• View in gallery
    Figure 1.

    Map of case distribution of alveolar echinococcus cases within the province of Alberta. Insert: location of the province of Alberta within Canada. Symbols: cases are represented by diamonds, and major urban centers are denoted by name.

  • View in gallery
    Figure 2.

    A 49-year-old female with biopsy-proven Echinococcus multilocularis (Em) (patient 2). A dual screen capture from an abdominal sonogram on the same patient. (A-1) Transverse and (A-2) sagittal images of the right hepatic lobe demonstrate that the lesions are heterogeneously echogenic compared with the background liver. There are scattered punctate bright foci corresponding to tiny calcifications. These findings in the appropriate clinical context should raise the possibility of Em. A corresponding axial unenhanced CT image (B) shows that the three lesions demonstrate curvilinear peripheral calcifications (*), again, evocative of the diagnosis. (C) An axial T2-weighted fat-suppressed image shows three ovoid lesions in the right hepatic lobe. There are numerous tiny cysts (*) at the periphery of the lesions. (D) An axial post-gadolinium enhanced T1-weighted fat-suppressed image shows that the lesions have irregular margins and are predominantly poorly enhancing. These features are typical for Em.

  • View in gallery
    Figure 3.

    Alveolar echinococcosis in explanted liver (before transplant). (A) Patient 9: histology preparations—routine H&E staining (B) shows microcystic structures lined by a laminated grayish membrane on a background of necrosis. Staining with GMS and PAS (C and D) further highlights the laminated membranes.

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Epidemiological and Clinical Characteristics of Alveolar Echinococcosis: An Emerging Infectious Disease in Alberta, Canada

Stan HoustonUniversity of Alberta, Edmonton, Canada;

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Sara BelgaUniversity of Alberta, Edmonton, Canada;
University of British Columbia, Vancouver, Canada;

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Klaus ButtenschoenUniversity of Alberta, Edmonton, Canada;

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Ryan CooperUniversity of Alberta, Edmonton, Canada;

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Safwat GirgisUniversity of Alberta, Edmonton, Canada;

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Bruno GottsteinUniversity of Bern, Bern, Switzerland;

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Gavin LowUniversity of Alberta, Edmonton, Canada;

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Alessandro MassoloUniversity of Pisa, Pisa, Italy;

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Clayton MacDonaldUniversity of Alberta, Edmonton, Canada;

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Norbert MüllerUniversity of Bern, Bern, Switzerland;

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Jutta PreiksaitisUniversity of Alberta, Edmonton, Canada;

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Philippe SarlieveUniversity of Alberta, Edmonton, Canada;

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Stephen VaughanUniversity of Calgary, Calgary, Canada

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Kinga Kowalewska-GrochowskaUniversity of Alberta, Edmonton, Canada;

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ABSTRACT

Human alveolar echinococcosis (AE) is a zoonotic cestode infection which is usually fatal in the absence of treatment. Treatment involves major surgery or indefinite antiparasitic therapy. The incidence is rising in Europe and Asia, with an increased risk observed in immunocompromised individuals. Previously, AE acquisition in North America was extremely rare, except for one remote Alaskan Island. Recent studies have demonstrated a new European-like strain of Echinococcus multilocularis (Em) in wildlife and in human AE in western Canada. We report the experience of all AE patients diagnosed in Alberta. Each was diagnosed by histopathology, serology, and PCR-confirmed by a reference laboratory. Seventeen cases of human AE, aged 19–78 years, nine females, were diagnosed between 2013 and 2020: all definitely or probably acquired in Alberta. Six lived in urban areas, and 14 had kept dogs. In eight, the lesions were found incidentally on abdominal imaging performed for other indications. Six were immunocompromised to varying degrees. Six were first diagnosed at surgery. All have been recommended benzimidazole therapy. One died of surgical complications. Clinicians should be aware of this diagnostic possibility in patients presenting with focal nonmalignant hepatic mass lesions. Greater urbanization of coyotes, the predominant definitive host of Em in Alberta, and growing numbers of immune suppressed individuals in the human population may lead to increasing recognition of AE in North America.

INTRODUCTION

Echinococcus multilocularis (Em) is the etiological agent of human alveolar echinococcosis (AE), a globally important cestode parasite1,2 with more than 18,000 cases/year and an estimated burden of 660,000 disability-adjusted life years.3 The first human cases were reported from southern Germany in 1852, and a parasite etiology was recognized by Rudolf Virchow in 1855.4

The 2–3-mm adult worms live in the small intestine of the definitive hosts—commonly canids (fox, coyote, wolf, or domestic dog), less frequently cats, which are not thought to contribute significantly to transmission, and eggs are shed in feces. Once ingested by the intermediate host, usually a small rodent, the eggs hatch and larvae migrate to the liver where they develop into a multivesicular, infiltrating metacestode stage, subsequently producing infective protoscolices. These in turn develop into adult tapeworms when the intermediate host is preyed upon by a definitive host.5 Domestic dogs occasionally act as aberrant intermediate hosts, developing AE with progressive liver lesions.6 Humans are infected on accidental ingestion of eggs from contaminated food or soil, or from close contact with canids which have fur contaminated by parasite eggs associated with intestinal infection or the “scent rolling” behavior.7

The incubation period of AE in humans is thought to be up to 15 years.8 The asexual replication of metacestodes produces a slowly infiltrating tumor-like mass which involves the liver in almost all cases, but with the potential for local invasion and distant metastatic spread. Recent reports from Europe indicate that immunocompromised patients are at increased risk for AE and may manifest a shorter incubation period and atypical presentations.9,10 The natural history, radiographic appearance, diagnosis, and management of AE are quite distinct from those of cystic echinococcosis (hydatid disease) caused by members of the Echinococcus granulosus complex.

Advanced AE may present with malaise, fatigue, weight loss, right upper quadrant discomfort, and/or jaundice, but asymptomatic early stages of the disease are often diagnosed following an incidental finding on abdominal imaging for an unrelated indication. Diagnosis requires a high level of suspicion in a patient with abnormal liver imaging followed by confirmation by histopathology, serology, and PCR.11

Mortality is high without treatment, but outcomes have improved markedly with current medical and surgical management.11 Complete surgical excision is the treatment of choice when technically feasible. Non-curative “debulking” surgery does not appear to be beneficial.12 The use of benzimidazole agents is indicated in all patients; indefinite therapy is necessary when definitive surgery is not possible because these agents are only parasitostatic.11 Albendazole is generally recommended because its systemic absorption is better than that of mebendazole. No other agent has been shown to be effective in human AE.13 Liver transplantation has been used in a small number of patients.14

EMERGENCE OF A NEW STRAIN OF ENZOOTIC ECHINOCOCCUS MULTILOCULARIS IN CANADA

The endemic North American sub-strains of Em, N1 (tundra zone), and N2 (central regions), which are genetically distinct from the European or Asian strains, have long been recognized in animals in North America.15,16 However, only two cases of autochthonous human disease had previously been confirmed in North America outside of St. Lawrence Island, Alaska—one in Manitoba, Canada, in 192817 and one in Minnesota, USA, in 1977.18,19 The latter case was retrospectively shown by molecular typing to have been caused by the N2 strain of the parasite.18 The endemic focus in St. Lawrence Island, Alaska, appears to be associated with an Asian strain of the parasite.20 Recently, a human case with genetic characteristics of the European strain was diagnosed in Vermont.21

The assumption that the endemic North American strain had low virulence for humans is supported by the consistent paucity of human AE cases on the continent, by animal studies,22 and by the absence of serologic evidence of infection in trappers at high risk of exposure in North America.23

Since 2012, the presence of a novel strain of Em has been documented in definitive hosts, primarily coyotes, and rodent intermediate hosts in western Canada. This strain has been shown to be genetically very close to the European strain but distant from the previously endemic N2 strain.15,2427

In the first seven cases of human AE (Table 1; patients 1–7), molecular typing was available from tissue samples of five. All five showed the presence of a European-like Em strain. In four of these from whom adequate material was available, a single nucleotide polymorphism (SNP) in position 235 of the cob gene, which has been shown to be unique to North American specimens and predominant in local wildlife, was found.24

Table 1

Demographic characteristics, epidemiologic risk factors, clinical features, diagnostic results, disease classification, and treatment interventions of 17 cases of alveolar echinococcosis in Alberta, Canada

PtAge (years)/year of diagnosisGenderTravel: Europe or AsiaDog ownerRural/urbanImmunocompromisedIncidental finding# Of lesionsIWGE-WHO stage (10, 40)SerologyPCRTherapy
149/2013FemaleYesYesRuralYesYes7P3N0M0 IIIaPOSPOSAlbendazole
247/2016FemaleYesYesRuralNoNo4P4N1M0 IVPOSPOSAlbendazole
378/2016MaleNoYesUrbanNo?1P1M0N0 IPOSPOSSurgery and albendazole
452/2016FemaleNoYesRuralYesNo2P1N0M0 IINDPOSSurgery and albendazole
519/2017MaleYesYesUrbanYesYes3P1N0M0 IINDPOSSurgery none (refused)
655/2018MaleYesYesUrbanNoYes5P1N0M0 IPOSPOSAlbendazole
765/2018FemaleYesYesRuralNoNo2P1N1M0 IIIbPOSPOSSurgery and mebendazole
852/2018FemaleYesYesRuralYesNo2P1N1M0 IIIbPOSPOSSurgery and albendazole
957/2018MaleNoYesRuralNoYes1P1N0M0 IPOSPOSSurgery and albendazole
1075/2018FemaleYesNoUrbanNoYes3P3N0M0 INEGPOSAlbendazole
1156/2018MaleNoYesRuralYesYes3P1N0M0 INEGPOSSurgery and albendazole
1268/2018MaleNoYesRuralNoNo2P4N1M0 IVPOSNEGAlbendazole
1360/2019FemaleYesNoUrbanNoYes1P4N1MX IVPOSPOSAlbendazole
1472/2019MaleNoYesRuralYesNo4P2N0M1 IVPOSPOSAlbendazole
1536/2019FemaleNoYesRuralNoNo1P4N1M1.IVPOSPOSSurgery and albendazole
1666/2020FemaleNoYesRuralNoNo5P3N0M0 IIIaPOSPOSAlbendazole
1762/2020MaleNoYesRuralNoYes1P3N0M0 IPOSPOSSurgery; died

NEG = negative; POS = positive; IWGE-WHO = World Health Organization Informal Working Group on Echinococcosis.

We describe the epidemiological and clinical characteristics of human AE cases diagnosed over 7 years in Alberta, Canada, including the clinical and epidemiologic characteristics of the seven cases whose molecular epidemiology has been reported.28

METHODS

Diagnosis was initiated in every case following abnormal hepatic imaging, whether an incidental finding in the course of investigation for other conditions or precipitated by symptoms likely caused by AE. All cases were confirmed according to the criteria established by the WHO Informal Working Group on Echinococcosis, and by imaging, tissue histopathology, serology, and PCR.11 Serology and PCR were performed at the Institute of Parasitology, Vetsuisse Faculty, the University of Bern, Switzerland. Serologic testing used in-house Em2 ELISA29 and Em18 ELISA,30 which were confirmed by in-house Western blot.31 Multiplex PCR was carried out on gDNA isolated from formalin-preserved core needle biopsies32 or from gDNA directly isolated from resected tissue according to Trachsel et al.33 Each patient was interviewed regarding the place of residence, detailed travel history, dog ownership, and potential environmental exposure.

RESULTS

Seventeen human AE cases were diagnosed in Alberta, Canada, between 2013 and 2020 (Table 1). In terms of exposure risks, 15 were long-term dog owners, and 12 had lived predominantly in rural areas (Figure 1). One patient (patient 4) had performed autopsies on wolves, and three patients (patients 11, 12, and 17) were farmers who described frequent exposure to coyote feces and/or carcasses. Nine had never travelled to any part of Europe or Asia known to be endemic for AE, and in several of those with a European travel history, the duration was very short (e.g., 2 weeks in Paris) or the timing of exposure (e.g., 44 years before diagnosis) was extremely unlikely to be consistent with Europe having been the site of Em infection. There were no clusters or linked cases.

Figure 1.
Figure 1.

Map of case distribution of alveolar echinococcus cases within the province of Alberta. Insert: location of the province of Alberta within Canada. Symbols: cases are represented by diamonds, and major urban centers are denoted by name.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 5; 10.4269/ajtmh.20-1577

Six patients were immunosuppressed to varying degrees: one renal transplant recipient (patient 1), one on methotrexate for psoriatic arthritis (patient 4), one on corticosteroids for inflammatory bowel disease (patient 5), one on methotrexate and prednisone for inflammatory arthritis (patient 8), one who had undergone chemotherapy and radiation for metastatic colon cancer (patient 11), and one who had a stem-cell transplant and chemotherapy for myeloma (patient 14).

In eight patients, investigation for abdominal symptoms led to the initial finding of a hepatic lesion. In eight patients, including two patient (patients 4 and 11) with known malignancies which prompted the screening, the initial finding of a liver lesion was incidental, following imaging for an unrelated indication. In most cases, malignancy was initially suspected as the explanation for the liver lesion(s). Hepatic lesions ranged in size from 0.7 to 14.1 cm (Figure 2).

Figure 2.
Figure 2.

A 49-year-old female with biopsy-proven Echinococcus multilocularis (Em) (patient 2). A dual screen capture from an abdominal sonogram on the same patient. (A-1) Transverse and (A-2) sagittal images of the right hepatic lobe demonstrate that the lesions are heterogeneously echogenic compared with the background liver. There are scattered punctate bright foci corresponding to tiny calcifications. These findings in the appropriate clinical context should raise the possibility of Em. A corresponding axial unenhanced CT image (B) shows that the three lesions demonstrate curvilinear peripheral calcifications (*), again, evocative of the diagnosis. (C) An axial T2-weighted fat-suppressed image shows three ovoid lesions in the right hepatic lobe. There are numerous tiny cysts (*) at the periphery of the lesions. (D) An axial post-gadolinium enhanced T1-weighted fat-suppressed image shows that the lesions have irregular margins and are predominantly poorly enhancing. These features are typical for Em.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 5; 10.4269/ajtmh.20-1577

Seven patients had an elevated alanine transaminase enzyme level between two and 13 times the upper limit of normal at the time of diagnosis; four patients had mild cholestatic enzyme elevations. No patient had an elevated eosinophil count.

Patients 1 and 8 required three liver biopsies before the diagnosis was made; three others (patients 2, 6, and 10) required two liver biopsies to establish the diagnosis. In six patient (patients 3, 7, 9, 11, 15, and 17), the initial diagnostic specimen was obtained only at surgical excision Figure 3.

Albendazole therapy was initiated in all patients as soon as possible after diagnosis (Table 1). One patient declined to continue it post-surgery, and one had an elevation of her transaminase enzymes to 20 times the upper limit of normal, replicated on rechallenge, but is tolerating mebendazole (although the recommended dose requires 36, 100 mg tablets daily).

Figure 3.
Figure 3.

Alveolar echinococcosis in explanted liver (before transplant). (A) Patient 9: histology preparations—routine H&E staining (B) shows microcystic structures lined by a laminated grayish membrane on a background of necrosis. Staining with GMS and PAS (C and D) further highlights the laminated membranes.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 5; 10.4269/ajtmh.20-1577

In total, nine patients have undergone surgery. In the six in whom the diagnosis was made only after surgery, primary (patients 3, 7, 15, and 17), or metastatic (patient 11) tumor was suspected. In one patient (patient 9), it was an unexpected finding at liver explant in the course of transplantation for hepatitis C and alcohol-related cirrhosis. Only three patients (patients 4, 5, and 8) underwent planned surgery with curative intent following a biopsy diagnosis; one patient (patient 5) then declined albendazole, one patient (patient 4) has completed 2 years of albendazole with presumptive cure and has remained disease free at follow-up, and one patient (patient 8) was found to have extrahepatic extension of the disease at operation. The patient who underwent complete excision during liver transplantation has also completed 2 years of therapy for presumed cure.

In terms of complications, one patient (patient 13) has experienced secondary bacterial infection in a necrotic parasitic liver mass, and several patients have experienced significant persistent pain at the site of disease and/or surgery. None of our patients have had clinical or imaging evidence of distant metastases. However, four patients (patients 3, 7, 8, and 15) had surgical and/or histological findings of peritoneal or pleural involvement. One patient (patient 17) died of postoperative complications following excision of what was thought preoperatively, to be cholangiocarcinoma, after the incidental finding of a hepatic lesion on imaging for an unrelated problem.

DISCUSSION

The unprecedented appearance of 17 human cases of AE in a circumscribed region of continental North America over 7 years is a novel and significant development in the epidemiology of this disease. The annual incidence of diagnosed AE in Alberta of 0.064 per 100,000 inhabitants over the past 7 years is within the range observed in endemic countries of Europe—from 0.03 to 0.20/100,000 inhabitants/year.10

Travel-related AE in North America has never been well documented despite millions of travelers to endemic areas of Europe over many decades; hence, the geographic and temporal clustering of our cases is compelling evidence of local transmission. In nine patients, local acquisition was confirmed definitively by the absence of any lifetime history of travel to an endemic area. Even in those who had ever been to Europe, their limited exposure history there was unlikely to explain their infection. This cluster of 17 human cases is also temporally and geographically associated with the emergence of a European-like strain of Em in local wildlife. Finally, in several cases, it has been possible to demonstrate the presence of an SNP unique to Canada (19).

The postulated greater virulence of the European strain may explain its emergence in humans and rapid dominance in animal hosts in North America. The observed concurrent reduction in the detection of the previously endemic North American sub-strain N2 in the animal reservoir following introduction of this more virulent strain is consistent with the competitive exclusion principle.34 The presence of European-like strains of Em in North America in wildlife, dogs, and humans since 201225,27 is best explained by the recent importation of dogs or foxes from Europe because screening or anthelmintic treatment of imported animals is not required.25,35

A relatively high prevalence (from 25% to 60%) of Em has recently been found in urban coyotes in Calgary and Edmonton, Alberta.3638 Five hundred to 1,000 coyotes are estimated to live within the city of Edmonton with similar numbers estimated for Calgary. The potential access of domestic dogs to infected rodents increases the risk of intestinal infection in pets.39 The presence of infected coyotes also increases the potential for contaminating garden produce and for the adherence of Em eggs to dogs’ fur associated with “scent rolling” behavior involving coyote feces. Even at a low prevalence of infection, the presence of more than 125,000 domestic dogs in Calgary could significantly contribute to the parasite sylvatic cycle as well as serve as a potential direct source of human exposure.

Fifty (9.8%) AE cases in a European registry between 1982 and 2009 had one or more immunosuppressive conditions before or at the time of diagnosis of AE, including five patients with organ transplants.9 An accelerated disease course has been seen in AE patients with HIV coinfection.40,41 Six of our 17 AE patients had received immunosuppressive therapies, a higher proportion than has been seen in Europe. These patients not only comprise a group at increased risk of AE but may serve as a sentinel population for the disease in North America. The high proportion of immunocompromised individuals among our patient group suggests that we may be at an early stage of emergence of the disease in North America because these patients are likely to have shorter incubation periods. This conjecture is supported by the high proportion who were found incidentally, at an early stage before progression to symptomatic disease.

Imaging findings in AE are often initially interpreted as malignant,11 particularly in patients with a history of malignancy. The diagnosis of AE would have been missed in patient 11 had the decision to excise the presumed malignant lesion not been made.

A biopsy may readily miss the diagnosis, as was the case with the initial biopsy in five of our patients,42 particularly if histopathologists lack familiarity with the disease. Serology and PCR may be helpful if histology is nondiagnostic. A biopsy diagnosis can critically inform the treatment strategy, specifically in regard to a decision around surgery. A team approach to care of AE is desirable as decisions regarding the feasibility of curative surgery require surgical and imaging expertise. Pharmacologic treatment options remain extremely limited13 and are uniquely complicated in North America; the drug of choice, that is, albendazole, is very expensive in the United States and accessible only through a complex application process in Canada, although widely and cheaply available worldwide.

CONCLUSION

As a result of these new findings, clinicians in North America must now consider AE in the differential diagnosis of mass lesions in the liver.

The emergence of SARS-CoV-2 is a reminder of the potential impact of emerging infections of zoonotic origin and of the importance of a One Health perspective. Animal studies to better understand and track local parasite epidemiology along with monitoring of the disease in human populations in North America are needed to inform public health policy.

ACKNOWLEDGMENTS

We thank Sandra Cockfield who pressed for a repeat biopsy to diagnose patient 1. We also thank Banu Sis who first made the pathological diagnosis and Jamil Kanji who cares for patient # 16.

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Author Notes

Address correspondence to Stan Houston, University of Alberta, 1-124 Clinical Sciences Bldg., 11350 83 Ave., Edmonton T6G 2G3, Canada. E-mail: shouston@ualberta.ca

Disclosure: The University of Alberta (REB Pro00097735) approved the study.

Authors’ addresses: Stan Houston, Department of Medicine/Public Health, University of Alberta, Edmonton, Canada, E-mail: shouston@ualberta.ca. Sara Belga, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada, and Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada, E-mail: sara.belga@ubc.ca. Klaus Buttenschoen and Jutta Preiksaitis, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada, E-mails: klaus.buttenschoen@ualberta.ca and jutta@ualberta.ca. Ryan Cooper, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada, E-mail: rdcooper@ualberta.ca. Safwat Girgis, Department of Anatomical Pathology, University of Alberta, Edmonton, Canada, E-mail: sgirgis@ualberta.ca. Bruno Gottstein, Institute of Parasitology, University of Bern, Bern, Switzerland, E-mail: bruno.gottstein@ifik.unibe.ch. Gavin Low and Philippe Sarlieve, Department of Radiology and Diagnostic Imaging, University of Alberta Faculty of Medicine and Dentistry, Edmonton, Canada, E-mails: low1@ualberta.ca and sarlieve@ualberta.ca. Alessandro Massolo, Department of Biology, University of Pisa, Pisa, Italy, E-mail: alessandro.massolo@unipi.it. Clayton MacDonald, University of Alberta Faculty of Medicine and Dentistry, Alberta, Edmonton, Canada, E-mail: clayton.macdonald2@vch.ca. Norbert Müller, Department of Parasitology, Vetsuisse Faculty Bern, Bern, Switzerland, E-mail: norbert.mueller@vetsuisse.unibe.ch. Stephen Vaughan, Department of Infectious Diseases, Universiity of Calgary, Calgary, Canada, E-mail: stephen.vaughan@albertahealthservices.ca. Kinga Kowalewska-Grochowska, Provincial Laboratory of Public Health, University of Alberta Faculty of Medicine and Dentistry, Edmonton, Canada, E-mail: kinga.kowalewska-grochowska@albertaprecisionlabs.ca.

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