Guidelines for treatment of cystic and alveolar echinococcosis in humans. WHO Informal Working Group on Echinococcosis.

Update/Le point Guidelines for treatment of cystic and alveolar echinococcosis in humans* WHO Informal Working Group on Echinococcosis1 Summarized in this article are recent experiences in the treatment ofhuman cystic echinococcosis (CE) and alveolar echinococcosis (AE) of the liver caused by the metacestode stages of Echinococcus granulosus and E. multilocularis, respectively. For CE, surgery remains the first choice for treatment with the potential to remove totally the parasite and completely cure the patient. However, chemotherapy with benzimidazole compounds (albendazole or mebendazole) and the recently developed PAIR procedure (puncture-aspira- tion-injection-re-aspiration) with concomitant chemotherapy offer further options for treatment of CE cases. Chemotherapy is not yet satisfactory; cure can be expected in about 30% of patients and improvement in 30-50%, after 12 months' follow-up. AE is generally a severe disease, with over 90% mortality in untreated patients. Radical surgery is recommended in all operable cases but has to be followed by chemotherapy for at least 2 years. Inoperable cases and patients who have undergone nonradical resection or liver transplantation require continuous chemotherapy for many years. Long-term chemotherapy may significantly prolong survival, even for inoper- able patients with severe AE. Liver transplantation may be indicated as a life-saving measure for patients with severe liver dysfunction, but is associated with a relatively high risk of proliferation of intraoperatively undetected parasite remnants. Details of indications, contraindications, treatment schedules and other aspects are discussed. * This article is based on the findings of two meetings of the WHO Informal Working Group on Echinococcosis, held in Besan9on, 10 October 1992 (unpublished document WHO/CDSNPH/93.118), and Al-Ain, United Arab Emirates, October 1994. The activities of the Working Group are coordinated by Dr Vuitton, Besan,on, France, and Dr F.-X. Meslin, Division of Emerging Diseases, World Health Organization, Geneva, Switzerland. The participants at the meetings are listed below. Meeting in Besan9on. J. Eckert, Switzerland (Chairman); Z. Pawlowski, Poland (Vice-Chairman); P. Schantz, USA (Rapporteur); R. Ammann, Switzerland; S. Breson-Hadni, L. Doson-Girete, A. Gerard, J.P. Miguet, F. Sallin, and D.A. Vuitton, France; N. Sato, K. Suzuki, M. Takahashi, and J. Uchino, Japan; C.E. Tanner, Canada; T. Todorov, Bulgaria; and H. Wen, China. WHO Secretariat T. Fujikura. Meeting in Al-Ain, United Arab Emirates. Z. Pawlowski, Po- land (Chairman); F.K. Dar, United Arab Emirates (Vice-Chairman); J. Eckert, Switzerland (Vice-Chairman); P. Kern, Germany (Rapporteur); G. Al-Awar, Lebanon; A. Bchir, Tunisia; M. Caremani, Italy; P.S. Craig, J. Horton, United Kingdom; S. Gerami, United Arab Emirates; M. Kamiya, Japan; C.E. Tanner, Canada; M. Tineli, Italy; T. Todorov, Bulgaria; W.N. von Sinner (Saudi Arabia); D.A. Vuitton, France; and H. Wen (China). WHO Secre- tariat: L. Savioli. Requests for reprints should be sent to Professor J. Eckert, WHO Collaborating Centre for Parasitic Zoonoses, Institute of Parasitology, Winterthurerstrasse 266a, 8057 Zurich, Switzerland. Reprint No. 5696 Introduction Human echinococcosis is a zoonotic infection caused by larval forms (metacestodes) of tapeworms of the genus Echinococcus found in the small intestine of carnivores. The eggs of these tapeworms excreted by carnivores may infect various species of natural intermediate host animals and humans. Among the four recognized species of Echinococcus (20), two are of special medical importance, - E. granulosus and E. multilocularis - causing cystic echino- coccosis (CE) and alveolar echinococcosis (AE) in humans, respectively. The annual incidence of AE is generally low in most of the endemic areas (0.03-1.2 per 100000 inhabitants) but in untreated or in inadequately treated patients mortality is >90% within 10-15 years of diagnosis (1, 2, 17). The annual incidence of CE can range from <1 to 220 per 100000 in- habitants in various endemic areas (16, 17). The mortality rate (about 2-4%) from CE is lower than that from AE but it may increase considerably if medical treatment and care are inadequate (1, 2). Bulletin of the World Health Organization, 1996, 74 (3): 231-242 © World Health Organization 1996 231 WHO Informal Working Group In view of the public health significance of CE and AE in many countries (16,17), WHO initiated in 1981 a multicentre clinical study on the chemo- therapy of human echinococcosis, because individual studies undertaken since 1977 had produced incon- sistent results (6, 7).a Progress and problems in the treatment of human echinococcosis were discussed at two meetings by the WHO Informal Working Group on Echinococcosis (9).b The results of these discussions are presented here but it should be borne in mind that the efficacy and safety of some of the methods are not yet clearly defined and require fur- ther evaluation. Readers are referred for detailed information and scientific discussion to various pub- lished reviews and WHO reports (1, 2, 8, 14-18, 20- 24).a Cystic echinococcosis In primary echinococcosis, metacestode cysts de- velop in various sites from oncospheres after ingestion of E. granulosus eggs. In secondary echinococcosis, larval tissue spreads from the pri- mary site and proliferates after spontaneous or trauma-induced cyst rupture or after release of vi- able parasite material during invasive treatment procedures. Organ localization In primary echinococcosis, the metacestodes may develop in almost any organ. Most patients (up to 80%) have a single organ involved and harbour a solitary cyst, localized in approximately two-thirds of cases in the liver and in about 20% in the lungs. In each site cysts are surrounded by the host tissue (pericyst), encompassing the endocyst of meta- cestode origin. The endocyst consists of an outer acellular "laminated" layer, which is covered on its inner side by a multipotential germinal layer giving rise to the production of brood capsules and protoscolices. The central cavity of E. granulosus cysts is typically filled with clear fluid, which in "fer- tile" cysts contains brood capsules and protoscolices. In addition, "daughter" cysts of variable size are of- ten present inside or outside the "mother" cysts. a Treatment ofhuman echinococcosis. Report ofan Informal WHO Meeting, 29 June-1 July 1981. WHO unpublished document PDP/ 82.1, 1981. b Report of the WHO Working Group meeting on clinical medicine and chemotherapy of alveolar and cystic echinococcosis, Besangon, France, 10 October 1992. Unpublished document WHO/CDSNPH/93.118, 1992. Course of infection During the natural course of infection, the fate of E. granulosus cysts is variable. Some cysts may grow (average increase: 1-30mm per year) and then per- sist without a noticeable change for many years; others may spontaneously rupture or collapse and can com- pletely disappear. Spillage of viable protoscolices after spontaneous or traumatic cyst rupture or during interventional procedures, may result in secondary echinococcosis. Calcified cysts are not uncommon. After an undefined and variable incubation pe- riod, infections may become symptomatic if active cysts exert pressure on adjacent tissue and induce other pathologic events. Usually, cysts do not induce clinical symptoms until they have reached a particu- lar size; sudden onset of symptoms may be due to cyst rupture. Diagnosis The diagnosis of CE is based on clinical findings, morphological features detected by imaging tech- niques, and immunological as well as other labora- tory tests. Treatment The following comments concern liver echi- nococcosis; only certain aspects of the treatment of cysts in other organs are mentioned. Currently, sur- gery remains the treatment that has the potential to remove cysts and lead to compfete cure. However, the introduction of chemotherapy and of puncture- aspiration-injection-re-aspiration (PAIR) offers al- ternatives for treatment, especially for inoperable cysts and for cases with a high surgical risk. In order to make a rational decision, the risks and benefits, indications and contraindications must be consid- ered for each case, based on the following principles and observations. * Surgery Indications. Surgery is indicated for removal of large liver cysts with multiple daughter cysts; sin- gle liver cysts, situated superficially that may rup- ture spontaneously or as a result of trauma; cysts that are infected; cysts communicating with the biliary tree and/or exerting pressure on adjacent vital organs; and cysts in the lung, brain, kidney, bones, and other organs. Contraindications. Surgery is contraindicated, as defined for surgical procedures in general, i.e., patient refusing surgery, patient at the extremes of age, pregnant woman, patient with concomi- tant severe diseases (i.e., cardiac, renal or hepatic 232 WHO Bulletin OMS. Vol 74 1996 Guidelines for treatment of cystic and alveolar echinococcosis diseases, diabetes, or hypertension). In addition, surgery is contraindicated in patients with multi- ple cysts, cysts that are difficult to access, dead cysts, either partly or totally calcified cysts, and in patients with very small cysts. Choice ofsurgical technique. Surgical procedures include radical surgery (total pericystectomy or partial hepatectomy); conservative surgery (open cystectomy with or without omentoplasty); or palliative surgery (simple tube drainage of in- fected cysts or communicating cysts). The more radical the intervention, the higher the operative risk but with the likelihood of fewer relapses, and vice versa. With the inclusion of chemotherapy (see below), before or after surgery, it is possible to be less aggressive. Choice of protoscolicides. For intraoperative killing of protoscolices, there is no ideal protoscolicidal agent that is both effective and safe. The lethal action observed in vitro may be hampered in vivo by the instability of the sub- stance used, e.g., hydrogen peroxide, or by an unpredictable dilution by hydatid fluid, and diffi- culties in penetrating daughter cysts. Potential communication between the hydatid cyst and the biliary tree substantially increases the safety re- quirements for using protoscolicides, which can cause chemical cholangitis leading to sclerosing cholangitis; formalin should therefore not be used. At present, the following protoscolicides are effective and have a relatively low risk of toxicity: 70-95% ethanol, 15-20% hypertonic sa- line, or 0.5% cetrimide solution. For optimal effi- cacy the substances have to be left in contact with the cysts for at least 15 minutes. More experi- mental studies and clinical observations are ur- gently needed to evaluate the efficacy and safety of individual protoscolicides. Concomitant drug treatment. Preoperative treat- ment with benzimidazoles has been reported to soften the cysts, thus reducing intracystic pres- sure, enabling the surgeon to remove the endocyst more easily. However, neither the re- quired duration of such treatment nor its efficacy has been adequately determined. Preoperative chemotherapy with albendazole (ABZ) or mebendazole (MBZ) (for dosages, see below) may be indicated to reduce the risk of secondary echinococcosis and should begin at least 4 days before surgery and last for 1 month (ABZ) or 3 months (MBZ). Benefits. Radical surgery has the potential to cure completely the patient, but involves some peri- operative risks. - Risks. The risks include those associated with any surgical intervention (anaesthesia, stress, and infections, including those transmitted by blood transfusion, e.g., hepatitis, human immuno- deficiency virus (HIV)); anaphylactic reactions; secondary echinococcosis owing to spillage of viable parasite material (2-25% of cases); and possible recurrence, if other cysts are present. Operative mortality varies from 0.5% to 4%, but may be higher if surgical and medical facilities are inadequate. - Medical requirements. The medical staff must have experience in treating cystic echinococcosis. Hospitalization of patients is needed as well as an adequately equipped surgical ward. The costs of intervention and postoperative medical care may be considerable. * PAIR Ultrasound-guided cyst puncture, which was intro- duced in 1986 (3, 10, 11), has diagnostic and thera- peutic potential; however, diagnostic puncture should only be used if other diagnostic methods have failed. PAIR for treatment of CE includes the follow- ing: percutaneous puncture of cysts using ultrasonic guidance; aspiration of substantial amounts of cyst fluid; injection of protoscolicidal substances (20% sodium chloride solution or, better, 95% ethanol) for at least 15 minutes; and re-aspiration of the fluid cyst content. Favourable results have been reported from more than 500 PAIR interventions over a follow-up period of up to 5 years (3, 10, 11, 23). However, the efficacy and potential risks of PAIR have not yet been fully evaluated and require further properly controlled long-term studies. PAIR should be ac- companied by chemotherapeutic coverage to mini- mize risks of recurrence (see below). Indications. PAIR is indicated for inoperable patients (see contraindications for surgery) and those who refuse surgery. It has been used in the treatment of Echinococcus cysts in the liver and of cysts in the abdominal cavity, spleen, kidney and bones, but should not be used for lung cysts (11). The following types of liver cysts may be selected for PAIR: anechoic lesions >5-cm diameter; cysts of types I and II, as classi- fied by Gharbi et al. (12); cysts with a regular double laminated layer; cysts of >5-cm diameter with multiple septal division (Gharbi type III) except honeycomb-like cysts; multiple cysts 5-cm diameter in different liver segments (Gharbi types I, II and III) (12). PAIR can also be used in cases of relapse after surgery or in failure to respond to chemotherapy. Experience using WHO Bulletin OMS. Vol 74 1996 233 WHO Informal Working Group the technique on pregnant women and children aged <3 years is still limited; it might be indicated for pregnant women with symptomatic cysts but the risk associated with peri-interventional benzimidazole treatment has to be carefully as- sessed since benzimidazoles are contraindicated during pregnancy, notably during the first 3 months. - Contraindications. PAIR is contraindicated for inaccessible or superficially located liver cysts (in the latter there is a risk of spillage of cyst content into the abdominal cavity); in multiple septal di- visions of cysts (honeycomb-like cysts); for cysts with echogenic lesions; inactive cysts or calcified lesions; communicating cysts; and lung cysts. In order to avoid the induction of chemical cholangitis, aspirates from the cysts should be analysed for traces of bilirubin prior to injection of protoscolicides. If the cyst content is contami- nated with bile, which indicates that there is di- rect communication with the biliary ducts, there is a high risk of sclerosing cholangitis after injec- tion of protoscolicidal substances. - Concomitant drug treatment. Four days of treat- ment with benzimidazoles before PAIR is man- datory and should last for 1 month (albendazole) or 3 months (mebendazole) after the procedure. - Benefits. PAIR is minimally invasive and less risky than surgery. It confirms the diagnosis and removes a large number of protoscolices and antigens with the aspirated cyst fluid. The cost of puncture and chemotherapy may be less than that of surgery (fewer days of hospitalization are needed). - Risks. The risks include those associated with any puncture (haemorrhage, mechanical damage of other tissues, infections); anaphylactic shock or allergic reactions caused by leakage of cyst fluid; and secondary echinococcosis due to spillage. Transhepatic cyst puncture is strongly advised since puncture of superficially located cysts in- volves a higher risk of spillage. Other potential risks are chemical sclerosing cholangitis, sudden intracystic decompression leading to biliary fis- tulas, and persistence of satellite daughter cysts. - Medical requirements. PAIR should only be per- formed by experienced physicians and a surgi- cal back-up team well-prepared to deal with complications. * Chemotherapy Over 1000 well-documented cases of cystic echi- nococcosis have been treated with benzimidazoles, to date. When evaluated up to 12 months, 30% of patients show cyst disappearance (cure), 30-50% show degeneration of cysts and/or significant size reductions (improvement), but 20W-40% exhibit no morphological changes of cysts (i.e., failure). Chemotherapy is apparently more effective among young rather than older patients. Small cysts that have a thin wall without infection or communication, as well as secondary cysts (even when multiple) are mostly susceptible to chemotherapy; chemotherapy may, however, be less effective for thin-walled daughter cysts within a mother cyst. Some of the treated patients exhibit relapses but these are sensi- tive to retreatment in a high proportion of cases (up to 90%). - Indications. Chemotherapy is indicated for in- operable patients with primary liver or lung echinococcosis and for patients with multiple cysts in two or more organs and peritoneal cysts. Cysts localized in bones are less susceptible to chemotherapy. Another important indication for chemotherapy is the prevention of secondary echinococcosis. The pre-surgical use of ben- zimidazoles (ABZ or MBZ) can reduce the risk of re-occurrence of CE and/or facilitate the op- eration by reduction of intracystic pressure. Con- comitant chemotherapy is also recommended for PAIR. - Contraindications. Chemotherapy is contra- indicated for large cysts that have a risk of rupture (notably those superficially situated, in- fected cysts) and for inactive or calcified cysts. Patients with chronic hepatic diseases and with bone marrow depression should not be treated. Early pregnancy is a contraindication, and chemotherapy during the later stages of preg- nancy is rarely strongly indicated. - Choice of anthelmintics (see also, alveolar echi- nococcosis and Annex). Two benzimidazoles (albendazole (ABZ) (Eskazole®, SmithKline Beecham, England) and mebendazole (MBZ) (Vermox®, 500mg, Janssen Pharmaceutica, Bel- gium) have been evaluated using animal models and used on over 1000 patients. These drugs show (mostly partial) efficacy against CE and AE, and are generally well tolerated. For treatment of CE the usual oral dosage of albendazole is 10-15mg.kg-l.day-1 in several 1-month courses separated by 14-day intervals. Three courses are routinely suggested, and more than six are usu- ally not necessary. Cyclic treatment with intervals of 14 days was originally recommended, but new data on continuous treatment from China, Japan, and Italy show that this approach has better efficacy over WHO Bulletin OMS. Vol 74 1996234 Guidelines for treatment of cystic and alveolar echinococcosis 3-6 months or longer with no increase in adverse effects. The usual oral dosage of mebendazole is 40-50mg per kg per day for at least 3-6 months. Animal experiments have shown that the efficacy of mebendazole against Echinococcus metacestodes is positively correlated with serum drug concentration and the duration of treatment. In humans the serum drug levels of MBZ and ABZ may vary widely in individual patients, and correlation with efficacy is inconsistent. Drug dosing in conjunction with a fat- rich meal improves intestinal absorption. Use of praziquantel (PZQ), an isoquinoline de- rivative, has been proposed at a dose of 40mg/kg once a week concomitantly with benzimidazoles. PZQ might also be useful in cases of operative spill- age; however, the rationale for such treatment needs confirmation since available data are very limited. - Benefits. Chemotherapy is a noninvasive treat- ment that can be used on patients of any aMe (although there is little experience with under-6- year-olds) and is less limited by the patient's sta- tus (except pregnancy) than surgery. - Risks. The adverse effects of benzimidazoles include hepatotoxicity (transient increase of aminotransferases) (19, and Annex), neutro- penia, thrombocytopenia and alopecia. The potential risks of benzimidazoles include embryotoxicity and teratogenicity, which, how- ever, have only been observed in some labora- tory animals during the early stages of pregnancy. - Medical requirements. Hospitalization is not necessary, but regular follow-up examinations are required. The costs of anthelmintics and repeated medical examinations may be considerable. - Monitoring of patients. Medical and laboratory examinations for adverse reactions are necessary initially every 2 weeks then monthly. Leukocyte counts should be checked at 2-week intervals during the first 3 months because in rare instances severe and not always reversible leukopenia has been observed in the early phases of chemotherapy. Serum drug concentrations (ABZ-sulfoxide or MBZ parent compound) should be monitored after 2 weeks and 4 weeks of chemotherapy, respectively, in order to iden- tify levels that are too high (possibly toxic) or too low (ineffective). For MBZ it has been recom- mended that serum or plasma levels be deter- mined 4 hours after the morning dose. Oral drug doses can be adapted to individual patients in order to achieve adequate serum levels (see Annex), but such attempts are frequently unsuc- cessful. Only a few laboratories have the capabil- ity to determine ABZ-sulfoxide or MBZ serum drug levels (see also section on alveolar echinococcosis). Chemotherapy has to be applied over a prolonged period of time and its efficacy requires evaluation every 3 months. Each follow- up visit should include an imaging examination. Treatment of CE cases detected at screening. For ethical reasons mass screening should not be un- dertaken without the consent of the population involved and a clear idea of the medical attention to be offered to persons with a suspected diagno- sis of echinococcosis. These persons should be offered further clinical and serological examina- tions to confirm the diagnosis and to select those who may need treatment. Those infected who do not qualify for immediate treatment should be carefully monitored. Alveolar echinococcosis Alveolar echinococcosis is a very serious disease caused by the metacestode of E. multilocularis and is characterized by a tumour-like, infiltrative growth. Treatment of AE involves a variety of options, in- cluding chemotherapy, and requires specific clinical experience. Therefore, patients should be referred to recognized national/regional AE treatment centres. Early diagnosis is of special importance for suc- cessful treatment since population screening pro- grammes for AE in endemic areas of Japan and elsewhere have clearly shown that early diagnosis reduces morbidity and mortality. Organ localization Initially, metacestodes of E. multilocularis develop almost exclusively in the liver. The right lobe is pre- dominantly infected, but the liver hilus together with one or two lobes may also be involved. Parasitic lesions in the liver can vary from small foci of a few mm in diameter to large areas of infiltration (15- 20cm or more in diameter). Primary extrahepatic localizations of E. multilocularis metacestodes are extremely rare. From the liver, the metacestode tends to spread to other organs by infiltration or metastasis formation. Until recently it was believed that the metacestode of E. multilocularis usually re- tains an unlimited proliferative capacity until the death of the patient; however, under the influence of the host's defence mechanisms, the metacestode can degenerate, calcify, and finally die. Therefore, spon- taneous cure of AE is possible but its frequency is not known. WHO Bulletin OMS. Vol 74 1996 235 WHO Informal Working Group Course of infection Cases of AE are characterized by an inital asympto- matic incubation period of at least 5-15 years and a subsequent chronic course. The symptoms are pri- marily cholestatic jaundice (about a third of cases) and/or epigastric pain (about a third of cases). AE is detected in the remaining third of patients inciden- tally during medical examination for symptoms such as fatigue, weight loss, hepatomegaly, or abnormal routine laboratory findings. Mortality among un- treated or inadequately treated persons is high. In a series of 66 individuals with AE in the Federal Re- public of Germany (period, 1960-1972), 70% died within 5 years and 94% within 10 years of being diagnosed. According to recent data from Alaska, in 21 untreated persons the average survival time after diagnosis was 5.3 years, and all patients died within 14 years (1, 2, 25). Diagnosis Diagnosis of AE is based on the following: clinical findings and epidemiological data; lesion morphol- ogy reviewed by imaging techniques; and immuno- logical and other laboratory tests. Treatment The following principles are now commonly ac- cepted for the treatment of AE. - The first choice in all operable cases is radical surgical resection of the entire parasitic lesion from the liver and other affected organs. - Chemotherapy for a limited period of time is indicated after radical surgery. - Long-term chemotherapy is mandatory after in- complete resection of the lesions, in inoperable patients (including cases after interventional pro- cedures) and in AE patients after liver transplan- tation (for further details see below). * Surgery Excision of the parasitic lesion has been carried out using the procedures of radical tumour surgery. Radical or nonradical surgery and liver transplan- tation require concomitant chemotherapy, as discussed. - Indications. Resectability of the parasitic lesion in the liver is a prerequisite for radical surgery and must be assessed by imaging techniques be- fore the operation. - Contraindications. Inoperable lesions, extensive lesions, and lesions not confined to the liver and involving other organs must be managed using alternative therapies following interdisciplinary consultation. - Benefits. Radical surgery may eliminate the para- sites and cure the patient. An early diagnosis of AE can improve prospects for complete cure. Nonradical surgery is regarded as beneficial for reducing the parasite mass and for increasing the chances of effective chemotherapy. - Risks. Lesions cannot always be clearly defined by imaging techniques; incomplete resection leaves invisible remnants of parasitic tissue with a potential of regrowth and dissemination into other organs, even after years. General risks may be associated with surgical intervention (anaes- thesia, stress, etc.), immunosuppression, infec- tions (including those transmitted by blood transfusion) or other factors. - Medical requirements. Hospitalization in a surgi- cal ward is mandatory. The surgical team should be experienced in major liver surgery and in treating AE. * Chemotherapy Extensive studies in animals have demonstrated the significant parasitostatic efficacy of benzimidazoles against the metacestode stage of E. multilocularis, and based on this, chemotherapy of AE in human patients has been practised since 1975. Comparison of the survival of patients on chemotherapy with that of untreated historical controls shows that the 10-year survival rate of the treated group has increased from <10% to 85-90% (1, 2, 8, 25). Increased survival rates might not only be asso- ciated with chemotherapy but also with early diagnosis, improved surgery, and medical care of the patients (26). - Indications. There are several indications for chemotherapy. 1) Chemotherapy is indicated for a limited time after radical surgery. Since residual parasite tissue may remain undetected at radical surgery, post-operative chemotherapy for at least 2 years should be carried out and patients should be monitored for a minimum of 10 years for pos- sible recurrence. 2) Long-term chemotherapy for several years is mandatory in inoperable AE pa- tients, following incomplete surgical resection of the parasite lesions and after liver transplanta- tion. 3) Presurgical chemotherapy is not indi- cated for AE. However, in cases for whom surgery was contraindicated at the time of diag- nosis, surgery can be carried out after a pro- longed course of chemotherapy. WHO Bulletin OMS. Vol 74 1996236 Guidelines for treatment of cystic and alveolar echinococcosis - Contraindications. In view of the severity of AE and the relatively low toxicity of the drugs currently used (mebendazole or albendazole), there are only a few contraindications for che- motherapy. In some instances (e.g., pregnant women) certain precautions and limitations or modifications of drug administration are neces- sary (see Annex). - Choice of anthelminthics. Two benzimidazoles (mebendazole and albendazole) are preferen- tially used for chemotherapy of AE (see Annex). Mebendazole (Vermox®, 500mg, Janssen, Bel- gium) is given as 500-mg tablets in daily doses of 40- 50mg/kg body weight (in three divided doses postprandially). After an initial continuous treat- ment of 4 weeks it is advisable to adjust the oral doses in order to obtain plasma drug levels of >250 nmol/l (74 ng/ml). In special situations the dose may be higher than the recommended amount, but a daily dose >6 g per adult patient should not be given. The duration of treatment is at least 2 years after radical surgery, or continuously for many years in inoperable cases, as well as for patients who have undergone incomplete resection or liver transplanta- tion. For some patients, mebendazole has been ad- ministered for more than 11 years (1). Albendazole (Eskazole®, SmithKline Beecham, England) is given as 500-mg tablets in daily doses of 10-15 mg/kg (in two divided doses). Repeated cycles of 28 days should be followed by a "wash out" phase of 14 days as recommended by the manufacturer. The number of necessary cycles has not yet been determined, and it is not known whether this drug can be given over periods of several years. Data from 11 Chinese patients indicate that continuous treatment with 20mg/kg body weight per day (di- vided into two doses) for 1-5 years is well tolerated (13). Praziquantel has been used for the treatment of human AE, but experimental data obtained from animal models indicate that its efficacy against the metacestode stage of E. multilocularis is far less pro- nounced than that of albendazole or mebendazole, even if it is given in very high doses. - Benefits of benzimidazole treatment. This is a noninvasive treatment with a relatively low toxic- ity. However, in most patients, benzimidazoles are only parasitostatic. - Risks of benzimidazole treatment. The main risks are neutropenia, alopecia, and liver dysfunction. Because of the potential embryotoxicity and teratogenicity (only observed in laboratory ani- mals), such treatment should not be used in women of child-bearing age, unless contraceptive measures are taken, and during the early stages of pregnancy (see Annex). - Medical requirements. Hospitalization is not needed but regular medical and laboratory checks for adverse reactions and efficacy are nec- essary. The costs of anthelmintics and of re- peated medical examinations are high. - Monitoring ofpatients. In the initial phase, moni- toring of AE patients is similar to that of CE patients. Subsequently, routine haemograms, se- rum transaminase determinations, other labora- tory tests, and ultrasound imaging of the liver should be performed at intervals of 3 months. At intervals of 6-12 months the patients should be examined in a clinical reference centre where special imaging techniques, e.g., computer- assisted tomography, can be used to monitor parasitic lesions and their response to chemo- therapy. A long-term follow-up of more than 10 years is recommended. * Interventional procedures With AE patients for whom surgery is con- traindicated, a number of local complications may occur for which interventional procedures have to be considered. Dilatation and stent implantation in ves- sels, drainage of necrotic liver lesions and/or bile, and endoscopical sclerosing of oesophageal varices are the main interventional ultrasound or endo- scopically guided procedures performed in AE. In conjunction with chemotherapy, these procedures can be beneficial for patients. - Indications. Interventional procedures are in- dicated if surgery is inadvisable because of dis- turbances of essential organ functions, i.e., hyperbilirubinaemia due to cholestasis, vena cava, or portal vein thrombosis, colliquative liver necrosis with risk of rupture into the abdomen, and bleeding of oesophageal varices secondary to portal hypertension. - Contraindications. Interventional procedures have the potential to spread parasite material and are not indicated if post-interventional chemotherapy is not possible. - Benefits. Inclusion of interventional procedures together with chemotherapy as options for treat- ment can improve the life expectancy and quality of life of patients with AE. * Liver transplantation Liver transplantation has been carried out in ap- proximately 20 patients with inoperable AE and chronic liver failure (4). Recent experience shows that regrowth of metacestode remnants and for- WHO Bulletin OMS. Vol 74 1996 237 WHO Informal Working Group mation of distant metastases may occur under immunosuppression (5). - Indications. Liver transplantation may be indi- cated, following interdisciplinary consultation, in severe AE with chronic liver failure; it requires long-term post-operative chemotherapy. - Contraindications. Liver transplantation is not indicated in extensive AE that is not confined to the liver or for patients with contraindications for prolonged immunosuppressive treatment and/or concomitant benzimidazole treatment. - Benefits. Liver transplantation can be a lifesav- ing procedure for patients with severe liver dysfunction. - Risks. These include general surgical risks, specific risks of long-term immunosuppres- sive treatment, and induction of proliferation of metacestode remnants and metastases for- mation (particularily in the brain) under immunsuppression. - Medical requirements. Liver transplantation re- quires a highly specialized team and equip- ment. Supportive medical care includes post- transplantation clinical observation, adaptation of immunosuppressive drugs, and diagnosis and management of complications of immuno- suppressive treatment under continuous chemo- therapy with benzimidazoles. Acknowledgements We are grateful to many colleagues in various countries who have supported experimental and clinical studies on the treatment of echinococcosis and to WHO for coordina- tion activities. Janssen Pharmaceutica, Beerse, Belgium, and SmithKline Beecham, Brentford, Middlesex, England, are thanked for providing considerable amounts of drugs free of charge. Resume Directives pour le traitement de I'echinococcose cystique et alveolaire chez I'homme L'6chinococcose humaine est une zoonose due aux formes larvaires (m6tacestodes) de tenias appar- tenant au genre Echinococcus, qui parasitent l'intestin grele des carnivores. Les oeufs de ces vers, excr6t6s par les carnivores, peuvent infester diverses especes d'h6tes intermediaires naturels, dont I'homme. Deux especes d'importance medicale particuliere, E. granulosus et E. multilocularis, pro- voquent respectivement l'6chinococcose cystique et l'echinococcose alveolaire chez l'homme. Etant donne l'importance de ces maladies en sant6 publique dans un grand nombre de pays, deux r6unions du groupe de travail informel OMS sur l'6chinococcose ont fait le point sur leur traite- ment. On en trouvera ci-dessous les principales conclusions. Echinococcose cystique Dans l'6chinococcose primaire, les m6tacestodes peuvent se developper dans pratiquement n'im- porte quel organe. La plupart des malades (usqu'a 80%) n'ont qu'un organe touch6 et h6bergent un kyste unique, localis6 dans le foie dans environ les deux tiers des cas, et dans les poumons chez environ 20% des cas. Traitement chirurgical. Ce traitement permet l'exerese des kystes et la gu6rison totale. 11 existe toutefois des solutions alternatives, telles que la chimioth6rapie et la technique PAIR (ponction- aspiration-injection-r6aspiration) notamment pour les kystes inop6rables et les cas a haut risque chirurgical. Le traitement chirurgical est indiqu6 dans les cas suivants: kystes hepatiques de grande taille avec nombreuses vesicules filles; kystes hepatiques uniques, de localisation superficielle et susceptibles de se rompre spontan6ment ou a la suite d'un traumatisme; kystes infect6s; kystes communiquant avec l'arbre biliaire et/ou exer,ant une pression sur les organes vitaux voisins; kystes situ6s dans les poumons, le cerveau, les reins, les os et autres organes. Le traitement chirurgical est contre-indiqu6 chez les malades porteurs de kystes multiples, de kystes difficiles d'acces, de kystes morts, de kystes partiellement ou entierement calcifi6s, et de kystes de tres petite taille. Plus l'intervention chirugicale est radicale, plus le risque op6ratoire est 61ev6, mais plus le risque de rechute est faible. Pour la destruction intra- op6ratoire des protoscolex, il n'existe pas de protoscolicides a la fois efficaces et sans danger, mais des produits comme l'6thanol a 70-95%, le solute hypertonique a 15-20% ou une solution de cetrimide a 0,5% sont efficaces et relativement peu toxiques. Le traitement preop6ratoire par des benzimidazoles ramollit les kystes, ce qui entraine une baisse de la pression intrakystique et facilite l'evacuation chirurgicale de l'endokyste. PAIR. L'utilisation de la PAIR pour traiter I'echino- coccose cystique comporte les 6tapes suivantes: ponction des kystes par voie percutan6e, sous guidage 6chographique; aspiration d'une quantit6 WHO Bulletin OMS. Vol 74 1996238 Guidelines for treatment of cystic and alveolar echinococcosis importante de liquide hydatique; injection de sub- stances protoscolicides (solution de chlorure de sodium a 20% ou mieux d'ethanol a 95%) pendant au moins 15 minutes; r6aspiration du contenu du kyste. Cefte technique est indiquee pour les malades inop6rables et ceux qui refusent l'inter- vention chirurgicale, et peut etre utilis6e pour le traitement des kystes localises dans le foie, la cavit6 abdominale, la rate, les reins et les os. Elle peut aussi etre utilis6e en cas de rechute apres traitement chirurgical ou en cas d'6chec de la chimioth6rapie, mais est contre-indiqu6e lorsque les kystes hepatiques sont inaccessibles ou super- ficiels et en cas de kystes cloisonnes. Un traitement de quatre jours par les benzimidazoles est obliga- toire avant toute PAIR et doit etre poursuivi pendant un mois (albendazole) ou 3 mois (m6bendazole) apres l'intervention. Cette technique est tres peu invasive et comporte moins de risques que la chirurgie. Chimiotherapie Plus de 1000 cas bien document6s d'echino- coccose cystique ont ete traites jusqu'a pr6sent par les benzimidazoles. La chimiotherapie est indiqu6e pour les malades inop6rables pr6sentant une echinococcose primaire du foie ou du poumon et pour les porteurs de kystes multiples dans deux ou plusieurs organes, et de kystes p6riton6aux. La chimiotherapie est 6galement indiquee dans la prevention de l'6chinococcose secondaire. L'utilisa- tion pr6chirurgicale des benzimidazoles (ABZ et MBZ) peut r6duire le risque de rechute de l'6chino- coccose cystique et/ou faciliter l'intervention en abaissant la pression intracystique. Comme on l'a vu, une chimiotherapie concomitante est egalement recommand6e avec la technique PAIR. La chimio- therapie est contre-indiqu6e en cas de kystes de grande taille pr6sentant un risque de rupture (principalement les kystes superficiels et infect6s) et en cas de kystes inactifs ou calcifi6s. Le debut de grossesse constitue 6galement une contre- indication. Pour le traitement de l'6chinococcose cystique, la dose habituelle d'albendazole est de 10-15mg/ kg par jour en plusieurs cures d'un mois separees par un intervalle de 14 jours. Toutefois, le traitement continu est plus efficace lorsqu'il est administr6 sur trois a six mois ou plus, et n'entraine pas plus d'effets ind6sirables. La dose orale habituelle de m6bendazole est de 40 a 50 mg/kg par jour. Les effets ind6sirables des benzimidazoles consistent en hepatotoxicit6, neutropenie, thrombo- cytopenie et alopecie et leur utilisation comportent des risques potentiels d'embryotoxicit6 et de t6rato- g6nicit6. 11 est necessaire de proceder a un examen m6dical et a des analyses de laboratoire pour rechercher ces effets, toutes les deux semaines en debut de traitement puis une fois par mois. Echinococcose alveolaire L'6chinococcose alv6olaire est une maladie tres grave due aux m6tacestodes d'E. multilocularis et se caract6rise par une croissance infiltrante evoquant une tumeur. Le traitement comporte plusieurs options, dont la chimiotherapie, et exige une exp6rience clinique specifique. Au d6but, les metacestodes d'E. multilocularis se d6veloppent presque exclusivement dans le foie, puis ils tendent a gagner les autres organes par infiltration ou formation de m6tastases. Les cas d'6chinococcose alv6olaire se carac- terisent par une incubation silencieuse durant au moins 5 a 15 ans, puis 6voluent sur le mode chronique. Les principaux sympt6mes consistent en ictere cholestatique et/ou douleurs epigas- triques. Non trait6e ou insuffisamment trait6e, la maladie entraine une forte mortalite. Le traitement de l'6chinococcose alv6olaire repose actuellement sur les principes gen6raux suivants: * La premiere option, dans tous les cas op6rables, est l'ex6rese chirurgicale radicale de la l6sion parasitaire dans le foie et les autres organes touch6s. * Une chimioth6rapie de dur6e limit6e est indiqu6e apres ex6rese radicale. En revanche, une chimio- therapie prechirurgicale n'est pas indiquee dans le cas de 1'echinococcose alv6olaire. * Une chimioth6rapie de longue duree est obliga- toire apres ex6rese incomplbte des lesions, chez les malades inop6rables et chez les malades ayant subi une transplantation h6patique. Chimiotherapie. Le m6bendazole est administr6 en comprim6s dos6s a 500mg a raison de doses quotidiennes de 40-50 mg/kg de poids corporel (r6parties en 3 prises, apres les repas). Apres traitement initial continu de quatre semaines, il est conseille d'ajuster les doses orales afin d'obtenir un taux plasmatique >250 nmol/I (74 ng/ml). Le traite- ment doit etre poursuivi pendant au moins deux ans apres ex6rese radicale, et en continu pendant un grand nombre d'ann6es dans les cas inoperables. L'albendazole est administr6 en comprim6s dos6s a 500mg en doses quotidiennes de 10- 15mg/kg (en deux prises). Chaque cycle de traitement de 28 jours sera suivi d'une phase WHO Bulletin OMS. Vol 74 1996 239 WHO Informal Working Group d'6limination de 14 jours, comme le recommande le fabricant. Le nombre de cycles n6cessaires n'a pas encore ete d6termin6. Au d6but du traitement, la surveillance des malades est identique a celle des cas d'6chinococcose cystique. Tous les six a douze mois, les malades seront examin6s dans un centre de r6f6rence clinique, au moyen de techniques dcimagerie sp6cialis6es. Chirurgie. La lesion parasitaire devra etre excis6e suivant les techniques de l'ex6rese radicale des tumeurs. Que l'ex6rese soit radicale ou non, une chimioth6rapie concomitante est indispensable. 11 n'est pas toujours possible de d6finir claire- ment les l6sions par les techniques d'imagerie. Une r6section incomplete laisse des fragments invisibles de tissus parasitaires susceptibles de se deve- lopper a nouveau et de se disseminer dans les autres organes, parfois au bout de plusieurs ann6es. Transplantation hepatique. La transplantation h6pa- tique peut etre indiqu6e dans les cas graves d'echinococcose alveolaire avec insuffisance hepa- tique chronique. Elle exige une chimiotherapie postoperatoire de longue duree. Elle n'est pas indiqu6e en cas d'echinococcose alv6olaire 6ten- due, non limit6e au foie, et chez les malades pour lesquels un traitement immunod6presseur prolonge et/ou un traitement concomitant par le ben- zimidazole sont contre-indiqu6s. La transplantation h6patique exige une equipe chirurgicale et un mat6riel hautement sp6cialis6s. References 1. Ammann R, Eckert J. Clinical diagnosis and treat- ment of echinococcosis in humans. In: Thompson RCA, Lymbery AJ, eds. Echinococcus and hydatid disease. Oxon., CAB International, 1995: 411-463. 2. Ammann R, Eckert J. Cestodes: echinococcus. Gas- troenterology clinics of North America, (in press). 3. Ben Amor N et al. Treatment of a case of parietal hydatid cyst by puncture. Joumal Belge de radiologie, 1987, 70: 333-336. 4. Bresson Hadni S et al. Orthotopic liver transplanta- tion for incurable alveolar echinococcosis of the liver: report of 17 cases. Hepatology, 1991,13:1061-1070. 5. Bresson Hadni S et al. Recurrence of alveolar echinococcosis in the liver graft after liver transplanta- tion (letter). Hepatology, 1992, 16: 279-280. 6. Davis A et al. Multicentre clinical trials of ben- zimidazole carbamates in human echinococcosis. Bulletin of the World Health Organization, 1986, 64: 383-388. 7. Davis A et al. Multicentre clinical trials of benzimidazole carbamates in human cystic echinococcosis (phase 2). Bulletin of the World Health Organization, 1989, 67: 503-508. 8. Eckert J. Prospects for treatment of the metacestode stage of Echinococcus. In: Thompson RCA, ed. The biology of echinococcus and hydatid disease. London, Allan & Unwin, 1986; 250-284. 9. Eckert J et al. Medical aspects of echinococcosis. Parasitology today, 1995, 11: 273-276. 10. Filice C et al. A new therapeutic approach for hydatid liver cysts. Aspiration and alcohol injection under sonographic guidance. Gastroenterology, 1990, 98: 1366-1368. 11. Gargouri M et al. Percutaneous treatment of hydatid cysts (Echinococcus granulosus). Cardiovascular and interventional radiology, 1990, 13: 169-173. 12. Gharbi HA et al. Ultrasound examination of the hydatid liver. Radiology, 1981, 139: 459-463. 13. Liu YH et al. Computer tomography of liver in alveolar echinococcosis treated with albendazole. Transac- tions of the Royal Society of Tropical Medicine and Hygiene, 1993, 87: 319-321. 14. Kammerer WS, Schantz PM. Echinococcal disease. Infectious disease clinics of North America, 1993, 7: 605-618. 15. Morris DL, Richards KS. Hydatid disease. Current medical and surgical management. Oxford, Butterworth Heinemann, 1992. 16. Pawlowski ZS. Critical points in the clinical manage- ment of cystic echinococcosis. In: Andersen FL, Chai J, Liu F, eds. Compendium on cystic echinococcosis with special reference to the Xinjiang Uygur Autono- mous Region of the People's Republic of China. Provo, UT, Brigham Young University, 1993: 119- 131. 17. Schantz PM et al. Epidemiology and control of hydatid disease. In: Thompson RCA, Lymbery AJ, eds. Echinococcus and hydatid disease. Oxon., CAB International, 1995: 233-331. 18. Teggi A et al. Therapy of human hydatid disease with mebendazole and albendazole. Antimicrobial agents and chemotherapy, 1993, 37: 1679-1684. 19. Teggi A et al. Increase of serum glutamic-oxaloacetic and glutamic-pyruvic transaminases in patients with hydatid cysts treated with mebendazole and albendazole. Mediterranean journal of infectious and parasitic diseases, 1995, 10: 85-90. 20. Thompson RCA. Biology and systematics of Echinococcus. In: Thompson RCA, Lymbery AJ, eds. Echinococcus and hydatid disease. Oxon., CAB Inter- national, 1995: 1-50. 21. Todorov T et al. Chemotherapy of human cystic echinococcosis: comparative efficacy of mebendazole and albendazole. Annals of tropical medicine and parasitology, 1992, 86: 59-66. 22. Uchino J, Sato N. Alveolar echinococcosis of the liver. Sapporo, Japan, Hokkaido University School of Medicine, 1993. 23. Wang XZ et al. [Clinical treatment of hepatic and abdominal hydatid cyst by percutaneous puncture, drainage and curretage]. Chinese journal of parasitol- ogy and parasitic diseases, 1994, 12: 285-287 (in Chinese). 240 WHO Bulletin OMS. Vol 74 1996 Guidelines for treatment of cystic and alveolar echinococcosis 24. Wen H et al. Diagnosis and treatment of human hydatidosis. British joumal of clinical pharmacology, 1993, 35: 565-574. 25. Wilson JF et al. Parasiticidal effect of chemotherapy in alveolar hydatid disease: review of experience with mebendazole and albendazole in Alaskan Eskimos. Clinical infectious diseases, 1992, 15: 234-249. 26. Vuitton DA et al. The natural history of alveolar echinococcosis in patients before and after the era of benzimidazoles. In: Uchino J, ed. Proceedings of the Intemational Symposium on Alveolar Echinococcosis: Strategy for Eradication of Alveolar Echinococcosis of the Liver. Sapporo, Hokkaido University Press (in press). Annex Characteristics of benzimidazoles * Mebendazole is poorly absorbed (<10%) after oral administration. The rate of absorption is in- creased (up to 8-fold) if the drug is taken during a meal, especially one with a high fat content. After oral administration of standard doses, serum drug levels are highly variable among individuals and are not correlated with the doses given. In blood plasma >90% of the drug is protein-bound. Based on data from animal experiments, the serum drug concentra- tions required for effective chemotherapy are esti- mated to be >250nmol/I (74ng/1). However, several studies have shown that such serum levels may not be attained by more than 30% of patients and that lower (as yet undetermined) levels may be sufficient for long-term therapy. Mebendazole is rapidly me- tabolized in the liver and excreted via urine and bile. The elimination half-life times are short (2.5-5.Oh) and may be increased in patients with cholestasis and other disturbances of liver function. Serum mebendazole concentrations 4h after the morning dose have a high degree of predictability for the 24- h average serum concentrations, and the 4-h value has therefore been proposed for monitoring serum drug levels. * Albendazole has similar pharmacokinetic proper- ties to mebendazole with low absorption rates and high interindividual variability of serum drug levels that may lie in the range 200-6000nmol/l; average values are 1000-2000 nmol/l (albendazole sulfoxide). Serum drug levels are higher in patients with cholestasis and other liver dysfunctions, and intesti- nal absorption rates are increased by fatty sub- stances. The mean half-life elimination time in 14 persons was 8.5 h (SD, 6.0). The effective serum drug levels are not well defined; based on data from animal experiments, they are estimated to be 650- 3000nmol/l. * Drug efficacy. MBZ and the main metabolite of ABZ, albendazole sulfoxide, have antiparasitic properties. Animal experiments have shown that long-term treatment with benzimidazoles has the following effects against E. multilocularis metacestodes: in- hibition of metacestode proliferation, resulting in reduction of parasite masses; destruction of protoscolices and partial destruction of the germinal layer and of the cystic structure of the metacestode; prevention or suppression of metastasis formation; calcifications; and prolongation of host animal survival. Long-term animal studies have shown that E. multilocularis metacestodes are normally not killed by drug treatment but that their proliferation is in- hibited. The effect of the drugs in animals is there- fore not parasiticidal but parasitostatic. On the other hand, E. granulosus cysts may be killed by long-term benzimidazole treatment. * Adverse reactions. MBZ and ABZ are generally well tolerated and adverse reactions are relatively mild. Examples of such reactions from two larger series are presented below. - Adverse reactions in 70 patients with alveolar echinococcosis under long-term chemotherapy (mean duration, 6.5 years. No. of patients treated: MBZ: 61, ABZ: 4, MBZ/ABZ: 5) (1): elevation of transaminases (27%); proteinuria (21%); loss of hair (18%); gastrointestinal distur- bances (16%); neurological symptoms (e.g., ver- tigo) (11%); and leukopenia (6%). - Adverse reactions associated with albendazole treatment of 780 patients with cystic echi- nococcosis. (The duration of treatment is gener- ally shorter than that for alveolar echinococcosis (J. Horton, personal communication, 1994): el- evation of transaminases (14.7%); abdominal pain (5.7%); loss of hair (2.8%); headache (2.1%); abnormal liver biopsy (1.7%); vertigo/ dizziness (1.3%); nausea (1.3%); fever (1.2%); reversible leukopenia (1.2%); abdominal disten- sion (0.6%); urticaria (0.5%); jaundice (0.5%); thrombocytopenia (0.3%); allergic shock (0.3%); bone marrow toxicity (0.1%); and cyst pain (0.1%). Two-thirds of the patients experienced one or more side-effects, but they were mostly of minor importance and reversible. Only in rare instances was permanent discontinuation of chemotherapy in- dicated. Allergic reactions may also occur. Monitor- ing of serum drug levels is mandatory to avoid severe adverse reactions. WHO Bulletin OMS. Vol 74 1996 241 WHO Informal Working Group * Precautions. Patients with CE or AE under chemotherapy should be carefully monitored. * Pregnancy and nursing. Under certain conditions MBZ and ABZ may induce embryotoxic or teratogenic effects in animals. Although such effects have not been observed in humans, it is recom- mended that use of these drugs be avoided for preg- nant women, to postpone chemotherapy until after delivery, or to use the drugs only in urgent cases in the second or third trimester after a careful risk analysis. For women of child-bearing age, contra- ceptive measures are indicated during treatment. Experience with MBZ or ABZ treatment during breast-feeding does not appear to put the infant at risk of side-effects. * Liver disturbances. For patients with cholestasis or hepatocellular disturbances, the drug doses may have to be reduced. Such patients require frequent monitoring of liver function parameters and of serum drug levels, especially those with chronic cholestasis and portal hypertension. * Diabetes. Mebendazole may reduce insulin re- quirements; therefore, the serum glucose bood levels of diabetics receiving this drug must be carefully monitored. WHO Bulletin OMS. Vol 74 1996242