Fasciola Hepatica

CASE REPORT

Praziquantel failure in the treatment of Fasciola hepatica

DAVID MICHAEL PATRICK, MD, FRCPC, JUDITH ISAAC-RENTON, MD, FRCPC

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 fascioliasis 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. Key Words: Bithionol. F'asciola hepatica. Praziquantel. 1hclabendazole

Echec du praziquantel dans le traitement de la fasciolase RESUME: On presenle un cas de distomatose hepatique clue a Fasciola hepatica chez l' elre humain. Les sympt6mes ont persiste a pres traitement so us praziquantel et aulres agents lherapeuliques mais le patient a eventuellement reagi au biU1ionol. Les auteurs examinent les difficultes de lrouver un traitement medican1enteux efficace et tolerable en rapport avec le cycle de vie et Ia paU1ogenese du parasite. lis concluent que. si le bilhionol restc le medicament de choLx. le triclabendazole poUITait jouer une role preponderant dans un avenir proche.

HE I TRODUC"rlON OF THE BROAD SPEC"rRUM ANT­ Three years prior to presentation to the authors' clinic. T helmlntic praziquantel has simplified treatment of U1e patient had suffered fever. tachypnea and right­ many human metazoan infections. Fasciola hepatica. sided pleuritic chest pain, but had recovered spon­ the sheep liver fluke, has historically been a difficult taneously. Increasingly severe right upper quadrant parasite to eradicate. The a uthors add to U1e growing pain occurred three months later, bringing her to medi­ body of evidence for the inefficacy of praziquantel for cal attention. Although stools were negative for ova and this indication by reporting the failure of two separate parasites and t11ere was no peripheral eosinophilia, an regimens of the drug in a woman who was later cured irregularity of biliary mucosa on cholangiography led to of fasciola infection by alternative therapy. The relevant a diagnostic aspiration of the biliary tree. which yielded pharmacoilierapeutic literature is reviewed and recom­ ova of F hepatica on microscopy. The patient was mendations made regarding the most appropriate avail­ treated with praziquantel 25 mg/kg/ day for five days. able therapy. She tolerated the medicine well and was most careful to avoid future ingestion of watercress. Right upper quad­ CASE PRESENTATION rant pain recurred t.wo years later, and microscopy of a A 36-year-old woman was referred to the tropical common bile duct aspiration once again yielded F cliseases clinic with a past history of fascioliasis. She hepatica ova. The patient. was given mebendazole at and her husband had been resident on a large cattle that time; t11ree months later when U1e pain returned a and sheep farm in New South Wales, Australia. where stool exan1ination was positive for fasciola ova. she had consumed watercress on at least one occasion. Upon leaving Australia, the patient had no

Divisions of Microbiology and Infectious Diseases, Vancouver General Hospital and University of Blitish Columbia. Vancouver, British Columbia Correspondence and replints: Dr David M Patrick. Division of Infectious Diseases. GF Strong Research Laboratory. Vancouver General Hospital. Room 452. D Floor. 2733 Heather Street, Vancouver. British Co lumbia V5Z 3J5. Telephone (604) 875-4149, Fax (604) 875-4013 Received for publication June 23. 1990. Accepted November 20. 1990

CAN J INFECT DIS VOL 3 No 1 JANUARY ! FEBRUARY 1992 33 PATRICK AND ISAAC-RENTON symptoms, but stool examination on presentation to colic or cholangitis (2). Clinical manifestations of choles­ the authors' clinic revealed persistence of fasciola ova. tasis may be evident, and the liver is often enlarged. She was treated with praziquantel 75 mg/kg for one Complications such as hemobilia and biliary cirrhosis day in accordance with then current recommendations occur, but t11ere is no known association with cholan­ (l). One month later, her stools were still positive for giocarcinoma. Matu re adults have been known to sur­ fasciola ova and the abdominal pain subsequently vive in the liver for up to 13 years (6). recurred. The patient was started on bithionol 3 g every Diagnosis: The diagnosis might be suspected on the two days. Relief of abdominal pain was rapid, but basis of the above symptoms, particularly when a his­ because of vomiting and diarrhea, t11e dose was tory of aquatic plant ingestion is elicited. The reduced by 40% for the second half of the treatment leukocytosis and elevated erythrocyte sedimentation period. for a total of 15 doses. At four years of follow-up rate seen in acute infection are not specific, but the patient has remained symptom free with no recur­ eosinophilia is a frequent finding throughout all stages rence of ova on repeated coprological exanlination. of infection and may serve as a valuable clue. Definitive diagnosis has usually been based upon DISCUSSION demonstration of ova in feces or upon serological test­ Life cycle : F hepatica commonly infects livestock in ing. Sensitivity of fecal examinations is enhanced by the temperate climes. Though it is not a common cause of processing of several samples using parasite concen­ human disease. 2594 cases have been reported globally tration techniques. Since the number of ova produced in the past two decades (2). As with many infectious is small, multiple sedin1ents from each concentration diseases, this figure likely represents a substantial procedure should be examined. Rapid sedimentation underestimate of the true burden of clisease. The fully has proved more sensitive than merthiolate-iocline for­ grown, leaf-shaped, unsegmented and hem1aphroditic maldehyde concentration or string test, likely because 2 trematode measures 30x13 mm . It resides in t11e bile more stool is sampled in the former technique (7). ducts of sheep, the definitive host. as well as in ot11er Because of the long prepatent period, coprological livestock and. very occasionally, in humans. There it exan1ination is of little use in acute and early latent excretes its 140x70 11m2 oval and operculated eggs. infection. Serological testing based on somatic or ex­ These eggs hatch in the feces to free miracidiae. which cretory-secretory antigens may be positive within two to may infect the intermediate host. the freshwater lim­ four weeks of infection in experimental animals, and naea snail. The latter host excretes cerceriae which reach peak titres between four and 10 weeks after encyst upon waterside plants such as watercress. When infection in livestock (8) . Serology is also reactive prior such plants are conswned by sheep, cattle or humans. to positive stool exanlinations in man (9). Of the avail­ the immature flukes excyst. mature, invade the intes­ able tests, enzyme-linked immunosorbent assay (ELISA). tinal wall, and make their way to the liver. Having immunofluorescent antibody and counterimmuno­ penetrated Glisson's capsule, the flukes must then electr·ophoresis techniques have the best sensitivities burrow through the hepatic parenchyma to the bile and specificities (2). Genus-specific antigens have been ducts. where they mature to complete the cycle. used in ELISA to reduce cross-reactivity witl1 other Clinical manifestations: The incubation period after trematodes. and a reduction of ELISA titre has followed ingestion of the parasite is not well defined in humans. effective treatment in experimental animals (10). The but is probably about two months (3). The present present patient had a titr·e of 1:64 (l: 128 is considered patient suffered fever, tachypnea and pleuritic chest diagnostic) by ELISA for fascioliasis. As applied in pain some time after conslll11ing watercress. These Canada. however, tl1is test has limited usefulness due symptoms, as well as abdominal pain and headache. to the undefined cutoff and sensitivity of the procedure are classic manifestations of the acute phase of infec­ used. The assay used for the present patient's titre is tion. which corresponds to t11e migration of immature based on crude adult F hepatica antigen. also implying flukes through the peritoneum and liver. Urticaria has potential problems with cross-reactivity and specificity also been reported at this stage (4). The liver may be (personal communication). There is no current consen­ enlarged; mild anemia is common; and eosinophilia in sus on the best available serological test for use in excess of 5% is the rule (2). Hepatic scarring in the patl1 human cases. of the parasite may result. There follows a variable Treatment: The present case illustrated the difficulties period of latency during which the fluke matures. It is inherent in the selection of agents which are both usually during this period, about three or four months effective and well tolerated for the treatment of human after ingestion. that the first eggs are detectable in stool fascioliasis. Temporary improvement was seen after (5). Unexplained eosinophilia and a positive coprological treatment witl1 two separate regimens of praziquantel. examination may be t11e only clues to disease at this which later gave way to recurrent symptoms and excre­ point. The chronic or obstructive phase of infection, tion of ova. This late failure has been witnessed by other when symptomatic, usually presents as in the present clinicians and has been attributed to tl1e inability of patient. with symptoms indistinguishable from biliary most anthelmintic agents to kill the less mature flukes,

34 CAN J INFECT D1s VOL 3 No 1 J A NUARY/ FEBRUARY 1992 Praziquantel failure for Fasciola hepatica

which may later matu re to secrete ova and obstruct th e absen t when F hepatica is s u bject to the same therapy bile ducts (1 1). (27). One source recommends treatment ofF hepatica Historically, chloroquine was the fi rst li ne of defence wi th praziquantel 25 mg/kg tid for seven days (28). The for F hepatica infection. Its celebrated effects in improv­ a u tl1ors would not hold out m uch hope of success with ing symptomatology in acute disease are dan1pened by this drug. bu tifit is to be employed as a trial, the h igher its inabili ty to eradicate the par asite from the biliary dosage outlined above should be employed given the system (5). observed failure of lower dosage regimens. Emetine, an amebicidal alkaloid derived from ipecac. The present patient responded to tl1erapy with bitl1i­ has been recommended in the past as the drug of onol. This experience has been shared by the authors choice for F hepatica (12). It has been used successfully of several other case repor ts (29.30). The usual dosage in the treatment of large outbreaks (9) . The drug must has been 30 to 50 mg/ kg daily in tl1ree divided doses be given in repeated doses by deep intramuscular injec­ on alternate days for a total of 10 to 15 doses. Lower tion. causes substantial gastric irritation in 30 to 50% doses have been used when tl1is regimen is poorly of recipients. and more importantly, has been associat­ tolerated. Despite its success, most series reporting ed with arrhythmias, hypotension, congestive heart bithionol therapy of F hepatica report just under 50% failure and death. It is also toxic to skeletal muscle ( 13). long term cure (14,31). An approximate 50% incidence No deaths have been reported from emetine in the of vomiting and abdominal pain can be expected. Skin treatment of fascioHasis. Reasonable success of the rashes, urticaria. photosensitivity and diarrhea have order of 50% cure has been observed in the treatment also been reported. Bithionol is currently recommended of acute fascioliasis with an initial course of parenteral as the drug of first choice by at least one source (32). dehydroemetine in children (14.15). This agent is as­ In contrast to praziquantel. the new benzin1idazole sociated with fewer adverse effects than tl1e parent triclabendazole has more effect against F hepatica tl1an compound. against otl1er trematodes. In vitro, it has been shown to Niclofolan, a biphenyl compound, has been employ­ inhibit motility and to diminish U1e tegumentary poten­ ed in the treatment of two patients (16.17). While tial of flukes (33). In animals. it is well tolerated and favorable anthelmintic results were seen in both cases. nonteratogenic in doses well above tl1ose used thera­ treatment also induced severe sweating and abdominal peutically (34,35). In sheep and cattle, Lriclabendazole pain in one patient. and pruritis. jaundice and elevated in dosages of 5 to 10 mg/kg as a single dose has proven aspartate a.n1inotransferase and alanine aminotrans­ 90 to 100% effective against both immature and mature ferase in the other. flukes (36,37). Six patients with well documented fas­ Albendazole is an experimental benzimidazole an­ cioliasis have been treated with dosages of !Jiclaben­ thelmintic with demonstrated efficacy in Necator dazole in U1e neighbourhood of 10 mg/kg (38-40). Of americanus infections (18). hydatid disease (19). as­ these. two had transient fever and elevation of liver caris and trichu ris in fections (20), and strongyloidiasis function tests after treatment. All responded but two (21). Activity of albendazole in human fascioliasis later relapsed. These two responded well with relreat­ awaits clarification. ment. In the one patient for whom comparative data are Pra.ziquantel is a broad s pectrum anU1elmintic agent available. postprandial absorption was considerably possessing an excellent therapeutic ratio and demon­ better than absorption in the fasting state. In addition strated efficacy against several trematodes, including to these reports. five patients have been successfully clonorchis, Opisthorchis, paragon imus and most ces­ treated in Bordeaux, France witl1 indeterminate follow­ todes (22). Minimal toxicity in tl1e form of abdominal up. and some autl1ors are a.Iready recommending lri ­ pain. headache and dizziness has been reported. In clabendazole as tl1e drug of choice for human lower concentrations. the drug acts by causing contrac­ fascioliasis (41). Further work should clarify its role in tion and paralysis of the s usceptible adult flatworms. the treatment of fascioliasis. Higher doses result in vacuolization and vesiculation of the parasitic tegument and an increase in its per­ CONCLUSIONS meability to cations. Altl1o ugh success has been seen in F hepatica is a rare but treatable cause of biliary the treatment ofF hepatica witl1 dosages of 75 mg/kg tract symptomatology in first world populations. Pub­ tid for one day (23), there are many reports of post lished accounts of therapeutic e>..1Jerience suffer from therapy relapse in both acute and chronic fascioliasis, the absence of case control studies. It seems clear. even when dosages as high as 75 mg/kg/day are used however, that no drug approved for human use, includ­ for seven days (7.24-26). Such a treatment failure was ing praziquantel. has 100% efficacy against the trema­ observed in the present patient. Failure may relate to tode. Because of consistently acceptable cure rates. the resistive properties of the F hepaLica tegument. bithionol constitutes current first-line therapy. Tricla­ VacuoHzation of this layer is observed when Schis­ bendazole, if approved for regular use in humans, may tosoma mansoni and dicrocoeli um are treated wiU1 pra­ supplant bitl1ionol because of its generally more ziquantel in vitro. but such changes are conspicuously tolerable side effect profile.

C AN J INFECT DIS V O L 3 No l JANUARY; FEBRUARY 1992 35 PATRICK AND ISAAC-RENTON

As medications currently applied to treatment can hydatid disease in Kenya- A report on 12 cases. Tran s R cause symptomatic improvem ent without fully erad­ Soc Trop Med Hyg 1986;80: 193-5. icating the parasite. cure should n ever be taken for 20. Ran1alingam S, Sinniah B, Krishnan U. Albendazole, a n effective single dose broad spectrum anthelmintic drug. granted until long term follow-up fails to reveal the Am J Trop Med Hyg 1983:32:984-9. presence of ova on repeated and careful examination of 21. Rossignol J. Maissoneuve H. Albendazole: Placebo stool, or until endoscopic retrograde cholangiopancre­ controlled study in 870 patients \villi intestinal atography shows normal mucosa and biliary aspirate. heirninti1iasis. Tra ns R Soc Trop Med Hyg 1983 :77:707- 11. 22. Pearson R. Guerra11t R. Praziquantel: A major advance in REFERENCES a nti1elmintic th erapy. Ann Intern Med 1983;99: 195-8. l. Drugs for parasitic infections. Med Lett 1984:26:27-34. 23. Schiappacasse R, Mohan1111adi D. 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