and gastroenterologist should be consulted in patients with suspected fascioliasis.

A surgeon may be consulted.

Patients with an ectopic infection or a visceral larva migrans–like illness may require additional consultations for specific manifestations of the condition.

Consult the CDC Drug Service (404-639-3670) to obtain bithionol. See Drugs Available Through the CDC Drug Service. See CDC Drug Service: Bithionol.

Diet

A regular diet as tolerated is recommended.

Activity

Activity as tolerated is recommended.

Fascioliasis can be prevented through public education about avoiding consumption of contaminated water plants, water, and raw liver.

A vaccine candidate comprising activated dendritic cells shows promise in mouse infection.[39]

New fasciolicides are being used in small numbers of children with encouraging results and minimal toxicities. Triclabendazole is the drug of choice and was approved in the United States in 2019 after being available from the CDC for many years.[40] On the basis of limited data from the CDC, nitazoxanide might be effective therapy in some patients. Praziquantel, which is active against most trematodes (flukes), typically is not active against Fasciola parasites. Therefore, the CDC does not recommend praziquantel therapy for fascioliasis.[41]

Class Summary

Parasite biochemical pathways are different from the human host; thus, toxicity is directed to the parasite, egg, or larvae. The mechanism of action varies within the drug class. Antiparasitic actions may include the following:

- Inhibition of microtubules causes irreversible block of glucose uptake

- Tubulin polymerization inhibition

- Depolarizing neuromuscular blockade

- Cholinesterase inhibition

- Increased cell membrane permeability, resulting in intracellular calcium loss

- Vacuolization of the schistosome tegument

- Increased cell membrane permeability to chloride ions via chloride channels alteration

Triclabendazole (Egaten)

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, inhibition of tubulin function, and inhibition of protein and enzyme synthesis. It is indicated for treatment of fascioliasis in patients aged 6 years or older.

Nitazoxanide (Alinia)

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

Class Summary

Corticosteroids may ameliorate the treatment course in children with severe acute phase infection.

Prednisolone (Pediapred, Delta-Cortef, Econopred)

A short course that is given for 2 d preceding fasciolicidal therapy in children with severe acute phase infection is reported anecdotally to ameliorate the course of the illness and to decrease fever, pain, pruritus, and toxicity.