MAJOR TROPICAL SYNROMES BY BODY SYSTEM: SYSTEMIC INFECTIONS Hydatid Disease SECTION 6 MAJOR TROPICAL SYNDROMES BY BODY SYSTEM: SYSTEMIC INFECTIONS chapter 169 Hydatid Disease Bruno Gottstein EPIDEMIOLOGY apparent expansion of distribution within the north–central American continent. In Europe, relatively frequent reports of alveolar echinococcosis (AE) in humans occur in central and eastern France, Switzerland, Austria and Germany. The Asian areas where E. multilocularis occurs include the whole zone of tundra, from the White Sea eastwards to the Bering Strait, covering large parts of the Soviet Union, China and northern Japan. Worldwide there are scant data on the overall prevalence of human AE. Some well-documented studies demonstrate a generally low prevalence among affected human populations. The annual mean incidence of new cases in different areas including Switzerland, France, Germany and Japan has therefore been reported to vary between 0.1 and 1.2/100,000 inhabitants.1,2 PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL Echinococcus spp. are cestode parasites commonly known as small tapeworms of carnivorous animals. Their medical importance lies in the infection of humans by the larval stage of the parasites, predominantly including two species: ■ Echinococcus granulosus, which is the causative agent of cystic hydatid disease (or cystic echinococcosis, CE); and ■ Echinococcus multilocularis, which causes alveolar echinococcosis, AE.1,2 Two other species, namely Echinococcus vogeli and Echinococcus oligarthrus, are extremely rarely found in humans and will therefore not be covered in this chapter. Echinococcus granulosus Echinococcus granulosus lives as a small intestinal tapeworm of dogs and occasionally other carnivores. The shedding of gravid proglottids or eggs in the feces occurs within 4–6 weeks after infection of the definitive host (Fig. 169.1). Ingestion of eggs by intermediate host animals or humans results in the release of an oncosphere into the gastrointestinal tract, which then migrates to primary target organs such as liver and lungs, and less frequently to other organs (Fig. 169.2). Usually the fully mature metacestode (i.e. hydatid cyst) develops within several months or years. Infections with E. granulosus occur worldwide, predominantly in countries of South and Central America, the European and African part of the Mediterranean area, the Middle East and some subSaharan countries, Russia and China. The annual incidence rates of diagnosed human cases/100,000 inhabitants vary widely, for example 13 in Greece, 143 in some provinces of Argentina, 197 in the Hinjang province of China and 220 in the Turkana district of Kenya. Most cases observed in Europe and the USA are associated with immigrants from highly endemic areas. Various strains of E. granulosus have been described, and differ especially in their infectivity for intermediate hosts such as humans. The most important strains for human infection include sheep and cattle as intermediate host. Echinococcus multilocularis The natural life cycle of E. multilocularis involves predominantly red and arctic foxes as definitive hosts (Fig. 169.3), but domestic dogs or house cats can also become infected and represent an important infection source for humans in highly endemic areas.3 In the definitive host, egg production starts as early as 28 days after infection. After egg ingestion by a rodent or a human, larval maturation will occur within the liver tissue in more than 98% of the cases (see Fig. 169.2); subsequent metastases may occur in adjacent or distant tissues. Proliferation occurs by exogenous budding of metacestode tissue with a progressive tumor-like growth. The geographic distribution of E. multilocularis is restricted to the northern hemisphere. In North America, the cestode is present in the subarctic regions of Alaska and Canada. The parasite has been discovered in its wildlife cycle in several other states, therefore indicating an PATHOGENESIS AND PATHOLOGY Echinococcus granulosus Cystic echinococcosis (cystic hydatid disease) is clinically related to the presence of one or more well-delineated spherical primary cysts, most frequently formed in the liver, and then in the lungs and other organs such as kidney, spleen, brain, heart and bone (see Fig. 169.2). Tissue damage and organ dysfunction result mainly from this gradual process of space-occupying displacement of vital host tissue, vessels or parts of organs. Consequently, clinical manifestations are primarily determined by the site, size and number of the cysts, and are therefore highly variable. Accidental rupture of the cysts can be followed by a massive release of cyst fluid and hematogenous or other dissemination of protoscolices. Occasionally this results in anaphylactic reactions and multiple secondary cystic echinococcosis (as protoscolices can develop into secondary cysts within the intermediate host). The histology of a typical hydatid cyst demonstrates the germinal layer as the primary site of parasite development (see Fig. 169.1). It is surrounded by a parasite-derived thick laminated layer, which is rich in aminocarbohydrates, as shown by periodic acid-Schiff positivity. The germinal layer forms protoscolices and brood capsules within the cyst lumen. Granulae, calcareous corpuscules and occasionally free daughter cysts are often observed. The parasite evokes an immune response, which is involved in the formation of a host-derived adventitious capsule. This often calcifies uniquely in the periphery of the cyst, one of the typical features found in imaging procedures. In the liver there may be cholestasis. Commonly there is pressure atrophy of the surrounding parenchyma. Immunologically, the coexistence of elevated quantities of IFN-γ, IL-4, IL-5, IL-6 and IL-10 observed in most of hydatid patients supports Th1 and Th2 cell activation in CE. In particular, Th1 cell activation seemed to be more related to protective immunity, whereas Th2 cell activation was related to susceptibility to disease.4 Echinococcus multilocularis In infected humans the E. multilocularis metacestode (larva) develops primarily in the liver (see Fig. 169.2). Occasionally, secondary 1 GEOGRAPHIC AND TRAVEL MEDICINE PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL LIFE CYCLE OF ECHINOCOCCUS GRANULOSUS Fig. 169.1 Life cycle of Echinococcus granulosus. Adult tapeworms parasitize the small intestine of definitive hosts, mainly dogs (1). Parasite proglottids and eggs are shed with the feces (2), such eggs being infectious for intermediate hosts including humans (3). Hydatid cyst formation occurs predominantly in the liver (4), but also in lungs and other organs. Imaging techniques such as CT (5) demonstrate well-delineated, fluid-filled, usually unilocular bladder-like lesions. Internal daughter cysts may be visible in larger cysts as septated segments within the primary cyst. Histologically, the cyst by itself consists of a very thin inner germinal and nucleated layer with a predominantly syncytial structure (6). The germinal layer is externally protected by an acellular laminated layer of variable thickness. The endogenous formation of brood capsules and protoscolices is a prerequisite for completion of the life cycle (6), which occurs when definitive hosts ingest protoscolex-containing hydatid cysts. 2 lesions form metastases in the lungs, brain and other organs. The typical lesion appears macroscopically as a dispersed mass of fibrous tissue with a conglomerate of scattered cavities with diameters ranging from a few millimeters to centimeters in size. In advanced chronic cases, a central necrotic cavity containing a viscous fluid may form, and rarely there is a bacterial superinfection. The lesion often contains focal zones of calcification typically within the metacestode tissue. Histologically, the hepatic lesion is characterized by a conglomerate of small vesicles and cysts demarcated by a thin laminated layer with or without an inner germinative layer (see Fig. 169.3). Parasite proliferation is usually accompanied by a granulomatous host reaction, including vigorous synthesis of fibrous and germinative tissue in the periphery of the metacestode, but also necrotic changes centrally. In contrast to lesions in susceptible rodent hosts, lesions from infected human patients rarely show protoscolex formation within vesicles and cysts. Genetic and immunologic host factors are responsible for the resistance shown by some patients in whom there is an early ‘dying out’ or ‘abortion’ of the metacestode.5 Therefore, not everyone infected with E. multilocularis is susceptible t unlimited metacestode proliferation and develops symptoms 5–15 years after infection.2,3 The host mechanisms modulating the course of infection are most likely of an immunological nature, including primarily T cell interactions. Thus, the periparasitic granuloma, mainly composed of macrophages, myofibroblasts and T lymphocytes, contains a large number of CD4 T lymphocytes in patients with abortive or died-out lesions, whereas in patients with active metacestodes the number of CD8 T lymphocytes is increased. An immunosuppressive process is assumed to downregulate the lymphoid macrophage system. Conversely, the status of cured AE is generally reflected by a high in vitro lymphoproliferative response. The cytokine mRNA levels following E. multilocularis antigen stimulation of lymphocytes show an enhanced production of Th2-cell cytokine transcripts IL-3, IL-4 and IL-10 in patients, including a significant IL-5 mRNA expression in patients and not in healthy control donors.6 The phenomenon of immunological or constitutional resistance may be dependent upon a potential immunogenetic predisposition with a potential of a HLADR type association.7,8 Conversely, lack of Th cell activity such as in advanced AIDS is associated with a rapid and unlimited growth and dissemination of the parasite in AE.9 PREVENTION Prevention of both CE and AE focuses primarily on veterinary interventions to control the extent and intensity of infection in definitive Organ localization of Echinococcus granulosus cysts Organ localization of Echinococcus multilocularis metacestodes MAJOR TROPICAL SYNDROMES BY BODY SYSTEM: SYSTEMIC INFECTIONS Hydatid Disease PRIMARY SITES OF METACESTODE DEVELOPMENT IN HUMANS Fig. 169.2 Primary sites of metacestode development in humans. Organ distribution of the primary sites of metacestode development for Echinococcus granulosus (cystic echinococcosis) and Echinococcus multilocularis (alveolar echinococcosis) in human disease. Brain:<2% Heart/thorax: 2% Lungs: 20% Liver: 62% Liver: 98% Spleen: 6% Kidney: 2% Others: 2% Others: 2% PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL Bones/ muscles: 4% host populations, which may indirectly be approached by controlling the prevalence in animal intermediate hosts also. The first includes regular pharmacologic treatment and taking sanitary precautions for handling pets or meat to prevent infection and egg excretion.10 For the second, a vaccine for ruminant intermediate hosts is in evaluation.11 Prevention of human infection is strategically very difficult. CLINICAL FEATURES The initial phase of primary infection is always asymptomatic. The infection may then remain asymptomatic for years or even decades depending upon the size and site of the developing cyst or metacestode mass. After a highly variable incubation period, the infection may become symptomatic due to a range of different events. Cystic echinococcosis Dependent upon the size and the site of the developing hydatid cyst, the infection can remain asymptomatic for months, years or even longer. After a highly variable incubation period, the infestation may become symptomatic due to a range of different events. ■ The growing cyst exerts pressure on or induces dysformation of adjacent tissues, thus inducing dysfunction of the affected organ or vascular compromise. In the case of hepatic CE, signs and symptoms may include hepatomegaly with or without a palpable mass in the right upper quadrant, right epigastric pain, nausea, vomiting and occasionally cholestatic jaundice. In inoperable cases, hepatic compromise may lead to biliary cirrhosis and the Budd–Chiari syndrome. Infestation of the lungs may present with chronic cough, hemoptysis, bilioptysis, pneumothorax, pleuritis, lung abscess and parasitic lung embolism. Rare but often catastrophic infestations can affect the heart or the brain. In the heart this can present as tumor, pericardial effusion up to tamponade, complete heart block and sudden death. In the spine and brain presentation is as a tumor with the respective neurologic symptoms. Hydatid disease should be considered as a cause of stroke in young patients. ■ A cyst may rupture and spill its content into the adjacent site. Rupture into the biliary tree will mimic biliary colic or result in cholestatic jaundice and cholangitis or pancreatitis. This is the presenting symptom in 5–25% of patients. Ruptures in the liver but also in the lungs and other organs may result in acute anaphylactic shock reactions which usually represent the initial and life-threatening manifestation. ■ The cyst can become superinfected; in hepatic hydatid disease this occurs in about 9% of patients and is an indication for rapid surgical intervention.12 The majority of patients with CE have single organ involvement with solitary cysts. Simultaneous involvement of two or more organs is observed in 10–15% of patients, dependent on the geographical origin of the patient and the strain of the parasite. In hepatic CE, the right lobe is more frequently affected than the left lobe. Cyst size varies usually between 1 and 15cm in diameter. Cyst growth ranges between a size increase of a few mm (1/3 of the patients) to approximately 10mm (most of the patients); 1/10 of the patients exhibit a rapid increase with an annual average of 30mm. In Europe, the average age of patients at diagnosis is 36 years.Approximately 10% of the CE cases occur in children, and the rate of lung affection is significantly increased among this group of young patients. Pulmonary cysts occasionally become superinfected and this is best detected by CT scanning. The ratio of males to females may vary dependent on the geographical area but is statistically not significant overall. Hepatic alveolar echinococcosis In patients with hepatic AE, the size of the liver lesion will range between a few mm up to 50cm or more when patients present for diagnosis and initial treatment.2 Typical calcifications occur in 70% of cases and central or peripheral necrotic cavities are also found in approximately 70% of cases. Clinical signs at diagnosis include 3 GEOGRAPHIC AND TRAVEL MEDICINE PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL LIFE CYCLE OF ECHINOCOCCUS MULTILOCULARIS Fig. 169.3 Life cycle of Echinococcus multilocularis. This involves predominantly foxes as definitive hosts (1) and occasionally other carnivores such as domestic dogs or house cats. Egg production by the tapeworm starts as early as 28 days after infection (2). Eggs have to become ingested by a suitable intermediate host (3), including humans and various rodent species (4). As a result, the parasite metacestode primarily becomes established in the liver. Macroscopically, the typical lesion is characterized by a dispersed mass of fibrous tissue with a multitude of interconnected vesicles ranging from a few millimeters to centimeters in size (5). The lesion often contains focal necrotic zones with scattered calcifications, as demonstrated by CT (6). Histologically, the hepatic lesion consists of a conglomerate of small vesicles and cysts demarcated by a thin laminated layer with or without an inner germinal layer and, predominantly in the rodent intermediate host, protoscolex formation (7). Oral ingestion of protoscolex-containing metacestodes by definitive hosts completes the life cycle. 4 hepatomegaly-cholestasis-jaundice, secondary biliary cirrhosis, liver abscess, portal hypertension and Budd–Chiari syndrome. The disease starts frequently with nonspecific symptoms such as epigastric pain or cholestatic jaundice. In complicated cases, evidence of secondary biliary cirrhosis and/or cholangitis will be found. Evidence of cholestasis is frequently present, while transaminases are only rarely and moderately elevated, in particular when there is central necrosis. One of the most feared complications is infection of a necrotic cavity and/or obstructed bile ducts which are associated with very high mortality due to development of septic shock. Distant metastases can occur late in the disease; these have been described in brain, spine, lung and bone. Metastatic disease occurs in approximately 10–20% of patients. The growth rate of the metacestode tissue is usually slow in immunocompetent patients. Analysis by CT scans indicated an average volume increase of 15ml/year for progressive forms of AE. In Europe, the average age of AE patients at diagnosis is 55 years.2 Young children rarely develop AE, unless the cellular immune system is compromised.9 The ratio of males to females varies geographically, but any variation is not statistically significant. DIAGNOSIS Echinococcus granulosus In most cases, imaging procedures together with serology will yield the diagnosis. Sonography is the primary diagnostic procedure of choice for hepatic cases, although false positives occur in up to 10% of cases due to the presence of nonechinococcal serous cysts, abscesses or tumors.2 The main diagnostic features of hydatid disease include: ■ separation of the membrane from the wall, ■ daughter cysts, and ■ ruptured cysts. Computed tomography is the best investigation for detecting extrahepatic disease and volumetric follow-up assessment; MRI assists in the diagnosis by identifying changes in the intra- and extrahepatic venous system. Ultrasonography is also helpful in following up treated patients as successfully treated cysts become hyperechogenic. Calcification of variable degree occurs in about 10% of the cysts. Aspiration cytology appears to be particularly helpful in the detection of pulmonary, renal and other nonhepatic lesions for which human AE as well as cases in which the metacestode has died at an apparently early stage of infection (see above).3 Serologic tests are, however, of limited value for assessing the efficacy of treatment and chemotherapy. The best respective information is provided by the detection of anti-II/3–10 (and Em18) antibodies, a status reflecting the presence of viable metacestode lesions. Cellular immune tests show that the in vitro lymphoproliferative response to E. multilocularis antigen stimulation is high in cured patients who have had radical surgery and in patients with dead lesions, and is significantly lower in patients who have had partial or no surgical resection. Histopathological and immunohistochemical procedures to analyze surgically resected samples or biopsies obtained by FNAB include the use of species-specific MAbs such as MAbG1117 or molecular techniques such as PCR.18 MAJOR TROPICAL SYNDROMES BY BODY SYSTEM: SYSTEMIC INFECTIONS Hydatid Disease MANAGEMENT The management of CE and AE follows the strategy recommended by the guidelines produced by an OIE and WHO manual on echinococcosis, published in 2001.10 PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL imaging techniques and serology do not provide appropriate diagnostic support. The viability of aspirated protoscolices can be determined by microscopic demonstration of flame cell activity and trypan blue dye exclusion. Anti-Ag5 monoclonal antibody has been used for the detection of the respective antigen in diagnostic fine-needle aspiration biopsies (FNAB) from patients with suspected CE.13 Immunodiagnostic tests to detect serum antibodies or circulating antigens are used to support the clinical diagnosis of CE.14 The indirect hemagglutination tests and the enzyme-linked immunosorbent assay using E. granulosus hydatid fluid antigen are diagnostically relatively sensitive for hepatic cases (85–98%). For pulmonary cysts the diagnostic sensitivity is markedly lower (50–60%) and for multiple organ involvement very high (90–100%). These tests are usually used for primary serologic screening. Specificity is low for other cestode infections. To increase specificity, primary seropositive sera are retested using a confirmation test such as immunoblotting for a relatively specific 8kDa/12kDa hydatid fluid polypeptide antigen.14 Serologic studies to follow up patients with cystic echinococcosis postoperatively have emphasized the detection of circulating immune complexes or antigens. The detection of circulating parasite antigens proved useful for monitoring the course of disease and for assessing the extent of surgical removal of parasite lesions.14 Besides skin tests and basophil degranulation tests, diagnostic cellular immunodiagnosis has focused on in vitro lymphoproliferative responses to E. granulosus antigens. The diagnostic sensitivity of cellmediated immunodiagnosis is 75%, including the finding of seronegative patients with a positive proliferation test.14 Echinococcus multilocularis Among the imaging procedures, ultrasonography, CT and MRI are of greatest diagnostic value, none of those being uniquely superior.15 Irregularly dispersed clusters of calcifications on plain abdominal radiographs may give the first clue as to the etiology of the disease; the percentage of calcifications within the lesions increases from 30% to nearly 100% as the disease progresses. Hyperechogenic and hypoechogenic zones characterize the lesions. The cystic appearance may reflect central necrotic cavities. Similar findings can be found on CT and the lesions are typically not enhanced with contrast medium. The lesions are heterogeneous hypodense masses with irregular contours and lacking well-delineated walls. Hilar involvement can lead to liver atrophy, which is easily visualized by CT. Ultrasonography is the preferred imaging procedure for mass screening programs. MRI adds to diagnosis, in particular in cases with appropriate organ localization such as brain and bone, and to visualize pathologically altered microstructures in certain affected organs. Thus, MRI can give a precise analysis of the different components of the parasitic lesions such as necrosis and fibrosis.15 However, in contrast to CT microcalcifications are not visualized by MRI. Assessing the parasite via-bility in vitro following therapeutical interventions may be of tremendous advantage when compared to the invasive analysis of resected or biopsied samples. Such alternatives may be offered by magnetic resonance spectrometry (MRS) or positron emission tomography (PET). The PET technique has recently been used for assessing the efficacy of chemotherapy in AE.16 Immunodiagnosis represents a valuable secondary diagnostic tool complementary to imaging procedures and is useful for confirming the nature of the etiologic agent.14 Serologic tests are more reliable in the diagnosis of AE than CE. The use of purified E. multilocularis antigens such as the Em2 antigen or recombinant antigens II/3–10 (identical to EM10 and Em18) exhibits diagnostic sensitivities ranging between 91% and 100%, with overall specificities of 98–100%.14 These antigens allow discrimination between the alveolar and the cystic forms of disease with a reliability of 95%. Seroepidemiologic studies reveal asymptomatic preclinical cases of Echinococcus granulosus Surgery remains the mainstay in the treatment of hepatic hydatid disease. Cystectomy and pericystectomy offer a good chance for cure and should be undertaken wherever possible. Occasionally, formal hepatic resection will be required. Radical surgery – either pericystectomy or resection – is possible in 50–85% of cases. In the absence of complications this can be achieved with little mortality and an acceptable morbidity. Recently, laparoscopic pericystectomy has been demonstrated to be as safe and effective as open laparotomy in selected cases with hepatic and/or splenic involvement.19 If surgical removal of the cyst is contra indicated, treatment of CE has several alternatives such as PAIR (Puncture, Aspiration, Injection of an heminthicide and Reaspiration), chemotherapy or ‘wait and observe’ approach. Basically, indications for hepatic surgery include large liver cysts with putatively multiple daughter cysts; single liver cysts, situated superficially which may rupture spontaneously or as a result of trauma; bacterially superinfected cysts; cysts communicating with biliary tree and/or exerting pressure on adjacent vital organs; brain, heart and kidney cysts; spinal and bone cysts. Relative contraindications are inoperable cases as defined for surgical procedures in general; patients with cysts difficult to access; abortive cysts either partly or totally calcified. A direct communication between the hydatid cyst and the biliary tree may contraindicate the use of protoscolicidal solutions, which can cause chemical cholangitis leading to sclerosing cholangitis. Formalin should not be used for this reason. Effective protoscolicides with a relatively low risk of toxicity are 70–95% ethanol or 15–20% hypertonic saline solution. Preoperative chemotherapy with albendazole or mebendazole is indicated for reducing the risk of secondary echinococcosis after operation and should begin at least 4 days before surgery and be continued for at least 1 or preferably more months. Diagnostic puncture of hydatid cysts harbors the risk of cyst rupture and dissemination of protoscolices and is therefore not recommended. PAIR has become well justified in selected cases but it still needs to be practiced by experienced specialists.20 Indications for PAIR are: patients refusing surgery; infected cysts not communicating with the biliary vessel system; inoperable patients (see contraindications for surgery); pregnant patients; children 3 years; anechoic lesion ≥5cm in diameter; cysts with a regular double 5 GEOGRAPHIC AND TRAVEL MEDICINE REFERENCES 1. Gottstein B, Reichen J. Echinococcosis/hydatidosis. In: Cook GC, ed. Manson’s tropical diseases, 20th ed. London: Saunders; 1996:1486–508. 2. Amman RW, Eckert J. Cestodes: Echinococcus. Gastroenterol Clin North Am 1996;25:655–89. 3. Gottstein B, Saucy F, Deplazes P, et al. Is a high prevalence of Echinococcus multilocularis in wild and domestic animals associated with increased disease incidence in humans? Emerg Infect Dis 2001;7:408–12. 4. Rigano R, Profumo E, Siracusano A. New perspectives in the immunology of Echinococcus granulosus infection. Parassitologia 1997;39:275–7. 5. Rausch RL, Wilson JF, Schantz PM, McMahon BJ. Spontaneous death of Echinococcus multilocularis: cases diagnosed serologically by Em2-ELISA and clinical significance. Am J Trop Med Hyg 1987;36:576–85. 6. Sturm D, Menzel J, Gottstein B, Kern P. Interleukin-5 is the predominant cytokine produced by peripheral blood mononuclear cells in alveolar echinococcosis. Inf Immun 1995;63:1688–97. 7. Gottstein B, Bettens F. Association between HLA-DR13 and susceptibility to alveolar echinococcosis. J Infect Dis 1994;169:1416–7. 8. Eiermann TH, Bettens F, Tiberghien P, et al. HLA and alveolar echinococcosis. Tissue Antigens 1998;52:124–9. 6 and after surgery/PAIR when there is a risk of cyst rupture and release of protoscolices. Echinococcus multilocularis The following strategies are commonly accepted for treatment of AE: ■ the first choice of treatment is radical surgical resection of the entire parasitic lesion from the liver and other affected organs in all operable cases, with excision of the parasitic lesion following the rules of radical tumor surgery; ■ concomitant chemotherapy for all cases after radical surgery or after nonsurgical interventional procedures;21 and ■ long-term chemotherapy for inoperable or only partially resectable cases and all patients after liver transplantation.10 Presurgical chemotherapy is not indicated for AE. The daily dosage for albendazole and mebendazole treatment is the same as for CE. For albendazole, continuous treatment is well tolerated for a duration up to 6 years, and is replaced by the former discontinuous scheme (see above) only in cases with side-effects related to medication. For mebendazole, plasma drug levels should be over 74ng/ml (250nmol/1). Generally, the duration of treatment is at least 2 years after radical surgery or continuously for many years for inoperable cases or if resection is incomplete. As an ultimate goal liver transplantation has been proposed for a selected group of patients who have inoperable AE and chronic liver failure. However, the indications are limited and focus on cases with extensive lesions restricted to the liver and secondary liver disease leading to chronic liver failure,22 relapse rates frequently occurring due to extrahepatic metacestodes, which rapidly proliferate under immunosuppressed conditions. PR SA O M PE PL R E TY C O O F N E TE L N SE T V - N IE O R T FI N AL laminated layer; cysts with more than five septal divisions; multiple cysts (≥5cm in diameter) in different liver segments; relapse after surgery; failure to respond to chemotherapy. Relative contraindications for PAIR are inaccessible or risky location of the cyst in the liver; multiple septal divisions; cysts with echogenic lesions; inactive cysts or calcified lesions; communicating cysts; cysts located in the lung and bones and some others. It should not be performed when exophytic cysts or dilated bile ducts are observed on preoperative imaging. Treatment with benzimidazoles (preferably albendazole) is highly recommended for 4 days prior to intervention. After successful instillation of protoscolicides and reaspiration, benzimidazoles should be given for 3 months. Treatment of nonresected cysts with benzimidazoles (albendazole or mebendazole) results in cyst disappearance in 30% of cases; in 30–50% of patients there is cyst degeneration or a significant reduction in cyst size and in 20–40% of patients the cysts show no morphologic change.10 Indications for chemotherapy include inoperable patients as listed above. The formerly conventional dosage of albendazole (10–15mg/ kg/day in several 1-monthly courses with 14-day intervals) included three courses at minimum, and more than six courses were usually not necessary. This strategy is more and more replaced by continuous treatment, which demonstrated equal or improved efficacy without increased adverse effects when compared with cyclic treatment.21 For mebendazole, the usual dosage is 40–50mg/kg/day for at least 3–6 months. Praziquantel has been proposed as an additional antiprotoscolicidal drug to be given once a week in a dose of 40mg/kg along with benzimidazoles. It is also recommended before 9. Sailer M, Soelder B, Allerberger F, Zaknun D, Feichtinger H, Gottstein B. Alveolar echinococcosis in a six-year-old girl with AIDS. J Pediatr 1997;130:320–3. 10. Pawlowski ZS, Eckert J, Vuitton DA, et al. Echinococcosis in humans: clinical aspects, diagnosis and treatment. In: Eckert J et al., eds. WHO/OIE Manual on echinococcosis in humans and animals. Paris: WHO/OIE; 2001:20–71. 11. Lightowlers MW, Flisser A, Gauci CG, Heath DD, Jensen O, Rolfe R. Vaccination against cysticercosis and hydatid disease. Parasitol Today 2000;16:191–6. 12. Salinas JC, Torcal J, Lozano R, Sousa R, Morandeira A, Cabezali R. Intracystic infection of liver hydatidosis. Hepatogastroenterology 2000;47:1052–5. 13. Stefaniak J. Fine needle aspiration biopsy in the differential diagnosis of the liver cystic echinococcosis. Acta Tropica 1997;67:107–11. 14. Siles-Lucas S, Gottstein B. Review: molecular tools for the diagnosis of cystic and alveolar echinococcosis. Trop Med Int Health 2001;6:463–75. 15. Reuter S, Nüssle K, Kolokythas O, et al. Alveolar liver echinococcosis: a comparative study of three imaging techniques. Infection 2001;29:119–25. 16. Reuter S, Schirrmeister H, Kratzer W, Dreweck C, Reske SN, Kern P. Pericystic metabolic activity in 17. 18. 19. 20. 21. 22. alveolar echinococcosis: assessment and follow-up by positron emission tomography. Clin Inf Dis 1999;29:1157–63. Diebold-Berger S, Khan H, Gottstein B, Puget E, Frossard JL, Remadi S. Cytologic diagnosis of isolated pancreatic alveolar hydatid disease with immunologic and PCR analyses – a case report. Acta Cytologica 1997;41:1381–6. Kern P, Frosch P, Helbig M, et al. M. Diagnosis of Echinococcus multilocularis infection by reverse-transcription polymerase chain reaction. Gastroenterology 1995;109:596–600. Seven R, Berber E, Mercan S, Eminoglu L, Budak D. Laparoscopic treatment of hepatic hydatid cysts. Surgery 2000;128:36–40. Odev K, Paksoy Y, Arslan A, et al. Sonographically guided percutaneous treatment of hepatic hydatid cysts: long-term results. J Clin Ultrasound 2000;28:469–78. Reuter S, Jensen B, Buttenschoen K, Kratzer W, Kern P. Benzimidazoles in the treatment of alveolar echinococcosis: a comparative study and review of the literature. J Antimicrob Chemother 2000;46:451–6. Bresson-Hadni S, Miguet JP, Lenys D, et al. Recurrence of alveolar echinococcosis in the liver graft after liver transplantation. Hepatology 1992;16:279–80.
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