Echinococcus Species: Agents of Echinococcosis

Echinococcus Granulosus

Description of the Pathogen

Echinococcus granulosus , which causes cystic echinococcosis, is a cestode whose life cycle involves dogs and other canids as definitive hosts for the intestinal tapeworm. Domestic and wild ungulates are intermediate hosts for the tissue-invading metacestode, which is the larval stage of the tapeworm ( Fig. 281.1 ). The metacestode (i.e., echinococcal cyst) is a fluid-filled, spherical, unilocular cyst that consists of an inner germinal layer of cells supported by a characteristic acidophilic-staining, acellular, laminated membrane of variable thickness ( Fig. 281.2 ).

Figure 281.1, Life cycle of Echinococcus granulosus . The adult E. granulosus (3–6 mm long) resides in the small bowel of the definitive hosts (i.e., dogs or other canids). Gravid proglottids release eggs that are passed in the feces. After ingestion by a suitable intermediate host (i.e., sheep, goat, swine, cattle, horses, and camels under natural conditions), the egg hatches in the small bowel and releases an oncosphere that penetrates the intestinal wall and migrates through the circulatory system into various organs, especially the liver and lungs. In these organs, the oncosphere develops into a cyst that enlarges gradually, producing protoscolices and daughter cysts that fill the cyst interior. The definitive host becomes infected by ingesting the cyst-containing organs of the infected intermediate host. After ingestion, the protoscolices evaginate, attach to the intestinal mucosa, and develop into adult stages in 32–80 days. The same life cycle occurs for E. multilocularis (1.2–3.7 mm long), but the definitive hosts are foxes and, to a lesser extent, dogs, cats, coyotes, and wolves; the intermediate host are small rodents; and larval growth (in the liver) remains in the proliferative stage indefinitely, resulting in invasion of the surrounding tissues. For E. vogeli (≤5.6 mm long), the definitive hosts are dogs and bush dogs; the intermediate hosts are rodents; and the larval stage (in the liver, lungs, and other organs) develops externally and internally, resulting in multiple vesicles. E. oligarthrus (≤2.9 mm long) has a life cycle that involves wild felids as definitive hosts and rodents as intermediate hosts. Humans become infected by ingesting eggs, with resulting release of oncospheres in the intestine and the development of cysts in various organs.

Figure 281.2, Metacestode (i.e., hydatid cyst) of Echinococcus granulosus, showing the protoscolices (P) in brood capsules, germinative layer (GL), laminated membrane, and adventitial layer (AL) or ectocyst (hematoxylin & eosin stain, bar = 100 μm).

Each cyst is surrounded by a host-produced layer of granulomatous adventitial reaction. Small vesicles (i.e., brood capsules) bud internally from the germinal layer and produce multiple protoscolices by asexual division. In humans, the slowly growing hydatid cysts can attain a volume of several liters and contain many thousands of protoscolices. With time, internal septations and daughter cysts can form, disrupting the unilocular pattern typical of the young echinococcal cysts.

Epidemiology

Geographically distinct strains of E. granulosus have different host affinities. Molecular studies using mitochondrial DNA sequences have identified 10 distinct genetic types (i.e., G1–G10) of E. granulosus. ^, Taxonomic revision now defines E. granulosus sensu lato , which is composed of E. granulosus sensu strictu (G1, G2, and G3), E. equinus (G4), E. ortleppi (G5), E. canadensis (G6/G7/G8/G10), and E. felidis . ^, The genetic types that most commonly infect humans are E. granulosus s.s. (G1) and E. canadensis (G6 and G7), with about 73% of infections globally related to the G1 type. The genetic type affects the clinical presentation: the G6 type has more brain involvement and the G7 type rarely involves organs other than the liver.

Certain human activities (e.g., widespread rural practice of feeding dogs the viscera of home-butchered sheep) facilitate transmission of the E. granulosus s.s. and consequently raise the risk of human infection. Dogs infected with Echinococcus tapeworms pass eggs in their feces, and humans become infected through fecal-oral contact. Eggs adhere to hairs around an infected dog’s anus and are found on the muzzle and paws. Indirect transfer of eggs through contaminated water, uncooked food, or intermediary flies or other arthropods can result in infection of humans.

The highest prevalence of cystic echinococcosis in human and animal hosts is found in countries of the temperate zones in South America, the Mediterranean region, south and central Asia, China, and Eastern Africa. In the US, most echinococcis infections are in immigrants from endemic countries. Sporadic autochthonous transmission is recognized in Alaska, California, Utah, Arizona, and New Mexico.

Clinical Manifestations

After ingestion, Echinococcus eggs hatch and release embryos in the small intestine. Penetration through the mucosa leads to bloodstream or lymphatic distribution to the liver and other sites, where cyst development begins. Most primary infections in humans consist of a single cyst, but 20%–40% of infected people have multiple cysts or multiple organ involvement. The liver (>65%) and lungs (25%) are the most common sites for echinococcal cysts. Cysts occur less frequently in the spleen, kidneys, heart, bone, and central nervous system.

Clinical manifestations of cystic echinococcosis vary by the site, size, and condition of the cysts. Cysts in children tend to grow slowly, ranging from 1 to 5 cm per year. A slow-growing echinococcal cyst can be well tolerated unless it reaches a size causing dysfunction. Observational studies suggest that up to 75% of cysts do not cause symptoms and some infections resolve in the absence of treatment. ^, Although infections can be acquired in childhood, most liver and lung cysts become symptomatic and are diagnosed in adults, with only 10%–20% diagnosed in patients aged <16 years. Because even small cysts in the brain or eye can cause clinical symptoms, most cases of intracerebral echinococcosis are diagnosed in children.

Manifestations of hepatic echinococcosis can include hepatic enlargement with or without a palpable mass in the right upper quadrant, right epigastric pain, nausea, and vomiting. If a cyst ruptures, the sudden release of its contents can precipitate allergic reactions ranging from mild to fatal anaphylaxis. In the lungs, ruptured cyst membranes can be evacuated entirely through the bronchi or can be retained and serve as a nidus for bacterial infection. Dissemination of protoscolices can result in multiple secondary sites of echinococcosis. Larval growth in bones is atypical; when it occurs, invasion of marrow cavities and spongiosa is common and causes extensive erosion of the bone.

Laboratory Findings and Diagnosis

The finding of a cyst-like mass in a person with a history of exposure to sheepdogs in areas in which E. granulosus is endemic supports the diagnosis of cystic echinococcosis. However, echinococcal cysts must be differentiated from benign cysts, cavitary tuberculosis, mycoses, abscesses, and benign or malignant neoplasms.

Noninvasive confirmation of diagnosis usually can be accomplished with the combined use of radiologic imaging and immunodiagnostic techniques. Radiography permits detection of echinococcal cysts in lungs ( Fig. 281.3 ); in other sites, calcification is necessary for radiographic visualization. CT, MRI, and ultrasonography are useful for the diagnosis of lesions in all organs and for determination of the extent and condition of the avascular fluid-filled cysts. Abdominal ultrasonography is the most widely used imaging technique for echinococcosis diagnosis because of its availability and utility in defining the number, site, dimensions, and vitality of cysts. The World Health Organization (WHO) consensus criteria for the diagnosis and management of cystic echinococcosis are based on ultrasound findings. There are 5 categories of cysts in the WHO Informal Working Group on Echinococcosis (WHO-IWGE) system. Cysts in the CE1 and CE2 categories are considered to be active; CE3a and CE3b cysts are considered to be transitional; and CE4 and CE5 are considered to be inactive.

Figure 281.3, Cystic echinococcosis in a 15-year-old girl who came to medical attention in Philadelphia because of cough and pleuritic chest pain. She was referred for evaluation for malignancy. This Air Force family had been stationed in Spain and Germany for the preceding 7 years. Frontal (A) and lateral (B) plain radiographs show a homogeneous left paracardiac mass. Axial CT of the chest (C) and abdomen (D) without contrast demonstrate large cysts in the lung and liver. Notice the daughter cyst in the liver (D). The serum indirect hemagglutination titer against Echinococcus performed at the Centers for Disease Control and Prevention was 1:1024.

Antibody assays are useful to confirm presumptive radiologic diagnoses, although some patients with cystic echinococcosis do not demonstrate a detectable immune response. Hepatic cysts are more likely to elicit an immune response than pulmonary cysts. Regardless of location, the sensitivity of serologic tests is related inversely to the degree of sequestration of the echinococcal antigens inside cysts. For example, healthy, intact cysts can elicit minimally detectable response, whereas previously ruptured or leaking cysts are associated with strong responses. Enzyme-linked immunosorbent assays (ELISA) and the indirect hemagglutination test are highly sensitive for initial screening of sera but can provide false positive results in patients with other cestode infections. Specific confirmation of reactivity can be obtained by the enzyme-linked immunotransfer blot test. Eosinophilia occurs in <25% of infected people.

The diagnosis of echinococcosis can be made through microscopic examination of cyst contents after cyst aspiration when other testing modalities fail to confirm the diagnosis, but clinical suspicion remains high. Identification of hooklets can be facilitated by acid-fast stains. Protoscolices sometimes can be demonstrated in sputum or bronchial washings in addition to cyst aspirates.

Management

The WHO-IWGE recommends an image-based, stage-specific approach to the treatment of cystic echinococcus that includes options of surgery, chemotherapy, percutaneous treatment, or observation. ^, The size and stage of the cyst help to determine the treatment options.

Surgery

The aim of surgery is total removal of the cyst with avoidance of the adverse consequences of spilling the contents. Pericystectomy, or total removal of the cyst, is the usual procedure, but simple drainage, special drainage procedures, and resection of the involved organ can be performed, depending on the location and condition of the cyst. The more radical the intervention, the higher the operative risk but the lower the likelihood of recurrence.

Surgery is the preferred treatment for large CE2/CE3b cysts with multiple daughter vesicles and for infected cysts if percutaneous treatment is not available. Surgery also is preferred for single hepatic cysts that are situated superficially and may rupture spontaneously or from trauma if percutaneous treatment is not available, and for cysts that communicate with the biliary tree or are located in certain organs (i.e., brain, lung, or kidney). Surgery is contraindicated in patients who are pregnant, have pre-existing medical conditions that put them at increased surgical risk, or have multiple cysts that are difficult to access. Surgical risks include those associated with any surgical intervention and risks unique to echinococcosis (e.g., anaphylaxis, secondary recurrence). The operative mortality rate varies from 0.5% to 4% but rises with repeated interventions and when surgery is performed in inexperienced facilities.

Chemotherapy

Experience with chemotherapy using benzimidazole compounds is extensive, and the medical approach can be recommended for many patients. Approximately one-third of patients treated with benzimidazole drugs are cured (i.e., complete and permanent disappearance of cysts), and in those not cured, 30%–50% of patients have significant regression of cyst size and alleviation of symptoms. Chemotherapy should be considered for patients with inoperable lung or liver disease and in patients with cysts in 2 or more organs. Small (<5 cm) CE1 and CE3a cysts may be treated with benzimidazole compounds alone. Larger CE1 and CE3a cysts should be treated with a benzimidazole in combination with a percutaneous treatment, as should CE2 and CE3b cysts. CE4 and CE5 cysts are inactive and benzimidazole treatment is not recommended.

Albendazole (10–15 mg/kg/day in 2 divided doses) and mebendazole (40–50 mg/kg/day in 3 divided doses) have demonstrated efficacy against cystic echinococcosis, but the results for albendazole have been superior. ^, ^, Albendazole should be administered without interruption. The optimal duration is uncertain; 1–3 months may be adequate, but up to 6 months may be required in some cases.

Administration of albendazole with fat-rich meals facilitates absorption and bioavailability. Adverse reactions (e.g., neutropenia, liver toxicity, alopecia) have occurred in a few patients but are reversible on cessation of treatment. Examinations for adverse reactions (i.e., aminotransferase levels and blood counts) should be performed every 2 weeks during the first 3 months and then monthly for 1 year. Contraindications to chemotherapy include early pregnancy (albendazole may be acceptable under some circumstances), chronic hepatic disease, and bone marrow depression.

Praziquantel has protoscolicidal activity but variable efficacy in clinical studies and is therefore not recommended as primary therapy alone. ^, Human case series and experimental animal studies suggest the combination of albendazole and praziquantel may be superior to the use of albendazole alone.

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