Global Health Primer

What is Fascioliasis?

Fascioliasis is caused by a parasitic flat worm that primarily affects the liver and bile duct. The parasite is transmitted by consumption of Fasciola spp. cysts on plants from contaminated fresh water. Chronic infection with fascioliasis can result in pain, abdominal inflammation and the formation of scar tissue and fibrosis in the bile duct, but it is not fatal.

Global Burden


Areas endemic for Fascioliasis

Better known as a veterinary disease, human fascioliasis cases have been steadily rising since the 1970s, primarily in rural areas, and has until recently been severely neglected by the medical community. Due to its increased spread and chronic nature, it is now a disease of global human concern.1

Fascioliasis has the widest geographic spread of any emerging vector-borne zoonotic disease and affects more than 51 countries worldwide. It is most prevalent in the Andean region, especially Bolivia and Peru.2 Fascioliasis is a nearly-worldwide disease, also affecting people in Western Europe, Southeast Asia, and the Caspian Sea region, and less commonly in Africa, Oceania, and Eastern Europe. An estimated 17 million people are affected by fascioliasis.2,3 As fascioliasis has only more recently been recognized as a significant human disease, studies to determine the global morbidity caused by fascioliasis are ongoing.4 Indeed, most analyses of the global impact of fascioliasis focus on the economic impact caused by infections in domesticated herd animals. Depending on the disease prevalence in a herd, these losses can be significant. The direct economic impact of fascioliasis infection is increased condemnation of liver meat, but the far more damaging effects are decreased animal productivity, lower calf birth weight, and reduced growth in effected animals .5,6,16

Parasite Geographic Distribution
F. hepatica Europe, South and Central America, Oceania, Asia, Africa
F. gigantica Asia, Africa

Causative Agent and Transmission

Image

Fasciloa egg
(photo: CDC)

Fascioliasis is caused by infection with flat worms of the genus Fasciola (either F. hepatica or F. gigantica). Commonly known as liver flukes, the parasites cause a zoonotic infection that affects domestic herd animals (such as cattle, sheep, donkeys, horses, camels, pigs) and wild animals. The parasite is transmissible from animal to human by human consumption of infected animal livers and from human to human through the fecal oral route.3

Image

Fasciola life cycle
Click to view

Adult Fasciola flukes living in the bile duct release eggs, which are then passed through the host’s stool into water. These eggs hatch in the water and develop through three larval stages. First stage, free swimming miracidia infect snails, where they develop further. The second, also free-swimming, cercariae stage of the parasite are released from the snail and attach to fresh water plants as third stage resting encysted metacercariae. Humans or animals that eat plants with encysted metacercariae, or drink water that is contaminated with these cysts, can be infected with the parasite.


 

Pathogenesis

After ingestion, Fasciola cysts open in the small intestine. The acute stage of the disease occurs as the worms migrate through the lining of the small intestine into the liver and bile duct. While often asymptomatic, the onset of this stage can produce gastrointestinal bleeding, inflammation, abdominal pain, and diarrhea. The chronic phase of the disease occurs when the worms reach the bile duct. The long-term presence of the worms causes progressive inflammation from scar tissue and debris that can lead to fibrosis and obstruction of the ducts.7,3

Current Control Strategy

Because fascioliasis in humans is so poorly characterized compared to the infection in animals, control measures are difficult to devise and implement. However, as understanding of the human health impact of this disease increases, support for control measures has increased as well. This effort is buoyed by the World Health Organization’s (WHO) designation of fascioliasis as an extremely neglected disease.1,3

Because the infection can be difficult to detect and can be transmitted in so many ways, control of fascioliasis has represented a significant challenge. The role of domestic and wild animal reservoirs, coexistence of the various Fasciola and snail species, and varying types of endemic situations have rendered the creation of a universal control strategy unrealistic.1 Current WHO guidelines recommend that hospitals maintain stockpiles of triclabendazole and that further classification studies regarding the nature of fascioliasis endemnicity be undertaken in each endemic country, which vary widely in geography and socioeconomic status from endemic France to hyperendemic Peru and Bolivia.8,1

Existing Products

Drugs

The primary treatment for fascioliasis is a single oral dose of triclabendazole. Triclabendazole, a benzimidazole that inhibits parasitic microtubule formation, is highly safe and effective against both immature and adult parasites, and is donated by Novartis Pharma AG in developing endemic countries.3 Most Fasciola infections are cleared with a single oral dose of triclabendazole, though some heavy infections require two. Bithionol was formerly used to treat fascioliasis but is no longer frequently used primarily due to its long treatment schedule and ambiguous dosage as compared to the more effective triclabendazole.9

Triclabendazole was originally developed as a veterinary drug for animals infected with fascioliasis. Veterinary resistance to the drug is spreading but there have been no reports of resistance in humans. However, this underscores the need for multiple drugs.

Vaccines

There is currently no vaccine for the prevention of fascioliasis.

Diagnostics

Diagnosis of fascioliasis is often limited in resource-poor settings to discovery of eggs in a patient’s stool. This detection method can result in under-diagnosis, since the eggs do not appear in the stool until after the acute phase of infection. Additionally, in some cases, repeated stool ova tests occur with a negative result despite a laboratory-confirmed diagnosis of fascioliasis. If laboratory resources are available, ELISA or Western blot testing can confirm a diagnosis. Ultrasonic detection of liver lesions can determine the extent of the tissue damage from the parasite.10

 

References

  1. Mas-Comas et al (2009). “Chapter 2. Fasciola, lymnaeids and human Fascioliasis, with a global overview on disease transmission, epidemiology, evolutionary genetics, molecular epidemiology and control.” Advanced Parasitology 69.
  2. Marcos et al (2008) “Natural History, Clinicoradiologic Correlates, and Response to Triclabendazole in Acute Massive Fascioliasis.” American Journal of Tropical Medicine and Hygiene 78 (2).
  3. WHO Fascioliasis Factsheet.
  4. WHO Collaborating Centres Global Database.
  5. Njeruh et al (2004). Prevalence and Economic Importance of Fascioliasis in Cattle, Sheep and Goats in Kenya.” Kenya Veterinarian 27.
  6. Hillver, G.V. (2005). Fasciola antigens as vaccines against Fascioliasis and Schistosomiasis.” Journal of Helminthology 79.
  7. Khandewal et al. (2008). “Biliary Parasites: Diagnostic and Therapeutic Strategies.” Current Treatment Options in Gastroenterology 11.
  8. WHO Bulletin - New Opportunities for Fascioliasis Control, 1999
  9. Keiser J. and J. Utzinger (2010). “The Drugs We Have and the Drugs We Need Against Major Helminth Infections.” Advances in Parasitology 73.
  10. Shabrawi et al (1997). “Human Fascioliasis: Clinical Features and Diagnostic Difficulties in Egyptian Children.” Journal of Tropical Pediatrics 43.
  11. Favennec et al (2003). “Double-blind, randomized, placebo-controlled study of nitazoxanide in the treatment of fascioliasis in adults and children from northern Peru.” Alimentary Pharmacology and Therapeutics 17(2).
  12. Tendler M and A Simpson (2008). “The biotechnology-value chain: Development of Sm14 as a Schistosomiasis vaccine.” Acta Tropica 108 (2).
  13. Intapan et al (2004). “Development of Rapid Agglutination Test Using Fasciola Gigantica Specific Antigen for Serodiagnosis of Human Fascioliasis.” Southeast Asian Journal of Tropical Medicine & Public Health 35 (1).
  14. Rahimi et al (2010). “Evaluation of Fast-ELISA versus Standard-ELISA to Diagnose Human Fasciolosis.” Archives of Iranian Medicine 14 (1).
  15. Hillver, G. and M Soler de Galanes (1991). Initial Feasibility Studies of the FAST-ELISA for the Immunodiagnosis of Fascioliasis.” The Journal of Parasitology 77(3).
  16. Kaplan R. (2001). Fasciola hepatica: A review of the economic impact in cattle and considerations for control.” Veterinary Therapeutics 2(1).

 

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at globalhealthprimer@bvgh.org.

Drugs

PIPELINE

Product/Research ProgramDevelopersDiscoveryPre-clinicalPhase IPhase IIPhase III
ArtesunateHospital for Tropical Diseases
University of Oxford

 

 

On Hold

NitazoxanideLondon School of Hygiene and Tropical Medicine

 

 

On Hold

0Z78Swiss Tropical and Public Health Institute
University of Nebraska

 

On Hold

ArtemetherQueens University of Belfast Medical Center
Swiss Tropical and Public Health Institute
University of Nebraska

 

On Hold

 

ANALYSIS

Because of the high cure rates of triclabendazole, drug development for fascioliasis is not seen as a priority. However, due to concerns about rising veterinary resistance to triclabendazole, development of alternative treatments may become necessary.

All drugs in development for fascioliasis are ‘on hold’ because they are not being pursued for this specific indication. A target product profile (TPP) has never been published for drugs to treat infections with Fasciola. However, the TPPs for helminthes are very similar and should serve as a guide for fascioliasis drug discovery and development.1

New drug development for fascioliasis is primarily being explored through drug development programs for other parasitic infections. Nitazoxanide, an anti-helminthic used to treat cryptosporidium, has achieved moderately successful cure rates in clinical trials.2 Based on the antischistosomal properties of artemisinin-derived malaria drugs, testing is underway to determine their efficacy against fascioliasis. Artemether and artesunate have both undergone proof of concept studies in animal models with encouraging results.3 The synthetic endoperoxide OZ78 has been shown to be effective in a murine model. None of the drugs in development have progressed to the clinical stage, and for now, triclabendazole is more effective than any drug in development.3 Novel drugs to treat fascioliasis should have more than 80% worm burden reduction against adult worms, have a broad spectrum of activity against major human trematodes, and show high activity against all development stages in the vertebrate host.1

Vaccines

PIPELINE

Product/Research ProgramDevelopersDiscoveryPre-clinicalPhase IPhase IIPhase III
Sm14 (Fascioliasis)Brazilian Ministry of Health
Oswaldo Cruz Foundation

 

 

 

ANALYSIS

Several purified recombinant F. hepatica antigens are being studied for their immunogenic potential in domestic animals. Many of these cross-protect against Schistosomiasis infection. While not entirely preventing F. hepatica infection, these candidates reduced total fluke burden, decreased egg production, and reduced the severity of liver lesions as compared to controls. Primary preclinical testing of these antigens has been done in ruminant, murine, and sylvatic models, but no vaccines have yet reached the clinical stage and it is unclear whether any are being developed for use in humans. Sm14, an antigen being pursued by the Brazilian Ministry of Health for S. mansoni immunization, may cross-protect against fascioliasis. Lack of funding for this neglected disease remains problematic, and co-development of an S. mansoni/F. hepatica vaccine may be the surest way to success.4,5

Diagnostics

Accurate, rapid, and affordable point of care diagnostics that can detect both species of the parasite are a critical need to improve patient care. More specifically, there is a need for fascioliasis rapid diagnostic tests (RDTs) to improve the accuracy of field diagnoses. A latex agglutination test platform – previously used to develop tests for T. cruzi and T. gondii – has been shown to be 75% sensitive and 99% specific at diagnosing fascioliasis, and results are ready in five minutes without laboratory equipment.6

A fast ELISA test is in development that offers the same diagnostic accuracy as a standard ELISA test but with quicker results. While the test cuts down the result time to within a single patient visit, it is still a laboratory assay that requires laboratory infrastructure and a skilled technician, and therefore still prohibitive in some endemic areas that lack the facilities to perform the test.7,8

 

References

  1. Keiser and Utzinger, Advances in the discovery and development of trematocidal, Expert Opin. Drug Discov. (2007) 2(Suppl.1):S9-S23
  2. Favennec et al (2003). “Double-blind, randomized, placebo-controlled study of nitazoxanide in the treatment of fascioliasis in adults and children from northern Peru.” Alimentary Pharmacology and Therapeutics 17(2).
  3. Keiser J. and J. Utzinger (2010). “The Drugs We Have and the Drugs We Need Against Major Helminth Infections.” Advances in Parasitology 73.
  4. Hillver, G.V. (2005). “Fasciola antigens as vaccines against Fascioliasis and Schistosomiasis.” Journal of Helminthology 79.
  5. Tendler M and A Simpson (2008). “The biotechnology-value chain: Development of Sm14 as a Schistosomiasis vaccine.” Acta Tropica 108 (2).
  6. Intapan et al (2004). “Development of Rapid Agglutination Test Using Fasciola Gigantica Specific Antigen for Serodiagnosis of Human Fascioliasis.” Southeast Asian Journal of Tropical Medicine & Public Health 35 (1).
  7. Rahimi et al (2010). “Evaluation of Fast-ELISA versus Standard-ELISA to Diagnose Human Fasciolosis.” Archives of Iranian Medicine 14 (1).
  8. Hillver, G. and M Soler de Galanes (1991). “Initial Feasibility Studies of the FAST-ELISA for the Immunodiagnosis of Fascioliasis.” The Journal of Parasitology 77(3).

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at globalhealthprimer@bvgh.org.

The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for facioliasis. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development. The tools for fascioliasis are extremely limited.

Drug Development Tools

Basic Research: Target Identification Target Validation Screening: Hit/Lead Identification Optimization Pre-clinical Validation Clinical Validation
Genome: Fasciola Hepatica GenBank library available. Fasciola gigantica is reported to be sequenced, but the genome is unavailable.

Key databases: GenBank

In vitro culture: F. hepatica adult worms have been maintained in the laboratory for at most 3 days after being taken from the livers of dead cattle, and no reliable in vitro culture models exist.
Gene knock-outs: No

Conditional gene knock-outs:
No

Transposon mutagenesis:
No

RNAi:
Yes

Other antisense technology: 
Yes

Viability assays:
  Possible with adult flukes 

Transcription microarrays:
No

Proteomics:
 Limited, primarily only for analysis of excreted parasite products (in larval and adult stages)

Crystal structures:
  Yes
Whole-cell screening assays: No

Enzymatic screening assays: Yes
Animal models: Yes

Sheep, buffalo, cattle and mouse models

Both species of fluke can infect the same animals, but susceptibility to the species varies among the animal models: Buffalos are most susceptible to F. gigantica. Sheep susceptibility to each species varies by breed.
Monitoring treatment efficacy: Yes

Availability of endpoints:
 Yes, resolution of abdominal pain is commonly used. (More accurate endpoints are needed)

Availability of surrogate endpoints:
  No

Access to clinical trial patients/sites:
  Yes, but primarily in rural populations

 

Vaccine Development Tools

Basic Research: Antigen Identification Immune Response Characterization Clinical Validation
See drug development tools above Predictive animal models: Sheep and goats most commonly used.

Detection of endogenous antigen specific response in clinical samples: No

Natural immunity well characterized: Not well characterized
Surrogate markers of protection: No

Challenge studies possible:
Not in humans, but challenge studies have been done in sheep.

 

Diagnostic Development Tools

Basic Research: Biomarker Identification Biomarker Validation Clinical Validation
See drug development tools above Biomarkers known: Yes

Access to clinical samples: Yes

Possible sample types:
Stool
Access to clinical trial patients/sites: Yes

Treatment available if diagnosed:
Yes

 

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at globalhealthprimer@bvgh.org.

Return to listings