Review Article Clinical Management of Cystic Echinococcosis: State of the Art, Problems, and Perspectives

Thomas Junghanss, Antonio Menezes da Silva, John Horton, Peter L. Chiodini, and Enrico Brunetti* Section of Clinical Tropical Medicine, University Hospital Heidelberg, Heidelberg, Germany; Serviço de Cirugia Geral e Digestiva, Hospital de Pulido Valente, Lisbon, Portugal; Tropical Projects, Hitchin, United Kingdom;Department of Clinical Parasitology, Hospital for Tropical Diseases, London, United Kingdom; Division of Infectious and Tropical Diseases, University of Pavia, IRCCS S. Matteo Hospital Foundation, Pavia, Italy

Abstract. Clinical management of cystic echinococcosis (CE) has evolved over decades without adequate evaluation of important features such as efficacy, effectiveness, rate of adverse reactions, relapse rate, and cost. CE occurs in health care environments as different as Europe/North America and resource-poor countries of the South and the East. This creates setting-specific problems in the management of patients. Furthermore, studies carried out in either of the two fundamentally different environments lack external validity, i.e., results obtained in one setting may be different from those in the other and practices that can work in one may not be applicable to the other. In this paper, we review the current management procedures of CE with particular emphasis on the evidence base and setting-specific problems.

INTRODUCTION dures of CE with particular emphasis on the evidence base and setting-specific problems. Cystic echinococcosis (CE) is among the most neglected parasitic diseases. Development of new drugs and other treat- MATERIALS AND METHODS ment modalities receives very little attention, if any, and is Papers covering the subject were obtained by a Medline slow.1,2 Clinical management procedures have evolved over search of the literature published in English on this subject. decades without adequate evaluation of important features Key words were “Echinococcal cysts,” “hydatid cysts,” “cystic such as efficacy, effectiveness, rate of adverse reactions, re- echinococcosis,” “hydatidosis,” “hydatid,” “surgery,” “thia- lapse rate, and cost. bendazole,” “flubendazole,” “mebendazole,” “albendazole,” CE occurs in health care environments as different as Eu- “praziquantel,” “chemotherapy,” “PAIR,” “percutaneous rope/North America and resource-poor countries of the treatment,” “percutaneous drainage,” and “ultrasound.” Pa- South and the East. This creates setting-specific problems in pers published from 1970 to 2007 were included. The authors’ the management of patients: files were used as well. For each treatment modality, grade 3 1) In most developed countries, CE is an imported disease of and strength of the evidence is given. very low incidence and prevalence and is found almost IMAGING-BASED APPROACH exclusively in migrants from endemic regions. It thus meets the criteria of an orphan disease. As with all rare The advent of modern imaging techniques, in particular diseases two distinct subgroups are seen: ultrasound, represented a breakthrough in the diagnosis, a) Mismanaged patients because of lack of experience in treatment, and follow-up of patients with CE. With this new the health institutions where they present. tool at hand, clinicians have been striving for an imaging- b) Patients treated in centers with a special interest in CE. based classification of CE cysts for the past 25 years4–6 and to Here patients benefit from an exceptional concentra- correlate individual cyst stages with the natural history and tion of clinical experience and high technological diag- treatment-induced involution processes of the cysts. nostic and treatment facilities. Two classifications are most frequently used: the Gharbi 2) In endemic regions, predominantly settings with limited and the WHO Informal Working Group on Echinococcosis resources, patient numbers are high and medical doctors (IWGE) classification (Table 1). As shown in Table 1, the are very familiar with the disease. Whole communities do WHO classification is almost the same as Gharbi’s, with not have access to appropriate treatment, however. The Gharbi type II corresponding to CE3a and vice versa. How- choice of treatment modalities is limited because of poor ever, there are two important additions in the WHO classifi- infrastructure and shortage of equipment and drugs. In cation: the predominantly solid cyst with daughter cysts, this context, CE meets the criteria for a neglected disease. which was not explicitly included in Gharbi’s classification, has been found a place in the CE3 slot, and the types are now Furthermore, studies carried out in either of the two funda- grouped according to their biological activity (Table 1; far mentally different environments lack external validity (i.e., right column). This has important consequences for treatment results obtained in one setting may be different from those in decisions, as we will detail in the paper. Last but not least, the the other and practices that can work in one may not be WHO classification was the first to be proposed as the result applicable to the other). of the combined efforts of a group of experts, including In this paper, we review the current management proce- Gharbi himself. Controversies still exist about the natural history of the cyst and whether WHO numbering of cysts types 7,8 * Address correspondence to Enrico Brunetti, Division of Infectious appropriately reflects this. An internationally accepted, and Tropical Diseases, IRCCS S. Matteo Foundation, University of standardized classification system is of paramount importance Pavia, Via Taramelli 5, 27100 Pavia, Italy. E-mail: [email protected] for uniform guidelines and comparison of data. 301 302 JUNGHANSS AND OTHERS

TABLE 1 Ultrasound classification of echinococcal cysts Gharbi 1981 WHO IWGE 2001 Image Description Stage Type I CE1 Unilocular unechoic cystic lesion with double Active line sign

Type III CE2 Multiseptated, “rosette-like”“honeycomb” cyst

Type II CE3 A Cyst with detached membranes (water-lily-sign) Transitional

Type III CE3 B Cyst with daughter cysts in solid matrix

Type IV CE4 Cyst with heterogenous hypoechoic/hyperechoic Inactive contents. No daughter cysts

Type V CE5 Solid plus calcified wall

Comparison of the Gharbi and WHO ultrasound classifications of echinococcal cysts. A distinction between CE3a and CE3b is expressly made by the authors of this review on grounds of clinical response to PAIR and albendazole. Recent papers and our unpublished experience report that CE3b has a higher rate of relapses. With recent observations of high relapse rates in PAIR-treated CE3b cysts (see section on PT), other PTs should be explored for this cyst type. CE 3b also seems to respond poorly to albendazole (we thank Dr. W. Hosch, Department of Radiology, University Hospital Heidelberg, for contributing images in the table). WHO CE3b has not been explicitly described by Gharbi. CE3b might be classified as type III, although in the original Gharbi paper, there was no distinction between multivesiculated (honeycomb-like) cysts and cysts with daughter cysts in solid matrix. CLINICAL MANAGEMENT OF CYSTIC ECHINOCOCCOSIS 303

TREATMENT MODALITIES CURRENTLY IN USE with or without hepatic or lung resection. Peripherally located lung cysts of any size and small- to medium-sized centrally Surgery. For many years, surgery has been the only treat- located cysts can be excised without sacrificing lung paren- ment available for CE. Surgical procedures range from simple chyma. Standard radical procedures are wedge resection of puncture and aspiration of cyst content to partial resection of lung parenchyma of less than one segment, and for liver and the affected organ. We discuss here surgery of the liver and lung cysts, segmentectomy and lobectomy. Total cystectomy lungs, the two most frequently affected organs: 70% and 20%, is the ideal procedure25 to reduce complication and relapse respectively. The most common technique is total or partial rates. It can be performed by an open or a closed method cystectomy. Although surgical techniques have improved, (Napalkoff) and under videosurgery.22 With the small series there is considerable controversy as to what is the most ef- of laparoscopically treated patients available in the literature, fective technique, the role of cyst aspiration and external it is impossible to draw conclusions regarding comparison drainage, hepatic and lung resection, management of the re- with open surgery.26–28 Hepatic resection and lung segment- sidual cavity in CE of the liver, cyst recurrence after surgery, ectomy/lobectomy are rarely performed.14,29 Radical proce- and high rates of complications and mortality related to re- dures bear greater intraoperative risks, with less postopera- 9–14 operation in recurrent disease. An immediate cure is tive complications and relapses.9,10,15,25,30 Conservative pro- claimed for surgical treatment of liver cysts, but even with cedures are preferred for lung cysts, with radical procedures radical procedures, this is far from being achieved, with mor- such as segmentectomy and lobectomy necessary for ex- bidity, mortality, and relapse rates of 32%, 8%, and 20%, tended parenchymal involvement severe pulmonary suppura- 9,10,15 respectively. For surgery of lung cysts, reported morbity tion and complications such as pulmonary fibrosis, bron- ranges between 0% and 13% and mortality rates between 0% chiectasis, or severe hemorrhage13,14 [strength of recommen- 12,14,16–18 and 5%. dation: B, quality of evidence: II]. With alternative treatment modalities advancing, it is per- Adjunctive treatment. There is some evidence for the fol- tinent to clarify the current position of surgery among other lowing adjunctive measures to play a useful role. options.11,13,14,19 In patients with complicated cysts (rupture, cysto-biliary and most cases of cysto-bronchial fistulas, com- 1) Prevention of secondary CE and relapses pression of vital organs and vessels, hemorrhage, secondary a) Albendazole—starting 1 week before surgery and con- bacterial infection), surgery maintains its place as the treat- tinuing to up to 3 month after surgery.13,31–33 There is ment of choice. In uncomplicated liver cysts, surgery is in- no uniform recommendation, however, and the efficacy creasingly being replaced with other treatment options (per- is not known [strength of recommendation: B, quality cutaneous treatment in liver cysts, chemotherapy, watch and of evidence III] (Tables 5 and 6). wait) depending on the stage of the cyst. This is, however, not b) Surgical field protection with pads soaked with scoli- based on appropriate comparative prospective clinical trials cidal agents9,14,30,34 [strength of recommendation B, with long-term follow-up. The uncertainties of making the quality of evidence III] (Tables 5 and 6). right treatment choice on the basis of current evidence are 2) Prevention of cholangitis further highlighted by recently reported complications after a) In liver cysts, if deroofing is performed, search for cis- medical treatment of lung cysts with rupture into the bron- tobiliary fistulae, bile-stained fluid content, determina- chial tree, expulsion of its content, or, especially with large tion of bilirubin in the aspirated fluid, and anterograde cysts, rupture into the thoracic cavity and subsequent second- cholangiography if necessary [strength of recommenda- ary CE. These complications require surgical intervention, tion B, quality of evidence III] (Tables 5 and 6). which is burdened with its own set of serious complications, b) Strictly avoiding injection of scolicidal solution into such as empyema and lung abscess.20 Similar observations cysts that communicate with the biliary or bronchial have been made in patients with liver cysts treated with al- tree (cysto-biliary and cysto-bronchial fistulas).13,35–37 bendazole and rupture of the endocyst into the biliary tree 3) Management of the residual cavity during treatment (Junghanss, personal observations). a) Ideally, cysts are completely removed to avoid residual Surgical procedures. The most commonly used procedures cavities. This prevents suppuration, reduces the risk of can be divided in conservative and radical. biliary or bronchial fistulas, and achieves faster healing Conservative procedures aim at sterilization and evacua- and shorter hospital stay38–40 [strength of recommen- tion of cyst content, including the hydatid membrane (hydati- dation B, quality of evidence III] (Tables 5 and 6). dectomy), and partial removal of the cyst. The evacuation and b) When hydatidectomy or partial or subtotal cystectomy the hydatidectomy consists of puncture of the cyst and aspi- is performed, the residual cavities need attention. In ration of part of the content, to permit introduction of the liver cysts, simple drainage with suction and filling with scolicidal agent, and total aspiration thereafter. The risks are epiploon (omentoplasty) are options to reduce the risk anaphylactic shock,21,22 chemical cholangitis or alveolar/ of complications.39 In lung cysts, the residual cavity can bronchial damage, if the cyst communicates with the biliary or be obliterated by capitonnage using multiple purse- bronchial tree,23,24 and spillage of the cyst contents and sec- string sutures from the deepest level to surface ondary hydatidosis, with relapse rates of up to 20% being level13,14 [strength of recommendation B, quality of reported after surgery of liver cysts25 and up to 11.3% for lung evidence III] (Tables 5 and 6). cysts.13 After partial removal of the cyst, a residual cavity Risk, benefit, and safety profile. The principal advantage of remains, bearing the risk of secondary bacterial infection and cyst resection is the immediate cure of the disease. For he- abscess formation.25 [strength of recommendation: B, quality patic cysts, the more radical the intervention, the higher the of evidence: II] (see Tables 5 and 6). intraoperative risk and the lower the frequency of relapse, Radical procedures aim at complete removal of the cyst and vice versa in the more conservative approach.41 From 304 JUNGHANSS AND OTHERS current evidence, conservative surgery seems preferable for Risk, benefit, and safety profile. The major risks of percu- most lung cysts. Only in extensive lung disease is radical sur- taneous techniques are anaphylactic shock, secondary echi- gery given preference. nococcosis caused by spillage of cystic fluid, and chemical Percutaneous treatment. Percutaneous treatment of ab- cholangitis caused by contact of the scolicidal agent with the dominal CE was introduced in the mid-1980s.42 Initially re- biliary tree. It is imperative to have resuscitation measures in ceived with skepticism by some, it developed into an attrac- place, to choose a safe approach to the cyst, and to give peri- tive alternative to surgery and benzimidazole derivatives for interventional prophylaxis with benzimidazoles and to ex- certain cyst stages. clude communications with the biliary tree before injection of These treatment modalities aim to destroy the germinal any scolicidal agent. layer with scolicidal agents or to evacuate the entire endocyst. No systematic evaluation of side effects of the various per- Destruction of the germinal layer: PAIR. Historically, the cutaneous techniques has been undertaken thus far, with the first percutaneous treatment used was to puncture the cyst, exception of two preliminary reviews.48,57 aspirate cyst fluid, inject a scolicidal agent, and re-aspirate the Ninety-six publications reporting on percutaneous drainage 43,44 cyst content (PAIR). of 4,209 cysts in 3,005 patients were screened.48 One hundred 43,44 The classic PAIR technique is widely known. Several sixty-six cysts were punctured for diagnosis and 4,043 for series with minor variations of the essential steps have been treatment. Major and minor complications are listed in Table published.45–47 The technique is increasingly being used as 48 2. The references used are cited in ref. 48. documented in the literature. However, as with all other The statistics of the pooled data from published studies in treatment modalities of CE, systematic appraisal is far from Table 2 must be interpreted carefully. No information was satisfactory.49 available on 213 cysts in 19 studies, and heterogeneity of stud- Only two randomized clinical trials are available.50,51 Most ies limits the usefulness of such statistics. Publication bias is of studies lack sufficiently long follow-up periods to assess the particular concern, because adverse outcomes tend to remain long-term relapse rate. Three studies cover ∼3 years46,52,53 unpublished. With major life-threatening complications (e.g., and two other studies cover 4 years of follow-up.27,54 anaphylactic shock), details of the circumstances of fatal out- Khuroo and others51 found PAIR combined with peri- come need to be known to avoid discrediting a promising interventional benzimidazole derivatives to be as effective as technique58 for reasons that are setting specific. The setting in open surgical drainage with fewer complications and less cost. which PAIR can be performed safely needs to be defined. A recent paper from Turkey reported a single-center experi- Secondary echinococcosis as a result of spillage of fluid was ence comparing surgery, laparoscopic surgery, and percuta- not mentioned in any of the 96 studies reviewed. It is unclear neous treatments in 355 patients over a period of 10 years and whether this is because of spillage-free puncture, albendazole concluded that PAIR is an effective and safe option.27 prophylaxis, or underreporting because of incomplete follow- Giorgio and others54 showed that PAIR of multivesiculated up regarding length and imaging techniques used. cysts does not allow complete healing (solidification, i.e., pro- Safety and efficacy of percutaneous treatments is also re- gression to stages CE4 or CE5), and in 30% of cases resulted lated to the anatomical site of the cyst. Percutaneous treat- in an intracystic recurrence that required up to four repeat ment is mostly used in liver and extrahepatic abdominal cysts, procedures. including peritoneal. Cysts in other locations have also been Smego and others55 conducted a meta-analysis across 21 approached (Table 3), particularly when other methods have studies made up of 769 patients with 1,072 hepatic cysts un- failed. Some sites are intrinsically difficult to treat. For ex- dergoing PAIR and compared the findings with 952 era- ample, percutaneous puncture of spinal and paraspinal cysts matched surgically treated historical controls. They claimed have failed at long-term follow-up. It is well known that cysts that the rate of clinical and parasitologic cure was greater in in these sites are difficult to cure when radical surgery is not patients receiving PAIR plus chemotherapy than in those re- feasible.59 ceiving surgery. Disease recurrence, major complications A much less well-evaluated percutaneous technique to de- (anaphylaxis, biliary fistulas, cyst infection, liver/intra- stroy the germinal layer by means of high temperature is abdominal abscesses, and sepsis), minor complications, and radiofrequency (RF) thermal ablation. This procedure uses death occurred more frequently among patients treated with the same needle electrodes that are used for local treatments surgery than among patients treated with PAIR. The mean durations of hospital stay were 2.4 days for patients treated with PAIR and 15.0 days for the surgical control group. Such results are interesting but suffer from the same flaws TABLE 2 plaguing the studies that have been subjected to meta-analysis Complications and recurrences of percutaneous treatments 1983– (small series, retrospective, overlapping of patients in subse- 2004 quent publications, short follow-up, etc.).49 No. punctured No. of Percent cysts events complications Giorgio and others54 and Kabaalioglu and others56 reported repeated failures of PAIR in multivesiculated cysts Deaths caused by anaphylactic shock 4209 2 0.047 (CE2 and CE3B). These findings prompted most clinicians to Major complications* 4209 16 0.38 use PAIR exclusively for unilocular cysts, with or without Minor complications† 4043 268 6.62 detached endocysts. For this reason, CE2 and CE3b cysts are Recurrence‡ 3830 49 1.27 now preferably treated with cutting devices and large bore * Major complications were death, anaphylactic shock, chemical cholangitis, and secondary echinococcosis caused by spillage. catheters, which are more effective (see below) [strength of † Minor complications (detailed in text) were calculated only on cysts punctured for recommendation: A/B, quality of evidence: I/II] (Tables 5 therapeutic reasons. ‡ Rate of recurrence is calculated only on cysts punctured for therapeutic purpose. Data and 6). on recurrence unavailable for 213 cysts. CLINICAL MANAGEMENT OF CYSTIC ECHINOCOCCOSIS 305

TABLE 3 These complications prolonged hospitalization from 11.5 Anatomical location of cysts undergone percutaneous treatment (range, 8–14 days) to 72.3 days (range, 28–128 days). 68 Location of cysts punctured Number Percentage Recently, Akhan and others used a MoCaT to treat six Liver 2,278 54.1 echinococcal cysts of the muscle. The mean catheterization Lung 19 0.4 time was 13.7 days (range, 1–54 days). An average of 96.1% Kidney 23 0.54 volume reduction was obtained. No sign of re-activation was Spleen 21 0.5 observed during the mean follow-up period of 34.8 months Pancreas 4 0.09 Abdomen (peritoneal) 1,636 38.86 (range, 6–57 months) [strength of recommendation: C, quality Thyroid 3 0.07 of evidence: III] (Tables 5 and 6). Parotid 1 0.023 Medical treatment. During 1984–1986, the World Health Retrorbital 1 0.023 Organization took an early initiative and established two mul- Spine 7 0.16 ticenter studies in Europe to directly compare albendazole Breast 4 0.09 69 Soft tissues, muscle 12 0.28 and mebendazole, using a single standard protocol. Because Miscellaneous (thorax, bone, soft tissues, the available methods for following patients were limited at thyroid, breast, spine) 168 3.4 the time, the results were basic. The important finding was Not available 32 0.7 that, based on clinical outcome and in a limited number of patients, the two drugs look very similar. The differences lie in the longer duration of treatment and higher doses required of hepatocellular carcinomas. The experience with RF is still using mebendazole. very limited, however,60,61 and preliminary reports are rather The interest in investigating medical therapy of CE, facili- disappointing because nearly all the cysts treated relapsed tated by the increasing availability of ultrasound and a better after a few months.62 understanding of imaging features reflecting involution, re- Other percutaneous techniques. These are generally resulted in a series of clinical trials that made use of this new served for cysts that are difficult to drain or tend to relapse modality to evaluate the effect of medical treatment more after PAIR (multivesiculated cysts or cysts with predomi- objectively. Within 5 years, it was possible to analyze the data nantly solid content and daughter cysts). They are based on of a series of 253 patients with 456 cysts70 (Table 4). These the aspiration of the “solid” content of the cyst, the germinal data were used for SmithKline and French (now GlaxoSmith- and the laminated layer, through a large-bore catheter or Kline) to submit a license application for use of albendazole device. Two types of approaches are currently in use: the for CE in Europe. Although the evidence base was very lim- catherization technique63 and the modified catherization ited, the registration tended to standardize treatment, using techniques, in particular PEVAC (percutaneous evacuation) three cycles of 1 month with a break of 14 days between MoCaT (modified catheterization technique), and DMFT (di- courses, required because of the limited long-term toxicity latable multi-function trocar) (see below) [strength of recom- data available. It did not prevent some groups from continu- mendation C, quality of evidence III] (Tables 5 and 6). ing to use other regimens, however, and as a result, data have A large-bore cutting-aspiration device was used by Saremi also accumulated on continuous treatment, especially by and McNamara64 in 32 patients to fragment and evacuate Teggi and others in Rome.71 daughter cysts and the laminated membrane. A 2-year follow- In recent years, the question of treatment duration has up showed a high rate of success (90%) and a low incidence been investigated retrospectively in large series constructed of major complications (3%). by Horton72 that extended the data set produced 12 years Another group65 treated 699 multivesiculated abdominal earlier (Table 4). With larger numbers, it was possible to show cysts with a device called DMFT. This is linked to an aspira- that the number of patients showing evidence of clinical or tion apparatus to extract the endocyst, daughter cysts, and ultrasonographic/radiologic improvement (evidence of drug other cystic contents. Thereafter, the cavity is irrigated with effects on the cysts) increased with longer durations of treat- 10–20% saline, and, if necessary, curettage is done. The cath- ment, whereas the proportion of patients with cure (disap- eter remains in the cavity for 2–3 days. No deaths but four peared or calcified cysts) did not significantly change. Clearly, anaphylactic reactions were observed. The recurrence rate in duration of treatment of < 3 months produces less than opti- a 3-year follow-up was 2.3% in situ and 1% in other locations. mal response, whereas results of extension beyond 6 months Large-bore 14-Fr van Sonnenberg sump drainage catheters have yet to be gauged because clinicians tend to adopt longer under sonographic guidance were used by Haddad and oth- courses. Some of this effect may be because of longer periods ers66 to treat nine solid cysts with daughter cysts. They evacu- ated the cyst contents and irrigated the cyst cavity with hypertonic saline. At 15 months, there were no major compli- TABLE 4 cations, deaths, or recurrences. Accumulation of efficacy data: two data reviews of albendazole effi- Schipper and others67 treated 12 patients with unilocular cacy separated by 8 years and multivesiculated cysts, including complicated ones, with Number of No change/worse PEVAC. Aspiration and evacuation of cyst content were per- patients Cured (%) Improved (%) (%) formed with a 14-Fr catheter. Cysto-biliary fistulas were 1989 treated with an endoprosthesis, introduced endoscopically Patients 253 28.5 51.0 20.5 Cysts 456 35.1 41.0 23.9 into the common bile duct. In a mean period of 17.9 months 1997 (range, 4–30 months), seven cysts disappeared and five de- Patients 1,369 32.4 43.7 23.9 creased in size. The main complications of this procedure Cysts 3,347 24.6 48.0 27.5 were caused by cysto-biliary fistulas and secondary infections. Adapted from Horton.70,72 306 JUNGHANSS AND OTHERS of follow-up, allowing more change to occur in the period of before reaching the systemic circulation. A first pass effect observation. This was shown in a series of patients followed occurs in the intestinal wall.96 The key to the differences be- long term by Nahmias and others.73 They showed in their tween the two compounds lies in the metabolites that arise. series of patients followed for between 3 and > 5 years that, Albendazole is metabolized first to albendazole sulphoxide, even in the absence of further treatment, cysts continued to an active antihelminthic in its own right, and then to the change, and that this eventually led to a high proportion of relatively inactive sulphone, whereas mebendazole is con- cures recorded beyond 5 years. The study was small, however, verted to a number of poorly active hydroxylated products. and no control group was available to assess the contribution Thus, only very high doses of mebendazole that potentially of spontaneous involution to the total change observed. swamp metabolic conversion, allowing active parent drug into For many years, there has been a debate over whether cysts the systemic circulation or produce sufficiently high levels of spontaneously progress to calcification and that, therefore, metabolites, are likely to be effective. In contrast, with the intervention is unnecessary. Two studies are of importance in production of an active metabolite systemically, albendazole this respect. In an attempt to resolve the question, Keshmiri is likely to be effective at much lower total doses. Thus, in this and others74 examined the effects on cysts in patients treated situation, albendazole is acting almost like a prodrug. Given with albendazole and those not treated. At least in the short the much higher lipophility of both compounds, co- term, the effect of treatment is clear, with ∼80% showing administration with fatty food increases absorption97 and is of evidence of changes in the treated group in contrast to only importance when examining possible development of im- 13% in the untreated group. Similarly Gil-Grande and oth- proved formulations. ers75 conducted a surgically based study of two albendazole Looking at available data of medically treated patients, it dose regimens compared with no treatment. Evaluation in seems that without increasing drug activity though reformu- this case was made at surgery, and the cyst contents were lation or development of a new compound with greater effi- evaluated for viability by microscopy and supravital staining cacy, chemotherapy cannot be the sole approach to treat- after inoculation of the cyst content into mice and compared ment. it with the ultrasound characteristics of the cysts. They Thus far, improvement of systemic availability of available showed that treatment produced a clear effect on viability and benzimidazoles has only been explored with co-administration infectivity for mice, which was greater with the longer course with a fatty meal,97 liposomal encapsulation,98 and soya bean of treatment. Furthermore, this correlated well with the ul- oil emulsions,99 the latter two without attracting commercial trasound findings [strength of recommendation B, quality of interest. Addition of cimetidine100 and praziquantel101 have evidence II] (Tables 5 and 6). been tried, but the results were not unequivocal. Co- Many and substantial questions still remain unanswered, administration of other drugs for the sole reason of increasing however. What is the optimum duration of treatment? Is bioavailability is not without problems, however, and needs there a stage-specific difference in response to medical treat- careful consideration. ment? How does cyst stage relate to bioavailability of benz- Risk, benefit, and safety profile. The benzimidazole carba- imidazole carbamates and active metabolites at the site of mates are among the safest compounds available when used action (i.e., in the interior of cysts)? Would the reported re- for the treatment of intestinal worms involving only short- lapse rates hold had patients been followed up long term? To term treatment.72,102 The situation is somewhat different which extent and at which rate do cysts undergo spontaneous when it comes to long-term treatment. Although the evidence involution without treatment? No single published study gives is limited, side effects of treatment are seen, both clinically a clear picture of the efficacy of the benzimidazoles in its own and in laboratory tests. Perhaps the most common side effect right. Meta-analysis of published studies70,73–95 is not possible is alopecia, which, although the denominator is unclear, may because heterogeneity between studies is too high and there is occur in 1–5% of all those treated. Gastrointestinal symptoms substantial overlap of published cohorts. Studies vary widely are also not uncommon but rarely are sufficiently severe to in inclusion/exclusion criteria, cyst stages enrolled, criteria require cessation of treatment. used for defining treatment success, and failure and follow-up The best-known effect of long-term benzimidazole treat- procedures and time. To get around this problem and to make ment of CE is elevation of liver enzymes. This occurs to some as much use as possible of the data that have accumulated extent in up to 20% of treated cases and has often led to over decades, a study (EchinoMEDREV) was initiated in cessation of treatment. This would suggest that there is sig- Heidelberg 2005 to re-analyze benzimidazole-treated patients nificant hepatotoxic potential in using benzimidazoles. Al- from individual patient data of published studies. These data though there is no doubt that some cases of drug-induced are currently being extracted and analyzed. Results are ex- hepatocellular damage have occurred,75,103 the majority of pected in 2008 (T. Junghanss, personal communication). liver enzyme elevations are limited, are not progressive, and Setting-specific problems have not been addressed at all disappear on treatment cessation. Examination of the clinical thus far. Is medical treatment at all feasible in resource-poor conditions associated with these elevations suggests that the settings in the near future concerning drug delivery, compli- effect is not a simple drug effect on the liver. The findings are ance, long-term follow-up, and cost? uncommon in treatment of neurocysticercosis,104 which is Some of the unanswered questions on medical treatment much shorter, however, and in patients with echinococcal require more basic research on the clinically relevant phar- cysts remote from the liver. It has been suggested that these macologic features of the benzimidazole carbamates. Absorp- effects are because of the local release of antigens caused by tion of the two benzimidazole carbamates, albendazole and damage to the parasite by the drug. A retrospective analysis mebendazole, in humans is very variable and limited to be- of liver function by Teggi and others105,106 found that 85% of tween 5% and 20%. Absorption is mostly from the small all raised enzyme cases had liver cysts, and furthermore, that intestine, and they are both almost completely metabolized structural changes in the cysts were present in a significantly CLINICAL MANAGEMENT OF CYSTIC ECHINOCOCCOSIS 307 of those TABLE 5 (0.0001 ס higher proportion (98.4% versus 67.1%; P patients with elevated enzymes. Others have noted that in Infectious Diseases Society of America grading system (strength of many patients, after an initial rise, enzyme levels stabilize or recommendation) even fall. Therefore, careful management with regular testing Strength of recommendation is required, and unless enzyme changes are progressive, treat- A Good evidence to support a recommendation for use ment can be continued. B Moderate evidence to support a recommendation for use Similarly, it is known that benzimidazoles have the poten- C Poor evidence to support a recommendation tial to suppress bone marrow function, and cases of aplastic D Moderate evidence to support a recommendation against use E Good evidence to support recommendation against use anemia have been described with both compounds.107 Again, regular monitoring should eliminate the majority of these events. Finally, long-term treatment with benzimidazole com- on cyst stages and reliable correlation of ultrasound-defined pounds carries a risk to the fetus in the first trimester of cyst stages and parasite viability. Substantial research efforts pregnancy, and treatment should be avoided during preg- are needed to establish this firmly.112 Predicting complica- nancy where possible and should be screened for in all female tions, in particular those related to cysto-biliary/bronchial fis- patients of childbearing age. Although a number of accidental tulas, is essential113 Furthermore, availability of ultrasound exposures have occurred, these have not had untoward results 108 machines and training may be a problem in countries with thus far. However, the denominator for calculating fetal limited resources. Well-trained and equipped mobile teams risk is small. might be an option. In resource-rich countries, instead, the “Watch and wait.” The idea of leaving certain cyst types problem lies in the difficulty of acquiring experience because untreated and just monitoring them over time is a logical of the rarity of the disease. Center-based management of pa- consequence of two main findings: 1) a good proportion of tients seems to be the appropriate answer here. cysts are consolidating and calcifying (i.e., become completely 74,109 Imaging-based, stage-specific approach to treatment. Most inactive) without any treatment and 2) cysts that have clinicians around the world continue to rely exclusively on arrived at this stage and behave quietly (i.e., do not compro- surgery, and most patients in endemic countries do not re- mise organ functions or cause discomfort) seem to remain like 110 ceive any treatment at all until complications intervene. Pros- this or stabilize even further. pects for wider use and accessibility of medical treatment Long-term follow-up of patients with imaging, in particular (albendazole, mebendazole), percutaneous techniques, and ultrasound, which does not use ionizing radiations and is eas- “watch and wait” are poor at the current level of investment ily repeatable, has increased our confidence that we have to into this neglected disease. offer something spectacular to quite a substantial group of A few groups of clinicians around the world, under the patients: no treatment at all. This decision must, however, be umbrella of WHO IWGE, try to keep track of the develop- accompanied and verified by long-term ultrasonographic fol- ments in clinical management of CE.114 Sample sizes of stud- low-up. Ten years seem to be an adequate time frame. Again, ies are small, there is overlapping of patient cohorts in suc- the published evidence for this approach is far from adequate. cessive publications, many studies are retrospective, and In recent years, however, substantial positive experience with 111 problems related to the design and conduct of studies are “watch and wait” is accumulating in various centers. This frequent. Pooling published studies for meta-analysis is diffi- attractive approach to patients with advanced cyst stages cult because of unbridgeable heterogeneity of study design needs and deserves formal evaluation to define its indications and conduct. Nevertheless, the IWGE released guidelines in and limitations [strength of recommendation B, quality of 1996.114 The ranking of the WHO guidelines according to the evidence III] (Tables 5 and 6). Infectious Diseases Society of America grading system3 shown in Tables 5 and 6, is B-C for strength of recommenda- DISCUSSION tion and II-III for quality of evidence. In certain areas, the WHO guidelines have fallen behind CE is difficult to treat and, even more so, to cure for a current treatment practice of various clinical groups and cen- number of reasons. The disease is complex and dynamic with ters, particularly with respect to expanding indications for an evolving phase and quietly growing cysts. This is followed percutaneous and medical treatment and “watch and wait.” by an involution process during which the parasite is gradu- ally dying off leaving behind a solidified, often calcified cyst or a scar. Each successive active cyst stage carries its own risks for serious and even life-threatening complications. For com- TABLE 6 plex diseases, no “one size fits all” approach is available, and Infectious Diseases Society of America grading system (quality clinicians must take a stage-specific approach. This leads to a of evidence) wide range of treatment modalities with an equally wide Quality of evidence range of technological and training backgrounds necessary for I Evidence from at least one properly randomized, controlled implementation and delivery. This, in turn, clashes with tech- trial nical and economic difficulties in countries with limited re- II Evidence from at least one well-designed clinical trial, without randomization; from cohort or case-controlled analytic sources where the patient load is greatest and problems in studies; from multiple time series; or from dramatic results acquiring clinical competence in countries where few patients from uncontrolled experiments suffer from the disease. III Evidence from opinions of respected authorities, based on Imaging is crucial to new treatment approaches. Progress in clinical experience, descriptive studies, or reports of committees managing patients with CE is greatly facilitated by consensus 308 JUNGHANSS AND OTHERS

TABLE 7 Our aim here is to provide best practice therapy options to Complications requiring interventions other than standard protocol individual patients until more formally tested algorithms are Cysto-biliary fistulas available and to facilitate the design of appropriate clinical Plus biliary obstruction/obstructive cholangitis trials. Bacterial abscesses The way ahead. Awareness for CE must be raised under Cysto-bronchial fistulas Plus bronchial obstruction the umbrella of orphan disease (rich countries) and neglected Bacterial abscesses disease (poor countries) initiatives to stimulate funding for Secondary bacterial infection much needed clinical research, involvement of private-public Liver abscess (can be treated percutaneously) partnerships in the development of new drugs and other treat- Lung abscess (can be treated with antibiotics and surgical drainage if necessary) ment aids and commitment of health authorities to stepping Cyst rupture up the care for CE patients. Plus anaphylaxis It is also important that more reliable epidemiologic data Plus secondary dissemination are made available if one has to gauge correctly the burden of this disease.2 This may come from population-based surveys and from analysis of hospital records, where available.115 An update is underway. Growing experience with classifying Until major breakthroughs are seen, medium-term solu- and following up echinococcal cysts with ultrasound is gradu- tions need to be found. In countries where the disease has ally enabling clinicians in assigning treatment modalities to orphan disease status (i.e., where the disease occurs at low individual cyst stages. We are, however, still far from treat- incidence and prevalence), patients should be managed by ment algorithms in which we can put numbers to treatment interdisciplinary teams in referral centers. arms (i.e., reliable data and confidence intervals for efficacy, Few centers per country will suffice. Only then will patients effectiveness, relapse rates, adverse events, and cost effective- benefit from accumulating experience, and long-term follow- ness). up can be achieved, which is essential to control relapse. To carry out this demanding task, well-planned clinical tri- The task is much more difficult in high prevalence countries als are needed, taking into account setting-specific problems. because of the wide, almost unbridgeable discrepancy be- Furthermore, patients with complicated cysts or high risk of tween medical demands to treat CE and available resources. adverse reactions to accepted treatment modalities require A referral center approach might be the best solution in this individual management plans (Table 7). setting, supplemented by mobile teams to bring diagnosis and Treatment modalities stratified by cyst stage and level of management, including long-term follow-up, as close as pos- health care resources. Although we are well aware of the dif- sible to the community. ficulties in summarizing the current practice of treating CE Again, large, well-designed clinical trials are essential to patients and what seems feasible on the basis of current evi- develop treatment algorithms adapted to the specific require- dence, we made an attempt to summarize our suggestions in ments in a wide range of health care settings where patients regard to options by cyst stage and level of health care re- need treatment. sources (Table 8). It must be kept in mind that assignment of CE shares these problems with other neglected diseases. treatment options to cyst stage and level of health care is Getting CE on the agenda of the most neglected health prob- currently based on expert opinion. lems is overdue.

TABLE 8 Treatment modalities stratified by cyst stage (uncomplicated) and level of health care Current practice

WHO classification 2001 Surgery Percutaneous techniques Medical treatment Suggested Resource setting CE1 ⅥⅥ ⅥPAIR + ABZ, if > 5 cm Rich ABZ alone, if < 5 cm ⅥⅥ ‡ Poor CE2 Ⅵ ᭜ Ⅵ Non-PAIR PT + ABZ Rich Surgery + ABZ Ⅵ ‡ Poor CE3a* ⅥⅥ ⅥPAIR + ABZ, if > 5 cm Rich ABZ alone, if < 5 cm Ⅵ ‡ Poor CE3b† Ⅵ ᭜ Ⅵ Non PAIR PT + ABZ Rich Surgery + ABZ Ⅵ ‡ Poor CE4 and 5 Regarded as inactive and, unless complicated, they should not be treated Watch and wait * Cyst with detached membranes (“water-lily” sign). † Cyst with daughter cysts in solid matrix. ‡ All three current suggestions (i.e., percutaneous treatment, surgery, and albendazole) are, for obvious reasons (see text), equally difficult to implement in resource-poor settings at acceptable quality and affordable cost. CE shares these problems with other neglected diseases, and this urgently calls for setting specific development of treatment approaches and strategies. .rarely practiced ס practiced; ᭜סⅥ CLINICAL MANAGEMENT OF CYSTIC ECHINOCOCCOSIS 309

Received August 29, 2007. Accepted for publication April 13, 2008. 15. Little JM, Hollands MJ, Ekberg H, 1988. Recurrence of hydatid disease. World J Surg 12: 700–704. Disclosure: Some of the authors wish to disclose that they hold stock 16. Mawhorter S, Temeck B, Chang R, Pass H, Nash T, 1997. Non- in GlaxoSmithKline, makers of albendazole. This statement is made surgical therapy for pulmonary hydatid cyst disease. Chest 112: in the interest of full disclosure and not because the authors consider 1432–1436. this a conflict of interest. 17. Qian ZX, 1988. Thoracic hydatid cysts: a report of 842 cases Financial support: TJ, EB, and AMS are supported by the European treated over a thirty- year period. Ann Thorac Surg 46: 342– Union Grant INCO-CT2004-509102 (EchinoNET). 346. 18. Thameur H, Chenik S, Abdelmoulah S, Bey M, Hachicha S, Authors’ addresses: Thomas Junghanss, Section of Clinical Tropical Chemingui M, Mestiri T, Chaouch H, 2000. Thoracic hydati- Medicine, University Hospital Heidelberg, Im Neuenheimer Feld dosis. A review of 1619 cases. Rev Pneumol Clin 56: 7–15. 324, 69120 Heidelberg, Germany, Tel: 49-06221-564904, Fax: 49- 19. Menezes da Silva A, 2003. Hydatid cyst of the liver-criteria for 06221-565204, E-mail: [email protected]. An- the selection of appropriate treatment. Acta Trop 85: 237–242. tonio Menezes da Silva, Serviço de Cirugia Geral e Digestiva, Hos- 20. Keramidas D, Mavridis G, Soutis M, Passalidis A, 2004. Medical pital de Pulido Valente, Alameda das Linhas de Torres 117, 1769-001 treatment of pulmonary hydatidosis: complications and surgi- Lisbon, Portugal, Tel and Fax: 35-12175-87232, E-mail: mensilvapt@ cal management. Pediatr Surg Int 19: 774–776. yahoo.com. John Horton, Tropical Projects, 24 The Paddock, 21. Vaquerizo A, Sola JL, Bondia A, Opla JM, Madariaga MJ, 1994. Hitchin, Hertfordshire SG4 9EF, UK, Tel: 44-1462-451618, E-mail: Intraoperative hydatid anaphylactic shock. Rev Esp Anestesiol [email protected]. Peter L. Chiodini, Department of Clinical Para- Reanim 41: 113–116. sitology, Hospital for Tropical Diseases, London, and Department of 22. Manterola C, Fernandez O, Munoz S, Vial M, Losada H, Infectious and Tropical Diseases, London School of Hygiene and Carrasco R, Bello N, Barroso M, 2002. Laparoscopic pericys- Tropical Medicine, Capper Street, London WC1 6JA, UK, Tel: 44- tectomy for liver hydatid cysts. Surg Endosc 16: 521–524. 20-7387-4411, Fax: 44-20-7383-0041, E-mail: peter.chiodini@uclh. 23. Belghiti J, Benhamou JP, Houry S, Grenier P, Huguier M, nhs.uk. Enrico Brunetti, Division of Infectious and Tropical Diseases, Fekete F, 1986. Caustic sclerosing cholangitis. A complication S. Matteo Hospital Foundation, University of Pavia, Via Taramelli 5, of the surgical treatment of hydatid disease of the liver. Arch 27100 Pavia, Italy, Tel: 39-0382-502619, Fax: 39-0382-301987, E-mail: Surg 121: 1162–1165. [email protected]. 24. Castellano G, Moreno-Sanchez D, Gutierrez J, Moreno- Gonzalez E, Colina F, Solis-Herruzo JA, 1994. Caustic sclerosing cholangitis. Report of four cases and a cumulative re- REFERENCES view of the literature. Hepatogastroenterology 41: 458–470. 25. Atmatzidis KS, Pavlidis TE, Papaziogas BT, Mirelis C, Papazio- 1. Drugs for Neglected Diseases initiative. Available at: http:// gas TB, 2005. Recurrence and long-term outcome after open www.dndi.org/. Accessed March 30, 2008. cystectomy with omentoplasty for hepatic hydatid disease in an 2. Budke CM, 2006. Global socioeconomic impact of cystic echi- endemic area. Acta Chir Belg 105: 198–202. nococcosis. Emerg Infect Dis 12: 296–303. 26. Dervisoglu A, Polat C, Hokelek M, Yetim I, Ozkutuk Y, Buyuk- 3. Kish MA, 2001. Guide to development of practice guidelines. karabacak Y, Erzurumlu K, 2005. Videolaparoscopic treat- Clin Infect Dis 32: 851–854. ment of hepatic hydatid cyst. Hepatogastroenterology 52: 1526– 4. Gharbi HA, Hassine W, Brauner MW, Dupuch K, 1981. Ultra- 1528. sound examination of the hydatic liver. Radiology 139: 459– 27. Yagci G, Ustunsoz B, Kaymakcioglu N, Bozlar U, Gorgulu S, 463. Simsek A, Akdeniz A, Cetiner S, Tufan T, 2005. Results of 5. Caremani M, Benci A, Maestrini R, Accorsi A, Caremani D, surgical, laparoscopic, and percutaneous treatment for hydatid Lapini L, 1997. Ultrasound imaging in cystic echinococcosis. disease of the liver: 10 years experience with 355 patients. Proposal of a new sonographic classification. Acta Trop 67: World J Surg 29: 1670–1679. 91–105. 28. Dervenis C, Delis S, Avgerinos C, Madariaga J, Milicevic M, 6. WHO Informal Working Group on Echinococcosis, 2003. Inter- 2005. Changing concepts in the management of liver hydatid national classification of ultrasound images in cystic echino- disease. J Gastrointest Surg 9: 869–877. coccosis for application in clinical and field epidemiological 29. Sayek I, Onat D, 2001. Diagnosis and treatment of uncompli- settings. Acta Trop 85: 253–261. cated hydatid cyst of the liver. World J Surg 25: 21–27. 7. Wang Y, Zhang X, Bartholomot B, Liu B, Luo J, Li T, Wen X, 30. Demirleau JC, 1974. Treatment of hydatid cysts of the liver. Zheng H, Zhou H, Wen H, Davaadori N, Gambolt L, Mukhar Med Chir Dig 3: 1–3. T, al-Qaoud K, Abdel-Hafez S, Giraudoux P, Vuitton DA, 31. Morris DL, 1987. Pre-operative albendazole therapy for hydatid Fraser A, Rogan MT, Craig PS, 2003. Classification, follow-up cyst. Br J Surg 74: 805–806. and recurrence of hepatic cystic echinococcosis using ultra- 32. Erzurumlu K, Hokelek M, Gonlusen L, Tas K, Amanvermez R, sound images. Trans R Soc Trop Med Hyg 97: 203–211. 2000. The effect of albendazole on the prevention of secondary 8. Hosch W, Stojkovic M, Janisch T, Kauffmann GW, Junghanss T, hydatidosis. Hepatogastroenterology 47: 247–250. 2007. The role of calcification for staging cystic echinococcosis 33. Dhaliwal RS, Kalkat MS, 1997. One-stage surgical procedure for (CE). Eur Radiol 17: 2538–2545. bilateral lung and liver hydatid cysts. Ann Thorac Surg 64: 9. Taylor BR, Langer B, 1997. Current surgical management of 338–341. hepatic cyst disease. Adv Surg 31: 127–148. 34. Langer JC, Rose DB, Keystone JS, Taylor BR, Langer B, 1984. 10. Daradkeh S, El-Muhtaseb H, Farah G, Sroujieh AS, Abu- Diagnosis and management of hydatid disease of the liver. A Khalaf M, 2007. Predictors of morbidity and mortality in the 15-year North American experience. Ann Surg 199: 412–417. surgical management of hydatid cyst of the liver. Langenbecks 35. Little J, 1990. Hydatid disease of the liver. Hadfield J, Treasure Arch Surg 392: 35–39. T, eds. Current Surgical Practice. London: Hodder & Stough- 11. Demirci S, Eraslan S, Anadol E, Bozatli L, 1989. Comparison of ton, 146–161. the results of different surgical techniques in the management 36. Magistrelli P, Masetti R, Coppola R, Messia A, Nuzzo G, Pic- of hydatid cysts of the liver. World J Surg 13: 88–90. ciocchi A, 1991. Surgical treatment of hydatid disease of the 12. Dogan R, Yuksel M, Cetin G, Suzer K, Alp M, Kaya S, Unlu M, liver. A 20-year experience. Arch Surg 126: 518–522. Moldibi B, 1989. Surgical treatment of hydatid cysts of the 37. Settaf A, Bargach S, Aghzadi R, Lahlou MK, Oudghiri M, 1991. lung: report on 1055 patients. Thorax 44: 192–199. Treatment of cystobiliary fistula of hydatid cyst of the liver. 13. Ramos G, Orduna A, Garcia-Yuste M, 2001. Hydatid cyst of the Apropos of 33 cases. J Chir (Paris) 128: 133–138. lung: diagnosis and treatment. World J Surg 25: 46–57. 38. Sayek I, Yalin R, Sanac Y, 1980. Surgical treatment of hydatid 14. Isitmangil T, Sebit S, Tunc H, Gorur R, Erdik O, Kunter E, disease of the liver. Arch Surg 115: 847–850. Toker A, Balkanli K, Ozturk OY, 2002. Clinical experience of 39. Yalin R, Oguz M, Dulger M, 1989. Surgical treatment of hepatic surgical therapy in 207 patients with thoracic hydatidosis over hydatid cyst. Med Principles Pract 1: 154–159. a 12-year-period. Swiss Med Wkly 132: 548–552. 40. Salih OK, Topcuoglu MS, Celik SK, Ulus T, Tokcan A, 1998. 310 JUNGHANSS AND OTHERS

Surgical treatment of hydatid cysts of the lung: analysis of 405 complex hydatid cyst of the liver under sonographic control. patients. Can J Surg 41: 131–135. Report of the first case. Gastroenterol Clin Biol 29: 191–192. 41. Alfieri S, Doglietto GB, Pacelli F, Costamagna G, Carriero C, 62. Brunetti E, Gulizia R, Garlaschelli A, Filice C, 2004. Radio- Mutignani M, Liberatori M, Crucitti F, 1997. Radical surgery frequency thermal ablation of echinococcal cysts of the liver: for liver hydatid disease: a study of 89 consecutive patients. results at 12-month follow-up. Am J Trop Med Hyg 71: 182. Hepatogastroenterology 44: 496–500. 63. Akhan O, Dincer A, Gokoz A, Sayek I, Havlioglu S, Abbasoglu 42. Mueller PR, Dawson SL, Ferrucci JT Jr, Nardi GL, 1985. He- O, Eryilmaz M, Besim A, Baris I, 1993. Percutaneous treat- patic echinococcal cyst: successful percutaneous drainage. Ra- ment of abdominal hydatid cysts with hypertonic saline and diology 155: 627–628. alcohol. An experimental study in sheep. Invest Radiol 28: 43. Filice C, Pirola F, Brunetti E, Dughetti S, Strosselli M, Foglieni 121–127. CS, 1990. A new therapeutic approach for hydatid liver cysts. 64. Saremi F, McNamara TO, 1995. Hydatid cysts of the liver: long- Aspiration and alcohol injection under sonographic guidance. term results of percutaneous treatment using a cutting instru- Gastroenterology 98: 1366–1368. ment. AJR Am J Roentgenol 165: 1163–1167. 44. Gargouri M, Ben Amor N, Ben Chehida F, Hammou A, Gharbi 65. Vuitton DA, Zhi Wang X, Li Feng S, Sheng Chen J, Shou Li Y, HA, Ben Cheikh M, Kchouk H, Ayachi K, Golvan JY, 1990. Li SF, Ke Tang Q, 2002. PAIR-derived US-guided techniques Percutaneous treatment of hydatid cysts (Echinococcus granu- for the treatment of cystic echinococcosis: a Chinese experi- losus). Cardiovasc Intervent Radiol 13: 169–173. ence (e-letter). Gut. 45. Salama H, Farid Abdel-Wahab M, Strickland GT, 1995. Diag- 66. Haddad MC, Sammak BM, Al-Karawi M, 2000. Percutaneous nosis and treatment of hepatic hydatid cysts with the aid of treatment of heterogenous predominantly solid echopattern echo- guided percutaneous cyst puncture. Clin Infect Dis 21: echinococcal cysts of the liver. Cardiovasc Intervent Radiol 23: 1372–1376. 121–125. 46. Ustunsoz B, Akhan O, Kamiloglu MA, Somuncu I, Ugurel MS, 67. Schipper HG, Lameris JS, van Delden OM, Rauws EA, Kager Cetiner S, 1999. Percutaneous treatment of hydatid cysts of the PA, 2002. Percutaneous evacuation (PEVAC) of multivesicu- liver: long-term results. AJR Am J Roentgenol 172: 91–96. lar echinococcal cysts with or without cystobiliary fistulas 47. Men S, Hekimoglu B, Yucesoy C, Arda IS, Baran I, 1999. Per- which contain non-drainable material: first results of a modi- cutaneous treatment of hepatic hydatid cysts: an alternative to fied PAIR method. Gut 50: 718–723. surgery. AJR Am J Roentgenol 172: 83–89. 68. Akhan O, Gumus B, Akinci D, Karcaaltincaba M, Ozmen M, 48. Brunetti E, Troia G, Garlaschelli AL, Gulizia R, Filice C, 2004. 2007. Diagnosis and percutaneous treatment of soft-tissue hy- Twenty years of percutaneous treatments for cystic echinococ- datid cysts. Cardiovasc Intervent Radiol 30: 419–425. cosis: a preliminary assessment of their use and safety. Paras- 69. Davis A, Dixon H, Pawlowski ZS, 1989. Multicentre clinical itologia 46: 367–370. trials of benzimidazole-carbamates in human cystic echinococ- 49. Nasseri Moghaddam S, Abrishami A, Malekzadeh R, 2006. Per- cosis (phase 2). Bull World Health Organ 67: 503–508. cutaneous needle aspiration, injection, and reaspiration with or 70. Horton RJ, 1989. Chemotherapy of Echinococcus infection in without benzimidazole coverage for uncomplicated hepatic hy- man with albendazole. Trans R Soc Trop Med Hyg 83: 97–102. datid cysts. Cochrane Database Syst Rev 2: CD003623. 71. Teggi A, Lastilla MG, De Rosa F, 1993. Therapy of human 50. Khuroo MS, Dar MY, Yattoo GN, Zargar SA, Javaid G, Khan hydatid disease with mebendazole and albendazole. Antimi- BA, Boda MI, 1993. Percutaneous drainage versus albendazole crob Agents Chemother 37: 1679–1684. therapy in hepatic hydatidosis: a prospective, randomized 72. Horton RJ, 1997. Albendazole in treatment of human cystic study. Gastroenterology 104: 1452–1459. echinococcosis: 12 years of experience. Acta Trop 64: 79–93. 51. Khuroo MS, Wani NA, Javid G, Khan BA, Yattoo GN, Shah 73. Nahmias J, Goldsmith R, Soibelman M, el-On J, 1994. Three- to AH, Jeelani SG, 1997. Percutaneous drainage compared with 7-year follow-up after albendazole treatment of 68 patients surgery for hepatic hydatid cysts. N Engl J Med 337: 881–887. with cystic echinococcosis (hydatid disease). Ann Trop Med 52. Akhan O, Ozmen MN, Dincer A, Sayek I, Gocmen A, 1996. Parasitol 88: 295–304. Liver hydatid disease: long-term results of percutaneous treat- 74. Keshmiri M, Baharvahdat H, Fattahi SH, Davachi B, Dabiri ment. Radiology 198: 259–264. RH, Baradaran H, Rajabzadeh F, 2001. Albendazole versus 53. Goktay AY, Secil M, Gulcu A, Hosgor M, Karaca I, Olguner M, placebo in treatment of echinococcosis. Trans R Soc Trop Med Akgur FM, Dicle O, 2005. Percutaneous treatment of hydatid Hyg 95: 190–194. liver cysts in children as a primary treatment: long-term results. 75. Gil-Grande LA, Rodriguez-Caabeiro F, Prieto JG, Sanchez- J Vasc Interv Radiol 16: 831–839. Ruano JJ, Brasa C, Aguilar L, Garcia-Hoz F, Casado N, Bar- 54. Giorgio A, Tarantino L, de Stefano G, Francica G, Mariniello cena R, Alvarez AI, Dal-Re R, 1993. Randomised controlled N, Farella N, Perrotta A, Aloisio V, Esposito F, 2001. Hydatid trial of efficacy of albendazole in intraabdominal hydatid dis- liver cyst: an 11-year experience of treatment with percutane- ease. Lancet 342: 1269–1272. ous aspiration and ethanol injection. J Ultrasound Med 20: 76. Vutova K, Mechkov G, Vachkov P, Petkov R, Georgiev P, 729–738. Handjiev S, Ivanov A, Todorov T, 1999. Effect of mebenda- 55. Smego RA Jr, Bhatti S, Khaliq AA, Beg MA, 2003. Percutane- zole on human cystic echinococcosis: the role of dosage and ous aspiration-injection-reaspiration drainage plus albenda- treatment duration. Ann Trop Med Parasitol 93: 357–365. zole or mebendazole for hepatic cystic echinococcosis: a meta- 77. Chai J, Menghebat, Jiao W, Sun D, Liang B, Shi J, Fu C, Li X, analysis. Clin Infect Dis 37: 1073–1083. Mao Y, Wang X, Dolikun, Guliber, Wang Y, Gao F, Xiao S, 56. Kabaalioglu A, Ceken K, Alimoglu E, Apaydin A, 2006. Per- 2002. Clinical efficacy of albendazole emulsion in treatment of cutaneous imaging-guided treatment of hydatid liver cysts: do 212 cases of liver cystic hydatidosis. Chin Med J (Engl) 115: long-term results make it a first choice? Eur J Radiol 59: 65–73. 1809–1813. 57. Akhan O, Ozmen MN, 1999. Percutaneous treatment of liver 78. Radulescu S, Angelescu N, Horvat T, Lazar L, Cretu C, Popa L, hydatid cysts. Eur J Radiol 32: 76–85. Filiu P, Ene V, Burcos T, Ifrim S, Popa G, 1997. Clinical study 58. Yaghan R, Heis H, Bani-Hani K, Matalka I, Shatanawi N, of the efficacy of albendazole treatment in human hydatidosis. Gharaibeh K, Bani-Hani A, 2004. Is fear of anaphylactic shock Chirurgia (Bucur) 92: 331–335. discouraging surgeons from more widely adopting percutane- 79. Chai JJ, Monhebat, Sulitan Y, Jing Q, Chang Q, Zhang HL, ous and laparoscopic techniques in the treatment of liver hy- 2003. Dynamic observation on ultrasonographic image during datid cyst? Am J Surg 187: 533–537. chemotherapy of hepatic cystic echinococcosis and a proposal 59. El-On J, Ben-Noun L, Galitza Z, Ohana N, 2003. Case report: for ultrasonic classification. Zhongguo Ji Sheng Chong Xue Yu clinical and serological evaluation of echinococcosis of the Ji Sheng Chong Bing Za Zhi 21: 134–139. spine. Trans R Soc Trop Med Hyg 97: 567–569. 80. Franchi C, Di Vico B, Teggi A, 1999. Long-term evaluation of 60. Brunetti E, Filice C, 2001. Radiofrequency thermal ablation of patients with hydatidosis treated with benzimidazole carba- echinococcal liver cysts. Lancet 358: 1464. mates. Clin Infect Dis 29: 304–309. 61. Bastid C, Ayela P, Sahel J, 2005. Percutaneous treatment of a 81. Shcherbakov AM, Panteleeva E, Firsova RA, 1993. The efficacy CLINICAL MANAGEMENT OF CYSTIC ECHINOCOCCOSIS 311

of the mebendazole treatment of patients with hydatid disease. some-entrapped albendazole in experimental secondary alveo- Med Parazitol (Mosk) 4: 15–17. lar echinococcosis and effect of co- administration with cimet- 82. Chai J, Menghebat, Wei J, Deyu S, Bin L, Jincao S, Chen F, idine. Parasitology 113: 111–121. Xiong L, Yiding M, Xiuling W, et al., 2004. Observations on 99. Mingjie W, Shuhua X, Junjie C, Bin L, Cheng F, Weixia S, clinical efficacy of albendazole emulsion in 264 cases of hepatic Hotez P, 2002. Albendazole-soybean oil emulsion for the treat- cystic echinococcosis. Parasitol Int 53: 3–10. ment of human cystic echinococcosis: evaluation of bioavail- 83. Todorov T, Vutova K, Mechkov G, Georgiev P, Petkov D, ability and bioequivalence. Acta Trop 83: 177–181. Tonchev Z, Nedelkov G, 1992. Chemotherapy of human cystic 100. Nagy J, Schipper HG, Koopmans RP, Butter JJ, Van Boxtel CJ, echinococcosis: comparative efficacy of mebendazole and al- Kager PA, 2002. Effect of grapefruit juice or cimetidine coad- bendazole. Ann Trop Med Parasitol 86: 59–66. ministration on albendazole bioavailability. Am J Trop Med 84. el-Mufti M, Kamag A, Ibrahim H, Taktuk S, Swaisi I, Zaidan A, Hyg 66: 260–263. Sameen A, Shimbish F, Bouzghaiba W, Haasi S, Unaizi A, 101. Homeida M, Leahy W, Copeland S, Ali MM, Harron DW, 1994. 1993. Albendazole therapy of hydatid disease: 2-year follow-up Pharmacokinetic interaction between praziquantel and al- of 40 cases. Ann Trop Med Parasitol 87: 241–246. bendazole in Sudanese men. Ann Trop Med Parasitol 88: 551– 85. Teggi A, Lastilla MG, De Rosa F, 1993. Therapy of human 559. hydatid disease with mebendazole and albendazole. Antimi- 102. Horton J, 2000. Albendazole: a review of anthelmintic efficacy crob Agents Chemother 37: 1679–1684. and safety in humans. Parasitology 121 (Suppl): S113–S132. 86. Messaritakis J, Psychou P, Nicolaidou P, Karpathios T, Syri- 103. Morris DL, Smith PG, 1987. Albendazole in hydatid disease– opoulou B, Fretzayas A, Krikos F, Matsaniotis N, 1991. High hepatocellular toxicity. Trans R Soc Trop Med Hyg 81: 343– mebendazole doses in pulmonary and hepatic hydatid disease. 344. Arch Dis Child 66: 532–533. 104. Del Brutto OH, 2005. Neurocysticercosis. Semin Neurol 25: 243– 87. Todorov T, Vutova K, Mechkov G, Petkov D, Nedelkov G, 251. Tonchev Z, 1990. Evaluation of response to chemotherapy of 105. Teggi ALM, Grossi G, Franchi C, De Rosa F, 1995. Increase in human cystic echinococcosis. Br J Radiol 63: 523–531. serum glutamic-oxaloacetic and glutamic-pyruvic transami- 88. Todorov T, Mechkov G, Vutova K, Georgiev P, Lazarova I, nases in patients with hydatid cysts treated with mebendazole Tonchev Z, Nedelkov G, 1992. Factors influencing the re- and albendazole. Mediter J Inf Parasit Dis 10: 85–90. Bull sponse to chemotherapy in human cystic echinococcosis. 106. Teggi A, Giattino M, Franchi C, Lastilla M, 1997. A hypothesis World Health Organ 70: 347–358. on the significance of an increase in serum transaminases in 89. Teggi A, Capozzi A, De Rosa F, 1989. Treatment of Echino- patients with hydatidosis treated with benzimidazole carba- J coccus granulosus hydatid disease with mebendazole. mates. Recenti Prog Med 88: 452–458. Chemother 1: 310–317. 107. Opatrny L, Prichard R, Snell L, Maclean JD, 2005. Death re- 90. Gil-Grande LA, Boixeda D, Garcia-Hoz F, Barcena R, Lledo A, lated to albendazole-induced pancytopenia: case report and Suarez E, Pascasio JM, Moreira V, 1983. Treatment of liver review. Am J Trop Med Hyg 72: 291–294. hydatid disease with mebendazole: a prospective study of thir- 108. Bradley M, Horton J, 2001. Assessing the risk of benzimidazole teen cases. Am J Gastroenterol 78: 584–588. therapy during pregnancy. Trans R Soc Trop Med Hyg 95: 91. Gocmen A, Toppare MF, Kiper N, 1993. Treatment of hydatid 72–73. disease in childhood with mebendazole. Eur Respir J 6: 253– 257. 109. Romig T, Zeyhle E, Macpherson CN, Rees PH, Were JB, 1986. 92. Sciarrino E, Virdone R, Lo Iacono O, Fusco G, Ricca T, Cot- Cyst growth and spontaneous cure in hydatid disease. Lancet 1: tone M, Maringhini A, Della Monica A, 1991. Ultrasound 861. changes in abdominal echinococcosis treated with albendazole. 110. Frider B, Larrieu E, Odriozola M, 1999. Long-term outcome of J Clin Ultrasound 19: 143–148. asymptomatic liver hydatidosis. J Hepatol 30: 228–231. 93. De Rosa F, Lastilla MG, Franchi C, Teggi A, 1996. Advances of 111. Brunetti E, Troìa G, Gulizia R, Garlaschelli AL, Filice C, 2005. medical treatment of human hydatidosis. Recenti Prog Med 87: “Watch and Wait” as an alternative “treatment” for active and 346–352. transitional echinococcal cysts. Single-center experience. Am J 94. Wen H, Zou PF, Yang WG, Lu J, Wang YH, Zhang JH, New Trop Med Hyg 73: 29. RR, Craig PS, 1994. Albendazole chemotherapy for human 112. Hosch W, Junghanss T, Stojkovic M, Brunetti E, Heye T, Kauff- cystic and alveolar echinococcosis in north-western China. man GW, Hull WE, 2008. Metabolic viability assessment of Trans R Soc Trop Med Hyg 88: 340–343. cystic echinococcosis using high-field 1H magnetic resonance 95. Keshmiri M, Baharvahdat H, Fattahi SH, Davachi B, Dabiri spectroscopy of cyst contents. NMR Biomed Apr 3 [Epub RH, Baradaran H, Ghiasi T, Rajabimashhadi MT, Rajabzadeh ahead of print]. F, 1999. A placebo controlled study of albendazole in the treat- 113. Hosch W, Stojkovic M, Janisch T, Heye T, Werner J, Friess H, ment of pulmonary echinococcosis. Eur Respir J 14: 503–507. Kauffmann GW, Junghanss T, 2008. MR imaging for diagnos- 96. Redondo PA, Alvarez AI, Garcia JL, Larrode OM, Merino G, ing cysto-biliary fistulas in cystic echinococcosis. Eur J Radiol Prieto JG, 1999. Presystemic metabolism of albendazole: ex- 66: 262–267. perimental evidence of an efflux process of albendazole sulf- 114. WHO Informal Working Group on Echinococcosis, 1996. oxide to intestinal lumen. Drug Metab Dispos 27: 736–740. Guidelines for treatment of cystic and alveolar echinococcosis 97. Lange H, Eggers R, Bircher J, 1988. Increased systemic avail- in humans. Bull World Health Organ 74: 231–242. ability of albendazole when taken with a fatty meal. Eur J Clin 115. Ostanello F, Piccolomini LL, Martinello F, Vizioli M, Battelli G, Pharmacol 34: 315–317. 1997. Echinococcosis/hydatidosis in Emilia-Romagna: a study 98. Wen H, New RR, Muhmut M, Wang JH, Wang YH, Zhang JH, of hospital admissions in the period of 1989–1993. Epidemiol Shao YM, Craig PS, 1996. Pharmacology and efficacy of lipo- Prev 21: 41–47.