Alveolar Echinococcosis (AE) 

Updated: Nov 28, 2017
Author: Dominique A Vuitton, MD, PhD; Chief Editor: Burke A Cunha, MD 

Overview

Practice Essentials

Key observations and recommendations for alveolar echinococcosis (AE) in clinical practice are as follows:

  • Alveolar echinococcosis is a rare pseudotumor zoonotic parasitic disease of the liver that is distinct from cystic echinococcosis (also called hydatid disease).
  • The incidence of alveolar echinococcosis is increasing because of the urbanization of its animal hosts and the growing use of therapeutic immune suppression, which increases susceptibility.
  • The diagnosis of alveolar echinococcosis relies on imaging and may be confirmed with specific serology and/or molecular identification of the parasite  Echinococcus multilocularis in the lesions.
  • The treatment of alveolar echinococcosis is multidisciplinary and may (1) combine surgery (radical resection of alveolar echinococcosis lesions, possible in 30% of cases) with albendazole anti-infective treatment for 2 years or (2) consist entirely of very long-term continuous albendazole treatment.
  • Palliative surgery should be avoided; anti-scolicidal agents should never be injected into alveolar echinococcosis lesions.
  • Percutaneous drainage is indicated in advanced cases with bacterial infection of a central necrotic cavity.
  • Perendoscopic lavage, drainage, and stenting (with multiple plastic stents) via endoscopic retrograde cholangiopancreatography (ERCP) is indicated in complicated cases with biliary obstruction and/or cholangitis.
  • Disease prognosis has markedly improved over the past 30 years; however, the only drug alternative to albendazole in patients who experience life-threatening hepatic or hematological adverse effects is the parent drug mebendazole, which often results in similar adverse effects and is unavailable in many countries.

Background

Infection with the larval form of E 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 below) 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 family or stray dogs, is particularly important.

Foxes are the definitive hosts of the cestode Echi Foxes are the definitive hosts of the cestode Echinococcus multilocularis. Courtesy of Dominique A. Vuitton, MD, PhD.

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 below), which may develop in the liver and/or in various organs or tissues, especially the lungs, brain, and bones.

Macroscopic aspect of alveolar echinococcosis lesi Macroscopic aspect of alveolar echinococcosis lesions in the liver. Courtesy of Bernadette Kantelip, MD.

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 two main consequences, fibrosis and necrosis (see image below). 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).

Ultrasonographic, CT scan, and perioperative aspec Ultrasonographic, CT scan, and perioperative aspect of a typical lesion of alveolar echinococcosis with central necrosis. Courtesy of Jean-Philippe Miguet, MD.

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 below) exist and may occur in most cases, explaining the relatively low prevalence of this disease. Experimental studies in infected mice and immunologic studies in humans reveal the importance of cell-mediated immunity in the control of larval growth. Immune responses, characterized by a helper T cell TH 1 profile of cytokine secretion, can kill the larvae, thus protecting the host. The development of the periparasitic granuloma and the tolerance state to the parasite are associated with a sequential secretion of cytokines and chemokines.[1, 2] The progressive forms of the disease are characterized by a TH 2 profile consisting of increased interleukin (IL)–10, transforming growth factor (TGF)–beta, and IL-5 secretion.

Sonogram of an abortive form of alveolar echinococ 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.

Epidemiology

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 were described in 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 were diagnosed in Alaska from 1947-1990. Recent studies in the United States and Canada suggest that the risk in humans is currently increasing in the two countries.[3]

International

Alveolar echinococcosis occurs only in the northern hemisphere, in geographically limited foci (endemic areas) of west-central Europe, the Baltic countries, Turkey, most areas of the former Soviet Union, Iran, Iraq, central Asian republics, 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 is now well documented; 10% (in city centers) to 50% (in the suburbs) may be found in cities of the European endemic areas (such as Zurich or Geneva in Switzerland, Stuttgart in Germany, or Nancy in France). This 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

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 due to portal hypertension, Budd-Chiari disease, obstruction of the vena cava, and complications of heart, lung, or brain metastases (see image below).

Brain metastasis of alveolar echinococcosis. Court Brain metastasis of alveolar echinococcosis. Courtesy of Jean-Philippe Miguet, MD.

Alveolar echinococcosis 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. In developed countries, earlier diagnosis and well-managed treatment have improved average life expectancy at diagnosis from 3 years in the 1970s to 20 years in 2005.

A French study revealed an improvement in prognosis in most patients treated with benzimidazole; the mortality rates merged with that of the general population.[4]

Race

No known racial predilection exists; however, the genetic background, including human lymphocyte antigen (HLA) characteristics, linked to the intensity and/or to the TH 1/TH 2 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. However, the influence of slightly impaired immune defenses resulting from repeated pregnancies cannot be excluded.

Age

The typical age at onset is 55 years. However, the average age at diagnosis is younger in western China (age 40 years), and mass screenings have identified symptomatic and asymptomatic infections in patients ranging in age from 6 years to elderly persons.

Prognosis

Untreated alveolar echinococcosis is usually fatal, with an average 5-year survival rate of 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 that lead to death include biliary obstruction with bacterial and/or fungal superinfections (eg, cholangitis, septicemia), secondary biliary cirrhosis, bleeding from esophageal or duodenal varices due to portal hypertension, Budd-Chiari disease, obstruction of the vena cava, and complications of heart, lung, or brain metastases (see image below).

Brain metastasis of alveolar echinococcosis. Court Brain metastasis of alveolar echinococcosis. Courtesy of Jean-Philippe Miguet, MD.

Alveolar echinococcosis may markedly impair the patient’s 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 survival rates and quality of life. In European patients who survive more than one year after diagnosis, life expectancy does not significantly differ from that observed in the general population.[4, 5]

In a French 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. Of the 34 deaths with a clearly identified cause, 28 were related to the parasitic disease and/or its treatment.[4] Currently, in France, the life expectancy in patients with alveolar echinococcosis does not significantly differ from that in the general population. In a Swiss series of 155 patients, for an average 54-year-old patient diagnosed in 1970, the life expectancy was estimated to be reduced by 18.2 for men and 21.3 years for women. By 2005, this was reduced to approximately 3.5 and 2.6 years, respectively.

Patients undergoing radical surgery typically have a better outcome, whereas older patients have a poorer prognosis than younger patients. Alveolar echinococcosis-related mortality is mostly observed in the first 2 years after diagnosis and in symptomatic patients.[4]

Costs of treatment in Western Europe amount to approximately US $160,000 per patient. Assuming the improved life expectancy of patients is due to modern treatment, the cost per disability-adjusted life years (DALY) saved is approximately US $8,800.

Transplant recipients have a 5-year survival rate of 46%; in 1 per 6 of such patients, the survival rate exceeded 20 years; even patients with progressing residual lesions or recurrence due to anti-rejection immune suppression may thus survive long-term[6] ; however, adherence to albendazole treatment is crucial.

Patient Education

Patient education focuses on the following:

  • Precautions regarding albendazole treatment (strict adherence to a necessary long-term treatment, intake with fat-containing meal, possible adverse effects, and importance of biological measurements, including blood testing and alanine amino transferase studies)
  • Possible occurrence of bacterial infection in advanced cases, potentially resulting in chills, fever, and/or jaundice
  • Necessary long-term medical follow-up

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.

Patients with questions on alveolar echinococcosis may contact the following:

  • Association of Patients with Alveolar Echinococcosis (AIREA; email address, associationairea@gmail.com)
  • WHO-Collaborating Center for Prevention and Treatment of Human Echinococcosis (Besançon, France; email address, ccoms@chu-besancon.fr)
  • WHO-Collaborating Center for Prevention and Care Management of Echinococcosis (email address, renyong_lin@sina.com)
 

Presentation

History

The presenting symptoms below are from two series of patients diagnosed with alveolar echinococcosis (AE) 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 due to 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.[7]

In most regions, environmental features that favor the parasite cycle include hilly landscapes, cool and rainy climates, and pastures for cattle breeding.[7]

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 and between the prevalence in dogs and population densities of rodent or small lagomorph species in China. 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 below), or small lagomorphs (eg, Ochotona species) 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, lemurs, and apes.

Microtus larvalis (common vole) is one of the most Microtus larvalis (common vole) is one of the most common intermediate hosts of Echinococcus multilocularis in Europe. Courtesy of Patrick Giraudoux, PhD.

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.

Minor genetic differences between strains within the species E multilocularis may be recognized using mitochondrial and nuclear DNA sequencing. However, these genetic differences do not seem to greatly influence infectious and growth potential of the larva.

Immunologic factors

Various states of immunosuppression (eg, HIV infection, organ transplantation, chronic autoimmune or malignant disease treated with immunosuppressive drugs, pregnancy) are associated with a faster progression of alveolar echinococcosis.

Because these immunosuppressed populations are increasing, especially the patient population treated with immunosuppressants, echinococcosis is currently observed more and more frequently as an opportunistic disease.

A recent alveolar echinococcosis registry-based analysis shows that the number of alveolar echinococcosis cases associated with therapeutic immune suppression (chemotherapy and/or biotherapeutic agents, especially anti–tumor necrosis factor [TNF]) is increasing in Europe in patients with malignant and/or chronic inflammatory diseases. Alveolar echinococcosis diagnosis is problematic in such patients because of unusual presentation and imaging features, possible negative serology results, and confusion with signs and symptoms of the associated disease.[8]  Currently, patients with therapeutic immune suppression account for 15%-20% of patients with alveolar echinococcosis in areas with high healthcare standards (EurEchino AE database, 2014-2017, unpublished data).[8, 9]

Physical Examination

Left-lobe hepatomegaly may be found incidentally in patients with asymptomatic alveolar echinococcosis.

In complicated cases, physical examination may reveal the following:

  • Hepatomegaly due to the developing tumorlike parasitic liver lesion or liver enlargement of the centrolateral liver lobe
  • Jaundice due to bile duct obstruction, cholangitis, or secondary biliary cirrhosis
  • Swollen veins on the anterior abdominal wall and/or splenomegaly due to portal hypertension
  • Swollen veins on the thoracic wall due to chronic Budd-Chiari disease and obstruction of the vena cava

Ascites is rare and generally results from secondary biliary cirrhosis. Nonspecific signs related to alveolar echinococcosis metastases (eg, to the skin, lung, brain) may also be found in very rare cases.

Complications

Complications related to obstruction or invasion of bile ducts or hepatic vessels include the following:

  • 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 include the following:

  • Adrenal or kidney dysfunction
  • Small bowel obstruction
  • Gastric perforation
  • Skin tumorlike lesions (see image below)
    Skin metastasis of alveolar echinococcosis. Courte Skin metastasis of alveolar echinococcosis. Courtesy of Solange Bresson-Hadni, MD, PhD.
  • Right atrium parasitic thrombus
  • Pulmonary embolism
  • Communication between bile ducts and bronchi leading to bilious sputum

Complications related to distant metastases include the following:

  • Lung dysfunction (multiple metastases)
  • Focal cerebral disorders (eg, seizures, hemiparesis, aphasia)
  • Tumorlike bone lesions and fracture
  • Miscellaneous and anecdotal complications related to rare locations
 

DDx

 

Workup

Approach Considerations

A diagnosis of alveolar echinococcosis (AE) is most often suspected based on imaging results (ultrasonography or CT scanning).

In endemic European areas, suspected alveolar echinococcosis lesions are increasingly discovered incidentally (56% of AE cases in the EurEchino registry in 2016; unpublished data), in asymptomatic subjects during routine imaging workup for another disease, especially in patients with immunosuppression-associated conditions (malignant disorders, chronic inflammatory diseases, allotransplantation, AIDS).

In western China, because of the national program against echinococcosis, mass ultrasonography screening is systematically performed in some highly endemic areas and thus may uncover asymptomatic cases, but patients referred to hospitals are most often symptomatic (73% were incident cases in Xinjiang, People’s Republic of China, in 2016, according to the AE registry of the WHO-Collaborating Centre for Prevention and Care Management of Echinococcosis, Urumqi, Xinjiang; unpublished data).

After a suspected alveolar echinococcosis lesion is found on initial imaging, complementary imaging is the second step, followed by serology.

A two-step approach for serology is recommended, first with a highly sensitive test (hemagglutination or enzyme-linked immunosorbent assay [ELISA] using heterologous crude antigen) and then, second, with Western blot. Definitive diagnosis relies on pathology or identification of the parasite larva via molecular biology.

Laboratory 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. GGT 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 but is no longer performed. 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. This technique, as well as immunosyneresis, has inadequate sensitivity and is time-consuming so should be abandoned.

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. Considerations are as follows:

  • 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+, which combines Em2 and recombinant Em18, or recombinant Em18 alone) are positive in 95% of cases and have better specificity. Both are commercially available. Em18 is more suitable for follow-up of EA.
  • Dot immunogold filtration assay (DIGFA) 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 is present in the serum of 50% of patients, more frequently in patients with progressive and advanced cases, and cannot be used for diagnosis.

Cellular immunology

These tests are used primarily for research purposes. None of them is applicable to diagnosis.

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.

Diagnostic and prognostic value of contrast-enhanced ultrasonography and functional CT scanning and MRI need further evaluation.[10]

Classifications of sonograms and computed tomography (CT) scans, based on the morphological aspect of the lesions (eg, solid, pseudocystic, hemangiomalike, metastasislike) and the type of associated calcifications were recently proposed.[11, 12] Before being fully standardized and adopted at the international level, these classifications are currently being evaluated in a multicenter German/French/Chinese study.

Ultrasonography

Ultrasonographic examination (see image below) 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.

Sonogram of a typical form of alveolar echinococco 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.

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 hemangiomalike lesions, 1-2 cm diameter, may be associated with typical lesions and observed as a recurrence after surgery or observed in patients who are asymptomatic at screening. These lesions represent an early stage of development. They are more often observed in patients with immune suppression. Cancer metastasislike and abscesslike lesions may also be observed in such patients.[8]

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 below). If the calcifications are associated with a positive result on specific serology, they may represent aborted forms of the disease.

Sonogram of an abortive form of alveolar echinococ 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.

CT scanning

Abdominal CT scanning reveals the morphologic aspect of the lesions (see image below). 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.

Ultrasonographic, CT scan, and perioperative aspec Ultrasonographic, CT scan, and perioperative aspect of a typical lesion of alveolar echinococcosis with central necrosis. Courtesy of Jean-Philippe Miguet, MD.

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 (microcysts) 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 images below).MRI description of the lesions may use Kodama classification.[13]

Pathognomonic aspect of alveolar echinococcosis le 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.
Pathognomonic image of alveolar echinococcosis. Mu Pathognomonic image of alveolar echinococcosis. Multiple microcysts of alveolar echinococcosis, better seen at MRI on T2-weighted sequence. Courtesy of Prof. Eric Delabrousse and Dr. Amel Azizi, Department of Radiology, University Hospital, Besançon, France.

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 below). Use magnetic resonance (MR) cholangiopancreatography to study the relationship between the alveolar echinococcosis lesion and the biliary tree.

Pathognomonic aspect of alveolar echinococcosis le 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.

Cholangiography

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.[14]

Endoscopic retrograde cholangiopancreatography may also be used as the first stage of intrabiliary stent insertion.[14]

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

Fluorodeoxyglucose (FDG)–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.

FDG is actively metabolized by the cell immune response surrounding 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.

Delayed acquisition of PET images (3 hours after FDG injection) increases the sensitivity of the procedure and is recommended before any decision of medical treatment withdrawal is made.[15]

The presence of microcysts on MRI, as assessed in Kodama classification, well correlates with metabolic activity on PET.[16] ; the correlation between diffusion-weighted MRI and the metabolic status of the lesions should be confirmed in larger series of patients.[10]

Fluorodeoxyglucose (FDG) positron emission tomogra 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.
Fluorodeoxyglucose (FDG) positron emission tomogra 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.

Procedures

Esophagogastroduodenoscopy may show esophageal varices in cases that involve portal hypertension; it may be used as the first step of retrograde cholangiography and perendoscopic intervention (drainage and/or stenting) to relieve bile duct obstruction.

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 and should be followed by albendazole treatment if alveolar echinococcosis is confirmed.

Fine-needle aspiration (or needle biopsy, if necessary) 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 below) 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).

Histologic features of alveolar echinococcosis ves Histologic features of alveolar echinococcosis vesicles and periparasitic granuloma in humans, periodic acid-Schiff staining of the laminated layer. Courtesy of Bernadette Kantelip, MD.

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

A specific immunostaining using anti-Em2G11 monoclonal antibody may be used to better characterize the presence of E multilocularis metacestode materials.[17]

Staging

Staging the disease is essential to allow comparisons between series of patients and to perform multicenter trials. The World Health Organization (WHO) Informal Working Group on Echinococcosis has 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.

The currently proposed imaging classifications based on pure description of ultrasonography, CT scanning, and MRI images have no application to staging.[13, 11, 12] No studies have been specifically performed with the intent of associating the various morphological aspects of the lesions and/or the calcification in the lesions with therapeutic decisions or prognosis. They are being evaluated for this purpose on a larger collective of alveolar echinococcosis cases.

PNM classification and staging

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.

Staging is as follows:

  • 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

Neighboring organs include the diaphragm, lung, pleura, pericardium, heart, gastric and duodenal wall, adrenal glands, peritoneum, retroperitoneum, parietal wall (muscles, skin, bone), pancreas, regional lymph nodes, liver ligaments, and kidney.

Staging is as follows:

  • NX - Cannot be evaluated

  • N0 - No regional involvement

  • N1 - Regional involvement of contiguous organs or tissues

The absence or presence of distant metastasis

Locations include the lung, distant lymph nodes, spleen, CNS, orbital, bone, skin, muscle, kidney, and distant peritoneum and retroperitoneum.

Staging is as follows:

  • MX - Not completely evaluated

  • M0 - No metastasis (negative findings on chest radiograph and cerebral CT scan)

  • M1 - Metastasis

Determining stage

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, M

 

Treatment

Approach Considerations

A multidisciplinary approach and long-term follow-up are essential for optimal treatment of alveolar echinococcosis (AE). The first step consists of positive and differential diagnosis, as well as evaluation of the metabolic activity of lesions; the second step concerns the possibility of a complete resection of lesions (ie, radical or curative surgery). In 2016, a comprehensive review was published on the interventional strategy in alveolar echinococcosis.[18]

Medical Care

Alveolar echinococcosis is rare and can be severe. All cases merit prolonged follow-up. 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 and updated consensus recommendations in 2010,[19] long-term chemotherapy, for several years (and possibly for life), is mandatory in inoperable patients. The decision to withdraw treatment is particularly difficult without objective and irrefutable proof of definitive cure. An attempt at withdrawing benzimidazole treatment may rely on negative FDG-PET scanning findings, including delayed images and negative EM2+ or Em18 serology results. Follow-up with careful PET scanning and serology should be performed first 3 months after treatment interruption and then yearly for 10 years.

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. Pilot trials with interferon-gamma and nitazoxanide were unsuccessful. Interferon-alpha has yet to be tested in a pilot trial.

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.

Ursodeoxycholic acid may be used in patients with chronic cholestasis and/or biliary stenting; its use has not been evaluated by specific studies.

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, which supports the systematic prescription of albendazole for at least 2 years.

Recent retrospective studies of surgical series confirm the efficacy of the procedure if microscopic examination of the resected lesion confirms complete resection when the ”safety margin” is limited at least to 1 mm.[20, 21]

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). The current recommendation is to avoid palliative surgical procedures because of the relative efficacy of medical treatment, the use of interventional radiology and/or endoscopy, 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. Survival periods of more than 20 years have been observed in patients with alveolar echinococcosis who have undergone liver transplantation, even in those with residual or recurrent lesions.

Recurrences and metastases are common after transplantation (even those judged radical) in immunosuppressed patients. Benzimidazole treatment is mandatory as soon as possible after transplantation in all patients; such therapy can stop the progression of residual or recurrent lesions.

To avoid prolonged therapeutic immune suppression and make major hepatectomy possible, “bench-hepatectomy” (also called ”ex-vivo liver resection”) followed by autotransplantation has been performed in very advanced cases of alveolar echinococcosis by Chinese surgeons since 2011, with reasonable success.[22, 23]

Interventional radiology or endoscopy

Consider ultrasonographically guided percutaneous procedures (eg, internal/external biliary drainage, abscess drainage, stenting) to alleviate intrahepatic complications.

Consider perendoscopic stenting of the bile duct in patients with biliary obstruction. Retrospective evaluation of the technique in 19 European centers shows that it is efficient and safe and makes recalibration of the bile duct stricture possible by using iterative stenting with multiple plastic stents.[14, 24] )

When performing perendoscopic drainage and stenting, be careful to perform intensive lavage of bile ducts with saline, remove all stones and debris, and give appropriate antibiotics after the procedure.[24]

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.

Complications

Any type of complication that may be seen at presentation may also be observed after treatment initiation. The accepted time frame for late complications (especially regarding late biliary complications, which are most common) is 3 years after diagnosis and treatment initiation.

Other types of complications are directly associated with therapeutic procedures, as follows:

  • Complications of liver resection
  • Complications of palliative liver surgery: Iterative bile duct stenosis
  • Complications of anti-infective treatment with benzimidazoles (eg, hepatic toxicity, leucopenia, alopecia, abdominal discomfort, possibly weight gain)

Prevention

Alveolar echinococcosis is a zoonosis; thus, prevention should be considered both directly for humans and indirectly for the animal hosts.

Prevention in 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 better approach to environmental infection pressure is now made available through new molecular tools. Real-time PCR techniques well adapted to the identification and quantification of E multilocularis in environmental samples, including soil samples,[25, 26] and combined tests that identify both the parasite and the species of the definitive host’s feces have been developed.[27] Further evaluation is currently performed at a large scale and confirms the presence of E multilocularis eggs in gardens and in zoos/wildlife parks.[28, 29, 30] Global comparison of specific markers, such as the EmsB microsatellite, is now facilitated on a worldwide scale through a common website/database for data collection and phylogenetic studies.[31]

A vaccine prepared using a recombinant antigen protein has been successfully used to prevent larval infection by E granulosus in sheep.[32] The potential efficacy of this vaccine, demonstrated in a murine experimental model of E multilocularis infection[33] is questionable in humans, but it may be considered in endemic areas.[34]

Prevention in animal hosts

Regularly treating dogs and baiting of foxes with praziquantel in areas of Europe with demonstrated E multilocularis infection of urban areas showed encouraging results. However, this strategy fails when the prevalence of fox infection in the surrounding countryside is high.[35, 36]

Repeated and prolonged treatment is required, leading to logistic and financial concerns.

Long-Term Monitoring

Long-term monitoring (at least 10 years) is an essential component of the treatment plan for alveolar echinococcosis, even in patients who undergo radical surgery and receive appropriate 2-year albendazole therapy.

Long-term monitoring includes at least a yearly visit and, at the minimum, ultrasonography examination, blood count, transaminases and alkaline phosphatase measurements, and Em18 ELISA. Whenever available, FDG-PET and CT (with delayed acquisition of images) should be performed every 2 years. The decision to withdraw albendazole treatment should be made only if FDG-PET and Em18 serology results are negative.

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. The WHO-Collaborating Center for the Prevention and Treatment of Human Echinococcosis and the WHO-Informal Working Group on Echinococcosis (in France) may be contacted at ccoms@chu-besancon.fr; the WHO-Collaborating Center for Prevention and Care Management of Echinococcosis (in western China) may be contacted at renyong_lin@sina.com

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; their list is available through ccoms@chu-besancon.fr. In western China/Central Asia, ANZ sulfoxide measurement is also available at the WHO-Collaborating Center for Prevention and Care Management of Echinococcosis (Jian Hua Wang: jhw716@163.com)

Decision to stop chemotherapy

After several years of treatment, if serology findings using very specific antigens (eg, Em2+ or, preferably, Em18) have become negative and CT scanning shows massive calcification of the lesions, the decision of drug withdrawal may be made. The final decision is based on the morpho-PET (PET-CT or PET-RMI) images; absence of any FDG uptake 3 hours after injection supports withdrawal. Careful follow-up is necessary because recurrence may occur despite apparently inactive lesions. Persistently negative PET findings should be confirmed 3 months after withdrawal, then yearly for 10 years.

Further Inpatient Care

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

If perendoscopic procedures are indicated, perform extensive lavage of the bile ducts and use systematic antibiotic treatment before and after procedure.

Inpatient & Outpatient Medications

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. Information on specialized centers in endemic countries and their addresses/contacts may be obtained by contacting the WHO Collaborating Center in Besançon, France: ccoms@chu-fcomte.fr. 

 

Guidelines

Guidelines Summary

Guidelines for the treatment of alveolar echinococcosis (AE) were published in 1996[37] and updated in 2010[38] by the WHO-Informal Working Group on Echinococcosis. The most recent comprehensive review on the clinical aspects of alveolar echinococcosis was published by Kern et al in 2017.[39] Although the level of evidence is not high (no prospective controlled studies for this rare disease), the current guidelines are based on sound retrospective evaluation of treatment in reference centers, as follows:

  • Combined surgical and nonsurgical interventions contribute to the treatment of patients with alveolar echinococcosis.
  • Therapeutic decisions should be made by a multidisciplinary team, with a multimodality imaging approach, taking the number, size, and anatomical location of lesions into account, as well as the general status and the specific situation of the patient.
  • Surgery should be used only when it may reasonably be curative and accompanied by administration of albendazole for 2 years, regardless of the “safety margin” and the opinion of the surgeon at operation.
  • Ex-vivo lesion resection may be a technical solution to extend the indications of hepatic resection and to avoid liver allotransplantation more prone to disease recurrence because of the antirejection treatment.
  • All patients who cannot benefit from radical resection should be treated with lifelong albendazole therapy.
  • Percutaneous procedures are best indicated for bacterial/fungal infection of the central necrotic cavity, which is often present in advanced cases.
  • Perendoscopic procedures are best indicated for compression or obstruction of the bile ducts by the parasitic lesion, with resulting jaundice and/or cholangitis. To prevent recurrence of cholangitis and/or biliary obstruction, it is necessary to remove all intrahepatic gallstones and parasitic debris, to perform intensive lavage of the bile ducts with isotonic saline, to administer adapted antibiotics, and to use multiple plastic stents.
  • Palliative surgery should be reserved for extremely selected patients. 
 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to eradicate infection.

Benzimidazole anthelmintic drugs

Class Summary

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.

Mebendazole (Vermox)

Systemic bioavailability is low because MBZ is poorly absorbed and is subject to significant first-pass metabolism. Administering with a fatty meal enhances the extent and rate of absorption; resultant plasma concentration is 8 times higher than in fasting state. The decarboxylated inactive metabolite is excreted in urine and bile. Considerable between-patient variability in MBZ plasma concentrations. Measure MBZ radioimmunoassay and HPLC with ultraviolet or electrochemical detection. Individualize dosage by measuring plasma levels 4 h after administering the drug. Target MBZ concentration 4 h after morning dose averages 250 nmol/L (74 ng/mL).

Albendazole (Albenza)

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 currently recommended in all cases of alveolar echinococcosis.

Other Antifungal/antiparasitic drugs

Class Summary

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 in Europe was unsuccessful.

Amphotericin B (Amphocin, Fungizone)

Produced with a strain of Streptomyces nodosus, amphotericin B is a broad-spectrum antifungal drug but also has diverse antiprotozoal activity against Leishmania and Trypanosoma species. Its destructive mechanism against E multilocularis, shown in vitro, could be explained by formation of complexes with membrane phospholipids, which are major components of E multilocularis larval membrane; furthermore, amphotericin B affects membrane-bound enzymes and binds to sterols, thereby forming transmembrane channels. Importantly, amphotericin B is parasitostatic against only E multilocularis. In addition, IV administration and various side effects limit its use to salvage treatment in otherwise untreatable alveolar echinococcosis.

Immunomodulating agents

Class Summary

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.

Interferon alfa 2a (Roferon-A)

Protein produced by recombinant DNA technology. Efficacy in alveolar echinococcosis seems to be due to stimulation of Th1 cytokine production and reversal of the Th1/Th2 unbalance observed in patients with chronic infection by E multilocularis; stimulation of macrophage activation, phagocytosis, and killing has also been shown in experimental studies. Clinical experience with the drug comes from a single observation.

No information is available on interferon alpha-2a/albendazole combined efficacy or side effects.

Given the status of the clinical experience, interferon alpha-2a should be given only for salvage treatment for otherwise untreatable alveolar echinococcosis or as part of a controlled trial.