AUTHOR AND EDITOR INFORMATION

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• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Infection with the larval form of Echinococcus multilocularis causes alveolar echinococcosis (AE). The infection behaves as a slow-growing malignant tumor. Initially, it is located in the liver and then may spread to any other organ through metastases. Without appropriate therapeutic management, the infection is lethal.

Echinococci are platyhelminths of the cestode genus. The parasitic cycle of the organism involves definitive hosts and intermediate hosts, each harboring different stages of the parasite life cycle.

Carnivores are the definitive hosts for the adult form of the parasite, which is an intestinal worm also termed taenia. Numerous (ie, tens to thousands) adult worms that average 2-5 mm in length live in the small bowel of carnivores (taeniasis) and are attached to the small bowel mucosa by hooks and suckers. After 25-40 days, the worm's last gravid segment, each containing hundreds of microscopic eggs (6-hooked oncospheres or hexacanth embryos, 30-40 mm in diameter), detaches from the nonfertile segments. The egg-containing segments are then dispersed through the feces of the carnivore.

Various species act as intermediate hosts, serving the larval form of the parasite (ie, metacestode). The metacestode is a continuously growing tumorlike polycystic mass that is not clearly separated from host tissues. The larval-stage parasite is composed of vesicles that become fertile by producing a form termed the protoscolex, which is able to recreate the adult worm in the definitive host. The protoscoleces that fill the vesicles transform into adult worms once ingested into the intestine of the carnivore host.

The cycle of E multilocularis in Europe is predominantly sylvatic, involving red foxes (see Image 1) as definitive hosts and rodents as intermediate hosts. In some countries, dogs and cats have been identified as definitive hosts; however, all definitive host species acquire the infection from the sylvatic cycle by consuming rodents infected with metacestodes of E multilocularis. In Alaska and in the People's Republic of China, the domestic cycle, involving sled dogs, is particularly important.

E multilocularis eggs, which are the infectious agents for humans, are dispersed in the environment via the feces of carnivores. The eggs may contaminate various types of food, including fruits and vegetables collected from gardens or infected meadows, and drinking water. An oncosphere membrane protects Echinococcus eggs, making them extremely tolerant of environmental conditions. E multilocularis eggs may remain infectious at temperatures ranging from -30°C to +60°C. They are easily destroyed by heat but may survive months or years at low temperatures, especially if they are protected against drying. Freezing the eggs at -20°C does not affect their infectious potency.

Simultaneous occurrence of both alveolar echinococcosis and cystic echinococcosis resulting from Echinococcus granulosus infection is extremely rare but has occurred in endemic areas where both species are present in the environment (eg, western China).

Pathophysiology

Alveolar echinococcosis is a chronic disease with a presymptomatic stage that may last for years before signs and symptoms develop. The variability of the signs and symptoms depends on the location of the lesions (see Image 2), which may develop in the liver and/or in various organs or tissues, especially the lungs, brain, and bones.

E multilocularis larvae grow as tumorlike buds that transform into multiple vesicles filled with fluid and, in 15% of cases, with protoscoleces. The parasitic vesicles are lined with a germinal layer and a laminated layer, which are immediately surrounded by an exuberant granulomatous response generated by the host's immune system. This reaction has 2 main consequences, fibrosis and necrosis (see Image 3). Both reactions protect the host against larval growth but may also be deleterious. Fibrosis in alveolar echinococcosis is extremely active from the beginning of the infection. Irreversible acellular fibrosis composed of cross-linked collagens ensues and isolates the parasitic lesions from the host but also compresses and obstructs major vessels and bile ducts. Noncaseous necrosis in the center of the lesions may be superinfected by bacteria and fungi, possibly leading to complications (eg, liver abscesses, septicemia).

Similar to several other parasitic diseases, alveolar echinococcosis appears as a polar disease (as defined in leprosy). The ability of the organism to infect a host and the severity of disease once successfully inoculated depend on the receptivity of the host (ie, host immune defenses).

Mass screenings prove that abortive forms (see Image 6) exist and may occur in most cases, explaining the relatively low prevalence of this disease. Experimental studies on infected mice and immunologic studies on humans reveal the importance of cell-mediated immunity in the control of larval growth. Immune responses, characterized by a helper T cell T_H1 profile of cytokine secretion, can kill the larvae, thus protecting the host. The progressive forms of the disease are characterized by a T_H2 profile consisting of increased interleukin (IL)–10 and IL-5 secretion.

Frequency

United States

Foxes infected with E multilocularis are present in most of the northern and central states. The organism has been observed in all or parts of 11 contiguous states and 3 adjacent Canadian provinces in an area centered by southern Manitoba and North Dakota. However, only 2 cases involving humans living in this area have been described since the beginning of the 20th century. Transport of infected foxes from endemic areas to eastern and southern states for hunting purposes could create new areas at risk of becoming endemic. In Alaska, alveolar echinococcosis is observed in Eskimos, especially on St. Lawrence Island, where 30 of 53 cases in Alaska from 1947-1990 were diagnosed.

International

Alveolar echinococcosis occurs only in the northern hemisphere, in geographically limited foci (endemic areas) of west-central Europe, Turkey, most areas of the former Soviet Union, Iran, Iraq, western and central China, and northern Japan (Hokkaido Island). If considering only at-risk rural populations in regions in central Europe that are endemic for alveolar echinococcosis, the incidence is 1-20 cases per 100,000 persons per year, despite an overall country prevalence that may be very low. In endemic foci of China, prevalence averages 5% but may reach 10% in villages with specific risk factors. The prevalence of E multilocularis infection in foxes is 15-70% in endemic areas.

Recent trends are related to increasing percentages of infected foxes and increased distribution of those foxes. The presence of infected foxes in large cities of Europe and northern Japan and a newly recognized trend of infection in dogs and cats in endemic areas in Europe may lead to major changes in the human populations at risk in the near future.

Mortality/Morbidity

Untreated, alveolar echinococcosis is usually fatal. The survival rate at 5 years in untreated patients averages 40%. Therapeutic approaches that have been developed since the early 1980s have markedly improved the prognosis of the disease. The actuarial survival rate at 5 years was 88% in a series of 80 patients observed from 1983-1993.

• Major complications leading to death include biliary obstruction with bacterial and/or fungal superinfections (eg, cholangitis, septicemia), secondary biliary cirrhosis, bleeding from esophageal or duodenal varices resulting from portal hypertension, Budd-Chiari disease, obstruction of the vena cava, and complications of heart, lung, or brain metastases (see Image 8).
• The disease may markedly impair patients' quality of life, and the economic costs associated with treatment are high because the disease is chronic and requires life-long treatment and follow-up care.
• The outcome of treatment is unpredictable; however, since the beginning of the 1980s, a combination of surgery, interventional radiology, and benzimidazole treatment has improved patient survival rates and quality of life.

Race

No known racial predilection exists; however, the genetic background, including human lymphocyte antigen (HLA) characteristics, linked to the intensity and/or to the T_H1/T_H2 balance of the patient's immune response may be associated with the occurrence and/or severity of the disease.

Sex

Older reports indicate a male predilection for infection; however, these reports are not accurate. In endemic areas in Europe, the male-to-female ratio is approximately equal. In the endemic areas of China, women are affected more commonly than men. Sex differences in prevalence seem to reflect epidemiologic rather than strictly sex-related risk factors, such as caring for dogs in central China.

Age

The typical age at onset is 55 years. However, mass screenings have identified symptomatic and asymptomatic infections in patients ranging in age from 6 years to elderly persons.

CLINICAL

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History

The presenting symptoms below are from 2 series of patients diagnosed in the same hospital in eastern France in the 1970s and 1980s. Other series confirm these figures.

• Vague abdominal (right upper quadrant) pain is the most common presenting symptom (30%) and can last for years before lesions develop.
• Jaundice, which was the most common presenting symptom before the 1980s, is observed in 25% of cases. Progressive gradual cancerlike onset of jaundice is observed in most cases that involve symptomatic cholestasis. Intermittent jaundice may also be associated with acute right upper quadrant pain when parasitic material migrates through the common bile duct.
• Hepatomegaly is observed in 16% of cases.
• In the presence of bacterial superinfection, fever and chills may accompany gallstonelike symptoms. Fever and chills may also evoke liver abscess due to superinfection in the central periparasitic necrosis.
• Various symptoms, ranging from dyspnea and bile sputum to seizures and stroke, as well as bone pain or skin tumor, may be the presenting symptoms of a secondary location or metastasis of the parasitic lesions (approximately 10% of cases).

Physical

• The most frequent clinical finding is hepatomegaly, which may be found in patients who are otherwise asymptomatic. An enlarged left liver lobe, resulting from liver regeneration in the course of a lesion on the right lobe, may be found only during palpation of the epigastrium.
• Splenomegaly is present only in cases complicated by portal hypertension or those that involve spleen metastasis.
• Ascites and dilated periumbilical veins are rare.
• Caval collateral circulation between the inferior and superior vena cava may develop on the abdominal and thoracic skin in cases in which the hepatic veins and vena cava are obstructed.
• Other physical symptoms are dictated by the location of metastatic lesions.
• A significant number of patients undergoing diagnostic analysis are asymptomatic. Patients may present by chance (eg, at surgery, during ultrasonographic examination for another reason) or during mass screening performed in an endemic area.

Causes

Alveolar echinococcosis is a zoonosis. In nature, humans and other animals share the infection, which results in various factors that allow the parasite to complete its life cycle. Contact with the infectious form of the cestode (ie, oncosphere or egg) depends on human behavior and cultural habits. This explains why the disease is encountered in limited geographic areas. Changes in the environment, possibly related to economic or political decisions, and changes in behavior may be partially responsible for changes in the potential for humans to be exposed to the parasite. In general, humans are not susceptible hosts for infection with E multilocularis. In fact, genetic and immunologic aspects are also involved and may modify the overall prevalence of the disease in humans of a given endemic area.

• Geographic factors
• • Prevalence rates vary enormously (between 1 per 100,000 and 1 per 10 population) within the recognized distribution range of E multilocularis.
  • In most regions, environmental features that favor the parasite cycle include hilly landscapes, cool and rainy climates, and pastures for cattle breeding.
  • One factor that is key to the presence of the parasite is the abundance of suitable intermediate hosts. The occurrence and population size of these species depends on the presence of unplowed grassland (eg, pastures, meadows), which is the type of landscape most typical in mountainous regions with a cool climate where intensive agriculture is not feasible.
  • A correlation between E multilocularis prevalence in foxes and population densities of rodent species (suitable intermediate hosts) has been demonstrated in France. In addition, the number of human cases correlates well with the existence of a cyclic pattern of high densities of rodents. In Europe, high rodent population densities appear to occur only in areas without plowed fields and with permanent meadows or pastures for cow breeding.
  • The appearance of infected foxes in large cities, the overall increase in infected foxes in Europe and northern Japan, and the transport of infected foxes to new areas in the United States also increase the risk of human infection.
  • Although rodents, especially voles (see Image 4), are the normal intermediate hosts of E multilocularis in nature, various accidental hosts with a larval disease similar to that observed in humans have been described in cattle, pigs, boars, hares, horses, monkeys, and apes.
• Political factors
• • The European Economic Community agricultural policies that favored cow breeding for cheese-making on middle-altitude plateaus of the Jura and Alps mountain ranges since the 1960s may have led to particular changes of the landscape that are more favorable to alveolar echinococcosis development.
  • Similar landscape changes in central China (eg, deforestation) have led to high rodent population densities and an increase in cases of alveolar echinococcosis. In addition, on the Tibetan plateau, changes in land use, especially by fencing common pastures, may have increased the contamination risk by increasing the population of a small mammal, Ochotona curzoniae, which serves as intermediate host in this area.
  • Alveolar echinococcosis epidemiology is a striking example of unexpected public health consequences resulting from political or economic environmental decisions.
• Human behavioral factors
• • Regional cultural behaviors, such as collecting wild berries or vegetables and harvesting vegetables from open kitchen gardens, put rural populations at risk. In Asia, closer contact with dogs may be responsible for the higher prevalence in women.
  • Other behaviors that promote infection in human populations include hiking, hunting, and consumption of organic food.
• Genetic factors
• • A multicenter study of the HLA groups of patients with alveolar echinococcosis in France, Germany, and Switzerland suggests that HLA DR 11 is associated with protection against E multilocularis infection in humans, HLA DP 0401 is associated with susceptibility, and HLA B8, DR3, and DQ2 are associated with severe forms of infection. TAP polymorphism is also associated with alveolar echinococcosis occurrence and severity.
  • Similar results involving other HLA groups (because of ethnic differences) have also been observed in China.
  • Risk factors for alveolar echinococcosis include an agricultural occupation and a prolonged stay in an endemic area. Family cases are uncommon; however, a cluster of family cases was discovered in central China and may be due to common exposure combined with genetic characteristics of these families.
• Immunologic factors
• • Various states of immunosuppression (eg, HIV infection, organ transplantation, chronic autoimmune disease treated with immunosuppressive drugs, pregnancy) are associated with a faster progression of alveolar echinococcosis.
  • Because these immunosuppressed populations are increasing, echinococcosis may soon be observed more as an opportunistic disease.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Alcoholic cirrhosis
Cystic echinococcosis
Cholangiosarcoma
Hypergammaglobulinemia

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Blood cell count
• • Hypereosinophilia is a rare feature of disease (<10%).
  • Lymphopenia develops in 45% of cases.  
• Immunoglobulin concentrations
• • Increase in levels of gammaglobulins is common, primarily resulting from an increase in immunoglobulin G (IgG) levels and, to a lesser degree, levels of immunoglobulin A (IgA) and immunoglobulin M (IgM).
  • Increased immunoglobulin E (IgE) levels are uncommon.  
• Inflammatory proteins
• • Tests usually show increased levels of haptoglobin, alpha1 acid glycoprotein, C3 and C4, and ceruloplasmin despite the absence of increased C-reactive protein (CRP) levels.
  • CRP levels increase in cases complicated by bacterial superinfection. 
• Hepatic function
• • Results may be normal in asymptomatic cases.
  • Gamma-glutamyl transferase (GGT) levels usually increase before the patient is symptomatic. GGT levels also increase if bile ducts are obstructed. Levels can reach 20 times the reference range.
  • Alkaline phosphatase levels increase later than GGT levels and are observed only in symptomatic patients.
  • Conjugated bilirubin levels increase in symptomatic patients who are diagnosed with jaundice.
  • Levels of aminotransferases increase only when associated with necrosis. Aspartate aminotransferase (AST) is equal to alanine aminotransferase (ALT).
  • Prothrombin time decreases because of cholestasis, which can usually be corrected with vitamin K supplementation.
  • Factor V levels decrease in rare cases of hepatic failure (eg, secondary biliary cirrhosis, Budd-Chiari syndrome).  
• Specific serology
• • Serology results usually confirm a diagnosis suspected based on ultrasonography or CT scanning findings obtained in a clinical setting. These studies are also used for mass screenings.
  • Results from routine tests using heterologous antigen (E granulosus cyst fluid) are positive for indirect hemagglutination in 75-80% of cases with a threshold value at 1/300 dilution and 94% of cases with a threshold value at 1/80 (with a very poor specificity, often positive in other helminth infections). Immunofluorescence using protoscoleces as an antigen yields similar results.
  • Immunoelectrophoresis using Echinococcus crude extract yield low sensitivity and specificity. Arc 5, considered typical of E granulosus, is observed in nearly 60% of patients with alveolar echinococcosis.
  • Enzyme-linked immunosorbent assay (ELISA) results using heterologous antigen (E granulosus cyst fluid) are positive in 97% of cases, positive in abortive cases, and positive before species-specific tests in cases that recur after radical surgery or transplantation. ELISA results may also be positive in other types of cestode infections, especially cysticercosis (Taenia solium infection in humans) and, although less frequently, in other helminth infections.
  • • ELISA results using homologous antigen (E multilocularis extract) are positive in 95% of cases but may be positive in other cestode infections.
    • ELISA results using recombinant and purified antigens of E multilocularis (Em2+) are positive in 95% of cases and have better specificity. This test is commercially available.
    • Combined ELISA for the diagnosis of echinococcosis and discrimination between E granulosus and E multilocularis, as a rapid test that does not require laboratory facilities, is commercially available in the People's Republic of China.
    • ELISA using the purified alkaline phosphatase of E multilocularis is both highly sensitive and specific (nearly 100%) but is not commercially available.  
  • Western blot tests using combined extracts of E granulosus and E multilocularis or E multilocularis alone result in patterns specific for alveolar echinococcosis. Two narrow bands at 18 kDa are associated with 1 band at 26-27 kDa or only 1 band at 26-28 kDa. A pattern consisting of 1 band at 7 kDa and 1 band at 26-28 kDa without an intermediate band cannot differentiate E multilocularis infection from that of E granulosus. Western blot tests are highly sensitive (97%), and cross-reactions resulting in a similar pattern are observed only with sera from patients with neurocysticercosis. Western blot tests are commercially available. Specific Western blot using Em18 antigen or Em18 recombinant protein has comparable diagnostic value but is not commercially available.
  • Specific IgE are present in the serum of 50% of patients and cannot be used for diagnosis.
• Cellular immunology
• • These tests are used primarily for research purposes.
  • Specific histamine release by basophils, using a homologous antigen, is observed in all cases.
  • Specific proliferation of peripheral blood lymphocytes can be induced using specific homologous extracts but is not routinely used.
  • Spontaneous secretion of IL-10 by peripheral lymphocytes in culture is observed in most patients with a progressive form of the disease.

Imaging Studies

• Aspect and location of alveolar echinococcosis lesions in the liver
• • In 50% of cases, lesions are located in a single hepatic lobe (right liver, 75%; left liver, 15%). Involvement of both right and left liver lobes by a single lesion is observed in 50% of cases.
  • The infiltrative lesions may be larger than 10 cm in diameter and invade or surround vascular and/or biliary structures. Some lesions are more nodular, 3-6 cm in diameter, and more calcified.
  • Two or more distinct parasitic foci may be observed.
  • Thoroughly investigate ultrasonographic evidence of bile duct dilation, portal hypertension, ascites, and splenomegaly. Doppler studies are a useful complement to better characterize hepatic and portal vessels and blood flow.
• Ultrasonography
• • Ultrasonographic examination (see Image 5) is used to assess the morphology of alveolar echinococcosis both for diagnosis in hospital settings and in mass field screenings. It should be used as a first-line imaging technique.
  • In most cases, ultrasonographic images show a pseudoneoplastic intrahepatic mass with a heterogeneous ultrasonographic structure that is mainly hyperechoic and contains scattered calcifications and irregular, poorly defined edges.
  • A central necrotic cavity with a hypoechoic pseudoliquid structure and anfractuous borders may be observed.
  • Hyperechoic nodular homogenous lesions, 1-2 cm diameter, may be associated with typical lesions observed as a recurrence after surgery or observed in patients who are asymptomatic at screening. These lesions may represent an early stage of development.
  • Disclosure of nodular or scattered calcified lesions in the liver is common in mass surveys and can be observed in hospital settings in endemic areas (see Image 6). If the calcifications are associated with a positive result on specific serology, they may represent abortive forms of the disease.
• CT scanning
• • Abdominal CT scanning reveals the morphologic aspect of the lesions (see Image 3). This is the best examination to show the typical calcifications inside the lesions and is particularly useful for very calcified lesions that are difficult to delineate with ultrasonography because of the induced shadow.
  • Abdominal CT scanning is also useful for preoperative evaluation to assess vascular involvement and extension to adjacent organs and tissues (eg, diaphragm and lungs, stomach, spleen, left kidney, adrenal gland).
  • Perform thoracic and cerebral CT scanning before any radical surgery, especially liver transplantation. Metastatic lesions appear as tumorlike structures, single or multiple, in the lungs and/or brain.
• Magnetic resonance imaging
• • The cancerlike intrahepatic lesions appear as low signal intensity with a possible isointense component on T2-weighted images, and they produce variable signals on T2-weighted images, including necrotic areas in high signal intensity and some areas in low signal intensity.
  • MRI demonstrates a pathognomonic image of alveolar echinococcosis lesions that resembles bunches of grapes or a honeycomb. These lesions are more commonly observed on high-intensity T2-weighted images and are composed of many rounded cavities smaller than 1 cm in diameter (see Image 7).
  • Gadolinium reveals an absence of contrast enhancement of the focus and the perilesional area in 60% of the cases.
  • In 40% of cases, an abnormal and delayed contrast enhancement is observed on the flash 2D sequences after contrast medium enhancement, especially on delayed T1-weighted images. They may correspond to the active neovascularized granuloma surrounding the parasitic lesions.
  • MRI is not effective for showing typical calcifications, but it is the best technique, when available, to differentiate an early homogenous hyperechoic parasitic lesion and a more common hemangioma.
  • When available, use MRI for preoperative evaluation, especially to disclose invasion of vessels and neighboring organs and tissues (see Image 7).
• Cholangiography
• • Because lesions typically are intrahepatic, use percutaneous cholangiography instead of endoscopic retrograde cholangiopancreatography if jaundice is present.
  • Cholangiography may show the precise level of bile duct obstruction and/or may be used to assess communication between bile ducts and the central necrotic area of the lesions and/or demonstrate communication between bile ducts and bronchi.
  • Percutaneous transhepatic cholangiography may be the first stage of an interventional procedure.
• Angiography
• • MRI, ultrasonography with Doppler, and CT scanning have replaced angiographic procedures in most cases, but angiographic procedures may be indicated in rare cases before surgery.
  • Angiography may reveal invasion of hepatic arteries, portal vein obstruction or thrombosis, portocaval anastomoses, and obstruction or thrombosis of hepatic veins and vena cava.
• Chest radiography
• • Chest radiography is the initial examination to assess the presence of lung metastases.
  • Lung metastases may be unique or multiple and appear as nodular images that resemble primary or metastatic tumors.
  • Complement radiography with lung CT scanning is indicated before any surgical intervention is planned, especially liver transplantation.

Other Tests

• Positron emission tomography (PET) scanning: PET scanning, and especially morpho-PET scanning (PET combined with CT scanning, using image fusion), may be used to assess the viability of the parasitic lesions and the level of periparasitic cellular inflammation. Fluorodeoxyglucose is actively metabolized by the parasitic lesions; thus, lesional or perilesional enhancement ("hot spots") may be seen if the lesions are metabolically active. This technique may be used for the follow-up of patients treated with chemotherapy. Inactive lesions and calcified lesions do not uptake fluorodeoxyglucose.

Procedures

• Esophagogastroduodenoscopy may show esophageal varices in cases that involve portal hypertension.
• Bronchoscopy may be useful in cases of lung invasion or metastases.
• Avoid needle liver biopsy if the diagnosis has been assessed on epidemiologic grounds using ultrasonography and/or CT scanning/MRI and confirmed with serology. Needle liver biopsy carries the risk of dissemination and subsequent growth of parasitic cells.
• Fine-needle aspiration to characterize E multilocularis using polymerase chain reaction (PCR) may be used if all other techniques have failed to confirm alveolar echinococcosis.

Histologic Findings

Surgical liver biopsy results show parasitic vesicles delineated by a periodic acid-Schiff–positive laminated layer and surrounded by granulomatous infiltrate, either cellular in younger lesions or mostly fibrotic and acellular in older lesions. Protoscoleces are observed in 15% of lesions.

From the center to the periphery, the periparasitic granuloma (see Image 10) is composed of epithelioid cells lining the parasitic vesicles, macrophages, fibroblasts and myofibroblasts, giant multinucleated cells, and various cells of the nonspecific immune response. Collagen and other extracellular matrix protein deposits are present. The granuloma is usually surrounded by lymphocytes (mainly of the CD8⁺ subpopulation).

E multilocularis may be identified with polymerase chain reaction using specific probes; however, a negative result on a thin needle aspiration sample does not rule out disease.

Staging

Staging the disease is essential to allow comparisons between series of patients and to perform multicenter trials. Until recently, no international system of staging was available. The World Health Organization (WHO) Informal Working Group on Echinococcosis/Network on Alveolar Echinococcosis Staging has recently developed such staging. The PNM (parasite, neighboring organ and tissue invasion, metastases) staging system has been evaluated prospectively in 220 cases from 4 centers in France, Germany, China, and Japan.

• Hepatic localization of the parasite (For classification, the plane that projects between the bed of the gallbladder and the inferior vena cava divides the liver into 2 lobes.)
• • PX - Primary tumor cannot be assessed
  • P0 - No detectable tumor in the liver
  • P1 - Peripheral lesions without proximal vascular or biliary involvement
  • P3 - Central lesions with hilar vascular or biliary involvement of both lobes or involvement of 2 hepatic veins
  • P4 - Any liver lesion with extension along the vessels (vessels meaning inferior vena cava, portal vein, and arteries) and the biliary tree 
• Extrahepatic involvement of neighboring organs (diaphragm, lung, pleura, pericardium, heart, gastric and duodenal wall, adrenal glands, peritoneum, retroperitoneum, parietal wall [muscles, skin, bone], pancreas, regional lymph nodes, liver ligaments, kidney)
• • NX - Cannot be evaluated
  • N0 - No regional involvement
  • N1 - Regional involvement of contiguous organs or tissues
• The absence or presence of distant metastasis (lung, distant lymph nodes, spleen, CNS, orbital, bone, skin, muscle, kidney, distant peritoneum and retroperitoneum)
• • MX - Not completely evaluated
  • M0 - No metastasis (negative findings on chest radiograph and cerebral CT scan)
  • M1 - Metastasis
• Once the parasite (P), neighboring organ and tissue invasion (N), and metastases (M) are determined, they are combined, and an overall stage of I, II, III, or IV is assigned. Stage III is subdivided using letters such as A and B. The formal stage of alveolar echinococcosis does not change over time, even if the disease progresses. Alveolar echinococcosis that regresses or spreads is still referred to by the stage it was given when it was first diagnosed.
• The following is the PNM stage grouping of alveolar echinococcosis:
• • Stage I - P1, N0, M0
  • Stage II - P2, N0, M0
  • Stage IIIa - P3, N0, M0
  • Stage IIIb - P1-3, N1, M0 or P4, N0, M0
  • Stage IV - P4, N1, M0 or any P, any N, M1

TREATMENT

Section 6 of 11  

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• Medication
• Follow-up
• Miscellaneous
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Medical Care

Alveolar echinococcosis is rare and can be severe. Refer patients to reference centers to confirm their diagnosis and to obtain advice on therapeutic strategy.

• Antiparasitic chemotherapy
  
  
  • The basic medical treatment is chemotherapy with benzimidazoles (eg, mebendazole, albendazole) at high doses.
  • According to the 1996 WHO Informal Working Group on Echinococcosis, long-term chemotherapy (for several years, possibly for life) is mandatory in inoperable patients. The decision to withdraw treatment is particularly difficult without objective and irrefutable proof of definitive cure.
  • Complementary and continuous chemotherapy with, preferably, albendazole is mandatory for at least 2 years following surgery. Careful follow-up examinations in these patients must continue for at least 10 years. In all cases of palliative operations, either surgical or ultrasonographically guided, chemotherapy is mandatory and follows the same therapeutic schedule as for patients who have not undergone surgery.
  • Intravenous amphotericin B (preferably as lipid emulsion) may be used as a rescue chemotherapy in patients resistant or intolerant to benzimidazoles. Interferon gamma (currently in a pilot trial) and nitazoxanide (currently in a phase 3 clinical trial) are under evaluation.
  • Administer chemotherapy for at least 2 years after radical liver transplantation and for life in patients who demonstrate evidence of parasitic remnants in the liver area and/or of distant metastases outside the liver.
• Other medication
  
  
  • Additional medical treatment includes antibiotics and antifungal agents for bacterial and fungal superinfection of the lesions, cholangitis and/or septicemia (mostly gram-negative bacteria, antibiotic-resistant Streptococcus faecalis, Pseudomonas aeruginosa, and Candida species after surgical interventions), and chronic cholestasis (including vitamin K and D supplementation).
  • Use propranolol to prevent digestive bleeding related to portal hypertension.

Surgical Care

Except in cases of limited lesions located in the left liver lobe, attempt surgical procedures only if the team is trained and equipped for major liver surgery.

• Radical surgery
• • If operation is feasible and if resection of the entire parasitic lesion from other affected organs is possible, surgery is the first treatment choice.
  • Recurrence has been observed after liver resections judged radical by the surgeon based on macroscopic evidence.
• Palliative surgery
• • When radical surgery is impossible, one option is nonradical liver resection to reduce the parasitic mass and to increase the chances of effective chemotherapy. These palliative resections, as well as other types of palliative surgery performed to treat complications of disease (especially biliary obstruction), may generate specific complications (eg, recurrent biliary obstruction with cholangitis, septicemia, intrahepatic gallstones leading to secondary biliary cirrhosis). Long-term follow-up of patients shows that palliative or debulking surgery should be avoided.
  • The current tendency is to avoid palliative surgical procedures because of the relative efficacy of medical treatment, the use of interventional radiology, and a possible further indication of liver transplantation in patients with severe disease.
• Liver transplantation
• • Consider liver transplantation in very advanced cases. Since 1986, more than 50 liver transplantations have been performed in patients with alveolar echinococcosis. The overall associated survival rate is lower than that of other indications for liver transplantation but is acceptable.
  • Recurrences and metastases are common after transplantation (even those judged radical) in patients who are immunosuppressed.
• Interventional radiology or endoscopy
• • Consider ultrasonographically guided percutaneous procedures (eg, internal/external biliary drainage, abscess drainage, stenting) to alleviate intrahepatic complications.
  • Consider using endoscopic sclerosis of esophageal varices to prevent hemorrhages due to portal hypertension.

Consultations

• Before any therapeutic decision, especially if major hepatectomy or liver transplantation is considered, carefully assess for distant metastasis (ie, brain, lung, bone localizations). Include appropriate morphologic examinations and consultations. Discuss the case with liver and infectious disease specialists, radiologists, and all involved surgeons.
• Neurosurgery and thoracic surgery may be indicated if brain or lung metastasis is complicated and/or accessible to surgery. These decisions and procedures require appropriate consultations.

Diet

Patients require no special diet, except those with chronic cholestasis.

Activity

Activity modification is not indicated, but chronic inflammation and cytokine production usually result in fatigue, which typically limits activity and may greatly impair quality of life.

MEDICATION

Section 7 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to eradicate infection.

Drug Category: Benzimidazole anthelmintic drugs

Benzimidazoles have efficacy on E granulosus and E multilocularis larval stages. Mebendazole (MBZ) and albendazole (ABZ) are the only benzimidazoles effective in experimental models, but their efficacy is related to the clinical condition. These drugs bind to the free beta-tubulin of the parasite, thereby inhibiting both polymerization of tubulin and microtubule-dependent uptake of glucose. In E multilocularis infection, MBZ and ABZ are not parasiticidal, but they do reduce protoscolex viability in vitro and in vivo and inhibit the growth and development of germinal cells in vivo. Because of better bioavailability, better observance, and commercial availability and authorization worldwide, ABZ is usually the preferred drug. Although praziquantel is more effective against protoscoleces than benzimidazole, it is not indicated alone in the treatment of alveolar echinococcosis because it is totally ineffective against larval growth.

Drug Name	Albendazole (Albenza)
Description	Poorly and variably absorbed and subject to significant first-pass metabolism, resulting in a sulfoxide metabolite (ASOX) that may be the active form of the drug. Administering with fatty meal enhances extent and rate of absorption; resultant plasma concentrations are 4-5 times higher than in a fasting state. Considerable interindividual/intraindividual variation in ASOX plasma concentration/time curves. Continuous therapy has better efficacy without marked increase in adverse effects and is recommended in severe cases with multiple locations and in patients with immunosuppression.
Adult Dose	400 mg PO bid, preprandially/postprandially with a fatty meal; effective serum ASOX levels are estimated to be 650-3000 nmol/L (average of 1000-3000 nmol/L)
Pediatric Dose	Not established; weight-based dosing has been suggested for children >6 y (10-15 mg/kg/d PO)
Contraindications	Documented hypersensitivity; pregnancy (may be used during second or third trimester in urgent cases after careful risk analysis)
Interactions	Carbamazepine may decrease efficacy; dexamethasone, cimetidine, and praziquantel may increase toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Women of childbearing potential must use contraception during treatment (test for pregnancy prior to treatment); may reduce insulin requirement (monitor serum glucose concentrations in patients with diabetes mellitus); lower dose in cholestasis and/or hepatocellular dysfunction; GI distress; asymptomatic elevation of levels of serum aminotransferases occur and return to reference range after therapy withdrawal (measure serum aminotransferase levels before starting and regularly thereafter) (ie, q2wk for 3 mo, then q3mo); consider discontinuation if serum levels are >3 times the reference range; careful follow-up of increased rate may allow continuation of therapy; leukopenia and thrombocytopenia have occurred; leukopenia is less likely with ABZ than with MBZ and reverses when drug is withdrawn; monitor leukocyte count q2wk for 3 mo then q3mo thereafter; continue ABZ if aminotransferase levels and/or leukopenia are moderate and stable; cholestasis leads to delayed absorption and impaired elimination, resulting in increased ASOX area-under-curve

Drug Category: Other Antifungal/antiparasitic drugs

Although these drugs have not been formally authorized for use in this indication, evidence of their efficacy against E multilocularis in vitro and data from pilot trials in humans may support their use in rare cases in which inefficacy or contraindication of benzimidazoles is demonstrated. Only 2 such drugs may be proposed: amphotericin B and nitazoxanide. Among them, data are available only for amphotericin B; a pilot trial of nitazoxanide is ongoing in Germany.

Drug Category: Immunomodulating agents

Immune modulation of parasitic growth in alveolar echinococcosis has been demonstrated, with a markedly unbalanced Th1/Th2 profile. Efficacy of interferon gamma, which has been tested in the mouse model of alveolar echinococcosis and in a few patients, has not been demonstrated. Recombinant interleukin 12 (IL-12) is fairly efficient in E multilocularis–infected mice but may not be used in humans. Recombinant interferon alpha-2a was able to shrink alveolar echinococcosis lesions size in a patient with a combination hepatitis C and E multilocularis infection and was proven to protect infected mice against the development of alveolar echinococcosis lesions. No clinical trials are available yet. A pilot trial is ongoing in France.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Follow the usual rules for postoperative management of liver surgery (or of any other indicated surgical or interventional radiology procedures).

Further Outpatient Care

• Follow-up schedule
• • Because of the risk of recurrence, regular follow-up examinations are mandatory (eg, ultrasonographic examination, drug adverse effect monitoring), even after radical surgery.
  • Depending on the severity of the case, an experienced physician (with a permanent link to a reference center) must observe the patient every 3, 6, or 12 months. Addresses of the WHO-Collaborating Center for the Prevention and Treatment of Echinococcosis and of the WHO-Informal Working Group on Echinococcosis are available at WHO, Geneva.
• Drug availability and monitoring
• • Depending on the country, MBZ and/or ABZ at the recommended dosage may or may not be authorized or easily available. See regulations for availability.
  • In view of the large individual variations in the systemic availability of benzimidazole drugs, measure patients' plasma concentrations. If the techniques are available locally, measure concentrations at the beginning of treatment (after 4 wk of continuous treatment) and every 6 months during long-term treatment, especially in patients with cholestasis or hepatocellular disturbances.
  • Measuring MBZ and ABZ sulfoxide may be difficult because this test is performed only in highly specialized pharmacology laboratories.
• Decision to stop chemotherapy: After several years of treatment, if serology findings have become negative and CT scanning shows massive calcification of the lesions, decision of drug withdrawal may be made. The decision is based mostly on the morpho-PET (PET-CT) images. Careful follow-up is necessary because recurrence may occur despite apparently inactive lesions.

In/Out Patient Meds

• Prescription includes MBZ or ABZ at the recommended dosage and blood sampling at recommended intervals to monitor adverse effects.
• In cases that involve bacterial or fungal superinfection, administer antimicrobial drugs according to the usual rules of treatment for cholangitis, liver abscess, or septicemia.

Transfer

• Transfer the patient to a hospital with expertise in major hepatic surgery and, preferably, to a reference center familiar with this rare disease. Any physician under the guidance of a reference center specialist may institute follow-up care.

Deterrence/Prevention

• Humans
  
  
  • No known drug prophylaxis for echinococcosis exists.
  • Prevention is hampered by incomplete knowledge of the actual mode of contamination in most endemic areas, but basic advice is to avoid touching foxes and to avoid eating uncooked fruits or vegetables collected from fields.
  • A vaccine prepared using a recombinant antigen protein has been successfully used to prevent E granulosus larval infection in sheep. The potential efficacy of this vaccine in humans is questionable but may be considered in endemic areas.
• Animal hosts
  
  
  • Regularly treating dogs and baiting of foxes with praziquantel in Alaska and Germany has shown encouraging preliminary results.
  • Repeated and prolonged treatment is required, which leads to logistic and financial concerns.

Complications

• Complications related to obstruction or invasion of bile ducts or hepatic vessels
• • Obstructive jaundice
  • Cholangitis
  • Intrahepatic gallstones
  • Secondary biliary cirrhosis
  • Portal vein thrombosis
  • Portal hypertension resulting in esophageal variceal bleeding
  • Hypersplenism with anemia and thrombocytopenia
  • Budd-Chiari disease
  • Vena cava obstruction
• Complications related to invasion of neighboring organs and tissues
• • Adrenal or kidney dysfunction
  • Small bowel obstruction
  • Gastric perforation
  • Skin tumorlike lesions (see Image 9)
  • Right atrium parasitic thrombus
  • Pulmonary embolism
  • Communication between bile ducts and bronchi leading to bilious sputum
• Complications related to distant metastases
• • Lung dysfunction (multiple metastases)
  • Focal cerebral disorders (eg, seizures, hemiparesis, aphasia)
  • Tumorlike bone lesions and fracture
  • Miscellaneous and anecdotal complications related to rare locations

Prognosis

• The prognosis of echinococcosis has improved markedly during the past 20 years because of earlier diagnoses, better management, and medical treatment with benzimidazoles.
• In a series of 117 patients, the actuarial survival rate at 5 years improved from 67% in patients diagnosed from 1972-1982 to 88% in patients diagnosed from 1983-1993. The ages of patients were comparable in both series.
• Patients who receive transplants have a 5-year survival rate of 46%.
• Of the 34 deaths with a clearly identified cause in a series of 117 patients, 28 were related to the parasitic disease and/or its treatment.

Patient Education

• Regularly emphasize the importance of treatment compliance, which for some patients may be life long. In addition, inform patients that their medications are better absorbed when taken with a fatty meal.
• Stress the importance of regular follow-up care and good cooperation between the family care physician and a reference center.
• Despite the rarity of family-clustered cases, consider offering serology and/or liver ultrasonographic examinations to family members and relatives who share the same risk factors and immunogenetic background as the patient.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to secure proper consent before undertaking mass screenings
• Failure to offer medical attention to individuals suspected of having echinococcosis after a mass screening
• Failure to carefully monitor patients who do not qualify for immediate treatment
• Failure to explain advantages and risks of major liver surgery and liver transplantation to the patient before initiating treatment

Special Concerns

• Pregnancy
  
  
  • Pregnancy may be an opportunity for diagnosis via ultrasonographic examination.
  • Pregnancy may result in relative immunosuppression, which may predispose patients to lesion progression.
  • Benzimidazoles are contraindicated in pregnancy, further complicating successful treatment. 
  • Women with alveolar echinococcosis and their family physicians must be aware of all complications before making any decisions regarding pregnancy.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
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• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Foxes are the definitive hosts of the cestode Echinococcus multilocularis. Courtesy of Dominique A. Vuitton, MD, PhD.
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Media file 2:  Macroscopic aspect of alveolar echinococcosis lesions in the liver. Courtesy of Bernadette Kantelip, MD.
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Media file 3:  Ultrasonographic, CT scan, and perioperative aspect of a typical lesion of alveolar echinococcosis with central necrosis. Courtesy of Jean-Philippe Miguet, MD.
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Media file 4:  Microtus larvalis (common vole) is one of the most common intermediate hosts of Echinococcus multilocularis in Europe. Courtesy of Patrick Giraudoux, PhD.
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Media file 5:  Sonogram of a typical form of alveolar echinococcosis of the liver, discovered at a screening in China. Courtesy of Dominique A. Vuitton, MD, PhD; Brigitte Bartholomot, MD; and Philip S. Craig, PhD.
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Media file 6:  Sonogram of an abortive form of alveolar echinococcosis of the liver, discovered at a screening in China. Courtesy of Dominique A. Vuitton, MD, PhD; Brigitte Bartholomot, MD; and Philip S. Craig, PhD.
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Media file 7:  Pathognomonic aspect of alveolar echinococcosis lesions invading the adrenal gland (resembling a honeycomb) that shows a necrotic area in the contiguous left liver lesion; MRI showing multiple parasitic cysts smaller than 1 cm in diameter appearing in high signal intensity on T2-weighted sequence. Courtesy of Brigitte Bartholomot, MD.
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Media file 8:  Brain metastasis of alveolar echinococcosis. Courtesy of Jean-Philippe Miguet, MD.
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Media file 9:  Skin metastasis of alveolar echinococcosis. Courtesy of Solange Bresson-Hadni, MD, PhD.
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Media file 10:  Histologic features of alveolar echinococcosis vesicles and periparasitic granuloma in humans, periodic acid-Schiff staining of the laminated layer. Courtesy of Bernadette Kantelip, MD.
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Media file 11:  Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan aspect of active alveolar echinococcosis. White-yellow colors show a very high FDG uptake due to the periparasitic granulomatous infiltration and/or active germinal layer of Echinococcus multilocularis, and green-gray colors show the absence of the FDG uptake by inactive parasitic lesions (mostly necrotic). Courtesy of Solange Bresson-Hadni, MD, PhD, and Oleg Blagosklonov, MD, PhD.
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Media file 12:  Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan aspect of inactive alveolar echinococcosis. No abnormal FDG uptake by the parasitic lesions after several years of albendazole treatment. Courtesy of Solange Bresson-Hadni, MD, PhD, and Oleg Blagosklonov, MD, PhD.
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Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References