Praziquantel failure in the treatment of Fasciola hepatica

DM P ATRICK, J IsAAc-RENTON. Praziquantel failure in the treatment of Fasciola hepatica. Can J Infect Dis 1991;3(1):33-35. A case of huma n fasc ioliasis is presented in which U1e patient remained symptomatic after treatment with praziquantel and oilier agents but eventua lly responded to biU1ionol. The difficulties in finding an efficacious and tolerable drug U1erapy for this condition a re reviewed wiU1 reference to U1e life cycle and pathogenesis of U1e parasite. ll is concluded that while biti1ionol remains U1e current drug of choice. lriclabendazole may play a dominant role in U1e ncar future.

T HE I TRODUC"rlON OF THE BROAD SPEC"rRUM ANT- helmlntic praziquantel h as simplified treatment of many human metazoan infections.Fasciola hepatica.the sheep liver fluke , has historically been a difficult parasite to eradicate.The a uthors add to U1e growing body of evidence for the inefficacy of praziquantel for this indication by reporting the failure of two separate regimens of the drug in a woman who was later cured of fasciola infection by alternative th erapy.The relevant pharmacoilierapeutic literature is reviewed and recommendations made regarding the most appropriate available therapy.

CASE PRESENTATION
A 36-year-old woman was referred to the tropical cliseases clinic with a past history of fascioliasis.She and her husband had been resident on a large cattle and sheep farm in New South Wales, Australia .where she had cons umed watercress on at least one occasion.
Three years prior to presentation to the authors' clinic.U1e patient had s uffered fever.tachypnea and rightsided pleuritic chest pain, but had recovered spontaneously.Increasingly severe right upper quadrant pain occurred three months later, bringing h er to medical attention.Although stools were negative for ova and parasites and t11ere was no peripheral eosinophilia, an irregularity of biliary mucosa on cholangiography led to a diagnostic aspiration of the biliary tree.which yielded ova of F hepatica on microscopy.The patient was treated with praziquantel 25 mg/kg/ day for five days.She tolerated the medicine well and was most careful to avoid future ingestion of watercress.Right upper quadrant pain recurred t.wo years later , and microscopy of a common bile duct aspiration once agai n yielded F hepatica ova.Th e patient.was given mebendazole at that time; t11ree months later when U1e pain returned a stool exan1ination was positive for fasciola ova.
Upon leaving Australia, the patient ha d no symptoms, but stool examination on presentation to the authors' clinic revealed persistence of fasciola ova.She was treated with praziquantel 75 mg/kg for one day in accordance with then current recommendations (l).One month later, her stools were still positive for fasciola ova and the abdominal pain subsequently recurred.The patient was started on bithionol 3 g every two days.Relief of abdominal pain was rapid, but because of vomiting and diarrhea, t11e dose was reduced by 40% for the second half of the treatment period.for a total of 15 doses.At four years of follow-up the patient has remained symptom free with no recurrence of ova on repeated coprological exanlination.

Life cycle :
F hepatica commonly infects livestock in temperate climes.Though it is not a common cause of human disease.2594 cases have been reported globally in the past two decades (2).As with many infectious diseases , this figure likely represents a substantial underestimate of the true burden of clisease.The fully grown, leaf-shaped, unsegmented and hem1aphroditic trematode measures 30x13 mm 2 .It resides in t11e bile ducts of sheep, the definitive host.as well as in ot11er livestock and.very occasionally, in humans.There it excretes its 140x70 11m 2 oval and operculated eggs.These eggs hatch in the feces to free miracidiae.which may infect the intermediate host.the freshwater limnaea snail.The latter host excretes cerceriae which encyst upon waterside plants such as watercress .When such plants are conswned by sheep, cattle or humans.the immature flukes excyst.mature, invade the intestinal wall, and make their way to the liver.Having penetrated Glisson's capsule, the flukes must then burrow through the hepatic parenchyma to the bile ducts .where they mature to complete the cycle.

Clinic al m anifest ations:
The incubation period after ingestion of the parasite is not well defined in humans.but is probably about two months (3).The present patient suffered fever, tachypnea and pleuritic chest pain some time after conslll11ing watercress.These symptoms, as well as abdominal pain and headache.are classic manifestations of the acute phase of infection.which corresponds to t11e migration of immature flukes through the peritoneum and liver.Urticaria has also been reported at this stage (4).The liver may be enlarged; mild anemia is common; and eosinophilia in excess of 5% is the rule (2).Hepatic scarring in the patl1 of the parasite may result.There follows a variable period of latency during which the fluke matures.It is usually during this period, about three or four months after ingestion.that the first eggs are detectable in stool (5).Unexplained eosinophilia and a positive coprological examination may be t11e only clues to disease at this point.The chronic or obstructive phase of infection, when symptomatic, usually presents as in the present patient.with symptoms indistinguishable from biliary 34 colic or cholangitis (2).Clinical manifestations of cholestasis may be evident, and the liver is often enlarged.Complications such as hemobilia and biliary cirrhosis occur, but t11ere is no known association with cholangiocarcinoma.Matu re adults have been known to survive in the liver for up to 13 years (6).Diagnosis: The diagnosis might be suspected on the basis of the above symptoms, particularly when a history of aquatic plant ingestion is elicited.The leukocytosis and elevated erythrocyte sedimentation rate seen in acute infection are not specific, but eosinophilia is a frequent finding throughout all stages of infection and may serve as a valuable clue.
Definitive diagnosis has usually been based upon demonstration of ova in feces or upon serological testing.Sensitivity of fecal examinations is enhanced by the processing of several samples using parasite concentration techniques.Since the number of ova produced is small, multiple sedin1ents from each concentration procedure should be examined.Rapid sedimentation has proved more sensitive than merthiolate-iocline formaldehyde concentration or string test, likely because more stool is sampled in the former technique (7).
Because of the long prepatent period , coprological exan1ination is of little use in acute and early latent infection.Serological testing based on somatic or excretory-secretory antigens may be positive within two to four weeks of infection in experimental animals, and reach peak titres between four and 10 weeks after infection in livestock (8) .Serology is also reactive prior to positive stool exanlinations in man (9).Of the available tests , enzyme-linked immunosorbent assay (ELISA).immunofluorescent antibody and counterimmunoelectr•ophoresis techniques have the best sensitivities and specificities (2).Genus-specific antigens have been used in ELISA to reduce cross-reactivity witl1 other trematodes.and a reduction of ELISA titre has followed effective treatment in experimental animals (10).The present patient had a titr•e of 1:64 (l: 128 is considered diagnostic) by ELISA for fascioliasis.As applied in Canada.however, tl1is test has limited usefulness due to the undefined cutoff and sensitivity of the procedure used.The assay used for the present patient's titre is based on crude adult F hepatica antigen.also implying potential problems with cross-reactivity and specificity (personal communication).There is no current consensus on the best available serological test for use in human cases.Treatment: The present case illustrated the difficulties inherent in the selection of agents which are both effective and well tolerated for the treatment of human fascioliasis.Temporary improvement was seen after treatment witl1 two separate regimens of praziquantel.which later gave way to recurrent symptoms and excretion of ova.This late failure has been witnessed by other clinicians and has been attributed to tl1e inability of most anthelmintic agents to kill the less mature flukes, which may later matu re to secrete ova and obstruct th e bile ducts (1 1).
Historically, chloroqu ine was the fi rst line of defence for F hepatica infection .Its celebrated effects in improving symptomatology in acute disease are dan1pened by its inabili ty to eradicate the par asite from th e biliary system (5).
Emetine, an amebicidal alkaloid derived from ipecac.has been recommended in the past as the drug of choice for F hepatica (12).It h as been used successfully in the treatment of large outbreaks (9) .The drug must be given in repeated doses by deep intramuscu lar injection.causes substantial gastric irritation in 30 to 50% of recipients .and more importantly, has been associated with arrhythmias, hypotension , congestive heart failure and death .It is also toxic to skeletal muscle ( 13).
No deaths have been reported from emetine in the treatment of fascioHasis.Reasonable success of the order of 50% cure has been observed in the treatment of acute fascioliasis with an ini tial course of parenteral dehydroemetine in children (14.15).This agent is associated with fewer adverse effects than tl1e parent compound.
Niclofolan, a biphenyl compound, has been employed in the treatment of two patients (16 . 17) .While favorable anthelmintic results were seen in both cases.treatment also induced severe sweating and abdominal pain in one patient.and pruritis.jaundice and elevated aspartate a.n1inotransferase and alanine aminotransferase in the other.
Pra.ziquantel is a broad s pectru m anU1elmintic agent possessing an excellent therapeutic ratio and demonstrated efficacy against several trematodes, including clonorchis, Opisthorchis, paragon imus and most cestodes (22).Minimal toxicity in tl1e form of abdominal pain.headache and dizziness h as been reported.In lower concentrations .the drug acts by causing contraction and paralysis of the s u sceptible adult flatworms.Higher doses result in vacuolization and vesiculation of the parasitic tegument and an increase in its permeability to cations.Altl1o ugh success has been seen in the treatment ofF hepatica witl1 dosages of 75 mg/kg tid for one day (23), there are many reports of post therapy relapse in both acu te and chronic fascioliasis, even when dosages as h igh as 75 mg/ kg/day are used for seven days (7.24-26) .Such a treatment failure was observed in the present patient.Failure may rela te to the resistive p roperties of the F hepaLica tegument.VacuoHzation of this layer is observed when Schistosoma mansoni and dicrocoelium are treated wiU1 praziquantel in vitro .but such changes are conspicuo usly Praziqua nte l failure for Fasciola hepatica absen t wh en F hepatica is s u bj ect to the same therapy (27).One source recommen ds treatment ofF hepatica wi th praziquantel 2 5 mg/kg tid for seven days (28).The a u tl1ors wou ld not hold ou t m u ch hope of success with this drug.b u tif it is to be employed as a trial, the h igher dosage ou tlined above sho uld be employed given the observed failu re of lower dosage regimens.
Th e present patient responded to tl1erapy with bitl1ionol.This experience has been shared by the authors of several other case repor ts (29.30).Th e usual dosage has been 30 to 50 mg/ kg daily in tl1ree divided doses on alternate days for a total of 10 to 15 doses .Lower doses have been used when tl1is regimen is poorly tolerated.Despite its success, most series reporting bithionol therapy of F hepatica report just under 50% long term cure (14,31).An approximate 50% incidence of vomiting and abdominal pain can be expected.Skin rashes, urticaria.photosensitivity and diarrh ea have also been reported.Bithionol is currently recommended as the drug of first choice by at least on e source (32).
In contrast to praziquantel.the new benzin1idazole triclabendazole has more effect against F hepatica tl1an against otl1er trematodes.In vitro , it has been shown to inhib it motility and to diminish U1e tegumentary potential of flukes (33).In animals.it is well tolerated and nonteratogenic in doses well above tl1ose used therapeutically (34 ,35).In sheep and cattle, Lriclabendazole in dosages of 5 to 10 mg/kg as a single dose has proven 90 to 100% effective against both immature and mature flukes (36,37).Six patients with well documented fascioliasis have been treated with dosages of !Jiclabendazole in U1e neighbourhood of 10 mg/kg (38)(39)(40).Of these.two had transient fever and elevation of live r function tests after treatment.All responded but two later relapsed.These two responded well with relreatment.In the one patient for whom comparative data are available.postprandial absorption was considerably better than absorption in the fasting state.In addition to these reports.five patients have been successfully treated in Bordeaux, France witl1 indeterminate followup.and some autl1ors are a.Iready recommending lriclabendazole as tl1e drug of choice for human fascioliasis (41).Further work should clarify its role in the treatment of fascioliasis.

C ONCLUSIONS
F hepatica is a rare but treatable cause of biliary tract symptomatology in first world populations.Published accounts of therapeutic e>..1Jerience suffer from the absence of case control studies .It seems clear.however, that no drug approved for human use , including praziquantel.has 100% efficacy against the trematode.Because of consistently acceptable cure rates.bithionol constitutes current first-line therapy.Triclabendazole, if approved for regular use in humans, may supplant bitl1ionol because of its generally more tole rable side effect profile.
As medications c urrently a pplied to treatment can cause symptomatic improvem ent without fu lly era dicating the parasite.cure should n ever be taken for gr anted until long term follow-up fails to reveal the presence of ova on repeated and careful examination of stool, or until endoscop ic retrograde cholangiopancreatography shows normal mucosa and biliary aspirate.