Biological, Epidemiological, and Clinical Aspects of Echinococcosis, a Zoonosis of Increasing Concern

Johannes Eckert; Peter Deplazes

doi:10.1128/CMR.17.1.107-135.2004

. 2004 Jan;17(1):107–135. doi: 10.1128/CMR.17.1.107-135.2004

Biological, Epidemiological, and Clinical Aspects of Echinococcosis, a Zoonosis of Increasing Concern

Johannes Eckert ^1,^*, Peter Deplazes ¹

PMCID: PMC321468 PMID: 14726458

Abstract

Echinococcosis in humans is a zoonotic infection caused by larval stages (metacestodes) of cestode species of the genus Echinococcus. Cystic echinococcosis (CE) is caused by Echinococcus granulosus, alveolar echinococcosis (AE) is caused by E. multilocularis, and polycystic forms are caused by either E. vogeli or E. oligarthrus. In untreated cases, AE has a high mortality rate. Although control is essentially feasible, CE remains a considerable health problem in many regions of the northern and southern hemispheres. AE is restricted to the northern hemisphere regions of North America and Eurasia. Recent studies have shown that E. multilocularis, the causative agent of AE, is more widely distributed than previously thought. There are also some hints of an increasing significance of polycystic forms of the disease, which are restricted to Central and South America. Various aspects of human echinococcosis are discussed in this review, including data on the infectivity of genetic variants of E. granulosus to humans, the increasing invasion of cities in Europe and Japan by red foxes, the main definitive hosts of E. multilocularis, and the first demonstration of urban cycles of the parasite. Examples of emergence or reemergence of CE are presented, and the question of potential spreading of E. multilocularis is critically assessed. Furthermore, information is presented on new and improved tools for diagnosing the infection in final hosts (dogs, foxes, and cats) by coproantigen or DNA detection and the application of molecular techniques to epidemiological studies. In the clinical field, the available methods for diagnosing human CE and AE are described and the treatment options are summarized. The development of new chemotherapeutic options for all forms of human echinococcosis remains an urgent requirement. A new option for the control of E. granulosus in the intermediate host population (mainly sheep and cattle) is vaccination. Attempts are made to reduce the prevalence of E. multilocualaris in fox populations by regular baiting with an anthelmintic (praziquantel). Recent data have shown that this control option may be used in restricted areas, for example in cities, with the aim of reducing the infection risk for humans.

INTRODUCTION

Echinococcosis is a zoonotic infection caused by cestode species of the genus Echinococcus. The life cycles of these parasites involve two mammalian hosts (see Fig. 1). The adult cestode inhabits the small intestine of a carnivore (definitive host) and produces eggs containing infective oncospheres. Either cestode segments (proglottids) containing eggs or free eggs are released from the intestinal tract of the carnivore into the environment. After oral uptake of eggs by an intermediate host animal, a larval stage, the metacestode, develops in internal organs. Typically, the mature metacestode produces numerous protoscoleces, each having the potential to develop into an adult cestode after being ingested by a suitable definitive host. Accidentally, eggs are also ingested by humans and other “aberrant” hosts that do not play a role in the natural cycle. On rare occasions, the spectrum of aberrant hosts may even include definitive hosts (i.e., dogs). Whereas the infection of carnivores with immature or mature intestinal stages of E. granulosus does not cause morbidity, the invasion of various organs (mainly liver and lungs) of intermediate or aberrant hosts by metacestodes can cause severe and even fatal disease (echinococcosis).

FIG. 1. — Life cycle of *E. granulosus* (common sheep strain). (A) Adult parasite. (B) Domestic dog as principal definitive host; wild canids (dingo, hyena etc.) can be involved in the cycle. (C) Proglottid with eggs. (D) Egg with oncosphere. (E) Infection of humans. (F) Sheep as principal intermediate hosts; other ungulates are of lower significance. (G) sheep liver with cysts.

Of three forms of echinococcosis occurring in humans (Table 1) cystic echinococcosis (CE) and alveolar echinococcosis (AE) are of special importance due to their wide geographic distribution and their medical and economic impact. Polycystic echinococcosis is less frequent and is restricted to Central and South America.

TABLE 1.

Forms of echinococcosis in humans^a

Name of disease (according to WHO/OIE; [223])	Cystic echinococcosis	Alveolar echinococcosis	Polycystic echinococcosis
Causative agent	E. granulosus	E. multilocularis	E. vogeli	E. oligarthrus
Other names of the disease	Hydatid disease, hydatidosis	Alveolar hydatid disease	E. vogeli echinococcosis, neotropical echinococcosis	E. oligarthrus echinococcosis, neotropical echinococcosis
Adult parasite
Length (mm)	2.0-7.0	1.2-4.5	3.9-5.6	2.2-2.9
No. of proglottids	3 (4-6)	5 (2-6)	3	3
Definitive hosts	Domestic dog, wild canids (coyote, dingo, red fox, etc.)	Red fox, arctic fox, raccoon dog, coyote, domestic dog, cat	Bush dog, domestic dog	Wild felidae: pampas cat, Geoffroy's cat, ocelot, jaguar, cougar, jaguarundi, puma, bobcat
Intermediate hosts	Primarily ungulates, also marsupials	Rodents, other small mammals	Rodents: paca and agouti	Rodents: agouti, spiny rat, paca
Geographic distribution of the parasite	Worldwide	North America, northern and central Eurasia	Central and South America	Central and South America
Larval parasite in humans
Organ localization	Visceral, predominantly liver and lungs	Visceral, primarily liver, metastases in lungs, brain, bones, etc.	Visceral, mainly liver, abdomen, lungs	Orbita, heart
Morphology	Fluid-filled mostly solitary (and less frequently multiple) cysts, unilocular or multichambered, diam 1->15 cm (Fig. 2); often with protoscoleces	Masses of numerous small cysts (diam microscopic up to 3 cm), often interconnected, surrounded by dense connective tissue, no cyst fluid, appearance of cheeselike mass, sometimes with central necrosis (Fig. 7); rarely a few protoscoleces	Polycystic; fluid-filled cysts, diam up to 4-6 cm, solitary, but often aggregated, interconnected and multichambered; thick laminated layer; protoscoleces frequently present	Fluid-filled cysts with tendency for multicystic development, less subdivision than in E. vogeli, and laminated layer thinner; protoscoleces formed.
Type of growth in humans	Concentric expansion	Exogenous proliferation, tumorlike, infiltrative	Exogenous and endogenous proliferation	Expansive, no indication of exogenous proliferation

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Data from references 156 to 158 and 194.

This review is focused on selected biological, clinical, and edpidemiological aspects, including the emergence or reemergence of infections in regions where they were previously absent or found at lower levels.

E. GRANULOSUS AND CYSTIC ECHINOCOCCOSIS

The Parasite and Its Life Cycle

E. granulosus is a small tapeworm (approximately 2 to 7 mm in length) with typically three segments and other morphological characteristics which allow a species diagnosis (193) (Table 1). In the natural cycle, dogs and other canids are typical definitive hosts and ungulates (sheep, goats, pigs, horses, etc.) intermediate hosts (Fig. 1). The latter harbor the metacestode stage. This stage can also develop in a broad range of other mammals, such as marsupials, hares, rabbits, rodents, carnivores, nonhuman primates, and humans. These and other hosts play a role in the transmission cycle (intermediate hosts) or are dead ends of the development (aberrant hosts).

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.

TABLE 2.

Strains of E. granulosus^a

Strain or isolate^b	Definitive and intermediate hosts^b	Infectivity for humans	Probable geographic distribution
G1: common sheep strain	D: dog, fox, dingo, jackal, hyena	Yes	Europe, Middle East, Africa, Iran, India, Nepal, China, Russia, Australian mainland, Tasmania, New Zealand, United States, South America
	I: sheep, cattle, pig, camel, goat, macropods
G2: Tasmanian sheep strain	D: dog, fox	Yes	Tasmania, Argentina
	I: sheep, cattle?
G3: (buffalo strain)?	D: dog, fox?	?	Asia
	I: buffalo, cattle?
G4: horse strain^c	D: dog	No/?	Europe, Middle East, South Africa (New Zealand?, United States?)
	H: horse, other equines
G5: cattle strain^d	D: dog	Yes	Europe, South Africa, India, Nepal, Sri Lanka, Russia, South America?
	I: cattle, buffalo, sheep, goat
G6: camel strain	D: dog	Yes	Middle East, Iran, Africa, China, Nepal, Argentina
	I: camel, goat, cattle
G7: pig strain	D: dog	Yes	Poland, Slovakia, Ukraine, Russia, Argentina
	I: pig
G8: cervid strain (G8)	D: wolf, dog	Yes	North America, Eurasia
	I: cervids
G9: ?	?	Yes	Poland
Lion strain	D: lion	?	Africa
	I: zebra, wildebeest, warthog, bushpig, buffalo, various antelope species, giraffe?, hippopotamus?

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Data from references 150, 194, and 195.

G, genotype; D, definitive hosts; I, intermediate hosts.

proposed species status, E. equinus (195).

Proposed species status, E. ortleppi (195).

Cystic Echinococcosis in Humans

Course of infection.

CE is caused by the metacestode stage of various strains of E. granulosus, which is a cystic structure typically filled with a clear fluid (hydatid fluid). About 5 days after ingestion of eggs, the metacestode is a small vesicle (60 to 70 μm in diameter) consisting of an internal cellular layer (germinal layer) and an outer acellular, laminated layer. This cyst (endocyst) gradually expands and induces a granulomatous host reaction, followed by a fibrous tissue reaction and the formation of a connective tissue layer (pericyst). The size of cysts in the human body is highly variable and usually ranges between 1 and 15 cm, but much larger cysts (>20 cm in diameter) may also occur (3, 148, 184) (Fig. 2). The exact time required for the development of protoscoleces within cysts in the human host is not known, but it thought to be more than 10 months postinfection. Protoscoleces can already be formed in cysts of 5 to 20 mm in diameter (149); on the other hand, a proportion of cysts do not produce protoscoleces and remain “sterile.” Most of the cysts are univesicular (i.e., unilocular), but in some of them, smaller daughter cysts are formed within larger mother cysts. Mixed infections with metacestodes of E. granulosus and E. multilocularis are rare, although the two species occur simultaneously in large areas of endemic infection (149).

FIG. 2. — Hepatic CE in a patient (endocyst removed; lesion size approximately 3 by 3.5 cm).

In the human host, cysts may develop in many anatomic sites following oral ingestion of E. granulosus eggs. This form of echinococcosis is known as primary CE. Secondary CE, predominantly in the abdominal cavity, results from spontaneous or trauma-induced cyst rupture and the release of protoscoleces and/or small cysts, which can grow to larger cysts. Approximately 40 to 80% of patients with primary CE have single-organ involvement and harbor a solitary cyst (3, 149). Examples of the organ sites of cysts in hospital patients are presented in Table 3.

TABLE 3.

Organ sites of E. granulosus cysts in humans^a

Organ	Study A^b: single-organ involvement in 459 patients		Study B^c: single- and multiple-organ involvement in 15,289 Chinese surgical cases
Organ	No. of cases	% of cases	No. of cases^d	% of cases
Liver	316	68.8	11,499	75.2
Lungs	79	17.2	3,432	22.4
Kidneys	17	3.7	68	0.4
Spleen	15	3.3	160	1.0
Muscles and skin	10	2.2	29	0.2
Abdominal and pelvic cavity	9	2.0	794	5.2
Mediastinum, heart	5	1.1	4	0.03
Brain	4	0.9	61	0.4
Bones	3	0.6	30	0.2
Ovarium	1	0.2	9	0.06
Other organs: skin, eye, spinal cord, pancreas, urinary bladder, testis, etc.				Each <0.1

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Adapted from reference 149.

Data from reference 45. Single-organ involvement in 459 patients, originating predominantly from the Mediterranean region.

Data from reference 140.

The number of cases in this column exceeds the total of 15,289 since many patients had multiple-organ involvement; the same applies to the percentages.

A literature review of 9,970 patients (originating from regions in South America, Africa, Europe, and Australasia where the sheep strain is common and infection is endemic) has revealed that the average liver-to-lung infection ratio was 2.5:1 (126). A different situation exists in infected but asymptomatic individuals. Ultrasonographic and chest X-ray surveys of approximately 10,000 apparently healthy individuals living in areas of Argentina and Uruguay with endemic infection revealed liver-to-lung ratios of 6:1 and 12:1, respectively (126). An explantation for the shift from the higher liver-to-lung ratios in asymptomatic individuals to lower values (2.5:1) in hospitalized patients is that lung cysts cause more frequently morbidity than hepatic cysts (126).

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).

TABLE 4.

Tests for antibody detection in human CE and AE^a

Echinococcosis form and test	Antigen^b	Sensitivity (%)	Relative specificity^c (%)	Cross-reactions
Cystic
IgG ELISA	Crude EgCF	80->99	61.7	Cestodes (89%), trematodes (30%), nematodes (39%)
	Antigen B (native or synthetic peptide)	63-92	85-93	AE
IgG4 ELISA	Crude EgCF	61-67	>99	AE only (see AE)
EITB^d	Crude EgCF	71	>98^e	T. solium cysticercosis only
	Antigen B fraction	92	100	None
	Antigen B subunits	34-36	>90
Alveolar
IgG ELISA	Crude EgCF	97.1	61.7	See above
	Em2PLUS	97.1	98.9	CE (25%)
	Em2/Em2G11	89.3	100	CE (5.6%)
	Em II/3-10	86.4	98.4	CE (6.5%)
IgG4 ELISA	Crude EgCF	48-67	>99	CE (see CE)
EITB	Em18	97	100	None
	Glycoproteins	70-90	>95

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Data from references 84, 87, 90, 168, 186, and other sources.

EgCF, E. granulosus cyst fluid; Em, E. multilocularis.

Tested with panels of 80 to 184 sera from patients with different parasitic infections (excluding Echinococcus-infected patients).

EITB, enzyme-linked immunoelectrotransfer blot.

Including additional sera from patients with other diseases.

Ultrasonography-guided fine-needle puncture has been used in recent years as a diagnostic procedure in doubtful cases of CE, i.e., in the absence of detectable anti-Echinococcus antibodies, in patients with small lesions resembling hepatic cysts, and in patients with lesions which cannot be distinguished from liver abscess, neoplasms, or other conditions (149). Aspirated cyst fluid can be examined for protoscoleces, rostellar hooks, and Echinococcus antigens or DNA (186). To prevent secondary echinococcosis if a hydatid cyst is punctured, chemotherapy with albendazole is recommended for 4 days before the procedure. Chemotherapy should be continued for at least 1 month after puncturing a lesion that was diagnosed as an E. granulosus cyst (149), even after its immediate surgical removal.

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).

FIG. 3. — Ultrasonograms of hepatic cysts of *E. granulosus* (Top) Type CL of WHO-IGWE classification (see text): lesion (arrows) with uniform anechoic content, not clearly delimited by an hyperechoic rim (cvst wall not visible). (Bottom) Type CE2: multivesicular cysts. Reprinted with permission from P. Kern and Dr. W. Kratzer, University Hospital and Medical Center, University of Ulm, Ulm, Germany.

Great care must be taken to detect cysts with biliary communications in order to prevent an influx of parasitocidal solution into the biliary tree and the risk of chemical cholangitis. Therefore, it is a basic requirement to examine aspirates from liver cysts for traces of bilirubin. Furthermore, endoscopic retrograde cholangiopancreatography is used to rule out cyst-biliary communications (222). If bilirubin is present in the cyst fluid, the PAIR procedure must be discontinued.

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.

E. granulosus Infection in Animals

Defintive hosts.

The domestic dog is the principal defintitive host of E. granulosus, but in certain regions wild canids may be involved in the life cycle of the parasite (Table 1). Although E. granulosus penetrates deep between the villi of the small intestine of a definitive host, there are no pathogenic effects even in animals with a heavy infection (54). Therefore, infected definitive hosts are typically asymptomatic carriers of the parasite.

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).

TABLE 5.

Options for the diagnosis of E. granulosus in animals

Animal group	Material required	Test, sensitivity and specificity^a	Reference(s)
Live animals
Individual dogs	Feces in buffer	Screening: coproantigen ELISA. S, 65-77%; SP, >90%.	28, 40
		Secondary^b: copro-PCR. S, under evaluation; SP, close to 100%.	Mathis and Deplazes, unpublished
Dog populations	Fecal material discharged by dogs after arecoline treatment	Standard option: macroscopic examination of discharged material. S, 65% after single-dose arecoline, 78% after second dose; SP, close to 100%.	179
	Feces in buffer	New option. Screening: Coproantigen-ELISA.	28, 40
		S and SP, as for individual dogs.
		Secondary: copro-PCR. S and SP as for individual dogs.	Mathis and Deplazes, unpublished
Intermediate hosts: sheep, goat, cattle, horse etc.		No reliable in vivo method for detecting the infection in individual animals, except rare cases in which cysts can be identified by ultrasonography in conjunction with antibody detection, for example in individual horses.	54
		A new ELISA might be useful for the detection of E. granulosus in sheep flocks (sensitivity, 50-60%).	120
Dead animals
Dogs and other carnivores	Small intestine	Standard option: Parasite detection at necropsy by direct examination of the intestine or by sedimentation technique (S and SP, close to 100%).	54
	Feces from rectum or content from intestine in buffer	New option: coproantigen ELISA in conjunction with copro-PCR (details as for small intestine).
Intermediate hosts	Viscera	Cyst detection at meat inspection or necropsy; in doubtful cases histology and/or PCR.	54

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S, sensitivity, SP, specificity.

Secondary test for confirmation or exclusion.

Intermediate hosts.

Infections with E. granulosus cysts in intermediate hosts (sheep, goat, cattle, horses, etc.) are typically asymptomatic, except a few cases of long-standing and heavy infections, for example in horses (Fig. 4). There are no reliable methods for the routine diagnosis of the infection in living animals, but in rare cases cysts have been identified by ultrasonography alone or in conjunction with serum antibody detection (54). A new ELISA with a high specificity and a sensitivity of 50 to 60% might be useful for detecting E. granulosus cysts in sheep on a flock basis but cannot be used for reliable diagnosis of infected individual animals (120) (Table 5). The most reliable diagnostic method is cyst detection during meat inspection or at postmortem examination (Table 5). CE in farm animals causes considerable economic problems due to loss of the edible liver. Significant loss of meat and milk production and value of the fleece from infected sheep may also occur. These losses are of especial significance in countries of low economic output where sheep production is of particular importance (201).

FIG. 4. — Horse liver with multiple cysts of *E. granulosus* (cyst diameters approximately 1 to 10 cm). The horse exhibited clinical signs of the disease.

Epidemiology

Life cycle patterns.

The life cycles of E. granulosus strains (Table 2) can be classified as domestic, involving the domestic dog as the principal definitive host and various species of domestic ungulates as intermediate hosts, or as sylvatic, involving wild carnivores and ungulates as hosts (the wildlife cycle). Within the cycles, the specific role of various host species may differ considerably between regions of endemic infection. In many areas of endemic infection, domestic and sylvatic life cycles coexist or overlap (155). For example, the dog-sheep strain is globally the most widespread and important strain of E. granulosus and exists in its domestic form (dog-sheep/goat) in many regions. However, in Australia this strain is transmitted between domestic animals (dog/sheep) and wild-animal hosts (definitive hosts are dingoes [Canis lupus dingo], dingo-domestic dog hybrids, less frequently red foxes [Vulpes vulpes]; intermediate hosts are mainly macropod marsupials, also feral pigs [Sus scrofa] and wombats [Vombatus ursinus]) (105). On the other hand, the cervid strain of E. granulosus in the Arctic is transmitted almost exclusively between wolves and wild Cervidae (elk [Alces alces], reindeer [Rangifer tarandus], and red deer [Cervus elaphus]) but domestic dogs and domesticated reindeer can replace the wild hosts (155). Complex situations of coexisting or overlapping domestic and sylvatic cycles also exist in other regions (for example, in Africa and Eurasia) and represent special problems in echinococcosis control (105, 132, 133, 155).

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.

FIG. 5. — Approximate global distribution of *E. granulosus* (as of 2002). The exact identification of areas of normal and high endemicity is difficult because of incomplete or lacking data. Modified from WHO/OIE 2001 (223) with permission.

Factors associated with persistence, emergence, or reemergence.

Key factors associated with persistence, emergence, or reemergence of CE have recently been described in Bulgaria (196) and the Mediterranean region (12). They include (i) the presence of large numbers of dogs (especially stray dogs) infected with E. granulosus, (ii) easy access of dogs to organs of livestock infected with E. granulosus cysts, (iii) insufficient facilities for slaughter and destruction of infected viscera, (iv) illegal or uninspected home slaughter, (v) a close association of dogs and other animals on small rural lots of land, (vi) uncontrolled animal trade and movements within and between countries, (vii) poor living conditions (especially lack of tap water), (viii) lack of adequate health education, and (ix) economic instability and financial restrictions in control and prevention. In central Asian countries (Kazakhstan and Kyrgystan), the reemergence of CE is clearly associated with the transition from a planned to a free-market economy since their independence from the former Soviet Union and its several consequences, such as a decline of the economy and living standards, deterioration of veterinary and medical services owing to the lack of adequate funding, and reforms in agriculture with increase of smaller livestock enterprises, uncontrolled slaughter, and offal disposal (183, 203, 204, 205).

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.

Control Options and Prevention

Several options for the control of E. granulosus have been thoroughly evaluated and are described in detail elsewhere (13, 61, 62, 74-77, 153). One option (type I) emphasizes long-term measures of public health education with primary health care (147) and veterinary public health activities, such as the improvement of slaughter hygiene and meat inspection, dog registration and sanitation measures (77). Experience from several countries has shown that this option alone may not be sufficient and may be too slow for effective E. granulosus control (77). Another option (type II) is based on legislation and includes specific measures targeted to interruption of parasite transmission. Prior to the “attack phase” of the program, base-line data are collected to serve as references for measuring control progress. Important base-line data are the prevalence of E. granulosus in dog populations, the age-dependent prevalences of cysts in sheep and other domestic ungulates, and human cases of CE. Modern techniques can now be used for surveys; for example, the coproantigen ELISA can be used to detect E. granulosus in dog populations (instead of arecoline testing) and ultrasonography alone or in combination with serology can be used for mass diagnosis of CE in humans (24, 28, 71, 168, 179, 223). Specific control measures include stray-dog control, registration of all owned dogs, spaying of bitches, and treatment of all (or most) dogs with praziquantel at predetermined intervals, for example every 6 or 8 weeks. These measures are complemented by upgrading of meat inspection, slaughter hygiene, slaughter offal disposal, public health education, and other measures. Control programs in various countries have shown that the attack phase can be successfully concluded in less than 15 years if the necessary measures can be performed without major constraints and financial restrictions (76-78). Under suboptimal conditions, the attack phase can last much longer. For example, in the Rio Negro Province of Argentina, a control program including dog treatment with praziquantel (5 mg/kg of bodyweight) at 2-month intervals has, within about 20 years (1979/1980 to 1999), reduced the prevalence of cysts in sheep from 61 to 18% and of intestinal stages in rural dogs from an estimated 40 to 2-3% (124). After the parasite has been driven close to extinction during the attack phase, further measures are necessary in the following consolidation and maintenance phases (76, 77). Major problems of control programs against E. granulosus are long-term funding and perturbations due to political and administrative reasons. Control options of type II were predominantly successful in island situations (New Zealand, Tasmania, Falkland Islands, and Cyprus), and partially effective in continental regions (Argentina, Chile, Uruguay, Bulgaria, Spain, parts of China, and some other areas) (24, 61, 62, 76, 77, 124, 219).

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.