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Clinical Microbiology Reviews, January 2004, p. 107-135, Vol. 17, No. 1
0893-8512/04/$08.00+0 DOI: 10.1128/CMR.17.1.107-135.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Institute of Parasitology, University of Zurich, CH-8057 Zurich, Switzerland
SUMMARY INTRODUCTION E. GRANULOSUS AND CYSTIC ECHINOCOCCOSIS The Parasite and Its Life Cycle Cystic Echinococcosis in Humans Course of infection. Diagnosis. Treatment. (i) Surgery. (ii) Puncture-aspiration-injection-reaspiration. (iii) Percutaneous thermal ablation. (iv) Chemotherapy. E. granulosus Infection in Animals Defintive hosts. Intermediate hosts. Epidemiology Life cycle patterns. Transmission dynamics. Infection risk for humans. Global distribution of E. granulosus and CE in humans. Factors associated with persistence, emergence, or reemergence. Examples of emergence or reemergence. Control Options and Prevention E. MULTILOCULARIS AND ALVEOLAR ECHINOCOCCOSIS The Parasite and Its Life Cycle Alveolar Echinococcosis in Humans Course of infection. Diagnosis. Treatment. (i) Surgery. (ii) Chemotherapy. E. multilocularis Infection in Animals Defintive hosts. Intermediate and aberrant hosts. Epidemiology Parasite-host assemblages. (i) Arctic region. (ii) Sub-Arctic regions. Influences of landscape characters and rodent populations. (i) Factors related to larger regions. (ii) Factors related to macro- and microfoci. Eggs in the environment. Infection risk for humans. Global distribution in humans. Emergence and spread of E. multilocularis? (i) Risk areas and spreading. (ii) AE in humans as a risk indicator. (iii) Increasing fox populations and parasite prevalences. (iv) Invasion of urban areas by foxes. (v) Potential modes of spreading. Control Options and Prevention Control in definitive hosts. Precautions for individuals. Measures to reduce morbidity and mortality. Surveillance. E. VOGELI, E. OLIGARTHRUS, AND POLYCYSTIC ECHINOCOCCOSIS Life Cycles of the Parasites and Epidemiology Geographic Distribution and Prevalence Polycystic Echinococcosis in Humans Course of the infection. (i) E. vogeli echinococcosis. (ii) E. oligarthrus infection. Diagnosis. Treatment. Emergence or Spreading of Polycystic Echinococcosis? CONCLUSIONS ACKNOWLEDGMENTS REFERENCES
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| E. GRANULOSUS AND CYSTIC ECHINOCOCCOSIS |
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During the past four decades, considerable phenotypic and genetic variability has been observed within the species E. granulosus and several strains have been identified (Table 2) (150, 194, 195, 210). A common feature of all strains (except the lion strain) is the utilization of dogs and other canids as definitive hosts, but the strains exhibit several differences in intermediate host spectrum, geographic distribution, adult and metacestode morphology, maturation time in definitive hosts, organ localization of metacestodes, and protoscolex production (59). It has to be emphasized that at least seven of nine E. granulosus genotypes are infective to humans. Globally, most human cases of CE are caused by the sheep strain (G1) of E. granulosus. Information on the infectivity of the lion strain and the buffalo strain is not available. Currently, there is no evidence that the horse strain is infective to humans (59,195). This strain is widespread and common in Ireland, but to date autochthonous cases of human CE have not been observed. However, definitive conclusions regarding the infectivity of the horse strain should not be drawn unless strain typing has been performed for a larger number of human CE cases. An example in this respect is the camel strain of E. granulosus. Earlier, it was assumed that humans may not be susceptible to the autochthonous camel strain in Kenya since all 42 E. granulosus isolates of human origin were typed by restriction fragment length polymorphism-PCR as the sheep strain (216). However, the camel strain has recently been identified in human CE cases in Argentina, Nepal, and Iran (64, 175, 195, 224). According to Thompson and McManus (195) and Le et al. (128), special features revealed by genetic comparisons and phylogenetic analyses would justify recognition of the horse and the cattle strain of E. granulosus as separate species, namely, E. equinus and E. ortleppi, respectively.
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The initial phase of the primary infection is always asymptomatic. Small, well encapsulated, nonprogressive or calcified cysts typically do not induce major pathology, and patients may remain asymptomatic for years or permanently (3, 149). The induction of morbidity depends on the number, size, and developmental status of the cyst(s) (active or inactive), the involved organ, the localization of the cyst(s) within the organ, the pressure of cysts on surrounding tissues and structures, and the defense mechanisms of the infected individual. Ultrasonographic studies in South America have shown that the average diameter of cysts in asymptomatic carriers was significantly smaller (approximately 4 cm) than that in symptomatic patients (approximately 10 cm) (126). According to Perdomo et al. (151), approximately 88% of cysts detectable in asymptomatic carriers were <7.5 cm in diameter. An ultrasonographic survey in Italy revealed that 60% of 424 individuals with CE were asymptomatic (21).
Cyst growth is generally slow. In 14 asymptomatic cyst carriers in Argentina, the diameter of liver cysts increased by <3 to 4 cm in 6 patients and showed no modification in 8 individuals during a 10- to 12-year observation period (72, 126). Low growth rates were also reported for hepatic cysts in another Argentinian study of asymptomatic patients (126). There is evidence that liver cysts grow at a lower rate than lung cysts (126). However, the growth rates of cysts may vary between cysts in the same organ or in the same individual and between individuals in various regions. For example, in the Turkana district of Kenya, a region of high endemicity where CE caused high morbidity, higher growth rates of cysts were recorded. In an ultrasonography study of 66 patients, about 30% of the abdominal cysts grew slowly (1 to 5 mm per year), 43% showed moderate expansion (6 to 15 mm per year), 11% exhibited a more rapid increase (average of 31 mm and maximum of 160 mm per year), and 16% of the cysts did not expand or had collapsed (169,172). The latter finding shows that spontaneous involution of cysts is possible, which leads to changes in the ultrasonographic appearance of the cysts (see below).
Clinical signs may occur after a highly variable incubation period of several months or years. Frider et al. (72) observed that 21 (75%) of 28 carriers of liver cysts in Argentina remained asymptomatic during follow-up periods of 10 to 12 years after the initial diagnosis, while 7 (25%) developed symptoms related to their liver infection. Hepatic cysts can cause pain in the upper abdominal region, hepatomegaly, cholestasis, biliary cirrhosis, portal hypertension, ascites, and a variety of other manifestations (3, 149). Cysts may rupture into the peritoneal cavity, causing anaphylaxis or secondary CE, or into the biliary tree, leading to cholangitis and cholestasis. Abscess formation is possible after bacterial infection of cysts. Chronic cough, expectoration, dyspnea, hemoptysis, pleuritis, and lung abscess are selected symptoms caused by pulmonary cysts, and neurological disorders can be induced by cysts in the brain (3, 149). The modulation of T-lymphocyte responses plays an important role in the outcome of the infection. Th1 and Th2 responses have been associated with resistance and with susceptibility or severe forms of CE, respectively (215). The majority of patients produces various classes of serum antibodies which are not associated with protection but are valuable diagnostic indicators (28, 84).
CE occurs in age groups from younger than 1 to over 75 years. In some areas of endemic infection, most hospital cases are recorded in the age groups between 21 and 40 years, but the highest morbidity may also occur in younger individuals aged between 6 and 20 years (3, 149). An analysis of 8,596 individuals in areas of endemic infection in Uruguay has revealed a significant age-dependent increase of hepatic cysts detectable by ultrasonography from 0.33% in the age group from 0 to 9 years to 3.80% in the age group from 70 to 79 years (151). Similar observations were made in other areas of endemic infection (168). In most of the larger series of patients, there were no significant differences in the gender ratios of individuals with CE (25, 149, 151).
Diagnosis. The diagnosis of CE in individual patients is based on identification of cyst structures by imaging techniques, predominantly ultrasonography, computed tomography, X-ray examinations, and confirmation by detection of specific serum antibodies by immunodiagnostic tests (28, 84, 90, 114, 149, 192). For clinical practice it should be noted that the enzyme-linked immunosorbent assay (ELISA) using crude hydatid cyst fluid has a high sensitivity (over 95%) but its specificity is often unsatisfactory. If purified antigens (e.g., antigen B) or other techniques (immunoblot analysis, detection of immunoglobulin G4 (IgG4) antibodies, immunoelectropheresis, etc.) are used, specificity is improved but average sensitivity is much lower (Table 4). Furthermore, it should be remembered that approximately 10 to 20% of patients with hepatic cysts and about 40% with pulmonary cysts do not produce detectable specific serum antibodies (IgG) and therefore give false-negative results (3, 149). Cysts in the brain, bone, or eye and calcified cysts often induce no or low antibody responses (3). In routine laboratory practice, usually at least two different tests are used to get the most reliable results (for the differential diagnosis of CE and AE, see the discussion of diagnosis of AE, below). More details are given elsewhere (28, 84, 104, 168, 223).
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Classification of cyst types is an important basis for decisions about treatment options. A highly informative review of imaging techniques for diagnosing human echinococcosis has been published by von Sinner and Lewall (213). Recently, the World Health Organization (WHO) Informal Group on Echinococcosis has published an international consensus classification of ultrasonograms of hepatic cysts (222, 223).
Ultrasonography with portable equipment is used for surveys in the field. This technique is well accepted by the population, explores abdominal sites, identifies cyst types, and can be performed at relatively low cost (25, 149, 151, 185). Differential diagnosis of other space-occupying lesions (tumors, liver abscesses, etc.) can be difficult or impossible and may require the use of additional diagnostic techniques. A disadvantage of ultrasonography is that cysts in other sites (lung, brain, etc.) cannot be readily detected. Several comparative field surveys have shown that ultrasonography is much more precise in detecting abdominal cysts than are immunodiagnostic tests since the latter exhibit relatively high rates of false-negative and false-positive results (22, 28, 35, 168, 179, 185).
Treatment. There are several major options for treatment of CE, including surgery, puncture aspiration injection reaspiration (PAIR), and chemotherapy. For asymptomatic individuals, a "wait-and-observe" approach may be considered with supervision of the patient (101, 102, 115, 149).
(i) Surgery. Surgery, using various technical approaches (3, 142, 149), has the potential to remove the cysts and lead to complete cure. It can be successfully performed in a high proportion of patients with simple forms of CE (cyst number and organ involvement limited, cysts not in risky locations, disease not too far advanced). However, surgery may be impractical in other cases, predominantly in patients with multiple cysts in several organs, in patients with a high surgical risk, and if facilities for advanced surgery are inadequate. In such situations, PAIR or chemotherapy can be considered as alternative options of treatment.
The effect of pre- or postoperative chemotherapy for preventing secondary CE after spillage of cyst fluid during surgery is still unclear. For the PAIR technique (see below), experts recommend chemotherapy with albendazole 24 to 4 h before intervention and 15 to 30 days afterwards (222). The number of E. granulosus cysts developing from intraperitoneally inoculated protoscoleces in rodents could be reduced by 80 to 90% if albendazole treatment (10 mg/kg of body weight/day) for 1 week was initiated immediately after inoculation, but treatment starting 15 days after inoculation was ineffective (143). Data on praziquantel treatment are contradictory. In a previous study (165), the drug reduced protoscolex viablity by 65 to 82% when applied in vitro at a concentration of 0.1% for 10 min. According to a recent publication, a 0.1% praziquantel solution had no marked protoscolicidal effect in vitro after 1 h but was strongly effective at 1% after 30 min (100). In mice, treatment with high doses of praziquantel (600 mg/kg of body weight/day on 5 days per week) for 4 months did not significantly influence established E. granulosus cysts. When the same treatment was initiated 43 h after intraperitoneal application of protoscoleces, a high prophylactic effect was achieved, as indicated by a 99% reduction in cyst numbers (208). However, the drug doses used in this experiment are much higher than those used in humans (e.g., for a Schistosoma mansoni infection, a single dose of 40 mg/kg of body weight was recommended).
(ii) Puncture-aspiration-injection-reaspiration. PAIR was introduced in the mid-1980s (14, 67, 69, 73, 117). It is a minimally invasive technique and includes the following steps: (i) percutaneous puncture of the cyst under ultrasonographic guidance, (ii) aspiration of a substantial portion (for example, 10 to 15 ml) of the cyst fluid, (iii) injection of a parasitocidal solution (95% ethanol; approximately an equivalent of one-third of the amount aspirated), and (iv) reaspiration of the fluid content after 5 min (222). Hypertonic NaCl solution (at least 15% [final concentration] in the cyst fluid) can also be used as a parasitocidal solution, but its action is slower, so that reaspiration is performed only after 15 to 20 min (116, 222).
A guideline for the performance of PAIR has recently been published (222). PAIR should always be performed by skilled and experienced physicians well prepared to deal with complications. According to expert recommendations, PAIR should be accompanied by chemotherapeutic coverage to minimize the potential risk of secondary echinococcosis (149, 221, 222). In this indication, albendazole is applied in daily oral doses of 10 mg/kg of body weight 24 to 4 h before and 15 to 30 days after the intervention (222). More studies are needed to evaluate the efficacy and optimize this treatment schedule.
PAIR is indicated for univesicular hepatic cysts of 
5 cm in diameter (types CEL and CE1 according to the international classification [222]), for cysts with daughter cysts (type CE2) (Fig. 3), for cysts with detached membranes (type CE3), and also for multiple cysts if accessible to puncture (222). The main contraindications for PAIR are cysts communicating with the biliary tree, cysts in a risky or inaccessible location in the liver, cysts free in the abdominal cavity, and cysts in the lungs, heart, brain, or spine (149, 222).
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PAIR interventions in more than 2000 patients had a high rate of efficacy and generally a low rate of complications (67, 116, 137, 209, 222). There are indications that PAIR has several detrimental effects to the parasite, including (partial) detachment of endocyst membranes from the pericyst and/or damage of the germinal layer and protoscoleces by the parasitocidal solution. A recent international survey of PAIR treatments performed in various hospitals showed the following results (68). Treatment of 765 abdominal cysts, mostly hepatic, almost always resulted in various degrees of size reduction (at least 50%) and involution of the cysts, except for two failures (0.26%). A >5-year follow-up of approximately 10% of the cysts and a <5-year follow-up of 90% revealed 12 recurrences (1.6%). Major complications occurred in four patients (0.52%), with one death (0.13%) and spillage of hydatid fluid in four patients (0.52%); 13.7% of the patients had minor complications. Ustunsoz et al. (209) have reported a 97% cure rate of PAIR in 70 Turkish patients with a mean follow-up of 37 months and only two (3%) recurrences.
(iii) Percutaneous thermal ablation. A new approach of treatment involves percutaneous thermal ablation (PTA) of the germinal layer in the cyst by using a radiofrequency ablation device. Brunetti and Filice (18) have used PTA for treating two patients with hepatic cysts; more experience with this technique is needed. PTA would have the advantage that injection of parasitocidal substances into the cyst is unnecessary.
(iv) Chemotherapy. Chemotherapy with benzimidazoles (albendazole or mebendazole) is indicated for patients with inoperable CE and for those with multiple cysts in two or more organs. Cysts located in bones are less susceptible to chemotherapy. According to WHO recommendations, albendazole is given in daily doses of 10 to 15 mg/kg of body weight in two divided doses postprandially for 3 to 6 months. The usual dose of mebendazole is 40 to 50 mg/kg of body weight per day for at least 3 to 6 months (115, 221, 222). Results for over 2,000 well-controlled cases treated with benzimidazoles and evaluated for up to 12 months have shown that cysts disappeared in 10 to 30% of the patients (cure), there was objective evidence of response in 50 to 70% (degeneration or size reduction of cysts), and 20 to 30% did not exhibit morphological changes of the cysts (101, 102, 149, 197, 198). Relapses after chemotherapy have been observed in 14 to 25% of patients, but are usually sensitive to retreatment (149). In a comparative study with 448 patients, Franchi et al. (70) assessed the efficacy of mebendazole and albendazole treatment (3 to 6 months) and found degenerative changes in 82% of the cysts in the albendazole group and in 56% in the mebendazole group (P < 0.001). Relapses were observed in 25% of the cysts. Side effects of chemotherapy are generally mild and rarely treatment limiting (3, 101, 221, 223). Although the efficacy of chemotherapy is not satisfactory and the costs are high, it is an option of treatment, predominantly for inoperable cases.
The diagnosis of intestinal E. granulosus infection in living dogs is difficult because the small proglottids spontaneously discharged with feces are usually overlooked and eggs detected by routine coproscopic techniques cannot be differentiated by light microscopy from the eggs of other Echinococcus species or of Taenia species. ELISAs for detecting parasite antigens in fecal samples (coproantigens) have been used in specialized laboratories for the last few years (29, 40). Recently, a PCR for specific detection of DNA from E. granulosus eggs has been developed (A. Mathis and P. Deplazes, unpublished data) (Table 5). The coproantigen ELISA has a reasonable sensitivity and a high specificity and can be used as a screening test for individual dogs or for dog populations (Table 5). One of the advantages of this test is that about 200 samples can be examined by one person per day (41). The more sophisticated PCR can be used as a highly sensitive and specific secondary test for confirming or excluding an E. granulosus infection (Table 5). Postmortem examination of definitive hosts for Echiococcus species requires special techniques (Table 5), which are described elsewhere in detail (54). Praziquantel is the drug of choice for treating infected dogs (reviewed in reference 54) (see "Control options and prevention" below).
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Transmission dynamics. During the past four decades, considerable advances have been made in understanding the epidemiological key factors and the transmission dynamics of E. granulosus and other members of the family Taeniidae (notably Taenia hydatigena and T. ovis). A mathematical model was developed which allows us to quantify various factors contributing to the regulation and stability of the parasite populations and to draw conclusions for control (74, 78, 85, 166, 167, 199, 200). For Taenia species, the following key factors have been identified (78): (i) biotic potential of the parasite, (ii) immunity acquired by the intermediate host as a density-dependent constraint, and (iii) environmental factors as density-independent constraints in the free-living egg-phase.
T. hydatigena and T. ovis have high biotic potentials with the production of large numbers of eggs and large numbers of metacestode cysts developing in sheep. In contrast, the biotic potential of E. granulosus is relatively low, representing less than 5% of the potentials of T. hydatigena and T. ovis (75). Results of previous studies have suggested that the degree of immunity acquired by definitive hosts during natural infections with E. granulosus is negligible and does not play a role in regulating the intestinal parasite population (75). Experiments to stimulate strong immunity against intestinal stages of E. granulosus in dogs have failed so far (92). Recent observations from Tunisia and Kazakhstan, where young dogs are more heavily infected than older dogs, should stimulate new basic studies of the immune responses of dogs to intestinal cestode infections (199).
On the other hand, acquired immunity in intermediate hosts has clearly been identified as a density-dependent constraint reducing the parasite (metacestode) population of Taenia species. A considerable degree of immunity against T. hydatigena and T. ovis is acquired by sheep within about 2 weeks after ingestion of small numbers of eggs (as few as 10 eggs per animal); it persists life-long in the presence of eggs in the environment but is lost between 6 and 12 months in the absence of eggs, and it does not depend on the presence of metacestodes from a previous infection (74, 75). Strong immunity can also be experimentally induced against E. granulosus, but it requires much larger numbers of eggs (approximately 50,000 eggs per animal) (199). Consequently, sheep populations do not develop strong immunity against E. granulosus under natural infection pressure, as indicated by the fact that both the prevalence and intensity of the infection with cysts of E. granulosus increase with age of sheep (123, 124, 206).
Environmental temperature and humidity influence egg survival and infectivity but do not regulate the parasite population. E. granulosus eggs can survive under humid conditions for several weeks or months in areas of warm and cold climates, but they are sensitive to desiccation (55, 75). Several factors play a role in egg dispersal (75, 78) (see also "Eggs in the environment" below).
Infection risk for humans. Humans acquire primary CE by oral uptake of E. granulosus eggs excreted by infected carnivores. The infection may be acquired by handling infected definitive hosts, egg-containing feces, or egg-contaminated plants or soil followed by direct hand-to-mouth transfer. It has been shown that Echinococcus eggs adhere to the coat of dogs, particularly to the hairs around the anus and on the thighs, muzzles, and paws. The same applies to dogs infected with Taenia species and to foxes infected with E. multilocularis (55). Eggs can also be ingested with vegetables, salads, uncooked fruits, and other plants which have become contaminated. Foodstuffs or surfaces may possibly be secondarily contaminated with Echinococcus eggs via wind, birds, beetles, and flies (55). Also, drinking water contaminated with Echinococcus eggs by the feces of infected carnivores is a potential source of infection (see below). Prenatal transfer of E. granulosus does not play a role (26).
Very little is known about the relevant modes of E. granulosus egg transmission to humans. Campos-Bueno et al. (20) in Spain have evaluated several risk factors in a case-control study involving 127 patients with proven CE cases and 127 controls matched by sex, age, and residence. The risk of infection was highest in small places with up to 500 inhabitants and increased with the number of dogs in the family and the number of years of coexistence with them. Further important risk factors were dogs having access to raw viscera of slaughter animals and dogs kept loose and able to enter dwellings. Surprisingly, the ingestion of products from family vegetable gardens over prolonged periods was not associated with an increased risk for CE. In a case-control study in Argentina, one of the risk factors for CE was spending the first years of life surrounded by a large number of dogs (125). In Tibetan aeras of China (Sichuan), increased risks for CE were associated with nomadic life, age, playing with dogs, not protecting food from flies, and raising yaks or sheep (217). In studies in Jordan (43) and Kyrgystan (204), multivariate analysis revealed the use of potentially contaminated water as the only statistically significant risk factor for humans, but confounding factors could not be excluded. Water wells were also suspected as sources of infection with E. granulosus in arid areas of Africa where humans and carnivores frequently use the same water points (132). In a cross-sectional survey in an area of endemicity in mid-Wales (United Kingdom), no significant association could be found between treatment of humans for CE and many of the well-established risk factors, such as dog or farm ownership (44). The identification of risk factors is generally difficult for various reasons, such as small sample sizes, long time interval between infection and diagnosis of CE, and high mobility of patients and migration of definitive hosts. Molecular approaches allowing the species-specific identification of Echinococcus eggs in the environment will open up new opportunities for the study of transmission routes (see "E. multilocularis infection in animals" below).
Global distribution of E. granulosus and CE in humans. Due to the lack of well-documented data from many countries, the global picture of the current situation is incomplete. However, a recent review (58) has shown that E. granulosus is known to occur on all continents and in at least 100 countries (Fig. 5). High parasite prevalences are found in parts of Eurasia (for example, the Mediterranean region, the Russian Federation and adjacent independent states, and China), Africa (northern and eastern regions), Australia, and South America. In some European countries or regions, the annual incidences (AI) of hospital cases of human CE vary between <1 and >8 per 100,000 population. In China, CE is regarded as one of the major public health problems (220). In Xinjiang, the average AI was 8.7 per 100,000 in 1990 but the AI was up to 42 per 100,000 in one of the counties (140). In Sichuan province, human CE had a prevalence of 2.1% (85/3,998) in 1997 to 1998 (217). High incidence rates or prevelances have also been recorded from countries in northern and eastern Africa (prevalences of >3%) and South America (for example; an AI of 9.2 per 100,000 population in Uruguay in 1995). A few islands are free of E. granulosus (Iceland and Greenland), and in some islands only very sporadic, cases have been detected in domestic animals in recent years ("provisionally free") (New Zealand, Tasmania, southern Cyprus). The occurrence of E. granulosus is sporadic or has not been reported from other regions, including countries or regions in northern and central Europe, in North and Central America, in the Pacific Region, and in the Caribbean.
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Examples of emergence or reemergence. Reports from several countries provide documented evidence for the emergence or reemergence of E. granulosus and CE in recent years. For example, in Bulgaria the annual incidence of CE in children has increased from 0.7 per 100,000 in 1971 to 1982 to 5.4 in 1995 (196). Other reports indicate an alarmingly high prevalence of E. granulosus in humans and animals in some countries of the Mediterranean region (12). In Kazakhstan the annual surgical incidence of CE over the whole country was below 1.4 per 100,000 inhabitants from 1988 until 1995 but has increased to approximately 2.5 in 1997 and to 5.9 in 2000; 29% of the cases were in children younger than 14 years, indicating recent transmission (182, 183, 203). In the South Kazakhstan Oblast, the prevalence of E. granulosus cysts was 13.6% in 5,968 sheep prior to independence and 37.0% in 917 sheep in the same area in 1999 to 2000 (203). A similar trend has been identified in Kyrgystan (203, 204), where the annual incidence of CE per 100,000 inhabitants has increased over the whole country approximately threefold from 5.4 cases in 1991 to 18 in 2000. Hospital admissions due to CE in the capital, Biskek, have increased 5.9-fold from 21 cases in 1990 to approximately 124 in 1999; the increase of pediatric cases was 41 times higher in 2000 (82 cases) than in 1990 (2 cases) (204). These data are supported by ultrasonography cross-sectional surveys of 8,777 persons between 1989 and 1994 and 1,486 subjects between 1991 and 2000; in this period, the prevalence had increased significantly, from 0.42 to 1.35% (204).
The data from Bulgaria, Kazakhstan, Kyrgystan, and some other regions provide strong evidence for a real increase or reemergence of the incidences and prevalences in recent years, which is not attributable to improved diagnosis or reporting.
Great efforts have been made in Australia and New Zealand to develop vaccines which can protect sheep or cattle against infections with metacestode stages of taeniid cestodes. A recombinant vaccine against Taenia ovis in sheep has been successfully developed by using antigens derived from oncopheres (108, 129). Similar vaccines were developed against T. saginata in cattle, T. solium in pigs, and E. granulosus in sheep and cattle (93, 129). Large controlled studies with sheep have shown that vaccination with a recombinant oncospheral E. granulosus antigen (EG95) induces high degrees of protection, reducing the cyst numbers in vaccinated animals by approximately 90 to 100% (93, 95, 107, 129, 130). A high degree of immunity (about 80%) persists for 6 months (in the absence of reinfection), and pregnant ewes vaccinated before lambing transfer high levels of antibody to their lambs (94).
A recent mathematical simulation suggests that a combination of regular dosing of dogs with praziquantel and vaccination of intermediate hosts would destabilize the system more rapidly than other control options (200). Regrettably, the vaccine is not yet commercially available.
Problems of safety precautions and disinfection have been neglected in research. A review of the current state of art has been published in the WHO/OIE Manual on Echinococcosis (55). Essential precautions are summarized as follows. (i) Personnel involved in handling animals infected with mature intestinal stages of Echinococcus spp. or egg-contaminated materials should weare protective clothing (cap, face mask, safety glasses, single-use overall, plastic apron, rubber gloves, and boots). (ii) For work with infected definitive hosts (for example, treatment of dogs), their intestines, fecal matter, or other materials possibly containing infective Echinococcus eggs, special rooms or sterile bench systems should be used. In some countries, a BL-3 biohazard safety level is required. (iii) Whole carcasses of carnivores, intestines, or fecal sample possibly containing infective Echinococcus eggs can be decontaminated by deep-freezing at -70 to -80°C. Care should be taken that the effective temperature reaches all parts of the material and is maintained for at least 96 or 48 h, respectively. The temperatures of household deep-freezers are too high to inactivate eggs. Echinococcus eggs are killed within 5 min at +60 to 80°C and instantly at + 100°C. (iv) Persons who have had a single exposure to infected final hosts or egg-contaminated materials or who have ingested apparently contaminated food should receive serological screening for specific antibodies at the following intervals after the suspected contact: 4 weeks and 6, 12, and 24 months. Individuals with repeated infection risk (for example, laboratory personnel, field workers in echinococcosis control) should be serologically examined twice a year.
In areas which are free of E. granulosus or have only sporadic occurrence of the parasite, special measures should be taken in order to prevent the introduction of the parasite by living definitive or intermediate host animals.
| E. MULTILOCULARIS AND ALVEOLAR ECHINOCOCCOSIS |
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During the infection with E. multilocularis metacestodes, parasite-specific humoral and cell-mediated immune responses are both progressively established. The latter may play a crucial role in host defense (86). Immunological studies of mice experimentally infected with E. multilocularis have revealed an initial Th1 dominant cytokine secretion, including interleukin-2 (IL-2) and gamma interferon. This is associated with slow parasite proliferation. Rapid growth of the parasite was associated with secretion of Th1- and Th2-type cytokines including IL-5 and IL-10. Finally, in animals with advanced AE, suppression of immunity was observed associated with almost complete inhibition of cytokine secretion by lymphocytes on specific or unspecific in vitro stimulation, (63, 214, 215). A varying, spontaneous cytokine secretion was also observed in patients in different phases of AE. In patients with progressive disease, IL-10 secretion by peripheral mononuclear cells was more pronounced and IL-10 levels in serum were higher than in individuals with abortive forms (82, 83, 218).
Other studies suggest that the formation of the laminated layer by the metacestode inhibits or prevents immunological control of parasite proliferation. In recent studies of a laminated layer-associated antigen (Em2G11), a high-molecular-weight mucin-type glycosylated protein could be identified (103). This protein stimulates antibody production in the absence of major histocompatibility complex class II- restricted T-cell help. In addition, it does not stimulate cell proliferation in vitro. Therefore, it is claimed to be a relevant factor contributing to the lack of protection against the metacestode in vivo (31). The mouse model has provided much useful information; however, due to the rapid parasite development in mice, it might not be an appropriate model for the study of all mechanisms involved in human AE.
Diagnosis. Essentially the same procedures are used for diagnosing AE in human patients as for diagnosing CE (3, 112, 149). Among the imaging techniques, ultrasonography is the method of choice for screening; it is usually complemented by computed tomography, which detects the largest number of lesions and characteristic calcifications. Magnetic resonance imaging may facilitate the diagnosis in unclear cases (164). Immunodiagnostic tests (for primary diagnosis or confirmation of imaging results) are more reliable in the diagnosis of AE than of CE since more specific antigens are available (Table 4). For example, the Em2plus-ELISA, using a mixture of affinity-purified E. multilocularis metacestode antigens (Em2-antigen) and a recombinant antigen (EmII/3-10), exhibited a diagnostic sensitivity of 97% in 140 patients with confirmed AE and an overall specificity of 99% for infections due to other helminths (87). However, the use of this test in a broader spectrum of patients has revealed lower sensitivity (approximately 85%) and specificity (>95%) (168). Immunoblot tests using the EM18 antigen are reported to have sensitivities between 50 and 90% and specificities of >95% (168) (for further details, see references 84, and 104).
The diagnosis can be confirmed by parasite identification in surgical or biopsy material. In most of the cases, histological examination is sufficient, but recognition of characteristic structures in fine-needle biopsy specimens or calcified samples may be difficult or impossible. In such cases, the specific Em2G11 antigen can either be detected immunhistologically or in an ELISA using a monoclonal antibody (39). This antigen persists in calcified lesions within fragments of the laminated layer even after the death of the parasite. Furthermore, specific PCRs targeting the U1 small nuclear RNA gene or the mitochondrial 12S rRNA gene (16, 42) can be used. The viability of the parasite can be assessed by transplanting metacestode tissue samples to laboratory rodents (50). Another option is the use of reverse transcription-PCR (111). The sensitivities of both techniques depend on the amount and quality of the sample material. Puncture of the liver of a human with AE includes a risk of dissemination of parasite material and may require postinterventional chemotherapy.
Immunodiagnostic tests (alone or in combination with ultrasonography) have been used for screening human populations for AE in various countries, for example in Alaska, Austria, China, France, Germany, Japan, and Switzerland (10, 17, 30, 81, 88, 174, 189). In view of the low prevalence of the infection in most areas of endemic infection, it is essential to use highly sensitive and specific test systems. The largest mass-screening program was carried out in Japan (55, 178, 189). In Hokkaido (population of 5.8 million), 715,841 individuals received serological primary screening during 1984 to 1993. Overall, 5,159 individuals had a positive ELISA reaction, 1,272 persons underwent secondary ultrasonographic screening, and, finally, 60 persons (0.008% of the total) were shown to have asymptomatic AE (189). Eearly detection of AE by mass screening can be cost-effective and reduces morbidity, suffering, and mortality (55). In Hokkaido, the rate of complete surgical excision of liver lesions in the group of screened individuals was 100%, in contrast to a resectability rate of only 20% in nonscreened patients in whom AE was detected at a later stage (55).
Treatment. There are several options for treatment, including surgery, chemotherapy, and interventional procedures (2, 3, 113, 149, 221). Liver transplantation is rarely indicated and has a relatively high risk of postoperative metastasis formation (149). This is due to minor parasite remnants, which cannot be resected and proliferate under immunosuppression. Recommendations for treatment have been published by the WHO Working Group on Echinococcosis (221, 223).
(i) Surgery. The first-choice treatment in all operable cases is radical resection of the entire parasite lesion(s) from the liver and other affected organs by using procedures of radical tumour surgery (3, 113, 149, 221). Radical surgery is possible in virtually all cases diagnosed in an early stage but in only 20 to 40% of the advanced cases (3, 113, 178, 221). It may lead to complete cure, but resection is often incomplete because of diffuse and undetected parasite infiltration into host tissues. Therefore, according to WHO recommendations, postsurgical chemotherapy should be carried out for at least 2 years, with monitoring of the patients for a minimum of 10 years for possible recurrence (221, 223). In one case, despite postoperative medication with mebendazole for 2.5 years, a recurrence was observed in a patient 14 years after radical surgery (3).
(ii) Chemotherapy. Chemotherapy is recommended for a limited period (at least 2 years) after radical surgery (see above) and for long-term periods (from many years to life-long) after incomplete resection of lesions in inoperable cases and after liver transplantation (see the above remarks on liver transplantation) (221, 223). Chemotherapy of infected laboratory rodents with mebendazole and albendazole, applied at high oral doses over at least 2 months, causes destruction of protoscoleces, damage of the germinal layer, inhibition of metacestode proliferation, and metastasis formation but does not usually kill the parasite (46).
For chemotherapy of AE in humans, mebendazole is given at daily doses of 40 to 50 mg/kg of body weight in three divided doses. Albendazole is given at daily doses of 10 to 15 mg/kg of body weight in two divided doses (149, 221). Albendazole is licensed for cyclic treatment, i.e., 28 days of treatment followed by 14 days without chemotherapy, but continuous treatment is also practised (see below). Both drugs should be taken with a fat-containing meal (221, 223). The evaluation of treatment success in human AE is difficult because there are no methods allowing a direct assessment of the parasite's activity status (alive or dead). The most reliable indirect criteria are (i) long-term survival rates of patients, (ii) lack of disease progression and improvement of the clinical status, (iii) decrease or arrest of parasite proliferation, and (iv) lack of recurrence. The size and structure of the parasite lesions are evaluated at regular intervals (approximately 6 to 12 months) by ultrasonography and computed tomography. Serology using specific tests has only some value in cases after radical operation. In a Swiss study, 110 patients with nonresectable AE had received long-term chemotherapy (mainly with mebendazole) for 9.4 ± 5.8 years and were under follow-up observation for 12.8 ± 6.9 years (4). This therapy resulted in an increased 10-year survival rate of approximately 80% (versus 29% in untreated historical controls) and a 16- to 20-year survival rate of approximately 70% (versus 0% in historical controls) (4). The optimal duration of treatment has not yet been determined. In a group of 19 patients with nonresectable AE, long-term mebendazole therapy (average duration, 4.3 years) was ceased because there was no evidence of parasite activity (6). Recurrence occurred in seven patients (37%) within an average of 1.6 years after discontinuation of chemotherapy. On the other hand, there is evidence that in some cases long-term chemotherapy can be parasiticidal rather than merely parasitostatic (5).
Recently, Reuter et al. (163) have compared the efficacies of mebendazole and albendazole in 35 AE patients, 12 of whom had extrahepatic lesions. The average time of treatment was 24 months
