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Giant isolated hydatid lung cyst: two case reports 

  • Jay Lodhia 1 ,
  • Samwel Chugulu 1 , 2 ,
  • Adnan Sadiq 1 , 3 ,
  • David Msuya 1 , 2 &
  • Alex Mremi 2 , 4  

Journal of Medical Case Reports volume  14 , Article number:  200 ( 2020 ) Cite this article

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Echinococcosis is a parasitic disease caused by Echinococcus granulosus and causes cystic lesions in the liver and lungs commonly. It is endemic in many parts of the world, and though humans are incidental hosts of the parasite, the disease can have severe consequences.

Case presentation

We present two patients from pastoralist (Maasai) communities in rural Tanzania with long-standing chest pain accompanied by hemoptysis. Both were managed surgically after diagnosis, but one patient died of the complications following rapture of the cyst during surgery. Histopathological evaluation of the specimens confirmed the diagnosis of giant hydatid cysts.

Animal-keeping communities such as the Maasai are at risk of echinococcosis because of their close proximity to animals. The diagnosis can be made on the basis of history and radiological as well as laboratory findings. Surgery is a recommended mode of treatment, though it carries a high risk, especially when the cyst ruptures. Primary preventive measures are thus necessary in order to avoid the secondary and tertiary complications of the management of giant hydatid cysts, which is difficult in resource-limited endemic areas.

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Hydatid disease is a zoonotic parasitic infestation caused by tapeworms, particularly Echinococcus granulosus [ 1 ]. The life cycle of Echinococcus involves a definitive host and intermediate host [ 1 ]. Dogs (or other carnivores) harbor the adult tapeworms in their small intestine, and eggs are excreted into feces. The excreted ova, once ingested by the intermediate host (commonly sheep), develop into a hexacanth embryo in the liver through the portal circulation. Embryos in the liver develop cysts [ 2 ]. Humans are incidental intermediate hosts by ingestion of water or vegetables contaminated with echinococcal ova [ 2 ].

The treatment of hydatid lung cyst often requires surgical removal combined with chemotherapy (albendazole and/or mebendazole). The Maasai, a seminomadic indigenous group in northern Tanzania, are frequently in close contact with animals and therefore at higher risk of contracting the disease. Due to their culture and poor health-seeking behavior, such ethnic groups present late to medical facilities and opt for traditional remedies in the early stages, hence increasing their risk of poor treatment outcome. Disease awareness is therefore needed among the population and also health care workers for prevention and early management and to reduce complications.

A 64-year-old man, a Maasai from Ngorongoro District, Arusha Region, northern Tanzania, presented to our facility in February 2020 with chief complaints of chest pain and cough for the past 3 years. He further reported that, at times, he experienced a sore throat, blood-stained sputum, pain that was greater on the right side of the chest, and intermittent low-grade fevers. The patient also reported significant unintentional weight loss and generalized body weakness. He had been consuming local herbs with occasional relief and was unable to afford modern hospital care expenses. Despite using traditional medicines, he had no notable improvements. He had no significant past medical history, denied tuberculosis contact, and consumed local brew. He denied any formal education and was a farmer and livestock keeper. Upon examination, he was cachexic with mild conjunctival pallor and saturating at 97% on room air. His axillary temperature was 36.4 °C; his pulse rate was 95 beats per minute; and his blood pressure was 100/70 mmHg. His chest examination revealed reduced air entry on the right side. His abdomen was flat and moved with respiration with traditional marks on the upper quadrants, with no tenderness, and with a liver span of 10 cm. The finding of his neurologic examination was unremarkable. His hemoglobin level was 12.8 g/dl with an erythrocyte sedimentation rate (ESR) of 110 mm/hour. His creatinine level was 83 μmol/L, serum urea was 4.14 mmol/L, aspartate aminotransferase was 17.52 U/L, alanine aminotransferase was 23.78 U/L, and serum electrolytes were within normal range.

A CT scan of the patient’s thorax showed a massive cyst in the right lower lung measuring 19 × 11 cm with well-defined margins. A working diagnosis of bronchogenic cyst was reached with the possibility of hydatid cyst. Ultrasonography excluded the presence of the disease in the abdominopelvic region.

We performed a right-sided sixth-interspace thoracotomy. Intraoperatively, we found a large hydatid cyst occupying the middle and lower lobes. During blunt dissection, the cyst ruptured, but the middle and lower lobes were successfully removed (Fig. 1 ). Approximately 30 minutes after surgery, the patient died in the intensive care unit (ICU) of sudden cardiac arrest. The probable cause of death we speculate to be anaphylaxis triggered by leakage from the ruptured cyst. The specimen taken intraoperatively was analyzed and confirmed to be a hydatid cyst of the lung (Fig. 2 ).

figure 1

Ruptured cyst attached to lung parenchyma

figure 2

a Bilayered daughter cysts developing in large mother cysts and scolices. The worm produces sediment, so-called hydatid sand (Hematoxylin & eosin (H&E) staining; × 10 original magnification). b Lung sections with mixed chronic inflammation consisting mononuclear cells, eosinophils, and multinucleated giant cells. (H&E staining; × 20 original magnification)

A 13-year-old Maasai boy from rural Arusha, northern Tanzania, presented with a 2-month history of gradual and progressive dyspnea and cough that was dry initially but had started to produce blood-stained sputum in the past 2 weeks before admission. His past medical history was unremarkable, though his father reported that the child had lost significant weight through the course of the illness and had experienced intermittent low-grade fevers. The boy had no history of tuberculosis contact. The informant reported that before this admission, the boy had received treatment for his current illness from a local dispensary, which included antibiotics that he could not specify; however, the boy had no significant improvement. He is from a farming family and keeps livestock. Upon examination, the child was moderately pale, not cyanotic, and saturating at 98% on room air. His pulse rate was 85 beats per minute; his resting blood pressure was 108/60 mmHg; and he was afebrile with a temperature of 36.7 °C.

Chest expansion was more unilateral toward the right with reduced air entry and dull percussion note. No peripheral lymphadenopathy was appreciated. The findings of his abdominal and neurological examinations were unremarkable. A plain chest x-ray was obtained and showed a well-circumscribed cystic mass on the right hemithorax pushing the mediastinum toward the left (Fig. 3 ). A computed tomographic (CT) scan revealed a cystic lesion on the right upper and middle thorax measuring 15 × 11 × 14 cm, displacing the mediastinum to the left side of the chest and compressing the right middle and lower lung lobes. The lesion had a thick wall with clear fluid (Fig. 4 ). The finding of ultrasonography of the abdominopelvic region was unremarkable. His hemoglobin concentration was 12.4 g/dl, platelet count was 492 × 10 9 , leukocyte count was 7.39 × 10 9 /L, serum creatinine was 42 μmol/L, serum urea was 3.77 mmol/L, and ESR was elevated at 95 mm/hour. The finding of GeneXpert testing (Cepheid, Sunnyvale, CA, USA) for Mycobacterium tuberculosis was negative, and the boy’s serum electrolytes and bilirubin levels were within normal range. His urine test result was negative for leukocytes, nitrates, glucose, and proteins. We made a differential diagnosis of hydatid cyst of the right lung.

figure 3

Chest x-ray posteroanterior view shows a large, rounded opacity in the right hemithorax causing mediastinal shift toward the contralateral side. Left-sided tracheal shift is seen with right main bronchus compression. No rib destruction is visualized. Features are suggestive of a hydatid cyst

figure 4

Contrast-enhanced chest computed tomography in axial, coronal, and sagittal views demonstrating a large cystic lesion in the right upper and middle hemithorax measuring 15.5 cm (AP) × 11.3 cm (T) × 14.9 cm (CC) and displacing the mediastinum to the contralateral side of the chest. The cystic lesion has a thick rind with double membranes on its anterior and posterior walls. No internal architecture or daughter cysts are seen. Features are suggestive of hydatid cyst. AP Antero-posterior, T Transverse, CC Craniocaudal

The child underwent right-sided thoracotomy through the eighth interspace. The large cyst was attached to the lung parenchyma and hence could not be removed; therefore, we performed a standard right pneumonectomy and sent a specimen for histopathological analysis (Fig. 5 ). The child was kept on intravenous paracetamol 500 mg 6-hourly, ceftriaxone 500 mg 8-hourly, and metronidazole 250 mg 8-hourly for 10 days. He was monitored in the ICU for 8 days, during which time he developed acute urine retention on day 6, and the urology team inserted a suprapubic catheter (SPC). The chest tube was removed on day 11 postoperatively. The child was then discharged on day 12 with the SPC and an instruction to attend the urology outpatient clinic after 1 month with oral albendazole 400 mg daily for 6 months. Two weeks after discharge, the child was reviewed at the surgical outpatient clinic, where he was found to be clinically stable with a healed chest wound, and the SPC was patent. The histological reports confirmed the diagnosis of hydatid cyst of the lung (Fig. 6 ). The child was then reviewed at the outpatient clinic 2 months later jointly with the urology team, and he was found to have no chest symptoms and a healed chest wound. His SPC was blocked, and he was voiding normally per urethra with no lower urinary symptoms.

figure 5

Cyst attached to lung parenchyma

figure 6

a The cyst comprises three layers: The outermost pericyst is fibrous; the middle ectocyst layer is laminated, hyaline, and acellular; and the inner endocyst is the germinative layer, which consists of daughter cysts and brood capsules with scolices. b The chronic granulomatous inflammation reaction

This case report highlights the possible risk of serious complications, including a fatal outcome, of the surgical treatment of advanced giant isolated hydatid lung cysts, particularly in endemic areas with limited resources, contrary to most reports in the literature that have documented rather fairly good treatment outcomes.

Echinococcosis is a zoonosis caused by tapeworms of the genus Echinococcus . The two medically important species are E. granulosus , which causes cystic echinococcosis, and E. multilocularis , which causes alveolar echinococcosis. There are two other neotropical echinococcosis species, E. vogeli and E. oligarthrus [ 1 , 3 , 4 ]. They are also of public health importance due to their geographical distribution. Hydatid disease is endemic in sheep-rearing countries where sheep are in close contact with humans. Humans are infected as accidental hosts in the life cycle of the worms [ 2 , 5 ].

The World Health Organization (WHO) estimates the incidence of human infection to exceed 50 cases per 100,000 person-years in echinococcosis-endemic areas. The prevalence is as high as 5–10% in parts of Argentina, China, Central Asia, and East Africa. The burden of disease is said to be a loss of 1–3 million disability-adjusted life-years annually and US $3 billion for treating cases and for loss of livestock [ 5 ]. The average postoperative death rate of cystic Echinococcus is 2.2%, and 6.5% of cases relapse after intervention, as stated by the WHO.

Zoonosis is common among Tanzanians due to lack of knowledge and a lifestyle with close contact with livestock because more than 75% of the population lives in rural areas [ 6 ]. Like in other sub-Saharan African countries, the burden of zoonosis in Tanzania remains high due to lack of knowledge among rural communities and inadequate diagnostic capacity, leading to misdiagnosis and hence poor management. This has led to underreporting of such diseases in the area [ 6 ].

E. granulosus can cause one or many hydatid cysts and mostly affects liver; lungs; and, less commonly, the bones, kidneys, spleen, and central nervous system [ 5 ]. An infected individual can go up to years without symptoms during the incubation period until the cyst is large enough to produce symptoms. About 60% of humans infected with Echinococcus spp. remain asymptomatic. The incubation period of alveolar echinococcosis is 5–15 years, with metastasis to the spleen and brain occurring via the hematological and lymphatic systems [ 4 , 5 ]. Signs and symptoms arise when the lesion compresses adjacent structures and also depends on the locality. Both our cases presented with hemoptysis similarly to the case reported by Kant et al. [ 7 ]. Such cases can arise when the cyst ruptures in a bronchus, which was not present in our patients’ cases. However, when the cysts are considerably big, as in our patients’ cases, the local pressure, obstructive effect, and secondary inflammatory reaction to the adjacent bronchus may result in hemoptysis. Chest pain, breathlessness, and cough are common complaints in alveolar hydatid cysts [ 8 ]. Sarkar et al. also mentioned hypersensitivity reactions and anaphylaxis from the parasites or the ruptured cysts [ 8 ]. This is presumed to be the cause of death in our patient 1.

Alam et al. stated that in 60% the right side of the lung is affected, bilateral in 20% and 60% are located in the lower lobes. This was the case in both index patients having right-sided cysts [ 1 ]. Lodhia et al. previously reported a case of an isolated pulmonary hydatid cyst in a young boy that was also located on the right side of the chest and was successfully removed surgically [ 9 ]. Lungs are the second most common site for hydatid cysts, accounting for 20–30%, with the most common site being the liver at 60% [ 2 , 8 , 9 ]. Ramos et al . also mentioned a single lung cyst similar to the index cases presented, and those authors also stated that the initial period may be asymptomatic. They continued to mention rather rare but severe complications such as bronchial fistulization, intrapleural rupture, and secondary metastatic hydatidosis causing right ventricular failure, which should be taken into consideration because it makes management difficult [ 10 ].

Various investigative modalities are available for diagnosis of hydatid cysts. Numerous serological tests can be used, including enzyme-linked immunosorbent assay, indirect hemagglutination test, agglutination test, and immunoblot test, depending on availability, because humans do not discharge eggs. Radiological investigations such as plain x-rays or CT scans will provide further details of the locality of the cyst in relation to other structures and facilitate planning of surgery [ 5 , 11 ]. Radiological signs such as the serpent sign, water lily sign, signet sign, or inverse crescent sign can help determine the complexity of the cyst [ 2 , 11 ].

Management of lung hydatid cysts is essentially surgical, and the mortality is 1–2% with a recurrence rate of 1–3% [ 10 , 11 ]. Options include lobectomy, pneumonectomy, pericystectomy, or endocystectomy, depending on the nature and extent of the cyst with regard to the lung parenchyma [ 11 ]. Both index cases underwent thoracotomy, and pneumonectomy was performed in the second case; the cyst was adherent to the lung tissues. The cyst can be infiltrated with 20% hypertonic saline if it cannot be excised, but spillage should be avoided due to the adverse effects. Rupture of the cyst can cause severe anaphylaxis; hence, the puncture, aspiration, injection, and reinjection technique can be used to avoid this complication [ 3 , 12 ]. Pharmacotherapy can also be opted for when surgery is contraindicated, such as in a patient whose condition is fragile, and augmented with surgery to avoid recurrences [ 10 ]. Albendazole and mebendazole can be used. Albendazole is the drug of choice because its penetration and systemic absorption are high [ 1 , 11 ]. Treatment is indicated for 3–6 months. Generally, cysts less than 5 cm can be managed nonsurgically, and those larger are drained percutaneously or surgically excised following treatment with antihelmintics [ 9 ]. Follow-up needs to be individualized because there are no formal recommendations. Generally, albendazole should be prescribed for 6 months to avoid recurrence, which is as high as 11%, and plain chest x-rays should be obtained monthly for the first 3 months [ 1 , 13 ].

Cystic echinococcosis remains a significant problem worldwide in terms of medical, social, and economic impacts. Surgery is the mainstay of management of pulmonary hydatidosis, and pharmacological therapy can be sought in patients with surgical contraindications. Surgery carries a high risk of rupture, especially if the cysts are considerably big due to late presentation and thus pose a risk of fatal outcome, particularly in resource-limited settings. Disease control can be improved by increasing awareness among health care workers and educating the community before more importance is given to increasing diagnostic capacity and implementing prevention and control strategies suggested by the WHO and the Centers for Disease Control and Prevention, aiming at high-risk groups such as the Maasai in countries such as Tanzania, where the majority of the population are in close contact with cattle.

Availability of data and materials

All data used in this study are available from the corresponding author upon request.

Abbreviations

Computed tomographic

Erythrocyte sedimentation rate

Intensive care unit

Suprapubic catheter

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The authors thank the patients for allowing their information to be shared for learning purposes.

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Jay Lodhia, Samwel Chugulu, Adnan Sadiq & David Msuya

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Samwel Chugulu, David Msuya & Alex Mremi

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Contributions

JL and AM conceptualized and prepared the manuscript. JL and DM reviewed the patients’ medical records. SC was the lead surgeon and performed the surgeries. AM prepared and reported the histological slides. AS prepared and reported the radiological films. All authors read and approved the final manuscript.

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Correspondence to Jay Lodhia .

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The hospital institutional review board approved the publication of this case report. Facial images identifying the patients have not been used. The first patient provided written informed consent for sharing their case history and photographs for case publication and second patients’ legal guardians provided written informed consent for the surgery and for participation in this study.

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The first patient provided written informed consent for sharing their case history and photographs for case publication and second patients’ legal guardians provided written informed consent for the surgery and for participation in this study. The copies of the written consent are available for review by the Editor-in-Chief of this journal.

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Lodhia, J., Chugulu, S., Sadiq, A. et al. Giant isolated hydatid lung cyst: two case reports . J Med Case Reports 14 , 200 (2020). https://doi.org/10.1186/s13256-020-02524-4

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case study of echinococcosis

A Case-Study of the Molecular Diagnosis of Echinococcus multilocularis in Wild Boar with Comments on its Public Health Significance in Turkey

Affiliations.

  • 1 Department of Parasitology, Faculty of Veterinary Medicine, Bingol University, Bingol, 12000, Turkey.
  • 2 Department of Parasitology, Faculty of Veterinary Medicine, University of Firat, 23119, Elazig, Turkey.
  • 3 Department of Biosciences, COMSATS University Islamabad (CUI), Park Road, Chakh Shahzad, Islamabad, Pakistan.
  • PMID: 33260210
  • DOI: 10.1645/19-196

Echinococcus multilocularis is a parasite species of zoonotic importance which can be fatal to humans and causes Alveolar Echinococcosis (AE). This report describes the development of a cyst from the liver of a wild boar and molecular confirmation of its identification. The cyst material was obtained from the liver of a wild boar killed by hunters. Genomic DNA was extracted from the germinal layer of the cyst material, and 875 bp mitochondrial cytochrome c oxidase subunit I (COI) gene fragment was amplified by PCR and sequenced. A BLAST search matched 100% with published Echinococcus multilocularis sequences. This study confirms the occurrence of E. multilocularis in a wild boar for the first time in Turkey.

Keywords: Echinococcus multilocularis; PCR; Sequencing; Turkey; Wild Boar.

© American Society of Parasitologists 2020.

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  • Echinococcosis, Hepatic / veterinary*
  • Echinococcus multilocularis / classification
  • Echinococcus multilocularis / genetics
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Echinococcosis: Advances in the 21st Century

a State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia and WHO Collaborating Centre for Prevention and Care Management of Echinococcosis, Urumqi, China

Lucine Vuitton

b WHO Collaborating Centre for Prevention and Treatment of Human Echinococcosis and French National Centre for Echinococcosis, University Bourgogne Franche-Comte and University Hospital, Besançon, France

Tuerhongjiang Tuxun

c Department of Liver and Laparoscopic Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China

d Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China

Dominique A. Vuitton

Wenbao zhang, donald p. mcmanus.

e Molecular Parasitology Laboratory, Infectious Diseases Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

Echinococcosis is a zoonosis caused by cestodes of the genus Echinococcus (family Taeniidae). This serious and near-cosmopolitan disease continues to be a significant public health issue, with western China being the area of highest endemicity for both the cystic (CE) and alveolar (AE) forms of echinococcosis.

Echinococcosis is a zoonosis caused by cestodes of the genus Echinococcus (family Taeniidae). This serious and near-cosmopolitan disease continues to be a significant public health issue, with western China being the area of highest endemicity for both the cystic (CE) and alveolar (AE) forms of echinococcosis. Considerable advances have been made in the 21st century on the genetics, genomics, and molecular epidemiology of the causative parasites, on diagnostic tools, and on treatment techniques and control strategies, including the development and deployment of vaccines. In terms of surgery, new procedures have superseded traditional techniques, and total cystectomy in CE, ex vivo resection with autotransplantation in AE, and percutaneous and perendoscopic procedures in both diseases have improved treatment efficacy and the quality of life of patients. In this review, we summarize recent progress on the biology, epidemiology, diagnosis, management, control, and prevention of CE and AE. Currently there is no alternative drug to albendazole to treat echinococcosis, and new compounds are required urgently. Recently acquired genomic and proteomic information can provide a platform for improving diagnosis and for finding new drug and vaccine targets, with direct impact in the future on the control of echinococcosis, which continues to be a global challenge.

INTRODUCTION

Echinococcosis refers principally to two severe zoonotic tapeworm diseases, cystic echinococcosis (CE) and alveolar echinococcosis (AE), caused by Echinococcus granulosus sensu lato and Echinococcus multilocularis , respectively ( 1 ). CE is cosmopolitan and more common, although a few island countries have declared elimination ( 2 , 3 ). In areas of endemicity, the annual CE incidence ranges from <1 to 200 per 100,000, whereas that of AE ranges from 0.03 to 1.2 per 100,000 ( 4 ). Mortality in untreated or inadequately treated AE patients is >90% within 10 to 15 years of diagnosis ( 1 ). The CE mortality rate (2% to 4%) is lower but may increase considerably if inadequate care management is provided. Current estimates of the global burden average 285,500 disability-adjusted life years (DALYs) for human CE ( 5 , – 7 ) (>1 million if underreporting is taken into account) and 666,434 DALYs for AE ( 7 ). The World Health Organization (WHO) has listed echinococcosis as one of the 17 neglected diseases targeted for control or elimination by 2050 ( http://whqlibdoc.who.int/hq/2012/WHO_HTM_NTD_2012.1_eng.pdf ). Indeed, major recent advances are set to revolutionize the care management and control of echinococcosis. Nevertheless, improved diagnosis and identification of new drug and vaccine targets are urgently required given the limitations of current diagnostic procedures, the toxicity and poor efficacy of available drugs, the often-inadequate surgical strategy, and the challenges in control and prevention.

In this review we outline the biology and life cycle characteristics of the Echinococcus spp. and consider the epidemiology, transmission, and clinical features of echinococcosis. We discuss recent advances in the diagnosis, treatment, care management, prevention, and control of CE and AE and show how genome and transcriptome studies are unravelling details of the developmental biology of Echinococcus spp. and their interactions with mammalian hosts, providing important information that can lead to the development of novel interventions and therapies against echinococcosis.

BIOLOGY AND LIFE CYCLE CHARACTERISTICS

The life cycles of the Echinococcus spp. are dependent on predator-prey associations involving two mammalian hosts ( Fig. 1 ). Carnivores (canids and felids) serve as definitive hosts for the adult tapeworms, and their herbivorous prey (ungulates, rodents, and lagomorphs) act as intermediate hosts for the metacestodes; humans are generally not directly involved in the transmission of CE or AE, although under certain unique and unusual circumstances, such as reported in the Turkana region of Kenya, humans can act as intermediate hosts for E. granulosus ( 1 ). The developmental stages of the Echinococcus spp., exemplified by E. granulosus sensu lato , are shown in Fig. 2 ( 8 , 9 ). Hundreds to thousands of 3- to 7-mm-long Echinococcus sp. adult worms develop in the intestines of their definitive hosts; the last segment (or proglottid) of each worm matures to produce eggs that are released in the carnivore’s feces into the external environment. In turn, humans or the intermediate hosts ingest the eggs, which hatch in the intestine to release oncospheres that pass through the portal and lymphatic vessels and reach the liver, where they usually settle and develop as larvae (metacestodes or hydatid cysts); less frequently they may also reach the lungs, brain, bones, or any other organ of the human or intermediate host. Protoscoleces, the fertile forms of the parasite, produced asexually by the metacestode, are released into the hydatid fluid; when ingested by the definitive host, protoscoleces evaginate their scoleces, aided by bile salts, and, after attaching to the intestinal wall, they develop into mature, egg-producing adult worms.

An external file that holds a picture, illustration, etc.
Object name is CMR.00075-18-f0001.jpg

Life cycles of Echinococcus spp. Species responsible for human infection ( E. granulosus sensu stricto , E. ortleppi , and E. canadensis [belonging to E. granulosus sensu lato ] and E. multilocularis ) are shown at the top. Species at the bottom ( E. shiquicus , a species close to E. multilocularis , and E. equinus and E. felidis , belonging to E. granulosus sensu lato ) are not known to cause disease in humans. Only the most common definitive and intermediate hosts which play a major role in life cycle/transmission are shown; other hosts may be encountered (especially wildlife hosts for E. granulosus sensu lato and domestic hosts for E. multilocularis ). E. vogeli and E. oligarthra , which are responsible for polycystic echinococcosis in humans in Central and South America, are not represented in the figure.

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Different developmental stages in Echinococcus granulosus and E. multilocularis . Growth of the larval cyst is unlimited, and it can, for E. granulosus , grow to 30 cm or more in humans, while the adult worm, egg, and protoscolex are limited in size and shape. Echinococcus sp. tapeworms have no gut, circulatory, or respiratory organs and have a highly adapted relationship with their mammalian hosts which they exploit for nutrients, signaling pathways, and neuroendocrine hormones. Strobilization is a notable feature of cestode biology, whereby proglottids (segments) bud distally from the anterior scolex, resulting in the production of tandem reproductive units (proglottids) exhibiting increasing degrees of development. Echinococcus is monoecious, and the last segment (gravid proglottid) produces diploid eggs that give rise to ovoid embryos, the oncospheres. However, a striking feature of the biology of Echinococcus is that the protoscolex has the potential to develop in either of two directions: it may develop into an adult tapeworm producing sexually produced eggs in the dog gut, or, if a hydatid cyst ruptures within the intermediate or human host, each released protoscolex is capable of differentiating asexually into a new cyst, a process termed “secondary” echinococcosis. While a unilocular fluid-filled bladder (cyst) is a feature of E. granulosus sensu lato in its larval stage, the metacestode of E. multilocularis consists of a mass of small, multilocular vesicles embedded in the immune reaction of the host (granuloma and fibrosis). These multiple and aggregated vesicles grow by proliferation of cells in the germinal layer of the metacestode.

EPIDEMIOLOGY AND TRANSMISSION

Distribution of ce and ae.

The pattern of distribution for CE has remained essentially unchanged over the past 2 decades, with areas of high endemicity, including western China, Central Asia, South America, Mediterranean countries and eastern Africa ( Fig. 3 ), and the main risk factors being contact with dogs and raising livestock ( 3 , 10 , 11 ). However, studies in Africa have revealed a significant number of human cases and active transmission in animals, including wildlife, in countries hitherto considered not to be areas of endemicity ( 12 , 13 ). Five thousand new CE cases are still diagnosed annually in Argentina, Brazil, Chile, Peru, and Uruguay ( 14 , 15 ). Thirty years of dosing dogs with the anthelmintic drug praziquantel 8 times annually has significantly decreased transmission to humans, but CE is still present in a number of areas in South America ( 14 , 16 ). CE has been declared eliminated from New Zealand, and Tasmania in Australia is considered to be provisionally free of the disease ( 17 ); nevertheless, E. granulosus is present on the Australian mainland and is still found in Tasmanian wild and rural dogs, but at low prevalence ( 18 ). In Western Europe and North America, most human cases are imported, although an autochthonous cycle of various genotypes within the species group E. granulosus sensu lato (see below) is present. However, the lack of accurate case recording currently prevents any precise mapping of the true epidemiological picture; a European Registry of CE (the Heracles project) has been launched to improve this situation ( 19 ).

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Global distribution of Echinococcus granulosus sensu lato , responsible for cystic echinococcosis (CE), and Echinococcus multilocularis , responsible for alveolar echinococcosis (AE). The map is based on recent epidemiological studies ( 1 , 13 , 19 , 247 ) as far as the current situation has been studied in a given area. The different colors represent a proxy for human prevalence and infection in animal hosts in a given area (to take autochthonous human cases into account only). For AE, the represented disease density is based mainly on the presence of autochthonous AE cases in humans, E. multilocularis metacestodes in small mammals, and E. multilocularis adult worms in foxes and dogs. For CE, the represented disease density is based mainly on the presence of autochthonous human cases of CE and of E. granulosus sensu lato metacestodes (irrespective of species or genotype) in intermediate hosts, including sheep, cattle, equids, and camels. For more accurate and detailed data and maps, see a recent comprehensive review paper by Deplazes et al. ( 13 ).

AE has been a public health concern in northern Japan for the past 40 years ( 20 , – 22 ). Mass screening with ultrasound (US) and serology in China have confirmed a high incidence of AE on the Tibetan plateau (in Qinghai, Sichuan, and Tibet [ 23 ]) and show that AE prevalence, especially in children, is higher than that of CE in several areas ( 24 ). Among the 18,235 estimated new AE cases per year globally, 91% occur in China ( 7 ), with human prevalence of >3% in some areas ( 25 ). AE is also endemic in Central Asia, with high endemicity of both E. multilocularis and E. granulosus in Kazakhstan and Kyrgyzstan ( 26 , – 29 ). In Europe, the prevalence of E. multilocularis in definitive and intermediate hosts increased markedly within the first 15 years of this century, and the geographic distribution of fox infections is far broader than earlier reported; urban foxes may be involved in transmission ( 13 , 17 , 30 , – 33 ). Human cases have been found in European countries previously considered to be free of AE, and the situation in the Baltic region has become worrisome; in addition, AE incidence has doubled in the previously recognized areas of endemicity of France, Switzerland, Germany, and Austria ( 13 , 34 , – 36 ).

In regard to North America, the north-central United States, northwestern Alaska, and northwestern Canada have long been areas of E. multilocularis endemicity, but the parasite’s geographic range appears to be expanding due, at least in part, to increased and improved sampling efforts and the targeting of definitive hosts other than foxes (such as coyotes [ Canis latrans ]) ( 13 ). AE had not been considered a mainstream human health issue in North America other than in Alaska until recently, and E. multilocularis has not been reported from Mexico or the southern United States ( 13 ). However, human cases were reported in Alberta, Canada, in the past decade ( 37 ) as well as in Quebec and Manitoba (unpublished reports to a WHO Collaborating Centre); molecular analysis of E. multilocularis in Alberta suggests that coyotes are important definitive hosts and that a European strain is involved, perhaps through carnivores imported from Europe, and not the local endemic “Alaskan” strains ( 38 , 39 ).

The distribution of “neotropical echinococcosis,” i.e., echinococcosis due to Echinococcus vogeli and Echinococcus oligarthra (see comment below on its correct taxonomic spelling), remains limited to South America ( 40 ); newly recognized human cases of E. vogeli infection in new areas, such as French Guyana in eastern South America ( 41 , 42 ), are likely the result of improved diagnosis and molecular identification of the disease ( 43 ).

Genetics and Genetic Epidemiology

A major change in the epidemiological picture for CE has come about as a result of the redefinition of the Echinococcus spp. causing the disease. Until relatively recently, E. granulosus was considered a single species, but it is now recognized as having extensive genetic diversity, with distinct strains/genotypes exhibiting differences in pathology and differing responses to drugs and the defined recombinant vaccine EG95 (see “Vaccination of intermediate hosts” below) for ovine CE ( 3 ). The application of mitochondrial DNA sequencing has resulted in the recognition of 10 genotypes (G1 to G10) and their accurate identification in molecular epidemiological surveys of CE in different geographical settings and host assemblages ( 44 ). Accordingly, the 10 strains/genotypes of E. granulosus sensu lato have been demarcated into 5 species, including E. granulosus sensu stricto (the former “sheep strain,” G1 to G3), Echinococcus equinus (horse strain, G4), Echinococcus ortleppi (cattle strain, G5), Echinococcus canadensis (camel strain, G6; pig strain, G7; G9, probably a variant of the pig strain; and cervid strains, G8 and G10), and Echinococcus felidis (“lion strain”) ( 12 , 45 , – 48 ). Currently, 9 species, listed in Table 1 , are recognized in the genus Echinococcus ( 49 ); the life cycles of some of these are shown in Fig. 1 . E. granulosus sensu stricto is the most widely distributed ( Fig. 3 ), with other species being focal.

Current recognized species within the genus Echinococcus and their preferential hosts and geographic distribution

The use of mitochondrial DNA and/or DNA microsatellites, such as the EmsB marker ( 50 ), has made discrimination between distinct genotypes of E. multilocularis possible. The influence of these genetic differences on increased prevalence or severity of AE in humans is unknown, but such genetic analysis is useful for tracking the transmission of a particular genotype from one area to another ( 51 , – 54 ). The Alaskan origin of E. multilocularis found in the Norwegian Svalbard islands and the European origin of E. multilocularis found in Alberta, Canada, are examples where molecular markers have proved useful ( 37 , 55 ). Echinococcus shiquicus , which is transmitted between Tibetan foxes/dogs ( 56 ) and the plateau pika ( Ochotona curzoniae ), is a new species found only in the Tibetan region, with no human cases thus far recorded ( 56 , – 59 ). The less common E. vogeli and E. oligarthra (replacing the previously used incorrect taxonomic spelling “ E. oligarthrus ” [“arthra” being the plural of the Greek noun “arthron,” which means “joints” {i.e., proglottids}, and not an adjective subject to gender agreement with “ Echinococcus ” { 48 }]) are restricted to Central and South America ( 42 , 60 , 61 ). Analysis of nuclear and mitochondrial markers revealed that populations of E. vogeli (Brazilian Amazon) and E. oligarthra (Argentina) are genotypically variant ( 60 , 62 ).

CLINICAL FEATURES

The clinical features of echinococcosis have been comprehensively described ( 1 , 63 ). In CE these are associated with damage or dysfunction of target organs, particularly the liver (70%) and lungs (20%), with the remainder including the brain, spleen, kidney, and heart. Almost all primary AE lesions are in the liver. Clinically, most AE and CE patients present late at clinics or hospitals. Population screening has shown that CE liver cysts in humans grow very slowly, with more than half of cysts showing no change in size in 10 years and one-third growing less than 3 cm; mean cyst growth in cases with a prolonged follow-up was 0.7 cm ( 8 ). The early stages of CE and AE do not cause symptoms, and CE cysts and AE lesions can remain asymptomatic for 10 to 15 years; consequently, children comprise only a small percentage of echinococcosis patients. Clinical symptoms usually appear when a cyst reaches more than 10 cm in diameter in the liver or when more than 70% of the organ volume is occupied by a cyst or cysts, resulting in physical compression or damage to bile ducts, hepatic veins, the portal vein, or the hepatic artery. Various symptoms may be due to compression or damage to bronchia in the lungs or various structures of the brain, which can also result in life-threatening complications. In any organ, compression of vital structures may be symptomatic even with small or medium-sized cysts.

Symptomatic CE patients with liver cysts most often present with upper abdominal discomfort and poor appetite; compression of bile ducts may lead to jaundice. On palpation, a tumor-like mass, hepatomegaly, or abdominal distension may be found. Chest pain, cough, or hemoptysis can be indicative of cysts in the lung, and cyst rupture into the bronchi may result in the expulsion of hydatid materials. Any neurological symptom (signs of intracranial hypertension, epilepsy, all types of paralysis, etc.) may be observed in patients with brain cysts. In any organ, cyst rupture can induce fever, urticaria, eosinophilia, and anaphylactic shock. Potentially lethal allergic reactions due to cyst rupture and even minor fissures have long contraindicated any puncture of a CE cyst. Antigen leakage associated with such fissures may reveal the usual development of specific IgE antibodies, common for E. granulosus sensu lato and E. multilocularis , which is part of the predominant Th2-type immune response in echinococcosis, with high levels of interleukin-5 (IL-5) in both AE and CE ( 64 ). Despite the presence of IgE antibodies and demonstrated possible basophil activation ( 65 ), eosinophilia and allergic reactions are very uncommon in AE because of the different structure of the parasitic lesions, with dense fibrosis preventing vesicle fluid leakage; these reactions may be observed in rare cases of blood dissemination of lesion fragments ( 64 ). Routine imaging or population mass ultrasound (US) screening of the liver may identify asymptomatic cysts ( 66 ), and the procedure is extremely important for finding early-stage AE patients in areas of endemicity ( 23 ).

Faster growth of cysts in CE patients with AIDS suggests that immune suppression may play a role in CE progression ( 67 , 68 ). Conversely, the concept of an enhancing effect of CE on the occurrence of cancer in the population, because of a defect in immune surveillance linked to an Echinococcus -induced tolerance state, has been raised recently ( 69 , 70 ), although this hypothesis has not been rigorously evaluated. In areas where CE is endemic, the simultaneous occurrence of two frequent diseases cannot be ruled out, and preliminary assessment from hospital medical information systems of the occurrence of cancer in 2,350 patients with CE compared with patients without CE showed no difference (Bo Ran, First Affiliated Hospital of Xinjiang Medical University, personal communication). However, the promoting effect of cancer or its treatment on parasite growth seems to interfere far less with the occurrence and/or disease course in CE than in AE ( 71 ).

Genetic variation of the human leukocyte antigen (HLA) system is associated with the occurrence and/or progression of AE lesions in humans ( 72 , 73 ); patients with the HLA-DR3 DQ2 haplotype were shown to have more severe disease and a more pronounced Th2-type immune response, associated with a deeper tolerance status ( 74 , 75 ). The effects of immune suppression on E. multilocularis growth are well known in animal models ( 76 ). They were first reported in human cases after liver transplantation performed to treat AE and in patients with AIDS. Early recurrence of AE was observed in transplanted patients and was found associated with the level of immune suppression resulting from the treatment used to prevent liver rejection ( 77 ); unusually rapid progression of lesions and the corrective effect of antiretroviral therapy were observed in AIDS patients, including children ( 67 , 78 ).

After AE occurrence was reported in transplant patients, other than those undergoing liver transplantation for AE, and in patients treated for malignant or chronic inflammatory diseases ( 79 , – 81 ), a systematic study based on the French National Registry of AE (FrancEchino) confirmed the significant and recent increase (from the beginning of the 21st century) in the occurrence of AE in such patients ( 71 ). Acquired therapeutic immunosuppression (which combined chemotherapy, corticosteroids, and biotherapy such as anti-tumor necrosis factor [anti-TNF] agents) appears to be the main factor for AE occurrence and its fast progression. Unusual presenting symptoms, such as bacterial abscess-like acute clinical symptoms, and misleading imaging findings, such as abscess-like, metastasis-like, or hemangioma-like aspects on computed tomography (CT) scans, contributed to delayed diagnosis. This resulted in incorrect therapeutic management of a number of these patients, such as those undergoing cancer treatment intensification, which further enhanced metacestode growth, or ineffectual radiofrequency ablation attempts on the presumed liver “tumor” or “metastasis” ( 71 ). Negative serology, likely due to the patient’s immune suppression status, is also an issue and makes pathological and/or molecular identification of the metacestode often necessary before diagnosis can be confirmed ( 71 ). Whether the patients were actually infected with E. multilocularis eggs during the period of therapeutic immune suppression or the symptoms were due to a reactivated, dormant metacestode resulting from a previous infection remains to be established ( 71 ).

General comments.

Imaging techniques are essential for diagnosis, with the relatively inexpensive and portable ultrasound (US) widely used to diagnose CE or AE liver lesions; X-ray is used for lung cysts. Both techniques are used for diagnosis and population screening and for follow-up ( 82 , – 84 ). Serology, i.e., detection of specific antibodies against Echinococcus sp. antigens, is a confirmatory step with various levels of sensitivity/specificity correlating with the involved species, lesion location, or antigen used ( 63 ) ( Fig. 4 ). Mass population screening of CE and AE in areas of endemicity using US is considered the best method for early diagnosis. In addition to organized mass screening, routine health checks and systematic follow-up of associated diseases, including US examination, are now a major approach in echinococcosis diagnosis. This has contributed to the diagnosis of asymptomatic cases in the general population and to changes in the presentation of AE cases, especially in Europe ( 85 ). Systematic follow-up of patients with malignant diseases and a variety of chronic diseases, by using US, CT scan, and fluorodeoxyglucose-positron emission tomography (FDG-PET), may also have contributed to the early diagnosis of AE in such individuals ( 71 ).

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Algorithm for the diagnosis of cystic echinococcosis (CE) and alveolar echinococcosis (AE). Definitions of “possible,” “probable,” and “confirmed” cases refer to the “Expert consensus for diagnosis and treatment of echinococcosis in humans” ( 86 ). CE1 to CE5 refer to the “WHO-IWGE [World Health Organization Informal Working Group on Echinococcosis] international classification of ultrasound images in cystic echinococcosis for application in clinical and field epidemiological settings” ( 86 ) and Fig. 5 . FDG-PET, fluorodeoxyglucose-positron emission tomography (increased uptake of FDG by the periparasitic immune response is the currently accepted evidence for AE lesion metabolic activity) ( 94 ). MRI, magnetic resonance imaging (identification of typical microcysts on T2-weighted images at MRI is a surrogate marker for AE lesion metabolic activity) ( 98 ).

Imaging and classification of CE and AE lesions.

Based on US imaging, the World Health Organization Informal Working Group on Echinococcosis (WHO-IWGE) has classified hepatic CE cysts into five types, CE1 to CE5, and AE lesions into different PNM ( p arasite lesion, n eighbor organs, m etastases) types ( 1 , 86 , – 88 ), which provides basic information for clinicians to make treatment decisions ( Fig. 5 ; Table 2 ). Harmonization of disease assessment at the international level is crucial to progress toward an evidence-based and stage-specific strategy for treatment ( 89 ). New classification of US images and the associated classification of computed tomography (CT) images in AE have been proposed ( 90 , 91 ) and are currently being tested on patients at European and Chinese centers in order to evaluate their usefulness for diagnosis and follow-up.

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Imaging of cystic echinococcosis. The description of ultrasound images is according to the WHO Informal Working Group on Echinococcosis (WHO-IWGE) international classification ( 86 ) and corresponding images were obtained from plain computed tomography (CT) scanning and T2-weighted magnetic resonance imaging (MRI) in representative cases. In the international classification, types CE1 and CE2 correspond to “active stages,” types CE3a and b to the “transitional stage,” and types CE4 and CE5 to “degenerating stages” (CT and MRI images provided by Liu Wenya, Department of Radiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China).

WHO Informal Working Group on Echinococcosis PNM classification and staging of alveolar echinococcosis a

The challenge in imaging diagnosis of echinococcosis is detecting small cysts/lesions (<2 cm in diameter). Contrast-enhanced ultrasonography (CEUS) may be used for detecting small AE lesions and differentiating them from abscesses and tumors based on pulsating blood flow imaging ( 92 , – 94 ). Fluorodeoxyglucose (FDG) uptake surrounding AE lesions is higher than in other areas, and FDG-positron emission tomography (FDG-PET) has become the favored reference tool to evaluate their metabolic activity ( Fig. 4 and ​ and6) 6 ) ( 95 , – 98 ). Color and pulsed doppler US, dual-energy CT or spectral CT, and diffusion-weighted magnetic resonance imaging (MRI) might also be useful in detecting blood supply and the metabolism of lesions ( 97 , 99 ) but they cannot be recommended without further evaluation ( 97 ). In CE, MRI appears to be of better diagnostic value than CT scanning ( 100 ), and both procedures are complementary for AE and should be performed to provide sufficient information for therapeutic decision-making ( Fig. 4 ) ( 97 ). However, MRI T2-weighted microcystic images are pathognomonic of AE lesions ( Fig. 6 ), and in difficult cases US-guided core-needle biopsy is reliable and effective in combination with DNA diagnostic testing ( 101 ) or specific immunostaining ( 102 ).

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Complementarity of imaging techniques for the diagnosis and preoperative assessment of alveolar echinococcosis (AE) lesions in a patient with portal vein and bile duct invasion by the parasitic lesions. (A) On computed tomography (CT) scanning, the lesion shows the characteristic heterogeneous aspect of AE, with hyperdense calcifications (white arrow) and hypodense area (central necrosis) (black arrow). (B) Fat-suppressed T1-weighted magnetic resonance (MR) image after gadolinium injection at the portal venous phase shows an atrophy of the left liver and invasion of the left portal vein and of the left intrahepatic biliary tree. The lesion is at the contact of the gallbladder (white star) which is not invaded. (C) T2-weighted MR images show the presence of hyperintense microcysts (white arrows), pathognomonic of AE, but also a solid component (Kodama type II). (D) Fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) is markedly increased at the periphery of the lesion (white arrows). (E) Assessment of biliary tree involvement and treatment by perendoscopic stenting in a patient with late postoperative biliary complications of AE. Endoscopic retrograde cholangiopancreatography (ERCP) was performed (with a colonoscope because of previous gastrectomy), showing dilation of the extrahepatic and intrahepatic biliary tree with several defects (black arrows) because of biliary stones due to chronic biliary obstruction and bacterial superinfection. (F) Perendoscopic stenting via ERCP. After balloon dilation followed by extensive lavage with isotonic saline and stone extraction, 3 plastic stents (size, 7 and 10 French) are inserted in the stenosis of the bile duct (endoscopic view).

The sensitivities and specificities of serological tests for CE and AE have been comprehensively reviewed ( 103 ). Hydatid fluid (HF) is the major antigenic source for echinococcosis immunodiagnosis, with the HF lipoproteins antigen B (AgB) and antigen 5 widely used in serological assays for CE ( 1 ). Although the Casoni intradermal test exhibits low specificity and sensitivity ( 104 ), it may be used for confirming the results of US or other physical imaging methods (Xinyu Peng, personal communication). Poor standardization and ethical issues regarding reagents from animal origin injected into humans have, however, considerably limited the use of skin tests for echinococcosis diagnosis. Reported sensitivities and specificities of serological methods for testing CE patients confirmed by surgical resection vary from 60% to 90%. Use of enriched antigen 5 ( 105 ) and recombinant antigens based on repeated tandem E. granulosus AgB (2B2t antigen) and recombinant Ag5 ( 106 ) increases diagnostic value. A large number of other novel antigens, including the tegumental protein EgTeg ( 107 ), alkaline phosphatase (EgAP) ( 108 ), and EpC1 ( 109 ), exhibited greater than 90% sensitivity and specificity on selected serum samples. However, their performance has never been evaluated on a large scale, and none of the reported antigens are sufficiently sensitive or specific to be used as a first-intent tool for diagnosis or mass population screening ( 110 , 111 ). One major issue is the lack of appropriate antigens with the required sensitivity for the serological detection of small CE cysts in the liver and cysts of any size in lungs. Encystment of the metacestode, preventing the stimulation of antibody-producing cells and thus causing the absence of measurable levels of antibodies generated against Echinococcus sp. antigens, can explain many negative results.

AE serology is more reliable. Em2 and Em492, which represent constituents of the excretory/secretory (ES) fraction of intact metacestodes, as well as EmAP and EmP2, are specific for E. multilocularis infection ( 76 ). EM10, or its derivatives EmII/3 and Em18, which are encoded by part of the EM10 gene sequence, show high diagnostic performance for confirming AE ( 112 ). A commercialized Em2 plus enzyme-linked immunosorbent assay (ELISA) (Bordier, Crissier, Switzerland) has been used extensively for clinical diagnosis of AE ( 113 ), with sensitivity and specificity exceeding 90% ( 114 ). Nevertheless, serology cannot be used as a first-intent diagnostic tool for mass screening in areas of endemicity, where a proportion of the human population exhibits positive serology without AE lesions ( 115 ). Serology has also been shown to be frequently negative in immunosuppressed individuals with AE, and thus, it should not be used on its own as an argument against a diagnosis in such patients ( 71 ).

For both CE and AE, serology is thus now used only to confirm imaging results; it may also provide some insight into the infection pressure on a given population (e.g., children) in a particular geographic area. Serology results are included in the definition of “possible” and “probable” cases by the Expert Consensus of the WHO-IWGE ( 86 ). The uses of imaging, serology, and molecular identification of the metacestode in the diagnostic strategy are shown in the algorithm proposed in Fig. 4 .

Protein biomarkers.

Echinococcus spp. can survive in humans for a long time through active regulation of the host immune response by the secretion of proteins at the interface of parasite and host tissues. Profiling HF protein composition and excretory/secretory (ES) products provides valuable information on parasite survival strategies and the molecular mechanisms of parasite-host interaction. In addition, analysis of the protein profiles can help in identifying potential molecular markers for developing diagnostic and follow-up tools. Proteomic analysis of the composition of CE ( 116 , 117 ) and AE ( 118 ) cyst/vesicular fluids has identified hundreds of proteins from both Echinococcus spp. and the host that may help differentiate subpopulations of patients. Characterization of ES proteins from E. granulosus adult worms ( 119 ) and protoscoleces ( 120 , 121 ) and E. multilocularis protoscoleces ( 122 ) also shows promise for identification of potential diagnostic markers.

Application of proteomics to patient care management is in its infancy. Specific immunodominant epitopes of E. granulosus HF change as the disease progresses (e.g., from CE1 to CE2) ( 123 ), and the HF protein composition is different in different organ locations of the cysts ( 124 ); this could explain the well-known differences in the host antibody response correlating with the stage and location of cysts. Immunoreactive proteins from E. multilocularis vesicular fluid have been recently identified and quantified, and comparative proteomics revealed 9 proteins (actin modulator protein, fucosidase alpha L1 tissue, prosaposin a preprotein, glutathione S -transferase, beta-galactosidase, NiemannPick C2 protein, elongation factor 2, cathepsin b, and H17g protein tegumental antigen) that were more abundant in immunoprecipitation eluates from albendazole (ABZ)-nonresponders than in those from ABZ-responder AE patients, suggesting that detection of antibodies against these proteins by ELISA could be helpful in monitoring the course of AE under ABZ treatment ( 118 ).

DNA detection.

Recently developed DNA-based methods, such as quantitative and/or nested PCR assays, are highly sensitive, reasonably specific, and able to distinguish Echinococcus species from each other and from other cestodes; they can, as discussed above, discriminate the various genotypes of E. granulosus , including following clinical biopsy of a suspected CE or AE case, and identify infected mammalian host species ( 125 , – 130 ). Other examples include the identification of E. vogeli in patients infected in an area not previously considered to be an area of endemicity ( 42 ), in revealing the reemergence of E. ortleppi in France ( 131 ), in the retrospective identification of an E. multilocularis strain in a historical human case of AE in the United States ( 132 ), and in the detection of E. multilocularis infection in primates ( 133 ). DNA identification methods are now routinely used on biopsy or fine-needle cytology specimens for the diagnosis of AE in patients with unusual imaging aspects and/or with negative serology, typified by immunosuppressed patients ( 71 ), and they form part of the definition of “confirmed cases” of the WHO-IWGE Expert Consensus ( 86 ) ( Fig. 4 ). As is discussed further below, molecular diagnosis, including loop-mediated isothermal amplification (LAMP), can be used as a first-line screen for Echinococcus spp. in the field ( 134 , – 137 ) and to detect Echinococcus sp. egg DNA in environmental samples as an important step for identifying high-risk contaminated areas and for defining the actual routes of human infection ( 138 , – 142 ).

CARE MANAGEMENT

Based on image classification and following a stage-specific approach, various options are possible, alone or combined, for the treatment of both CE and AE, including (i) surgery, (ii) nonsurgical interventions, (iii) anti-infective benzimidazole drug treatment, and (iv) a “watch-and-wait” approach ( Fig. 7 ). The current recommendations for echinococcosis management take the cancer-like nature of the disease, which is prone to recurrence, into account and thus use the model of cancer care management which promotes a multidisciplinary approach, with interdisciplinary team consultations for therapeutic decisions, the combination of surgical and drug treatments, a long-term follow-up of patients, the establishment of international recommendations, and the creation of reference centers ( 86 ).

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Algorithm for the treatment of cystic echinococcosis (CE), based on “WHO-IWGE international classification of ultrasound images in cystic echinococcosis for application in clinical and field epidemiological settings” ( 86 ) and Fig. 4 and ​ and5. 5 . WHO-IWGE, World Health Organization Informal Working Group on Echinococcosis; ABZ, albendazole; PAIR, puncture-aspiration-injection-reaspiration (nonsurgical percutaneous interventional technique for treatment of CE cysts).

Treatment of CE

With CE, treatment centers on cyst type according to the WHO-IWGE US classification ( 1 ) ( Fig. 5 ), size, location, and presence/absence of complications, as well as available medical expertise and equipment ( 86 ). Curative treatment is achieved by the complete removal of the cyst, regardless of location. If the cyst with all its layers (including adventitia) cannot be removed totally, which is the case with sub-total cystectomy and all types of partial cystectomy and with the percutaneous “PAIR” (puncture, aspiration, injection, and reaspiration) technique, the therapeutic procedure should be complemented with the use of protoscolecidal agents. Intraoperative dissemination of protoscolex-rich fluid during surgery and insufficient killing of protoscoleces and germinal membrane during the percutaneous procedures are major causes of CE recurrence ( 86 ). An algorithm that describes the recommended therapeutic strategy for CE is given in Fig. 7 .

Use of protoscolecides during CE surgery.

The intraoperative dissemination of protoscolex-rich hydatid fluid during surgery or the PAIR procedure for CE is a major cause of cyst recurrence ( 86 ). Injection of a protoscolecide into CE cysts to reduce the risk of spillage of viable protoscoleces and possible recurrence is an integral part of the surgical technique employed by many surgeons around the world ( 143 ). A very broad spectrum of protoscolecidal agents, from warm water ( 144 ) to the highly toxic formalin ( 145 ), have been tested over the past 50 years, but the feasibility, safety, and efficacy of many of these compounds have generally not been determined. Details of the concentrations and modes of administration of currently available and tested protoscolecides are provided in Table 3 . Serious complications have limited the use of some of these; formalin and betadine should never be used under any circumstances. However, the majority, albeit less harmful than these two compounds, resulted in serious biliary, gas embolism, renal, and toxic complications that limited their use ( 146 ) ( Table 3 ); toxicity to bile duct mucosa explains why communication between the CE cyst and the bile ducts must be carefully checked before the use of any protoscolecidal agent. There have been considerable efforts made to discover additional potential protoscolecides, including plant extracts and the use of physical methods in vitro , but details of their clinical application are lacking. Currently, the WHO-IWGE recommends 20% hypertonic saline as the preferred protoscolecide in surgery and 20% hypertonic saline or 95% alcohol in PAIR ( 86 ), but rigorous, high-quality comparative studies on these protoscolecidal agents are still awaited.

Protoscolecides tested for use in CE surgery or PAIR a

Anti-infective treatment.

Systemic anti-infective treatment relies on continuous administration of 2 benzimidazole carbamates, ABZ and mebendazole, which are the only anti-infective drugs clinically efficient to interrupt larval growth of Echinococcus spp. ( 177 , 178 ). Mebendazole was the first benzimidazole that was proven efficient for the treatment of echinococcosis ( 179 , 180 ). Because of its increased bioavailability and easier administration to patients, ABZ was then preferred as the anti-infective treatment of choice for echinococcosis, at an average dosage of 15 mg/kg/day ( 181 ). Currently, mebendazole is only an alternative drug for those patients who have experienced severe hepatic adverse effects with ABZ. Most of these patients experience similar adverse effects with both drugs; however, some individuals may tolerate mebendazole, which is critical when the patients cannot be operated on and their survival totally depends on the anti-infective treatment, a situation more frequent in AE than in CE ( 182 ). In CE, anti-infective treatment alone is reserved for small or medium-sized isolated cysts or, alternatively, multiple and inoperable cysts in the liver and/or in multiple organs. A combination of interventional techniques with ABZ is recommended and is used routinely with PAIR and derived techniques; it is less widely used with surgery ( 86 , 89 , 183 , 184 ). However, criteria for curtailing anti-infective treatment are clearly missing and deserve prospective studies to be undertaken, and treatment length and schedule are still a matter of debate; a prospective study on a limited number of patients showed that 3 months of AE treatment was no better than 1 month of administration after PAIR ( 63 ). Based on pharmacological evidence and the relatively low and slow efficacy of ABZ to kill protoscoleces, a reasonable compromise would be to administer ABZ from 1 week before to 2 months after the interventional procedure (surgery or PAIR) whenever the cyst has been opened; however, firm recommendations should await the results of real studies, especially for the association with surgery. The “watch-and-wait” strategy is recommended for asymptomatic and small CE1 cysts, obviously degenerating CE4 cysts, and all CE5 type cysts ( 89 ).

A more systematic use of total cystectomy (also known as periadventitial cystectomy or, incorrectly “pericystectomy”), modified by the Chinese surgeon Peng Xinyu ( Fig. 8 ) ( 89 ), has increased over the past 15 years ( 185 , 186 ), and the attitude of surgical teams regarding total cystectomy is currently changing. To prevent recurrence, total cystectomy, which avoids cyst opening, is the technique of choice ( Fig. 7 ). When the cyst is adjacent to major vessels, sub-total cystectomy, which avoids dissection of these vessels, is encouraged. If both techniques are not feasible, hydatidectomy (also called “endocystectomy” or “partial cystectomy”), after cyst opening, may be used together with obsessional prevention of protoscolex spillage, the major cause of recurrence, during surgery and with perioperative ABZ administration.

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Schematic structure of the echinococcal cyst and different approaches for surgical removal. (A) The echinococcal cyst is made up of the adventitial layer, laminated layer, and germinal layer (from outside to inside). (B) Total cystectomy involves resection of the entire adventitial layer (“subadventitial resection”), the laminated layer, and the germinal layer. (C) Sub-total cystectomy involves partial resection of the adventitial layer and total resection of the laminated layer and the germinal layer, leaving parts of the adventitial layer in place whenever the operation is difficult because of the proximity of large vessels and/or adhesions. (D) Hepatectomy involves the en bloc resection of the echinococcal cyst along with part of the normal liver parenchyma. Partial cystectomy, which requires opening of the cyst, may leave all or part of the laminated layer and germinal layer and relies on the efficacy of a protoscolecide to destroy the metacestode; it should generally not be considered because of the potential for recurrence.

Since the first report of perlaparoscopic treatment of a CE patient in 1992 ( 187 ), robotically assisted ( 188 ) and single-incision laparoscopic total cystectomy and hepatic resection ( 189 ) have put laparoscopy into CE surgical practice ( 190 ). When laparoscopic surgery is performed, there must be no compromise to the principle of avoiding cyst content spillage and respecting cyst wall integrity; however, the influence of the laparoscopic approach on recurrence is controversial ( 191 ). For those CE patients with obvious biliary communication and unsuited for total cystectomy, “double drainage” of the fistula and cystic duct (i.e., drainage of the main bile duct with a Kehr T-tube through the cystic bile duct and drainage of the fistula or of the remaining cavity after partial cystectomy) is now preferred to reduce postoperative biliary leakage. In case of postoperative biliary leakage, a perendoscopic drainage (after endoscopic retrograde cholangiopancreatography [ERCP]) should be considered before any reoperation ( 192 , 193 ). Liver transplantation for CE could be the last option in selected cases ( 194 ).

PAIR has definitely become part of the interventional therapeutic options in CE for midsized CE1 and CE3a cysts ( 63 ) ( Fig. 7 ). A recent improvement in PAIR is the “modified catheterization technique” (MoCAT), a procedure appropriate for cysts up to 10 cm in diameter that includes aspiration of the parasitic membranes in addition to the cyst content and with a catheter left in place for the postintervention period of time. ( 195 ). When used by experienced operators, this technique may be an alternative to surgery for noncomplicated CE2 and CE3b cysts ( Fig. 5 and ​ and7). 7 ). Recent reviews have confirmed the efficacy and safety of PAIR and its variants if a stage-related strategy and technical recommendations are strictly followed ( 86 , 89 , 185 ).

Treatment of AE

With AE, therapeutic decision is based on the possibility of complete resection of liver lesions, after multidisciplinary assessment involving liver imaging, the general status of the patient, and the technical capabilities of the surgical team ( 86 , 178 , 182 ). As AE lesions are most often located in the right liver lobe and in advanced cases have invaded the major bile ducts and vessels (portal veins, hepatic veins, and vena cava), major hepatic surgery is often required, with significant morbidity and mortality resulting because of uncontrolled bleeding or liver failure. A number of cases cannot be safely operated on, even by highly experienced hepatic surgeons; only left hepatectomy in the less-frequent cases, where lesions are located in the left lobe, is accessible to less-experienced, nonspecialized surgeons. This explains why only one-third of patients with AE may benefit from curative liver resection, and the number is even lower in communities where AE is endemic and patients live in remote places and are late in seeking care ( 63 ). Palliative operations have been shown to be a source of complications without improving patient survival; it is the reason why they are now not recommended ( 63 , 86 ). Objectives for the treatment of AE thus include the following: (i) totally removing the parasitic lesion, which is achieved through “curative” surgery combined with 2 years of ABZ treatment at the same dosage and with the same precautions as for CE treatment; (ii) if this is not possible, reducing the proliferating potential of the E. multilocularis metacestode by continuous administration of ABZ; and (iii) alleviating complications, especially bile duct obstruction and cholangitis and bacterial infection of the necrotic cavity that develops in the centers of advanced lesions ( Fig. 6 ). Lesions which are massively calcified and/or negative by FDG-PET may benefit from a “watch-and-wait” approach. An algorithm that describes the recommended therapeutic strategy for AE is given in Fig. 9 .

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Algorithm for the treatment of alveolar echinococcosis. FDG-PET, fluorodeoxyglucose-positron emission tomography (increased uptake of FDG by the periparasitic immune response is the currently accepted evidence for AE lesion metabolic activity) ( 94 ). MRI, magnetic resonance imaging (identification of typical microcysts on T2-weighted images at MRI is a surrogate marker for AE lesion metabolic activity) ( 98 ). ABZ, albendazole; ELRA, ex vivo liver resection with autotransplantation.

In immunocompromised patients, reducing immunosuppressive treatment must be considered when this is possible. In the French cohort, ABZ efficacy was shown to be fast and excellent but with more adverse effects than in nonimmunocompromised patients treated in the same centers. Whenever possible, and depending on the prognosis of the associated disease, curative liver resection should be performed as early as is realistic because of the fast growth of the metacestode in this situation and in order to facilitate the care management of the associated disease. Liver allotransplantation ( 77 ) is still used in advanced cases, especially when hepatic veins and the vena cava are included in the parasitic lesions, in case life-threatening complications result, but the shortage of donors and life-long immunosuppressant administration, which is followed by higher susceptibility to disease recurrence, have discouraged application of this approach ( 182 ). The high rate of postoperative morbidity and mortality (30% within the first 6 months after transplantation), as well as the recurrence rate (10% locally and 20% for distant metastases), in a recent report from Turkey even raises an ethical question, especially when the livers are from living donors ( 196 ). Ex vivo liver resection followed by autotransplantation is a surgical procedure for excising lesions following removal of the liver from the patient; the remaining lesion-free liver is then reinserted, similar to a liver transplantation ( 197 ) ( Fig. 10 ). The procedure was initially developed to treat conventionally “unresectable” tumors as it does not require an organ donor and postoperative immunosuppressive treatment ( 198 , 199 ); it was first applied to patients with advanced AE in 2011 ( 197 , 200 , 201 ). AE patients often present with hypertrophy of the liver lobe not invaded by the parasitic lesion (because of chronic long-term portal vein obstruction and/or a specific influence of the immune response to the parasite which favors hepatic regeneration). This is one of the reasons for a relatively favorable outcome of the procedure (and of major hepatectomies in general) compared with cancers which develop rapidly and do not promote hypertrophy of the remaining liver lobe ( 202 ) ( Fig. 10 ). Midterm results of such operations seem acceptable in comparison to conventional major hepatectomy with complex bile duct and vessel reconstruction or to liver transplantation ( 203 , 204 ). With an average follow-up of 22.5 months (range, 14 to 89 months) in 69 patients, overall mortality was 12%, complications higher than IIIa (according to the Clavien classification) were observed in 10 patients, and there was no recurrence ( 204 ). However, long-term results and comparison with nonsurgical care management, including long-term ABZ and perendoscopic treatment of biliary complications, are not yet available.

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Three-dimensional reconstruction in the application of ex vivo liver resection and autotransplantation (ELRA). (A) Portal veins, hepatic veins, and segments of liver are visualized by three-dimensional reconstruction. (B) Calculation of remnant hepatic parenchymal volume after three-dimensional reconstruction and virtual resection. The volume of remnant liver is 1,065.83 cm 3 (yellow, giant AE lesion; blue, normal parenchyma). (C) Precise resection of giant AE lesion on bench (black arrow, normal liver parenchyma after resection). (D) The length (68.1 mm) of obliterated retro-hepatic vena cava is calculated through three-dimensional reconstruction (yellow, giant AE lesion; blue, retro-hepatic vena cava). (E) Hepaticojejunostomy is performed on the table (black arrow, anastomosis). (F) Postoperative follow-up demonstrating liver remnant and vasculatures (1, aorta and hepatic artery; 2, liver; 3, portal vein; 4, hepatic vein).

European data indicate a marked trend toward a reduction in the percentage of surgical operations for AE, whatever their type (complete or only partial resection of the lesions, or any surgical procedure such as bile duct derivation, or simple diagnostic laparotomy) but an increase in the percentage of radical/curative operations, i.e., liver resections capable of totally removing the metacestode tissue from the liver and/or other organs ( 178 , 205 , 206 ). However, the percentage of patients undergoing surgery has remained high in China ( 207 ). The differences are mainly due to recruitment of patients (either symptomatic with advanced lesions, most often in China, or asymptomatic with less-developed lesions, most often in Europe) and also, whatever the continent, to the specialization, experience, and boldness of the surgical teams and appreciation of the “safety margin” necessary to perform an R0 resection (according to the grading followed in cancer surgery). Evaluation of the influence of this safety margin suggests that at least a 1-mm distance is important (thus, being less than in cancer) combined with ABZ therapy ( 208 ). Difficulties in the strict follow-up of patients, because of their residence in remote areas, in measurement of ABZ sulfoxide (ABZ-SO) to monitor adherence to treatment (which is crucial for the success of an anti-infective drug approach) and the origin of adverse effects, and differences in the organization of health care management, may also be among the reasons that make Chinese teams more prone to favor a surgical approach.

Percutaneous puncture for treating AE patients with a necrotic cavity inside liver lesions and bacterial superinfection has been used for more than 30 years, and, in combination with antibiotics, the procedure may save patients and allows a reassessment of the resectability of the lesion ( 83 , 178 , 192 ). Injection of protoscolecidal agents should never be used in AE: in fact, the central cavity often observed in advanced cases of AE is due to the necrosis of the lesions, including the multiple degenerating microcysts of the metacestode and associated immune infiltrate and fibrosis; the still active microcysts are at the periphery of this cavity, as is well shown by FDG-PET images and T2-weighted MRI ( 98 ). These microcysts are embedded in the immune and fibrotic reaction and are not accessible to a protoscolecidal agent; in addition, at this stage, communication of this central cavity with bile ducts is the rule, and such an injection would be not only useless but also harmful ( 178 ). Early and/or late biliary complications clearly heavily impact the immediate prognosis of the disease, at presentation and within the first year of follow-up, and thus the final outcome of AE ( 85 , 209 ); they represent a negative turning point in the course of the disease ( 210 ). Percutaneous dilation of the bile ducts obstructed by the progression of the metacestode was widely performed until the end of the 20th century, instead of palliative surgical bile diversion ( 83 , 209 , 210 ).

A European survey of perendoscopic procedures (through ERCP) to treat biliary complications of AE in 18 clinical centers showed that such procedures are now used routinely and are generally successful in alleviating symptoms and in maintaining long-term permeability of the biliary strictures; to achieve good results, extensive saline lavage of the bile ducts, which removes necrotic debris and intrahepatic biliary stones that are common in such patients, and the use of multiple plastic stents are recommended ( 211 ) ( Fig. 6 ). Perendoscopic bile duct stenting is currently nearly totally replacing surgical palliative operations and percutaneous biliary drainage to treat biliary complications in AE patients ( Fig. 6 ). Although there have been no specific studies assessing the quality of life of patients receiving such treatment, we may anticipate that this has markedly contributed to the improved quality of life of those patients with chronic biliary obstruction and multiple cholangitis episodes; in the past, more than 10 reoperations in a single patient were not uncommon, and most patients had a very uncomfortable external biliary drainage tube for life ( 211 ).

In Europe, all retrospective evaluations of survival after AE diagnosis have indicated that there have been major improvements in the 21st century compared with the prior 30-year experience; improvement was already noted in the 1990s compared with the 1970s, being mostly due to earlier diagnosis, the introduction of anti-infective treatment, and the progressive abandonment of palliative surgery ( 85 , 212 ). The situation remains worrisome, however, in countries/regions with limited medical facilities and where diagnosis is performed only at an advanced stage of disease, as well as for those patients who experience severe side effects of benzimidazoles, as there is no alternative. Until now, the numerous attempts at finding new drugs or at converting drugs already used in other parasitic diseases for their application to the echinococcoses have essentially failed ( 213 ). Drugs that showed some promise in vitro and in experimental animals, and were effectively tested in humans or domestic animals, include other benzimidazole compounds such as flubendazole and oxfendazole, as well as nitazoxanide ( 182 ). Lists of those drugs that were tested in vitro and found not suitable for use in humans after being tested in vivo in experimental animals are available in more-specialized reviews ( 182 , 213 ). There is some hope from in vivo experiments with mefloquine ( 214 , – 218 ) and artemisinin ( 219 , 220 ) derivatives, and very recently, derivatives of carbazole aminoalcohols have been shown effective against cysts of E. granulosus both in vitro and in vivo ( 221 ). However, none of these compounds have, as yet, been subjected to pilot clinical trials.

CE and AE Disease Follow-Up

Long-term imaging follow-up after initiation of treatment (more than 10 years) has long been stressed for AE ( 86 , 222 ). It is now accepted that a close follow-up of patients with CE should also be undertaken for at least 5 years because of the high rates of relapse after surgery and the uncertainty of complete cure after drug treatment and/or percutaneous puncture. Regular tests of blood counts and serum transaminases are necessary to assess the safety of management within the first 6 months after initiation of anti-infective treatment, since hepatic toxicity and leukopenia are the most severe adverse effects and may prevent ABZ use in some patients. ABZ-SO or mebendazole measurements are extremely useful to assess the patient’s observance and to adjust drug dosages. ELISAs using HF antigens and/or purified AgB and Ag5 for CE and EM2-plus or Em18 ELISA, if available, for AE exhibit high performance in detecting disease recurrence after surgical resection of the cyst/lesion, although they are less accurate if all or part of the cyst/lesion remains in the infected organ ( 182 , 223 ). FDG-PET is currently considered the “gold standard” for the evaluation of the metabolic activity of AE lesions and for decisions about anti-infective treatment interruption; however, its predictive value is far from perfect, despite technical improvements (e.g., delayed image acquisition 3 h after FDG injection [ 224 , 225 ]), and all other imaging techniques deserve more evaluation ( 97 ).

There has been recent active searching for parasite viability/disease progression markers in the sera of AE patients ( 226 ), with antibodies against recEm18 showing promise for long-term monitoring ( 227 , – 229 ); however, when used alone, the test is not sufficiently discriminant to make a decision on treatment withdrawal. Double-negative results for FDG-PET and anti-recEm18 antibodies currently represent the best marker to consider treatment interruption ( 228 ). In all patients, recommended follow-up is at 1, 4, and 12 weeks for the first 3 months after diagnosis and initiation of ABZ, to check for ABZ adverse effects by measuring blood cell count and transaminases, and whenever possible, adjusting the treatment based on ABZ-SO measurement. The patient then is asked to present every 3 months for the first year and every 6 months until the end of the second year; this follow-up includes US, blood count, transaminases, and serology, and ABZ-SO is also measured 2 to 4 weeks after each dose adjustment, if necessary ( 182 ). In all patients FDG-PET is performed at the end of the second year. In patients with curative surgery, ABZ treatment is withdrawn 2 years after surgery if there is no recurrence as assessed by US, FDG-PET, and serology; yearly follow-up using US and serology is then recommended until 10 years after surgery. In patients without curative surgery, after the second year, yearly follow-up includes US, blood count, transaminases, and gamma-glutamyl transferase measurement, and serology, with FDG-PET-CT being performed every 2 years. A decision on anti-infective treatment withdrawal is made after at least 2 consecutive negative FDG-PET and Em18 serology assessments.

Detection of circulating serum or plasma Echinococcus sp. antigens (CAg) may be an alternative approach to serology. Early studies showed that E. granulosus sensu lato -specific circulating antigens, positive in 75% sera of antibody-negative CE patients, were associated with the growth dynamics and activity of cysts ( 230 ). Sensitivity of CAg detection, however, varied between 21% and 85%, mostly owing to the formation of circulating immune complexes. To our knowledge, only preliminary studies have been performed ( 231 ) to determine whether antigen detection may be a useful approach for assessing the efficacy of treatment, especially after removal of the cyst, and no studies using circulating antigens for long-term disease follow-up on a significant number of patients with CE or AE are available ( 36 ).

Assessing circulating cell-free DNA (cfDNA) could also be an option, as its detection as a biomarker has proved useful in cancer, and it has shown some promise in parasite diagnosis; for example, infections with all the three major human schistosomes ( Schistosoma mansoni , Schistosoma haematobium , and Schistosoma japonicum ) have been identified with PCR-based cfDNA assays using both species- and genus-specific target genes in animal models and patients ( 232 ). However, with the currently available detection methods, the approach does not seem sensitive enough for use in clinical practice, at least for AE, due to the low levels of cfDNA detectable in patient serum ( 233 ).

PREVENTION AND CONTROL

Current prevention and control of CE relies on the provision of safe animal slaughtering conditions (offal destruction and preventing dogs from feeding on infected organs of ungulates) and on dosing dogs with praziquantel ( 234 ). With notable exceptions, such as New Zealand, Tasmania, Iceland, Cyprus (at least temporarily), Chile, and some provinces in Argentina ( 3 ), other attempts at control have been generally disappointing. In countries where very strict slaughtering measures have been implemented, leading to the near disappearance of human CE cases, such as mainland Australia, persistence of a wild cycle of E. granulosus sensu stricto makes a reappearance of the disease always possible ( 39 ). Evaluation of control programs shows that (i) success is more readily achieved on islands, (ii) a combined multidisciplinary and multi-institution, and often multicountry, effort is necessary, and (iii) a One-Health approach is required ( 235 , 236 ). An ambitious, well-financed, and state-driven control program, including community US screening, care management of diagnosed patients, and monthly dog dosing with praziquantel, is in operation across western China. The monthly dosing of dogs is suitable for village-based communities ( 237 ) but is far less effective in seminomadic or pastoral areas ( 238 ).

Vaccination of sheep with the EG95 vaccine has been promoted as a complementary intervention to eliminate CE transmission ( 14 ), and there have been trials of this approach in China and South America. For most countries where CE is endemic, however, the logistics and costs of vaccinating sufficient numbers of animals may preclude widespread application of the vaccine. Dog vaccination would be an effective complementary intervention for controlling echinococcosis transmission ( 239 ), although recent progress has been slow ( 240 ). Nevertheless, development of a single vaccine, effective against both E. granulosus and E. multilocularis in canines, may be feasible and would be practical given that the two species are sympatric in many countries of the Northern Hemisphere. Besides the red fox, the main definitive host of E. multilocularis ( 241 , – 243 ), other carnivores such as the raccoon dog and domestic dog also act as definitive hosts ( 32 , 244 , 245 ). The role of dogs in AE transmission is especially important in western China and in central Asia ( 53 , 246 ) and may be more relevant in Europe than previously considered; conversely, a wildlife cycle may also be of concern for CE, especially in Africa ( 13 , 247 ). Baits impregnated with praziquantel have been applied against E. multilocularis ( 248 , 249 ), and a bait-delivered vaccine, when available, could be used to interrupt the parasite’s transmission cycle in wildlife, notably foxes, in cities and parks ( 250 ) and in selected rural areas ( 31 , 251 ).

A successful control campaign should focus on the most at-risk areas and on those animal hosts mainly involved in transmission, with progress constantly monitored ( 10 , 17 , 252 , 253 ). Close surveillance of the prevalence of Echinococcus spp. in dogs/foxes is extremely important for evaluating the progress of a control program ( 254 ). Detecting and quantifying Echinococcus sp. eggs/proglottids in canine fecal samples is recommended as an alternative to necropsy. Major improvement in parasite DNA detection in feces and environmental samples has occurred in the last 15 years, and this is currently preferred to antigen-based diagnosis ( 126 , 140 , 255 , – 259 ). As indicated above, LAMP-based assays are useful as a first-line screen for Echinococcus spp. in the field ( 134 , – 137 ), and PCR methods allow combined identification of definitive host species and Echinococcus sp. infection status using feces collected in the field ( 260 ). Adaptation of the available molecular methods to detect Echinococcus sp. egg DNA in environmental samples (e.g., in soil, water, and sewage and on vegetables) is an important step to better identify high-risk areas and the actual routes of human infection ( 138 , – 140 ), leading to more effective control.

RECENT APPLICATIONS OF OMICS TECHNOLOGIES

Improving understanding of the complexity of echinococcus species life cycles and unravelling species-specific phenotypic differences.

Gene transcript analysis of representative CE life stages (protoscoleces, cyst germinal cells and membranes, adult worms, and oncospheres) has allowed exploration of different aspects of tapeworm biology and parasitism ( 261 ). Further, the recent publication of the complete genomes of E. granulosus ( 261 ) and E. multilocularis ( 262 ) has revealed other key features associated with parasitism, including a description of a number of domain families gained during the course of evolution. Other important genes identified include those associated with strobilization and reproduction, signaling pathways, and neuroendocrine and nervous systems and others involved in evasion of immune recognition and regulation of host immunological responses. The genome and transcriptome data therefore provide a critical basis for more-detailed understanding of cestode biology, differentiation, development, evolution, and pathogenesis and other host-parasite interactions.

The complex life cycles of E. granulosus sensu lato and E. multilocularis provide a platform for addressing the functions of the expressed products of novel genes. Up- or downregulation of gene expression likely underpins the phenotypic changes associated with the different life cycle stages and the respective modulation of the immune response that each species determines. In-depth transcription analysis is critical for searching for key genes associated with these changes and for identification of their specific functions. One of the unique characteristic physiological features of E. granulosus sensu lato and E. multilocularis is the remarkable ability of the protoscolex to differentiate into an adult worm or to dedifferentiate into a cystic stage. Specific host stimuli (bile acids) govern the direction of development ( 263 , – 265 ), and relevant parasite-expressed receptors and transporters likely stimulate the relevant developmental pathways. Gene function prediction analysis was unable to attribute a function to 3,900 of the 11,325 genes predicted to be present in E. granulosus sensu stricto ; among these, 361 genes were transcribed in adult worms, of which 21 were highly expressed and may be associated with adult worm development ( 261 ). The morphology of the adult worms of Echinococcus spp., though following the typical taeniid cestode pattern, has only up to 5 immature, mature (with reproductive organs), and gravid proglottids sequentially present, which are replicated through strobilization. The gravid proglottid contains eggs which are released into the environment to infect intermediate and human hosts. Of the 361 genes shown by mRNA transcript analysis to be highly expressed in adult E. granulosus , 55 were specifically expressed compared with the oncosphere and cyst stages, in which these genes are silenced. The metacestode stage is associated with unlimited asexual development, whereas adult worms have limited, sexual development; of 8,361 genes expressed in the two stages, 498 and 502 genes were highly expressed in the adult worm and in the metacestode, respectively ( 261 ). Future work aimed at posttranscriptional suppression of these genes through RNA interference (RNAi) and gene knockout techniques may unravel their functional characteristics.

A comprehensive comparison of the genomes and transcriptomes of E. granulosus and E. multilocularis will also be central to our understanding of the biological/pathological differences between the two species. A major difference between the two is the morphology of the metacestode. E. granulosus has a unique cyst formation, with a shell-like adventitia which clearly separates the cyst from the surrounding (liver, lung, and brain) parenchyma. Conversely, the E. multilocularis metacestode is an infiltrating lesion composed of aggregated microvesicles, cells of the intermediate host’s immune response, fibrosis and necrosis, with no clear edge to the lesion, which continuously progresses eccentrically and damages the liver or other target organs. Comparative analysis of divergent and convergent gene pairs and their pattern of expression using microarray technology or RNA sequencing (RNA-Seq) is a relatively recent approach that can be used to identify patterns that are shared by more than one species or are unique to a particular species, with the capacity to reveal differences in biological phenotype. Although in its infancy for studying Echinococcus spp., such gene pair analysis has revealed that E. granulosus and E. multilocularis have 10,018 genes with high sequence similarity, with 5,418 being identical. The next stage will be to identify and characterize nonsimilar/unique genes so as to shed light on the inherent differences in morphology or pathology between the two tapeworms.

Improving Diagnosis and Drug Treatment of Echinococcosis

The currently available rich genomic and transcriptomic data may be useful for developing new public health interventions against echinococcosis; these include improved diagnostic tests and the identification of new drug targets. BLAST sequence analysis of the E. granulosus sensu stricto genome indicated that one-third ( n  = 3,903) of the genes present have no gene homologues or orthologues in other taxa, suggesting that these genes are probably Echinococcus specific, likely underpinning the unique features and biological characteristics of E. granulosus sensu lato . The products of these genes may also be of value as new candidates for diagnosis and as novel drug targets for the treatment and control of echinococcosis. Some proteins likely serve as messengers for cross talk between E. granulosus and its hosts and may prove useful as chemotherapeutic targets as well as for improved immunodiagnosis or immunotherapy ( 261 , 262 ). Potentially “druggable” proteins (i.e., polypeptides which might be the targets of new or existing drugs) expressed by genes in the germinal layer of the metacestode include G-protein-coupled receptors (GPCRs), serine proteases, ion channels, and neuropeptides ( 266 ) and components of the mitogen-activated protein kinase (MAPK) pathway ( 267 , – 270 ).

Hormone- and cytokine-activated pathways have been identified in both E. granulosus sensu stricto and E. multilocularis metacestodes ( 271 , – 273 ), and their activation/inactivation by host components is highly suggested ( 267 , 269 , 270 , 273 , – 281 ). Importantly, comparison of the E. granulosus and E. multilocularis genomes indicates a high level of gene sequence similarity, suggesting that the two parasites may share many common molecules that can be targeted for developing new interventions. MAPK inhibitors are currently being actively studied for their killing effects on the metacestode and/or protoscoleces. An ATP-competitive pyridinyl imidazole inhibitor (ML3403), targeting the P38-like MAPK from E. granulosus sensu stricto, effectively suppressed Egp38 activity, which led to significant protoscolex death within 5 days in vitro ( 267 ). Similar results were obtained with E. multilocularis ; ML3403, in particular, and SB202190, another pyridinyl imidazole, tested on metacestode vesicles cultured in vitro led to dephosphorylation of the parasite’s EmMPK2 and subsequent killing of the parasite vesicles at concentrations that did not affect cultivated mammalian cells ( 270 ).

As a direct result of the unveiling of the complete genomes of the Echinococcus spp., several metabolic pathways have been explored, and other inhibitors are currently being studied ( 177 , 282 , – 287 ). Nilotinib, an ABL (Abelson murine leukemia viral oncogene homologue)-tyrosine kinase inhibitor, and everolimus, a serine/threonine kinase inhibitor, caused alterations of E. multilocularis metacestode vesicles in vitro ; however, neither of these compounds resulted in any reduction of parasite growth in E. multilocularis -infected mice, and combined application of the kinase inhibitors with ABZ did not lead to synergistic or additive treatment efficacy ( 282 ). BI2536, a Polo-like kinase (a kinase containing Polo box domains) inhibitor that has been tested in clinical trials against cancer, was shown to inhibit EmPlk1 activity and to block the formation of metacestode vesicles from cultivated E. multilocularis germinal cells; furthermore, it eliminated the germinal cell population from mature metacestode vesicles in vitro , yielding parasite tissue that was no longer capable of proliferation ( 286 ). Similarly, imatinib, another ABL tyrosine kinase inhibitor used to treat cancer, has been shown to interact with the ABL-like kinases present in E. multilocularis and to be highly effective in killing Echinococcus stem cells, metacestode vesicles, and protoscoleces in vitro ( 287 ). However, the potential of these kinase inhibitors to treat AE in vivo is as yet unknown.

Improving Understanding of Immunological Mechanisms of Host-Parasite Interactions To Develop Immunotherapy

Although the extreme susceptibility of Echinococcus spp., and especially of E. multilocularis , to the cellular immune response of the host has been well recognized since the 1980s ( 288 ), much of the comprehensive knowledge of the immunological mechanisms at work in the subtle balance between host protection and parasite growth has been gained in the 21st century ( 76 , 289 ). In this field, advances in genomics have been of help by suggesting additional molecular mechanisms/pathways and new therapeutic targets. In particular, studies of the transcriptional profiles observed in the livers of E. multilocularis -infected mice and the use of mouse models with specific gene deletions have been crucial ( 290 , – 293 ). Recently obtained information suggests strongly that immunotherapy could complement the anti-infective drug approach to treat echinococcosis. Conversely, a better understanding of the immunological profiles of intermediate hosts infected with Echinococcus spp. may add new tools to the therapeutic arsenal targeting chronic inflammatory diseases.

The predominance of a T helper 2 (Th2) profile, including interleukin-5 (IL-5)- and IgE-dependent reactions, and high levels of IL-10 cytokine at the chronic stage of both AE and CE in humans have been known for some time ( 64 ). In CE, a dominant Th2/T regulatory (Treg) cytokine profile is rapidly established after the formation of the adventitial fibrous barrier ( 293 , 294 ). In AE, the immune response follows a 3-stage course characterized by a mixed Th1/Th2 profile at the early stage, a dominant Th2/Treg profile, including IL-10 and transforming growth factor β (TGF-β) regulatory cytokines, at the chronic middle stage, and a T-cell exhaustion status at the final stage of infection ( 289 , 295 ). Clinical studies on CE have shown the response to anti-infective therapy (or of “inactive” cyst) is associated with a Th1 profile, whereas on the other hand, resistance to treatment (or of “active” cyst) is associated with a Th2 profile and elevated IL-10 levels ( 289 , 293 ). Clinical studies in AE suggest that a combination of Th2-related cytokine serum levels, such as those of IL-23 and IL-5, could be used as a surrogate marker of AE metabolic activity in humans ( 294 ). Some proteins likely serve as messengers for cross talk between E. granulosus and its hosts and may also prove useful as targets for improved immunodiagnosis or patient follow-up ( 261 , 262 ).

The composition and type of the periparasitic immune response elicited by Echinococcus sp. infection causatively influence the outcome and progression of disease, ranging from resistance (self-cure) to rapidly evolving host fatality (high susceptibility) ( 291 ). In E. multilocularis , the parasite load, which can be quantitatively assessed in an experimental model involving infection by intraportal injection of protoscoleces, significantly influences this periparasitic response as well as the systemic cell and cytokine profile ( 295 ). Recent experimental studies show that Th1/Th17 polarization is a pivotal factor for resistance, while FoxP3 + Tregs are key players in the immune regulatory processes favoring E. multilocularis metacestode survival ( 296 ). In vivo treatment of mice by a single intravenous injection of 200 µl recombinant IL-17A at the optimal concentration of 125 pg/ml 2 weeks after E. granulosus sensu stricto infection decreased the infectivity rate by 2/3 and reduced metacestode growth by more than 90% ( 297 ). FoxP3 Treg depletion after infection using the DEREG (depletion of regulatory T cell) model in mice ( 296 ) and also genetic inhibition of the synthesis of fibrinogen-like protein 2 (FGL-2), a CD4 + CD25 + Treg effector molecule ( 298 ), are able to control E. multilocularis secondary infection.

In the per-oral model of infection, which better mimics AE in humans, the potential of FoxpP3 as a good target for application in immunotherapy has been confirmed ( 299 ). Another promising candidate is the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) signaling pathway, which plays a critical role in the induction of Foxp3 + CD25 + CD4 + Tregs, positively influences IL-10 and TGF-β secretion, inhibits effector T-cell proliferation and activation, and prevents Th1 cytokine production ( 300 ). Elevated soluble PD-L1 levels ( 301 ) and increased number of PD-1-expressing follicular helper T cells were observed in patients with CE compared with healthy controls ( 302 ); in experimental AE, percentages of PD-1 + Tregs and PD-L1 + dendritic cells (DCs) increased significantly together with levels of Foxp3, IL-10, and TGF-β during the chronic middle stage of infection ( 303 ). Preliminary experiments with a PD-1/PD-L1 engagement blockade are promising ( 304 ). Several PD-1/PD-L1 inhibitors already used in cancer treatment ( 305 ) are available to clinicians for pilot immunotherapeutic trials in AE. Combined anti-infective and immune therapy could also help clinicians in the management of severe, multiorgan cases of CE.

The specific immunological profile of the chronic stage of Echinococcus spp. infections has attracted attention as an established tolerance state that could be used to alleviate deleterious effects of inflammatory reactions in a variety of clinical conditions. Concomitant E. multilocularis infection in the rat delays rejection of a liver allograft ( 306 ), whereas concomitant E. granulosus sensu lato infection also reduces ovalbumin-induced airway inflammation of mice ( 307 ); in both situations, the effects were associated with raised IL-10 levels in the experimental animals. Although the potential efficacy of Echinococcus sp. components to treat rheumatoid arthritis was also evoked, it does not seem to have been demonstrated yet ( 308 ). The strongest evidence for the immunoregulatory role of established Echinococcus sp. infection in its murine intermediate host on an inflammatory disease has come from observations in experimental colitis. Both E. granulosus sensu stricto infection ( 309 ) and E. multilocularis infection ( 310 ) are able to reduce the development of dextran sulfate sodium (DSS)-induced colitis in mice. The possible use of noninfective Echinococcus sp. extracts is supported by observations made after treating mice daily, starting 3 days before colitis induction, with extracts from E. granulosus sensu stricto laminated layer; the treatment significantly improved the clinical symptoms and intestinal histological scores and maintained mucus production by goblet cells, while causing a significant decrease in gamma interferon (IFN-γ) and TNF-α and an increase in IL-10 production ( 311 ).

The immunomodulatory properties of Echinococcus sp. laminated layer have been well studied by reference to the shift they may induce in the immune response of the host to enhance metacestode growth and thus reduce host protection ( 76 , 312 ). A variety of immunomodulating molecules produced by Echinococcus spp. have been identified, including antigen B (AgB) subclasses, Eg2 heat shock protein (Hsp) 70, and EgTeg from E. granulosus sensu lato ( 313 ) and Em2 (G11), EmAP, and E. multilocularis activin-like (EmACT) from E. multilocularis ( 290 ); they should certainly be reconsidered with a positive view to obtain the best combination of immunomodulating components to be used in inflammatory bowel diseases and, more generally, in all clinical situations that require tolerance induction.

Improving Vaccine Development

Vaccination of intermediate hosts..

Vaccination of intermediate hosts of E. granulosus with the EG95 antigen has resulted in remarkable protective efficacy in pilot and field trials and is currently being used in areas of endemicity in China and South America ( 17 , 314 , – 317 ). The Echinococcus oncosphere is the infective stage for humans and intermediate hosts. Products of other genes differentially expressed by this stage likely represent potential additional vaccine candidates given that the protein expressed by the oncosphere-specific eg95 gene induces a high level of protection against egg challenge infection in sheep and cattle ( 317 , 318 ). Gene transcript analysis revealed that eg95 is highly expressed in oncospheres ( 261 ), and recent studies show that eg95 comprises a family of 7 distinct genes. Gene transcript analysis also showed that 340 (out of 3,811) genes were highly up-regulated in oncospheres compared with those in the adult and cyst stages of E. granulosus ( 261 ). Of the oncosphere-expressed genes, 2% (74/3,811) encode secreted proteins which likely play a key role in the penetration of the hatched oncosphere through the mammalian intestinal wall and in subsequent oncospheral development.

Vaccination of definitive hosts.

A dog vaccine effective against adult Echinococcus sp. infection would be highly desirable as an intervention in integrated echinococcosis control. Such a vaccine is not currently available. The protoscolex is the stage which develops into an adult worm in the canine intestine. Proteins of genes highly expressed in the protoscolex or in the adult may provide suitable vaccine candidates against adult worms in the definitive host. Products of a novel, highly expressed egM gene family (e gM4 , egM9 , and e gM123 ) in mature adult worms, which may be associated with adult worm maturation and/or egg development, showed encouraging protective efficacy against adult worm infection in vaccine trials where dogs were vaccinated and necropsied 45 days after challenge infection ( 319 , 320 ). Adult Echinococcus worms are localized to the middle of the small intestines of their definitive hosts, where abundant nutrients, especially amino acids, are present together with high levels of trypsin and trypsin-related enzymes. The worms secrete serine protease inhibitors (serpins) which counteract the potentially lethal effects of these host intestinal proteases and thereby likely play a key protective role in preventing proteolytic enzyme attack, ensuring survival of E. granulosus within its canine hosts. These, along with molecular chaperones, neurotransmitter receptors and transporters, and other protease inhibitors, specifically expressed in adult worms, likely represent additional vaccine candidates that warrant future study ( 261 , 285 , 321 , – 323 ).

CONCLUSIONS AND FUTURE PERSPECTIVES

Awareness of clinicians and medical researchers of the public health importance of echinococcosis, even in areas where it is not endemic, is crucial, and an improved knowledge of echinococcosis imaging is essential for diagnosis and a prerequisite for multidisciplinary decisions on treatment strategy. For diagnostic confirmation, standardization and quality control of the currently available serological tests, both for diagnosis and for disease monitoring, is more of a priority than an everlasting quest for the “perfect antigen”; an easier recourse to molecular identification of the parasites ensures a more rapid and reliable species diagnosis.

For the care management of both CE and AE, a new concept, akin to that considered for cancer patients, has emerged, and the issue of recurrence, and thus of prolonged patient follow-up, is now taken seriously in CE. New surgical techniques make the complete resection of CE cysts easier and complete resection of AE lesions possible even in very advanced cases. The currently available techniques of nonsurgical interventional treatments have improved the quality of life of patients. However, prospective studies with prolonged follow-up are still needed to base echinococcosis therapeutic strategy on evidence. In addition, more than 30 years after the first trials of mebendazole and ABZ, there is no available alternative to these two drugs as anti-infective therapy, a situation unique in the field of infectious diseases. Fortunately, new biological or immunological therapeutic targets may now be more easily identified because of new proteomics information, the complete sequencing of the E. granulosus and E. multilocularis genomes, and increased understanding of the host-parasite interactions in both AE and CE.

Controlling the transmission of Echinococcus spp. continues to be a considerable obstacle, but precise identification of the infecting species/genotypes may help public health institutions better focus and optimize the effectiveness of control programs. Involvement of wild animals in the life cycle of all Echinococcus species makes disease control dependent on landscape and climate changes and is, consequently, more challenging now than hitherto. Important improvements in molecular biology-based tests to detect Echinococcus spp. in definitive hosts and in the environment, however, make control program monitoring potentially easier. One challenge in the control of AE and CE in coming years will be to define optimum targets for developing vaccines effective in definitive canine hosts to interrupt the chain of transmission to humans if echinococcosis elimination, slated for 2050 by WHO, is to be achieved.

ACKNOWLEDGMENTS

Our studies have received financial support from the National Health and Medical Research Council of Australia (APP1102926, APP1037304, and APP1098244), the National Nature Science Foundation of China (81460308 and U1303203), and Public Health France, through the funding of the National Reference Centre on Echinococcosis.

Biographies

Hao Wen , M.D., Ph.D., FACS, is an honorary fellow of the French Academy of Surgery, Head and Senior Principal Research Fellow of the State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, and Professor of Surgery and Senior Consultant Hepatobiliary & Pancreatic and Transplant Surgeon at The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China. He completed his Ph.D. at the Faculty of Life Science, Salford University, United Kingdom, and completed postdoctoral study at the Institute of Medicine and Pharmacy, Franche-Comte University, France, from 1994 to 1995. He has been Vice Chairman of the Chinese Medical Doctor Association Organ Transplant Branch since 2014, Vice Chairman of the World Association of Echinococcosis since 2009, and Director of the WHO Collaborating Centre for Echinococcosis Prevention and Management since 2016. Professor Wen has published 150 refereed papers/articles in international journals in his research career. He has spent more than 30 years working on the prevention, diagnosis, and treatment of echinococcosis in China and has pioneered ex vivo liver resection and autotransplantation in end-stage alveolar echinococcosis globally. Most of his publications focus on clinical management, diagnosis, epidemiology, molecular biology, and immunology of echinococcosis.

Lucine Vuitton , M.D., Ph.D., is a Hospital Physician in the Gastroenterology and Endoscopy Department at the University Hospital of Besançon, France, and a postdoctoral fellow at University Bourgogne Franche-Comté (UBFC). She trained in gastroenterology in Besançon and Marseille, France, and had a 1-year research fellow position at the Inflammatory Bowel Disease (IBD) Unit of Nancy University Hospital in 2017. Her daily clinical activity is related to perendoscopic interventions and care of IBD patients. Her research deals with clinical endoscopy, IBD care management, and the relationship between IBD and infection, namely, human papillomaviruses and E. multilocularis . Dr. Vuitton has published 58 scientific articles, which have been cited more than 600 times. She is a member of the French Society of Digestive Endoscopy and of the French Endosonography Group. As a member of the WHO Collaborating Centre for Prevention and Treatment of Human Echinococcosis, she has coordinated the European survey on the endoscopic management of echinococcosis by endoscopic retrograde cholangiography. She is a member of the board of the GETAID (French IBD Therapy Study Working Group) and of the GETAID’s educational committee.

Tuerhongjiang Tuxun , M.D., Ph.D., is an Associate Professor of Surgery at The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China. He is a research fellow of the State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China, and the Clinical Medical Research Institute. He received his M.Sc. from Xinjiang University in 2010 and completed his doctoral study at Xinjiang Medical University in 2016. He has been a member of the Youth Committee of the Chinese Medical Doctor Association Hydatid Surgery Branch since 2014. He was the winner of the Shulan Talent Foundation award for “outstanding young transplant surgeon” in 2017. He has spent more than 10 years working on the treatment and control of echinococcosis. Most of his publications focus on the clinical management, diagnosis, and immunology of echinococcosis. Associate Professor Tuxun has published 100 refereed papers/articles, including 30 in international journals, in his research career.

Jun Li , B.Sc., Ph.D., is a Professor at the Xinjiang Medical University and a senior research fellow of the State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China. She received her B.Sc. from Xinjiang Medical University, and in 2004 she obtained her Ph.D. at the University of Queensland, Australia, working on the development of diagnostic tools for detecting cystic echinococcosis. She then spent 3 years working at the commercial company PanBio developing diagnostic kits for infectious diseases. From 2008 to 2013, she worked on the molecular biology of Echinococcus as a senior research officer in the Molecular Parasitology Laboratory, Infectious Diseases Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. She has published over 30 papers/articles in international journals in her research career.

Dominique A. Vuitton , M.D., Ph.D., is a Professor Emeritus of Clinical Immunology at University Bourgogne Franche-Comté, France, and a scientific consultant at the State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China. A major part of her research work has been dedicated to the interactions between Echinococcus spp. and their hosts, to the epidemiology and of risk factors for cystic and alveolar echinococcosis in the areas of endemicity in western China, and to the care management of patients with echinococcosis; she was involved in the first clinical trials of mebendazole and albendazole, in the first attempts at liver transplantation for AE, and in the definition of international classifications and recommendations for the care management of echinococcosis patients. Professor Vuitton has published 355 scientific articles, which have been cited 8,680 times. She was the coordinator of the WHO Informal Working Group on Echinococcosis (WHO, Geneva) and the head of the WHO Collaborating Centre for Prevention and Treatment of Human Echinococcosis (Besançon, France). She received the Chinese “Friendship Prize” in 2010 and the French “Légion d’Honneur” in 2011 for her professional achievements and was elected Fellow of the French National Academy of Medicine in 2017.

Wenbao Zhang , B.Sc., Ph.D., is a senior research fellow of the State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China, and of the Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China. He received his B.Sc. from Xinjiang University in 1983. From 1999 to 2003, he was an Australian International Postgraduate Research Scholar, and he completed his Ph.D. at the University of Queensland. He has spent more than 30 years working on the treatment and control of zoonoses, including echinococcosis, tuberculosis, brucellosis, and schistosomiasis. Most of his publications focus on the molecular biology, immunology, diagnosis, and epidemiology of these diseases. Professor Zhang has published 150 refereed papers/articles, including 58 in international journals, in his research career.

Donald P. McManus , B.Sc., Ph.D., D.Sc. (Wales), is an NHMRC Senior Principal Research Fellow, Senior Principal Research Fellow, and Senior Scientist at Berghofer Medical Research Institute, Professor of Tropical Health, University of Queensland, and Professor, Australian National University. He researches the molecular biology, immunology, diagnosis, and epidemiology of parasitic worms. Professor McManus has published over 600 articles, which have been cited over 21,000 times. He was made Honorary International Fellow of the American Society of Tropical Medicine and Hygiene in 2010 and received honorary membership in the American Society of Parasitologists in 2012. He was elected Fellow of the Royal Society of Biology (United Kingdom) in 2013 and was the recipient of the 2014 Ralph Doherty QIMR Berghofer Prize for Outstanding Achievement and Leadership in Medical Research. In 2015 he was elected Fellow of the Australian Academy of Health and Medical Sciences. He is the winner of the 2018 Sornchai Looareesuwan Medal “for outstanding achievements in experimental and clinical topical medicine research.”

Volume 30, Number 2—February 2024

Confirmed Autochthonous Case of Human Alveolar Echinococcosis, Italy, 2023

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In September 2023, a patient in Italy who had never traveled abroad was referred for testing for suspected hepatic cystic echinococcosis. Lesions were incompatible with cystic echinococcosis; instead, autochthonous alveolar echinococcosis was confirmed. Alveolar echinococcosis can be fatal, and awareness must be raised of the infection’s expanding distribution.

The main human echinococcal infections are caused by Echinococcus granulosus sensu lato, which causes cystic echinococcosis (CE), and E. multilocularis , which causes alveolar echinococcosis (AE). The parasites have different life cycles and cause different diseases ( 1 ). E. granulosus s.l./CE is endemic worldwide in livestock-raising areas, including Italy, and accounts for most human echinococcal infections ( 2 ). The parasite is transmitted in a domestic cycle between dogs and livestock and causes generally benign disease in humans marked by the formation of well-defined fluid-filled cysts mostly in the liver ( 1 , 2 ). E. multilocularis /AE is endemic to the Northern Hemisphere and is transmitted in a sylvatic cycle between wild canids (e.g., foxes) and small rodents (e.g., voles) ( 2 ).

Humans become infected with the 2 pathogens by accidental ingestion of parasite eggs from material contaminated with infected definitive host feces. In Europe, North America, and Asia, expanding distribution has been observed in recent decades ( 2 ). In Europe, the historical endemic areas are Austria, France, Germany, and Switzerland, and that range has expanded to include Eastern and Northern Europe ( 3 ). In Italy, infected foxes have been reported over the past 20 years in the Trentino-Alto Adige region ( 4 – 7 ). Autochthonous animal transmission might occur in the area ( 8 ), and prevalence in foxes seems to be increasing ( 9 ). A 2017 survey conducted in the Liguria region first detected E . multilocularis in fecal samples of dogs and wolves, suggesting a southward expansion of the parasite ( 10 ) ( Appendix Figure), as predicted by modeling ( 3 ). Surveillance of E. multilocularis in Europe is usually conducted voluntarily ( 11 ), and no structured surveillance program for animal infection in Italy occurs beside targeted surveillance through research projects.

We report a confirmed autochthonous human AE case in Italy. Ethics approval was not necessary because data were derived from routine clinical practice. The patient consented to the publication of this report.

In September 2023, a 55-year-old man in Italy was referred from his local hospital in Bolzano province, Trentino-Alto Adige region, to IRCCS Sacro Cuore Don Calabria Hospital, upon suspicion of CE. The patient was born and lived in Trentino-Alto Adige and had never traveled abroad; he worked in the tertiary sector and did not report contact with wild carnivores. He also did not report risk factors for E. granulosus infection.

Diagnostic tests for patient in Italy with confirmed autochthonous case of human alveolar echinococcosis, 2023; white arrows indicate lesions. A–D) Contrast-enhanced computed tomography arterial phase. E–H) T2-weighted magnetic resonance imaging. I–L) Ultrasonography and contrast-enhanced ultrasonography. M–P) 18F-FDG-PET scan delayed acquisition (4 hours). Q–T) Em2 immunohistochemistry indicating small particles of Echinococcus multilocularis (spems) stained in red in patient’s sample (original magnification ×2.5 [Q] and ×20 [R]); positive alveolar echinococcosis sample control (original magnification ×20 [S]); Em2 negative control (cystic echinococcosis case, negative laminated layer; original magnification ×20) (T).

Figure . Diagnostic tests for patient in Italy with confirmed autochthonous case of human alveolar echinococcosis, 2023; white arrows indicate lesions. A–D) Contrast-enhanced computed tomography arterial phase. E–H) T2-weighted magnetic resonance imaging....

The suspicion of CE was posed in June 2023, when he underwent abdominal ultrasound for a mild thrombocytopenia, revealing 5 recently developed small hepatic lesions (ultrasound results in 2016 were unremarkable). The lesions were described as septated and hypodense with no contrast enhancement and no calcifications on computed tomography performed in June 2023 ( Figure , panels A–D), hypointense in T1-weighted magnetic resonance imaging (MRI), and hyperintense in T2-weighted MRI ( Figure , panels E–H), with no diffusion restriction. No other lesions were present on total body imaging. Results of Echinococcus serologic testing using Western blot method were positive, but banding pattern was not reported.

We excluded the diagnosis of CE on the basis of the lesions’ morphology on ultrasound, which did not show any CE pathognomonic or compatible features. We observed 5 lesions: 1 with 2.3 cm diameter in hepatic segment I, 1 of 0.9 cm in VI, 2 subcapsular of 2.7 cm and 0.5 cm in VII, and 1 of 1.6 cm in segment VIII (adjacent to the median hepatic vein). The lesions were hypoechoic with irregular margins, particularly the lesion in segment I, which had fine and tightly packed septations ( Figure , panels I–L). The lesions were not enhancing on contrast-enhanced ultrasound ( Figure , panels I–L). Serologic testing using the Echinococcus Western Blot IgG (LDBIO Diagnostics, https://ldbiodiagnostics.com ) was positive for Echinococcus spp., showing genus-specific 7 kDa and 26–28 kDa bands, not assignable specifically to a species. Results of an 18 F-FDG-PET scan showed light hypermetabolism in delayed (4-hour) acquisitions ( Figure , panels M–P). Taken together, those results made the lesions highly indicative of AE.

We performed a biopsy of the only accessible lesion, located in segment VI, and submitted the specimen to the German Reference Laboratory for Tropical Parasites at the Bernhard-Nocht Institute for Tropical Medicine (Hamburg, Germany). A serum sample also submitted for further serologic testing showed low antibody titers against crude antigen preparations of E. multilocularis and E. granulosus (1:40–1:80 in indirect hemagglutination [negative <1:20] and 30–40 arbitrary units in ELISA [negative <20]). Results of Em18-ELISA ( 12 ) were negative. Histology revealed necrotic granuloma and fibrosis without PAS-positive structures. Results of PCR testing targeting cestode cytochrome oxidase and Echinococcus -specific 12S rDNA ( 13 ) were negative. In contrast, immunohistochemistry with the monoclonal antibody Em2G11 ( 14 ) stained positive for small particles of E. multilocularis (spems) ( Figure , panels Q–R). Spems consist of outer laminated layer of Em2 antigen in close proximity to AE lesions and thus confirmed the diagnosis of AE, defined by the WHO Informal Working Group on Echinococcosis (WHO-IWGE) as the presence of clinical-epidemiologic factors plus compatible imaging findings plus seropositivity for echinococcosis plus compatible histopathology ( 15 ). The laboratory uses Em2G11-IHC regularly for suspected AE. The immunohistochemistry has been extensively validated and is also used by other laboratories; CE lesions and other cestode lesions stain negatively ( 14 ), whereas lesions by neotropical E. vogeli stain faintly ( Appendix reference 16 ).

Staging according to the WHO-IWGE ( 1 , 15 ) was P2N0M0 (i.e., central lesions with proximal vascular and/or biliary involvement of 1 lobe, no regional involvement, no metastasis). We adopted a conservative management approach because removing the lesions would require major surgery and because the results of Em18 serologic testing and 18 F-FDG-PET scan suggested low-viability parasites ( 1 , 13 ). At the time of publication, the patient was receiving albendazole (400 mg 2×/d) with fat-containing meals and tolerating the medication well. Follow-up with contrast-enhanced ultrasound and serologic testing was scheduled every 6 months, MRI in 1 year, and 18 F-FDG-PET scan in 2 years ( 1 ).

Conclusions

AE is a complex disease with a high fatality rate (0%–25% 10-year survival) if untreated ( 1 ). It primarily affects the liver and is characterized by infiltrating, metastatic, tumor-like behavior ( 1 ). Unlike CE, AE lesions have no pathognomonic signs on imaging, and the differential diagnosis is mainly tumors ( 1 ). Even in AE-endemic areas, misdiagnosis and consequent incorrect treatment occurs frequently ( 1 ; Appendix reference 17 ).

Curative treatment options include surgery and albendazole if radical resection is achievable, or albendazole alone indefinitely in other cases ( 1 ). Treatment interruption can be envisaged in selected cases when serologic testing and 18 F-FDG-PET scans become negative ( 1 ). In this case, the Western blot banding pattern, low antibody concentrations against crude parasite antigens, negativity of Em18 ELISA, and faint hypermetabolism on 18 F-FDG-PET scan indicate low parasite viability ( 1 , 13 ). PCR on bioptic material was negative, explained by the absence of cell-containing larval structures on histology; however, E. multilocularis –specific immunochemistry was positive, confirming the diagnosis ( 1 , 13 ).

A report from 1928 mentioned 2 human AE cases identified in South Tyrol in 1906 and 1922 ( 2 ), but reports of human confirmed AE in Italy are otherwise lacking; a 2019 research review identified no reports from this country ( 12 ). Italian Hospital Discharge Records reports cases labeled as AE according to International Classification of Diseases, 9th Edition ( Appendix reference 18 ). From the analysis of cases that we could examine ( Appendix reference 19 ), those cases seem to be CE with multiloculated cyst morphology (CE2 and CE3b stages according to WHO-IWGE), erroneously recorded as E. multilocularis ( 1 ).

An expanding area of endemicity of E . multilocularis in Europe has been observed and predicted by modeling ( 3 ). Because of the high lethality of this disease if misdiagnosed and mistreated, physicians, especially in Italy’s alpine regions, must be informed about this infection and its possibility even in patients who have never lived in or traveled to known endemic areas.

Dr. Tamarozzi is a senior research physician and cohead of the WHO Collaborating Centre on Strongyloidiasis and other NTDs at the Department of Infectious-Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, in Negrar di Valpolicella, Verona, Italy, as well as a member of the steering committee of the WHO Informal Working Group on Echinococcosis. Her main field of work is the laboratory- and imaging-based diagnosis of neglected helminthic infections, in particular echinococcal infections.

Acknowledgments

We thank Andrea Angheben, Paola Rodari, Maria Luca D’Errico, and the infectious-tropical diseases ward at IRCCS Sacro Cuore Don Calabria hospital in Negrar for clinical management during the patient’s hospitalization; Stefano Tais for support with sample management; Ansgar Deibel for the discussion on the case diagnosis and management; and Dora Buonfrate for critically reviewing the manuscript.

Funding was provided through Italian Ministry of Health “Fondi Ricerca Corrente –L2” to IRCCS Sacro Cuore Don Calabria hospital, Negrar di Valpolicella, Verona, Italy.

F.T., M.D., E.O., and T.D. performed and interpreted imaging and laboratory tests; F.T., N.R., B.G., and F.G. clinically managed the patient. F.T., D.T., and G.B. wrote the manuscript. All authors reviewed and approved the published version of the manuscript.

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  • Barth  TF , Herrmann  TS , Tappe  D , Stark  L , Grüner  B , Buttenschoen  K , et al. Sensitive and specific immunohistochemical diagnosis of human alveolar echinococcosis with the monoclonal antibody Em2G11. PLoS Negl Trop Dis . 2012 ; 6 : e1877 . DOI PubMed Google Scholar
  • Brunetti  E , Kern  P , Vuitton  DA ; Writing Panel for the WHO-IWGE . Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop . 2010 ; 114 : 1 – 16 . DOI PubMed Google Scholar
  • Figure . Diagnostic tests for patient in Italy with confirmed autochthonous case of human alveolar echinococcosis, 2023; white arrows indicate lesions. A–D) Contrast-enhanced computed tomography arterial phase. E–H) T2-weighted magnetic resonance...

DOI: 10.3201/eid3002.231527

Original Publication Date: January 18, 2024

Table of Contents – Volume 30, Number 2—February 2024

Please use the form below to submit correspondence to the authors or contact them at the following address:

Francesca Tamarozzi, Department of Infectious-Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Via don A Sempreboni 5, 37024, Negrar di Valpolicella, Verona, Italy

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Parasites - Echinococcosis

Echinococcus granulosus

Echinococcosis is a parasitic disease caused by infection with tiny tapeworms of the genus Echinocococcus . Echinococcosis is classified as either cystic echinococcosis or alveolar echinococcosis.

Cystic echinocccosis (CE), also known as hydatid disease, is caused by infection with the larval stage of Echinococcus granulosus , a ~2–7 millimeter long tapeworm found in dogs (definitive host) and sheep, cattle, goats, and pigs (intermediate hosts). Although most infections in humans are asymptomatic, CE causes harmful, slowly enlarging cysts in the liver, lungs, and other organs that often grow unnoticed and neglected for years.

Alveolar echinococcosis (AE) disease is caused by infection with the larval stage of Echinococcus multilocularis , a ~1–4 millimeter long tapeworm found in foxes, coyotes, and dogs (definitive hosts). Small rodents are intermediate hosts for E. multilocularis. Although cases of AE in animals in endemic areas are relatively common, human cases are rare. AE poses a much greater health threat to people than CE, causing parasitic tumors that can form in the liver, lungs, brain, and other organs. If left untreated, AE can be fatal.

Image: L to R: Echinococcus granulosus adult, stained with carmine. Close-up of the scolex of E. granulosus . In this focal plane, one of the suckers is clearly visible, as is the ring of rostellar hooks. (Credit: DPDx )

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  • Published: 23 February 2024

An innovative strategy for deworming dogs in Mediterranean areas highly endemic for cystic echinococcosis

  • Martina Nocerino 1 ,
  • Paola Pepe 1 ,
  • Antonio Bosco 1 , 2 ,
  • Elena Ciccone 1 , 2 ,
  • Maria Paola Maurelli 1 , 2 ,
  • Franck Boué 3 ,
  • Gérald Umhang 3 ,
  • Justine Pellegrini 3 ,
  • Samia Lahmar 4 ,
  • Yousra Said 4 ,
  • Smaragda Sotiraki 5 ,
  • Panagiota Ligda 5 ,
  • AbdElkarim Laatamna 6 ,
  • Giorgio Saralli 7 ,
  • Orlando Paciello 1 ,
  • Maria Chiara Alterisio 1 &
  • Laura Rinaldi 1 , 2  

Parasites & Vectors volume  17 , Article number:  86 ( 2024 ) Cite this article

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Cystic echinococcosis (CE), caused by the larval stage of Echinococcus granulosus sensu lato , is a zoonotic parasitic disease of economic and public health importance worldwide, especially in the Mediterranean area. Canids are the main definitive hosts of the adult cestode contaminating the environment with parasite eggs released with feces. In rural and peri-urban areas, the risk of transmission to livestock as well as humans is high because of the free-roaming behavior of owned/not owned dogs. Collecting data on animal movements and behavior using GPS dataloggers could be a milestone to contain the spread of this parasitosis. Thus, this study aims to develop a comprehensive control strategy, focused on deworming a dog population in a pilot area of southern Italy (Campania region) highly endemic for CE.

Accordingly, five sheep farms, tested to be positive for CE, were selected. In each sheep farm, all shepherd dogs present were treated every 2 months with praziquantel. Furthermore, 15 GPS dataloggers were applied to sheep and dogs, and their movements were tracked for 1 month; the distances that they traveled and their respective home ranges were determined using minimum convex polygon (MCP) analysis with a convex hull geometry as output.

The results showed that the mean daily walking distances traveled by sheep and dogs did not significantly differ. Over 90% of the point locations collected by GPS fell within 1500 mt of the farm, and the longest distances were traveled between 10:00 and 17:00. In all the sheep farms monitored, the area traversed by the animals during their daily activities showed an extension of < 250 hectares. Based on the home range of the animals, the area with the highest risk of access from canids (minimum safe convex polygon) was estimated around the centroid of each farm, and a potential scheme for the delivery of praziquantel-laced baits for the treatment of not owned dogs gravitating around the grazing area was designed.

Conclusions

This study documents the usefulness of geospatial technology in supporting parasite control strategies to reduce disease transmission.

Graphical Abstract

case study of echinococcosis

Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by the larval stage of taeniid cestode Echinococcus granulosus sensu lato , with a considerable economic and public health significance worldwide. Recently, human CE was included by the World Health Organization (WHO) in the list of the 20 neglected tropical diseases (NTDs) and priority neglected zoonotic diseases (NZDs) for which effective control measures are needed [ 1 , 2 ]. Among E. granulosus s.l. species, E. granulosus sensu stricto ( s.s. ) is the most relevant one of public health importance being responsible for 88.5% of worldwide documented human CE infections [ 3 ]. The life cycle of E. granulosus s.s. includes dogs (mostly shepherd dogs) as definitive hosts and small ruminants (particularly sheep) as intermediate hosts [ 4 ]. Humans act as accidental, dead-end intermediate hosts, acquiring the infection through ingestion of parasite eggs [ 5 ]. CE is highly endemic in the Mediterranean regions with high prevalence rates among communities where pastoral activities predominate [ 3 , 6 ]. In southern Europe, the average annual national incidence rate of documented human CE cases ranges from one to six cases per 100,000 people, covering the years 1997–2020 [ 3 ]. Dogs, the main definitive hosts, play a pivotal role in the transmission of CE due to their free roaming in grazing areas and farms, having access to Echinococcus -infected offal from slaughtered livestock or by scavenging on carcasses. Eggs excreted in the environment with feces by infected canids are the source of infection for humans and other intermediate hosts [ 6 , 7 ]. Compared to owned dogs, not owned ones cover a larger roaming range and thus have more access to metacestodes in carcasses or not properly destroyed infected organs, posing a higher risk of infection [ 8 , 9 , 10 ]. However, the contribution of stray dogs in maintaining transmission of CE has still often been neglected to date. Recently, Karshima et al. [ 11 ] conducted a meta‑analysis on the prevalence and distribution of canine E. granulosus infections in Africa, and the obtained results revealed the highest prevalence rates prominently in not owned dogs in North Africa. The prevalence rates reported in not owned dogs from North Africa countries range from 5.2% to 42% [ 12 , 13 ]. Additionally, a prevalence of 4.2% of Taeniidae eggs, which could likely be E. granulosus , was reported in not owned dogs from central Italy [ 14 ]. For this reason, not owned dogs are a challenging category in the management of dog populations to control CE [ 11 , 15 ], and their treatment should be much more intensive than for owned dogs [ 9 , 10 ]. In this context, the “Humane Dog Population Management Guidance, 2019” [ 16 ], developed by the International Companion Animal Management Coalition (ICAM), recommended a comprehensive canine population management program, encompassing both owned and not owned dogs, based on preventive veterinary treatments such as vaccinations and parasite control to reduce zoonotic diseases, including echinococcosis. From a control perspective, canids are therefore the main targets for interventions aiming to reduce or eliminate adult worm burdens. Accordingly, praziquantel (PZQ) is an excellent cestocide for dogs, with very high and reliable efficacy against mature and immature adult stages of intestinal taeniid cestodes [ 17 ]. Over the years, control programs focusing on deworming and managing domestic dogs have been successfully implemented in several large insular areas, such as New Zealand, Iceland and Tasmania [ 17 ]. Control programs against E. granulosus are considered long-term measures that require an integrated approach [ 18 ]. Usually, these measures (or programs) include a combination of several strategies: (i) regulation and monitoring of slaughter activity and disposal of offal; (ii) prevention of dog access to offal from slaughtered livestock; (iii) regular deworming of dogs; (iv) public health education; (v) the introduction of EG95 recombinant vaccine for protection of lambs against E. granulosus infections [ 19 , 20 ]. However, despite the implementation of such control initiatives in several countries and regions (i.e. Argentina, Chile, China, Italy, Morocco and Uruguay), resulting in a marked decrease in the incidence of the disease, CE remains a major public health problem worldwide [ 2 , 18 , 20 , 21 , 22 , 23 , 24 ]. Thus, new sustainable tools, especially applicable at level of definitive hosts, are needed to implement the CE control programs.

Collecting detailed data on movements and spatial behavior of hosts (definitive and intermediate) could support the planning of comprehensive control strategies. In this regard, the use of geospatial technologies and GPS dataloggers could be an optimal tool to measure animal movements with a fine spatial and temporal resolution. GPS collars have already been successfully used to evaluate the role of dog behavior in the transmission of Echinococcus multilocularis in the Sichuan Province of China [ 25 ]. In addition, GPS tracking data of peri-urban stray dogs have been recently used to calculate the home ranges of these animals and to investigate the spatial variation in E. granulosus prevalence within wild dog population in peri-urban areas of southeast Queensland, Australia [ 26 ].

Given the potential application of geospatial technologies and GPS dataloggers, the main objective of the present study was to develop and validate a comprehensive strategy for deworming both owned and not owned dogs in a pilot area of southern Italy (province of Salerno in Campania region), highly endemic for CE [ 16 , 18 ], to implement control strategies against this disease.

With the primary objective in mind, the specific aims were the following: (i) implement the treatment of owned dogs on sheep farms that tested positive for CE; (ii) define the travel distances of both sheep and free-roaming owned dogs along with their spatio-temporal activity patterns; (iii) estimate the home range areas covered by sheep and dogs during their grazing activity; (iv) develop a scheme for the targeted delivery of praziquantel-laced baits to treat not owned dogs present in the grazing areas.

Study design

The strategies described in the present study are part of the project ECHINO-SAFE-MED “ New sustainable tools and innovative actions to control cystic ECHINOcoccosis in sheep farms in the MEDiterranean area: improvement of diagnosis and SAFEty in response to climatic changes ” (supported by PRIMA-Partnership for research and innovation in the Mediterranean area), which aims to improve surveillance and control activities for definitive (dogs) and intermediate hosts (sheep) of E. granulosus in four Mediterranean countries (Italy, Greece, Algeria and Tunisia) where CE is highly endemic.

ECHINO-SAFE-MED is divided into five inter-linked Work Packages (WPs) as described in Fig.  1 . Specifically, this study was a task of WP3, which focused on evaluating new approaches to control CE, based on the treatment of definitive hosts (owned and not owned dogs) as described in detail in the following sections. In addition to the conventional control activities, an innovative strategy based on praziquantel-laced baits was designed for use in the treatment of not owned dogs or other canids in grazing areas identified by tracking animal movements through GPS dataloggers.

figure 1

ECHINO-SAFE-MED work packages

Activities have been ongoing since August 2021 in a pilot area of southern Italy highly endemic for CE [ 16 , 18 ] to evaluate whether it is feasible to extend the use of these technologies to other countries of Mediterranean area.

Study area and recruitment of sheep farms

The study was conducted in a peri-urban area of the Salerno Province (Campania region, southern Italy), where owned and not owned free-roaming dogs are common. To select the sheep farms to be included in the study, in-depth interviews were conducted with farmers in the pilot area to gather information on farm management practices. Special attention was paid to selecting representative farms (e.g. similar farm size, breeding systems, number of shepherd dogs). To use these data while protecting the privacy of people (i.e. farmers), farm(ers) names, ID and addresses were transformed into anonymous data using progressive numbers. Each farmer received information about the research and how their data were used. A letter of consent was filled by each farmer involved into the project.

Based on the questionnaire survey, a total of 40 sheep farms with approximately 200 animals each were selected and underwent surveillance activities, using both ultrasound (US) [ 27 ] and post-mortem examinations. The results obtained were collected and analyzed, and 10 sheep farms, with a mean intra-flock prevalence of CE > 30%, according to the US analysis, were selected for the study. Specifically, five sheep farms were selected to start the treatments of dogs (owned and not owned) whereas the other five sheep farms were selected to be used as control farms without any treatment activities for dogs.

The location of the sheep farms included in the study was then geo-referenced using a Geographical Information System (GIS) (ArcGIS Pro 2.7 software, Environmental Systems Research Institute, Inc., Redlands, CA, USA) (Fig.  2 ).

figure 2

Localization of the five sheep farms (green points) in which the treatments of dogs (owned and not owned) were carried out and the five control farms (without treatment of dogs) (orange points), selected for the pilot study in the Salerno province, Italy

Treatment and diagnosis of dogs in sheep farms

The shepherd dogs in each sheep farm included in the study were treated and underwent post-treatment parasitological examination. Treatments were performed orally with chewable tablets containing a combination of praziquantel (5 mg/kg) and milbemycin oxime (0.5 mg/kg) (Milbemax®-chewable tablets, Elanco Italia S.p.A). The intervention interval was set at 2 months for the entire duration of the project. To facilitate the treatment of the dogs and collection of fecal samples, specifically designed and purpose-built modular mobile cages (EchinoCage) were used, as previously described [ 18 ]. After 48 h, all fecal samples were collected individually using the Fill-FLOTAC [ 28 ] while confinement areas of the dogs were disinfected with 5% sodium hypochlorite to avoid environmental contamination by Taeniidae eggs [ 18 ].

Fecal samples were stored at − 80 °C for 3 days prior to copromicroscopic analysis to inactivate E. granulosus eggs [ 29 ].

The Mini-FLOTAC technique [ 18 ], with zinc sulfate (specific gravity = 1.35) as flotation solution [ 30 ], was used to detect and count Taeniidae eggs (analytical sensitivity = 5 eggs per gram of feces, EPG). All fecal samples testing positive for Taeniidae eggs underwent molecular analysis to detect E. granulosus s.s.

The molecular diagnostic was realized from 300 mg of fecal sample mixed with 1 ml of CTAB buffer in a Lysing Matrix E tube (MP biomedicals) before heating 5 min at 95 °C. After cooling, the tube was submitted to three grinding cycles in the FastPrep (MP biomedicals) with one cycle composed of 1 min at 5 m/s followed by 1 min on ice. The DNA extraction was then continued as recommended using the Maxwell 48 with the Maxwell RSC PureFood Pathogen Kit protocol (Promega). A real-time PCR multiplex, combining the detection of E. granulosus s.s. with primers and probe as described by Maksimov et al. [ 31 ], and an internal control, which is a plasmid artificial construct allowing the amplification with the same primers as for E. granulosus s.s. but requiring a specific probe, was performed. The reaction was performed in duplicate with Maxima Probe qPCR Master Mix (ThermoScientific) in a final volume of 25 μl, including 5 μl of DNA from the fecal sample, and run on a QuantStudio5 thermocycler (Applied Biosystems). The final concentrations of 1.3 μM for primers and 0.2 μM and 0.1 µM were used for the probes of E. granulosus s.s. and the internal control, respectively. One hundred copies of the internal control were added in each tube. The multiplex qPCR program used was 10 min at 95 °C and then 45 cycles of 15 s at 95 °C and 60 s at 60 °C.

Additionally, the presence of Taenia species was detected using PCR primers Cest4–Cest5 targeting the 12S mitochondrial gene as described by Trachsel et al. [ 32 ]. A private company (Eurofins Genomics, Germany) sequenced the amplicons obtained through conventional PCR, while the Geneious prime software was used to align nucleotide sequences.

GPS tracking data and identification of points for the delivery of praziquantel-laced baits

On each sheep farm selected for the treatment, three GPS datalogger collars (Qtrack GPS, 4G LTE Iot Network Technology, Austria) were attached to the sheep acting as “flock leader” and to two shepherd dogs to monitor animal movements. The movements of sheep and dogs were monitored at the same time for 1 month (April) on all the farms (Fig.  3 ). GPS devices were selected based on their suitability for field studies, which included ease of programming, light weight (140 g), small size (87 × 51 × 30 mm), battery capacity of 2400 mAh, long battery life (> 2 months) and water resistance. Since the GPS devices used the Global System for Mobile Communication (GSM) to transmit the acquired locations to the server, the mobile network coverage over the entire pilot area was verified before starting the tests.

figure 3

GPS devices used for tracking sheep and dog movements

The GPS devices were programmed to record the geographic coordinates of the animals every hour. Before starting GPS tracking, signal reception and network coverage were checked in two different typical micro-habitats of the study area (agro-forestry and natural grassland) by installing four GPS collars on medium-sized shepherd dogs that were allowed to roam freely for 5 h in an area of 3 hectares (ha). The point locations recorded at 1-h intervals for the preliminary test showed an accuracy of up to 3 mt.

Only on one sheep farm (ID 4), where animals were performing vertical transhumance, two pens at different altitudes (4 M: high altitude pen, 4 V: low valley pen) were monitored.

Positions recorded by the GPS dataloggers were downloaded, grouped per animal species (sheep and dogs) and processed using Microsoft Excel (Microsoft Corp., Redmond, WA, USA) for further statistical analysis (see below). Only data points which included all the information (i.e. date, time, latitude and longitude) were selected.

A GIS platform was developed using ArcGIS Pro 2.7 software (Environmental Systems Research Institute, Inc., Redlands, CA, USA) to project the point locations onto the study area.

For each farm, the daily walking distances (mt) traveled by sheep and dogs were calculated by summing the Euclidean distance between consecutive GPS point locations collected in a day. Then, these values were averaged over 1 month to calculate the mean daily walking distance (mt/day).

A multiple ring buffer analysis was implemented to estimate the size and spatial distribution of the positions of collared animals. Ten concentric buffers were created around the centroid of each farm, spaced 100 mt apart, and the number of sheep and dog point locations which crossed each ring buffer was counted. The area traversed by sheep and dogs during their daily activities (home range) was determined using minimum convex polygon (MCP) analysis with a convex hull geometry as output. The estimation of the home range area was performed considering 100% MCP method [ 33 ] to identify the maximum extension of the grazing area. To protect the grazing area from the intrusion of potentially infected animals, a minimum safe convex polygon (MSCP) was constructed around the centroid of each farm by enlarging the MCP within the circular area with a radius of 5 km, which is assumed to be the home range for free-roaming canids [ 8 ]. On the perimeter of these surfaces, points for the delivery of the anthelmintic treatment were fixed. At each point, highly attractive baits laced with 125 mg praziquantel + 12.5 mg milbemicine [ 34 ] were manually disseminated at 2-month intervals, maintaining an average bait density of 20–25 baits/km 2 [ 35 ]. Every 2 months, praziquantel-laced bait application sites were advanced 50 mt on the MSCP to distribute the drugs evenly along the perimeter of the grazing area.

Statistical analysis

A multi-distance spatial cluster statistical analysis, based on Ripley's K-function, was implemented to investigate how the spatial dependence (clustering/dispersion) of sheep and dog point locations changed at different distances from the farm (0–3000 mt; distance increment: 100 mt) [ 36 ]. For each farm, t-test statistical analysis was conducted to establish whether there was a significant difference between the mean daily walking distances traveled by sheep and dogs. In addition, the distances of the point locations from the centroids of the farms resulting from the multiple ring buffer analysis were related to the temporal data to identify daily peak activity patterns of the animals; Pearson statistical analysis was conducted to test the significance of these spatio-temporal correlations. All statistical analyses were performed with IBM SPSS V.26 statistical software package. P  < 0.05 was considered statistically significant.

A total of 27 shepherd dogs were recorded on the five treated sheep farms, with an average of 5.4 dogs per farm (minimum 3–maximum 6). All dogs had received anthelmintic treatment with praziquantel at 2-month intervals. Taeniidae eggs were found in two fecal samples only in one sheep farm directly after the first treatment (T0) with praziquantel (mean EPG = 842), which did not correspond to E. granulosus s.s. but one to Taenia hydatigena and the other to T. pisiformis . Since T1 treatment, none of the fecal samples, analyzed every 2 months, tested positive for Taeniidae eggs.

Due to unstable network coverage, a total of 6973 point locations were recorded. Data were extracted from 13 of 15 GPS installed devices, since two collars (GPS installed on two shepherd dogs belonging to farms 1 and 5) became unusable during the study. The number of point locations acquired ranged from 285 to 642 for sheep and from 242 to 1204 for dogs.

In each sheep farm, > 90% of sheep and dog point locations were within 1500 mt from the centroid of the farm but the core areas of roaming space used for sheep and dogs were found to be within 500 mt (70%) (Table 1 ). These results were confirmed by multi-distance spatial cluster analysis, which reported the presence of statistically significant clusters of sheep and dog punctual positions over a range of 0–500 mt distance from the centroid of the farm, with a confidence envelope value equal to 99%.

Sparsely frequented zones were found in all grazing areas, alternating with zones of high density of point locations (Fig.  4 ).

figure 4

The spatial distribution of the point locations of sheep (red points) and dogs (blue points) logged by GPS dataloggers in the five studied farms. The multiple concentric buffer rings (100 mt) provide the measurement of the animal distance from the centroid of the farms

In the five sheep farms monitored, the extent of the home range areas of sheep and dogs was ≤ 250 ha; the farthest point locations recorded were 2004 mt and 2500 mt for sheep and dogs, respectively (Table 2 ).

No significant differences in the mean daily walking distance traveled by sheep and dogs were found across the examined farms. This distance ranged from 1028 to 1938 mt for sheep and from 1030 to 2430 mt for dogs ( P  > 0.05).

The t-test analysis conducted to test the difference between the mean daily distances traveled by sheep and dogs showed no significance ( P  = 0.7).

Spatial-temporal distributions of sheep and dog point locations

The analysis of the spatio-temporal profiles of sheep and dog point locations revealed that they were most active during daytime hours (06:00–18:00). Since in each sheep farm the point locations of the two collared dogs were not significantly different ( P  > 0.05), the data points of only one dog were compared to sheep data points for the construction of the spatio-temporal profiles.

All the examined farms were characterized by the same management of the grazing activity: out of the stable and start of the activity between 06:00 and 07:00 in the morning, greatest distances from the centroid of the farms generally covered during the 10:00–17:00 time slot and return to the farm between 17:30 and 18:00 (Fig.  5 ). Pearson’s test conducted on the spatio-temporal correlations of sheep and dog movement data showed low values in each farm analyzed (Pearson’s coefficient: 0.25–0.43; P  = 0.05). No significant differences in peak temporal activity periods between sheep and dog movements emerged.

figure 5

Example of spatio-temporal activity patterns produced by the positions of sheep (red triangles) and free-roaming owned dogs (blue circles). The point locations collected by GPS devices between 06:00 and 17:00 were classified according to the time of day (horizontal axis) and the distance from the centroid of the farm (vertical axis)

Figure  6 shows the home range (MCP) calculated for each sheep farm, considering sheep and dog point locations. The area with the highest risk of access from stray canids was estimated for each farm (MSCP), and a potential scheme for the delivery of praziquantel-laced baits was designed. The number of points for the delivery of the baits ranged from a minimum of 40 to a maximum of 70, depending on the extension of the MCP, and were positioned at a fixed distance of 100–200 mt.

figure 6

Home ranges of sheep and dogs estimated using minimum convex polygons (orange area). The points for the delivery of the medicated baits (yellow points) for the treatment of stray canids were fixed on the boundaries of the minimum safe convex polygon (pink polygons)

The present study has illustrated a comprehensive strategy for deworming owned and not owned dogs, developed and validated in a Mediterranean area highly endemic for CE. This strategy could be included in the control programs for CE with the final aim to significantly reduce the transmission of this parasitosis. Since the mid-nineteenth century, the public health importance of CE has been recognized, and considerable efforts have been made to reduce the disease [ 19 , 20 ]. However, despite the implementation of such control initiatives in several countries, CE remains a problem in the Mediterranean areas with a high rate of infection. One of the factors statistically associated with the perpetuation of CE in endemic areas is the presence of stray dogs and their free access to carcasses of intermediate hosts [ 37 ]. This was supported in this study, where E. granulosus was not detected in any shepherd dogs belonging to the five sheep farms with animals testing positive for CE, confirming the involvement of stray canids in the transmission of CE.

While the regular treatment of owned dogs using an effective cestocidal anthelmintic such as praziquantel is possible [ 38 ], as also demonstrated in this study, the treatment of free-roaming populations of unowned dogs is extremely difficult [ 15 ]. Thus, new sustainable tools for the treatment of stray canids are needed to implement CE control programs. In this regard, the control approach described here is based on a high spatial resolution analysis of the sheep and dog movements using innovative GPS dataloggers combined with traditional and innovative treatment strategies for owned and stray dogs, respectively.

In recent years, thanks to breakthroughs in GPS-based technologies, including improved precision, lower costs and greater battery efficiency, there has been growing use of these technologies to precisely collect large data sets on the positions of individuals in the landscape [ 39 ]. In particular, several studies have demonstrated the potential for using GPS tracking to study animal behaviors and their interaction with the environment, and how these affect parasite transmission [ 40 ]. In this regard, a preliminary analysis was done to define the movements of sheep and dogs, belonging to CE farms, and their spatio-temporal activity patterns. The results obtained showed that the distances traveled by collared sheep and shepherd dogs were comparable in terms of mean daily walking distance with a maximum value of 2.4 km. A much longer daily walking distance (13 km) was reported when, for example, dogs had to scavenge for food or follow owners in their daily commitments [ 41 ], as shown by Mutwiri et al. [ 42 ] in a study conducted with 10 free-roaming owned dogs collared with a GPS tracker in the pastoral communities of Kenya. Concerning the temporal activity of sheep and shepherd dogs, few data have been published yet. According to Sparkes et al. [ 43 ], in this study, sheep and dogs were active from 06:00–20:00 with a wide peak activity period in the middle of the day (10:00–17:00), in contrast to other studies [ 33 , 44 , 45 ] in which animals exhibited two peak activity periods during the day (07:00–10:00, 16:00–19:00), probably because of different management systems on the farms. However, in this study, the variability of animal space use across seasons was not estimated, since the movements of sheep and dogs were monitored only for 1 month. Further studies need to be undertaken to investigate the interplay between animal behavior and Echinococcus to effectively define strategies to mitigate parasite exposure.

The GPS point locations acquired were also used to construct the home ranges of the animals within the grazing areas. The home range was defined as bounded regions representing the areas used by the animals for some purpose with different rates of usage by individuals [ 39 ]. For almost all the farms (farms 1, 2, 3, 4 M) the home range areas of the collared animals did not differ significantly (mean = 168.4 ha, range = 51–250), except for farm 5 which showed a reduced extension of the home range (50 ha) probably due to fewer potential attractions (e.g. houses, farms) surrounding the grazing area. The mean home range resulting from this study was in accordance with the data published by Sparkes et al. [ 46 ] (mean = 290.1, range = 0.8–1776.2 ha). Moreover, collared shepherd dogs spent most of their time within a few meters of the farm centroids (10–500 mt), as reported for community dogs in western China (10–250 mt) [ 25 ] and roaming dogs of rural communities in southern Kyrgyzstan (11–931 mt) [ 47 ] as a confirmation of the fact that a fixed home base and food provided by owners reduces the movements of the dogs [ 46 ].

The estimation of sheep and dog home ranges proved very useful to design a scheme for the delivery of praziquantel-laced baits for the treatment of not owned canids gravitating around the farms. In a previous study conducted in the Autonomous Prefecture in Sichuan by Yu et al. [ 48 ], to deworm stray dogs and wild canines using praziquantel-laced baits, the area was divided in a mesh of 20 × 100 mt units, each containing a fixed point for bait delivery. In contrast, in this study, MSCPs were designed for the delivery of anthelminthic baits on the border zone of the study area; these boundaries follow the trends of flocks and were positioned sufficiently far from the home range areas (MCP) to avoid over-dosing of the shepherd dogs already treated. In general, it is suggested that in a bait-based strategy, spacing of baits should be within the radius of attraction to baits, i.e. the average distance between an animal’s home range centroid and bait sites that they visit [ 49 ].

The distribution of praziquantel-laced baits along the area adjacent to that of pasture could represent a good strategy to limit the intrusion of infected animals in the grazing area, considering that the targets of the treatment were mainly not owned canids gravitating around the sheep farms. As the life cycle of E. granulosus also includes wild species as definitive and intermediate hosts, application of praziquantel-laced baits against wild and stray canids could lead to a significant reduction in CE prevalence. In several European contexts, including the study area, it is well known that the life cycles of E. granulosus and other important cestodes often overlap with wildlife, resulting in somewhat semi-domestic life cycles [ 50 ]. It has also been shown that wild boar carcasses may contain many metacestode specimens, thus acting as an infection reservoir for a potentially large number of wild canids [ 51 ]. Another aspect that should be considered is the role of hunting dogs in the transmission of CE during hunting activities. Many wild boars are hunted in the study area, and a high prevalence of metacestodosis has been reported in wild boar populations [ 52 , 53 ], which could confirm the role of hunting dogs in maintaining a sylvatic cycle of CE and the importance of targeted treatments.

In several European countries, the distribution of praziquantel-laced baits for removing the adult form of E. multilocularis from wild canids, in endemic urban [ 54 , 55 ] and rural [ 56 ] areas, has already yielded encouraging results [ 57 ], showing a considerably lower contamination of foxes with Echinococcus eggs [ 57 ].

Although it has already been demonstrated that praziquantel baiting campaigns against E. granulosus with a frequency > 1 month are less effective because of the parasite’s prepatency period [ 56 , 58 ], in this study a 2-monthly frequency of treatment was proposed to test the efficacy of a control measure also applicable in less-developed countries, where the lack of economic and logistical resources makes the monthly treatment not sustainable.

The dissemination of the drug in the environment could be a problem for other animal species accidentally ingesting the baits and for the ecosystem itself. However, PZQ is a very safe drug, and overdosing or inadvertent treatment of nontarget species usually does not cause problems [ 15 , 59 ].

One of the main factors influencing the effectiveness of a baiting campaign is the use of attractive baits to ensure bait uptake by canids. Therefore, highly palatable praziquantel-laced baits, with double-layer coverage, were used in this study. Specifically, Ciccone et al. [ 34 ] showed that these types of bait are highly resistant over time (up to 10 days) and to different climatic conditions, preserving their palatability for dogs. Praziquantel-laced baits were at first manually released. The next step will be the use of unmanned aerial vehicles (UAVs), designed for the ECHINO-SAFE-MED project [ 60 ], for the delivery of baits to deworm stray canids as already tested by Yu et al. [ 48 ] in areas highly endemic for alveolar echinococcosis (AE) in China. This methodology has the potential to help cut cost and labor needs in areas highly endemic for echinococcosis and makes it possible to access hard to reach grazing areas. A limitation of this study is that the prevalence of E. granulosus was not determined before starting the treatment so there was no initial value with which to compare subsequent measurements.

An additional analysis to evaluate the extent of soil contaminated by E. granulosus eggs could be useful to obtain information about a potential reduction of exposure of sheep to infection by eggs released with feces in the environment. Recently, Da Silva et al. [ 61 ] showed that analyses of feces and soil complement each other to describe the contamination of vegetable gardens by E. multilocularis , with the advantage of being able to design soil sampling in advance, which reflects long-term contamination when feces are only a proxy assessing an instant indication of environmental contamination.

The present study confirms the usefulness of geospatial technology in supporting parasite control strategies and demonstrates that the collection of detailed data regarding the movements and the behavior of animals might be a useful method to interrupt the Echinococcus life cycle and to reduce the spread of the disease. The outcome of this approach will be evaluated for 4–5 years following the initiation of the activities through the assessment of (cystic) echinococcosis infection levels in sheep and dogs belonging to the selected farms (treated and controls).

The newly developed strategy could be part of an integrated control program against CE, combining anthelmintic dog treatment with livestock vaccination and public health information.

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Acknowledgements

Thanks to Marshall W. Lightowlers (Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Australia) and Peter Deplazes (Institute of Parasitology, Vetsuisse, and Medical Faculty, University of Zürich, Switzerland) for their support in the planning of the project. Thanks to Emanuele Bambacaro, Giuseppe Grande, Nicola Lattero, Giuseppe Mangieri and Pierluigi Quaranta for the research in field activities. In addition, thanks to Alessio Mirarchi (Language Centre—CLA, University of Naples Federico II) for English language editing.

This research was funded by: (i) the project “New sustainable tools and innovative actions to control cystic ECHINOcoccosis in sheep farms in the MEDiterranean area: improvement of diagnosis and SAFEty in response to climatic changes-ECHINO-SAFE-MED,” supported by PRIMA (Partnership for Research and Innovation in the Mediterranean Area) and (ii) the Regional Reference Centre for Animal Health (CRESAN), Campania Region, Italy.

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LR, MN and PP conceived and designed the study. MN and JP conducted data gathering. MN and PP performed statistical analyses. Writing—original draft preparation MN, PP, AB, EC, MPM, JP, YS, PL, MCA. Writing—review and editing: LR, FB, GU, SL, SS, AL, GS, OP. Supervision: LR. All authors have read and agreed to the published version of the manuscript.

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Nocerino, M., Pepe, P., Bosco, A. et al. An innovative strategy for deworming dogs in Mediterranean areas highly endemic for cystic echinococcosis. Parasites Vectors 17 , 86 (2024). https://doi.org/10.1186/s13071-024-06184-x

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  • Echinococcus granulosus
  • Control programs
  • GPS dataloggers
  • Geospatial data

Parasites & Vectors

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case study of echinococcosis

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Osseous cystic echinococcosis: A case series study at a referral unit in Spain

Roles Formal analysis, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing

* E-mail: [email protected] (BMM); [email protected] (RLV)

Affiliation National Referral Unit of Tropical Diseases, Infectious Diseases Department, Ramón y Cajal University Hospital, IRICYS, Madrid, Spain

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Roles Formal analysis, Investigation

Roles Investigation, Visualization

Roles Formal analysis, Investigation, Methodology

Roles Formal analysis, Investigation, Visualization

Roles Conceptualization, Formal analysis, Investigation, Methodology, Writing – review & editing

  • Begoña Monge-Maillo, 
  • María Olmedo Samperio, 
  • José Antonio Pérez-Molina, 
  • Francesca Norman, 
  • Carla Ruth Mejía, 
  • Sandra Chamorro Tojeiro, 
  • Rogelio López-Vélez

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  • Published: February 19, 2019
  • https://doi.org/10.1371/journal.pntd.0007006
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Fig 1

Cystic echinococcosis (CE) is present in all continents, except for the Antarctica. Characteristically, CE lesions are found in the liver and the lungs, but virtually any part of the body may be affected (the spleen, kidneys, heart, central nervous system, bones, among others). It is estimated that the incidence of bone involvement in CE is 0.5% to 4%.

Methodology

A retrospective study was performed of patients with osseous CE treated at the National Reference Unit of Tropical Diseases of the Ramon y Cajal Hospital, Madrid, Spain, between 1989 and December 2017. Epidemiological, clinical, diagnostic and therapeutic data of patients with long-term follow-up were collected.

Main findings

During the study period, of the 104 patients with CE, 27 exhibited bone involvement (26%). The bones most frequently affected were the spine, followed by the ribs, pelvis, femur, tibia and the scapula. The most common symptom was pain followed by medullar syndrome and pathologic fracture. In total, 81.5% of patients underwent surgery for osseous CE at least once. As many as 96% received albendazol either in (mostly long-term) monotherapy or in combination with praziquantel.

Conclusions

The diagnosis and management of osseous CE is challenging. In many cases osseous CE should be considered a chronic disease and should be managed on a case-by-case basis. Lifelong follow-up should be performed for potential recurrence and sequels.

Author summary

Echinococcosis occurs in humans as a result of infection by a cestodes of the genus Echinococcus . One of the species, E . granulosus , causes cystic echinococcosis (CE) in humans worldwide. In the lifecycle there is a definitive host (generally dogs) which host this parasites at the small bowel. From there, ground is shed with the eggs of the parasite through feces and the intermediate host (usually a sheep or other herbivores get infected). Humans act as an incidental intermediate host when they become infected through the consumption of water or food contaminated with Echinococcus eggs. Once the egg has been ingested, it penetrates the intestinal mucosa and through the circulatory system finds an anatomical site forming a cystic lesion (hydatid or hydatid cyst). Characteristically, CE are found in the liver and the lungs, but virtually any part of the body may be affected. Incidence of osseous CE is low, its diagnosis and management is challenging and there is little information published. In this study we report our experience at a referral unit during nearly 30 years in the management of a series of patients with osseous CE. Such information may be useful for other physicians when treating osseous CE.

Citation: Monge-Maillo B, Olmedo Samperio M, Pérez-Molina JA, Norman F, Mejía CR, Tojeiro SC, et al. (2019) Osseous cystic echinococcosis: A case series study at a referral unit in Spain. PLoS Negl Trop Dis 13(2): e0007006. https://doi.org/10.1371/journal.pntd.0007006

Editor: Francesca Tamarozzi, Istituto Superiore di Sanità, ITALY

Received: August 2, 2018; Accepted: November 19, 2018; Published: February 19, 2019

Copyright: © 2019 Monge-Maillo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interest exist.

Introduction

Echinococcosis occurs in humans as a result of infection by the larval stages of cestodes of the genus Echinococcus [ 1 ]. Four species pose a risk to human health, namely: E . granulosus species complex, (which is subdivided into E . granulosus sensu stricto, Echinococcus felidis , Echinococcus equinus , Echinococcus ortleppi and Echinococcus canadensis ) which causes cystic echinococcosis (CE) and occurs worldwide including tropical and subtropical regions [ 2 ]; E . multilocularis , which causes alveolar echinococcosis and is confined to the northern hemisphere; and E . vogeli which cause neotropical polycystic echinococcosis and E . oligarthrus which cause neotropical unicystic echinococcosis that only occur in Latin America. Several studies have shown that Echinococcosis present an increasing risk to public health and can be regarded as an emerging or re-emerging disease [ 3 ].

In CE, the lifecycle of the parasite involves two hosts: a) the definitive host–generally dogs, although other carnivores such as wolves, dingoes, hyenas can also host this parasite. Adult parasites attach to the mucosa of the small bowel through hooklets and suckers and, from there, ground is shed with the eggs of the parasite through feces. b) The intermediate host–usually a sheep or other herbivores such as goats, horses, camels or pigs, among others–gets infected by the ingestion of ground contaminated with the eggs of the parasite. Once the egg has been ingested, the embryo hatches and penetrates the intestinal mucosa, enters host’s circulatory system and develops in the vesicular metacestode when it finds a suitable anatomical site. This stage of the parasite is a unilocular, fluid-filled cystic lesion (hydatid or hydatid cyst). When the definitive host eats the viscera with the hydatid cyst, the cycle is completed. Humans act as an incidental intermediate host when they become infected with oncospheres through the consumption of water or food contaminated with Echinococcus eggs [ 4 ].

Cystic echinococcosis is present in all continents except for the Antarctica. It primarily occurs in the Mediterranean basin, the Middle East, central Asia, western China, the Russian Federation, Latin America and north and east Africa. The prevalence of CE may exceed 5%, with incidence rates of 50/100 000 person-year in some areas such as South America (mainly Peru and Argentina), east Africa (mainly Kenya) and Asia (mainly China) [ 3 , 5 ].

In Spain, only infections with E . granulosus have been identified. Human CE was a mandatory notifiable disease from 1982 to 1996, being an important anthropo-zoonosis in terms of incidence and morbidity [ 6 ]. In 1985, epidemiological data showed an incidence of CE of 2.5/100,000 per year, with nearly 1000 new cases every year. The incidence of CE progressively decreased from 600–700 new cases per year in the 1980s to 300–500 new cases/year in the 1990s. In 1997, the incidence of CE was 0.78/100,000 per year. This decrease was probably the result of national control programs mainly based on slaughterhouse hygiene, public education and the regular administration of praziquantel to dogs [ 7 ]. However, incidence rates might be underestimated. The reason is that CE stopped being a mandatory notifiable disease in 1996 and, since then, surveillance has been primarily carried out in the autonomous communities where CE is endemic. Underestimation of incidence was shown in an epidemiological study of CE in Spain in the 1997–2012 period based on data from a Centralized Hospital Discharge Database. Incidence rates were found to be higher than the ones reported in previous studies [ 8 ].

Characteristically, CE lesions are found in the liver (70%) and the lungs (20%), but virtually any part of the body may be affected (the spleen, kidneys, heart, central nervous system, or bones). Based on published data, it is estimated that the incidence of bone involvement in CE is 0.5% to 4% of all cases of CE [ 5 ]. Sixty per cent of cases of osseous CE have been reported in Europe (especially in Turkey, Germany and Spain) and the former Soviet Union [ 6 ]. CE usually affects a single bone and the most frequent site of bone lesions is the vertebral column (40%-50%), followed by large bones (25%-30%), the pelvis (15%-20%) and–less frequently–the cranium, sternum, scapula and the phalanges [ 9 , 10 ].

Published literature on the management of osseous CE–a rare manifestation of a neglected disease–is scarce. This article describes the symptoms and management of patients with osseous CE treated in the National Referral Unit of Tropical Diseases in Madrid with long follow-up and compare the results obtained with the ones reported in the literature. The objective of this study is to increase the knowledge on the management and evolution of this neglected tropical disease and to be of use a reference for other physician who have to manage patients with osseous CE.

Ethics statement: As this is a retrospective analysis, data were analyzed anonymously, and written informed consent was not required from patients. The database from which patients’ information was obtained was approved by the Ramón y Cajal Hospital’s Ethics Committee (Comité Ético de Investigación Clínica, CEIC, Hospital Ramón y Cajal) and was used in accordance with current laws in Spain (Ley Orgánica de Protección de Datos de Carácter Personal 15/1999) that guarantee personal data protection.

A retrospective study was performed of patients with osseous CE treated in the National Referral Unit of Tropical Diseases of Ramon y Cajal Hospital of Madrid, Spain between 1989 and December 2017. The data collected included: a) Epidemiological data: age at diagnosis, gender and epidemiological risk factors for CE infection; b) Characteristics of osseous CE: location–categorized as axial skeleton (spinal, ribs and pelvis CE), appendicular skeleton (only limbs) and others–; number of sites involved, and evidence of concomitant CE in other visceral or soft tissues. The Dew/Braithwaite & Lees classification was not included to describe the spinal CE cases because it was not considerate necessary for the purpose of this study. c) Clinical presentation by bone location. d) Diagnostic variables: how the disease was first diagnosed, specific serological test, and the presence (or absence) of eosinophilia. e) Treatment: antiparasitic treatment (drugs administered, duration and toxicity of treatment), surgical treatment and percutaneous treatment. f) Follow-up: mean follow-up, complications after surgery, clinical outcome and sequela.

A total of 104 cases of CE were managed during the study period, of which 27 corresponded to osseous CE (26%).

Epidemiological data

-Sixteen patients were male (59.2%).

-The average age at diagnosis was 36 (IQR 24–62 years) being three patients under 20 years-old.

-All patients had lived in rural regions of Spain for a long time. Yet, exposure was limited to childhood in a case and to summer vacations in the second.

Characteristics of osseous CE

-In total, 44 bone sites were identified in the 27 patients with osseous CE.

-Twelve patients had only a bone involved; another 12 patients had two bones affected, and three patients had three or more bones involved. Therefore, more than half of patients had two or more bones affected by CE. The bones most frequently involved were the spine (17), followed by the ribs (11), pelvis (6), femur (5), tibia (2) and the scapula (1) ( Fig 1 ).

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- In the 17 patients with spinal osseous CE, lesions were located in the thoracic spine in eight patients (47%), the thoraco-lumbar spine in three (17.7%), the lumbo-sacrum spine in three (17.7%), the lumbar spine in one (5.8%), the sacrum in one (5.8%), and the thoraco-lumbo-sacral spine in a patient (5.8%).( Fig 2 ).

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-Twelve of the patients had concomitant extraosseous CE: four in the lungs, two in the liver and six in both, the lung and the liver.

Clinical presentation by bone location

-The most frequent clinical presentation was pain, which was reported in 16 patients (59.2%): seven located in the spine, six in the pelvis, two in the ribs and one in the scapula, followed by medullar syndrome in 10 patients (37%) all located in the spine. A patient had a pathologic fracture (3.7%) in the femur.

Diagnostic variables

-The disease was first diagnosed by radiology (plain X-ray, computed tomography or magnetic resonance) in 18 patients (66.7%), surgery on suspicion of another illness in seven patients (26%), or by a biopsy of the lesion on suspicion of a bone tumor in two patients (7.4%).

-Serology (IHA followed by ELISA) was performed in 17 patients, with heterogeneity of the serology tests employed a long the study period, with 10 (59%) positive results.

-A hemogram was performed to all the patients. Six patients were positive for eosinophilia (22.2%).

Treatment characteristics

-Antiparasitic treatment: of the 27 patients included, 26 received antiparasitic therapy with albendazole 400mg/12 hours. A total of 18 received continuous long-term treatment with albendazole for an average of six years (IQR 0.25 to 16 years). Another seven patients received albendazole discontinuously for long periods. In a patient, treatment with albendazole was interrupted due to side effects. Sixteen (59.3%) patients were administered a combination therapy of albendazole plus praziquantel 600mg/8 hours for an average of five years (IQR 4 months to 15 years). Five patients with spinal involvement received a combination therapy with albendazole plus praziquantel plus nitazoxanide 500mg/12 hours. The duration of this combination therapy was four years in two patients and one year in a patient. Two patients were lost to follow-up and no data were available on the duration of treatment. Despite the long duration of antiparasitic therapy, tolerability was good. In fact, most patients had received antiparasitic drugs (Albendazole +/- Praziquantel) for more than 10 years on average with no side effects. A slight increase in transaminases was reported in seven patients, although treatment discontinuance was not required. Treatment had to be stopped due to side effects in only three patients: a patient developed alopecia and oral ulcers due to albendazole; another patient manifested angioedema under praziquantel treatment; and a patient developed exanthema during nitaxozanide treatment.

-Surgery: Twenty-two patients (81.5%) underwent at least a surgical intervention for osseous CE, none of which was curative. The average number of surgical interventions per patient for osseous CE by body site was: 10.2 (ranging from none to 32 interventions per patient) times for pelvic CE; 3.95 (ranging from 1 to 10 interventions per patient) times for spinal CE, 2.00 times for femur CE, and 1.00 time for rib CE ( Table 1 ). In patients with spinal CE, the most common intervention was laminectomy. Eight patients needed surgical fixation. Total limb amputation was performed in two of the six patients with pelvic CE, and another two needed iliac osteotomy. Patients with femur CE required bone resection and prosthesis.

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-Percutaneous treatment: the PAIR technique (Puncture, Aspiration, Injection and Re-aspiration) was used in four patients. In three cases, puncture was in patients with CE in soft tissues next to osseous CE sites (two in the spine and one in the ribs). In the fourth patient, PAIR was performed for spinal decompression. Initially, neurological symptoms improved, but the patient ultimately relapsed.

-The average duration of follow-up was more than 20 years. Distribution of duration of follow up was: < 5 years follow up: 4 patients; 5–10 years follow up: 1 patient; 10–20 years follow up: 7 patients; >20 years follow up: 15 patients.

-Twenty-six episodes of complications associated with surgery were reported, being secondary bacterial infection the most frequent (16). A patient had the fixation material broken, another had iliac thrombosis and one died due to probable infectious abscess in the surgical area and respiratory infection three months after surgery ( Table 1 ).

-The most frequent sequels in spinal CE was medullary syndrome (13 patients) and severe pain (3 patients). Two patients with pelvic CE had a limb amputated and another patient developed severe functional disability. In patients with rib CE and femur CE, the most frequent sequel was severe residual pain.

-Despite surgery and long-term antiparasitic treatment, 25 of the 27 (92.6%) patients ultimately relapsed. Recurrence was not reported in two patients. Yet, these patients had been recently diagnosed patients and only had one-year follow-up.

Osseous CE is a rare location of hydatid diseases. In fact, 29 years of study were needed to get 27 cases. However, the prevalence of osseous CE among all cases of hydatid disease in this study was much higher than the one reported in the literature (26% vs 0.5%-4%) [ 11 ]. This may be due to the fact that our center is a referral unit of tropical and parasitological diseases, where less frequent o more complicated infectious diseases are managed.

The average age at diagnosis in our sample was 36 years mostly affecting men. This is consistent with the results of other series, where osseous CE was found to mostly occur in immunocompetent men with a median age of 37 years (peak age of disease is 21–40 years) [ 10 , 12 ].

According to the literature, osseous CE prevailingly invades the spine (45%), pelvis (14%), femur (10%), ribs (8%), humerus (2%), and less frequently other sites as the cranium, sternum, scapula and the phalanges [ 10 , 11 , 13 , 14 ]. This supports our results, except for the fact that, in our study, the ribs were more frequently affected than the pelvis or the femur, being rib involvement generally associated with spine involvement. As reported in the literature, in our series multifocal osseous involvement was prevailingly observed in patients with spinal echinococcosis, being the thoracic and lumbar spine the sites most frequently involved [ 1 ]. In fact, when several bones are affected, spread usually occurs by direct propagation, which would explain that most multifocal osseous sites were associated with spinal and rib involvement.

Osseous CE can remain asymptomatic for long due to its slow growth inside the bones. When symptoms appear, pain is the most frequent followed by pathological fracture, functional impairment or local swelling. Based on our data, nearly 60% of patients presented with pain. However, when the spine is involved, the most common symptoms are those associated with spinal cord compression or vertebral bone destruction [ 1 ] as it was observed in our series, where medullar syndrome was the second most frequent symptom. The symptom of spine CE may vary depending on the localization of the cystic which has been classified on five types (Dew/Braithwaite & Lees classification): type 1, medullar; type 2, intradural; type 3, extradural; type 4, vertebral; and type 5, paravertebral [ 15 , 16 ].

In most of our cases, diagnosis was performed by radiology with computed tomography or magnetic resonance. In patients with epidemiological risk factors, radiological findings are the most common initial signs suggestive of osseous CE. However, differential diagnosis with bone tumor, infection or inflammatory disease is required. Diagnosis based on radiological scanning is challenging, as there are no specific radiological findings for osseous CE. Generally, the most common findings are a single or multiple extensive osteolytic lesion containing trabeculae with cortical thinning. In other cases, pathological fractures with a periosteal reaction or lesions with calcification in neighboring soft tissues due to proximal spread can also be found [ 17 , 18 ]. In the spine, lesions can be described as a “bunch of grapes”. In this case, it is important to determine if there is neurological involvement or not. Initially, lesions are located at the vertebral body, but it can affect the canal, the perirachial space, the ribs or neighboring vertebrae [ 19 ].

Serology was performed in 63% of patients, although different testing techniques were used over the long period of study. This is important, because the sensitivity of serology can vary depending on the serological test employed [ 20 – 23 ]. Yet, the sensitivity of serology also depends on the integrity of CE and its location. In osseous CE, serology may be more sensitive due to the absence of a fibrous capsule and the contiguity of cyst CE to the tissues. Yet, the specific sensitivity of serology in these cases is unknown. In our series, we obtained a 60% sensitivity (taking into account the heterogeneity of the serology tests employed and the localization of osseous CE).

In some cases, uncertainty about diagnosis and the urgent need for differential diagnosis with bone tumors led to a surgical procedure for confirmation of diagnosis. However, except for cases where surgery is a therapeutic option, surgery and also the aspiration of the cyst must be avoided due to the risk for potential local dissemination, sensitization or even anaphylaxis [ 24 ]. Unfortunately, in many cases this cannot be avoided. In our series, 26% of patients underwent surgery on suspicion of another illness, and aspiration for anatomopathological diagnosis was performed in 7.4%.

Regarding therapeutic options, we found that more than 80% of patients underwent surgery, although complete curative results were not achieved. It is known that the only real curative approach for osseous CE is radical resection surgery. Yet, this is rarely possible, especially when the axial bone-spine, the pelvic bone or the femur are affected [ 14 ]. Several interventions are generally required, as observed in our series and in other series previously published [ 10 ]. In long bones, osseous CE can occasionally be completely resected with severe sequels from the potential amputation of the limb [ 25 ]. When osseous CE affects the pelvis, prognosis may depend on whether the coxo-femoral or the sacroiliac joints are affected or not [ 26 ]. When these joints are affected, complete resection may not be possible or cause severe functional disability. In our series, two of the six patients with pelvic CE needed total limb amputation and two required an iliac osteotomy.

In spinal CE, the type of surgery will depend on the location and extent of the disease. The primary purpose of surgery is decompression and stabilization of the spinal cord. Decompression is generally performed by laminectomy [ 27 , 28 ]. In our series, the most common interventions for spinal osseous CE were laminectomy and surgical fixation.

As surgical treatment is challenging, in most cases a combined treatment based on surgery and long-term antiparasitic therapy is the therapy of choice. In our series, apart from surgery, 96% of patients received albendazole. Adjuvant medical therapy can be given preoperatively and/or postoperatively to control the disease locally and prevent systemic spread and recurrence. In other cases, antiparasitic drugs are the only therapeutic option when surgery is not possible or involves severe risk or sequels [ 29 ]. However, there is no consensus on how antiparasitic drugs must be administered, whether therapy must be administered in combination or not, or the duration of treatment. Most authors suggest that when surgery is not curative or osseous CE is inoperable, medical treatment must be lifelong to control cyst growth [ 19 ]. In our series, the duration of therapy in patients who received albendazole was long, with an average of six years, reaching in some cases 16 years of medical treatment.

Albendazole was the first therapeutic option, as recommended in the literature [ 30 ]. The role of praziquantel in CE has not been well defined and there is insufficient data to support a clear recommendation for the use of praziquantel in prolonged chemotherapy [ 31 ]. Praziquantel seems to have a synergistic effect by increasing albendazole plasma levels and there is some evidence to support a role for the use of praziquantel in combination with albendazole during surgery or percutaneous procedures [ 31 – 33 ]. Although there is no consensus on when combination therapy must be administered, it has been given when the patient does not respond to albendazole alone [ 27 ]. In our series, due to the severity of some cases, mainly those suffering from spinal CE, or those with inoperable or non-responding lesions, nearly 60% of our patients received combination therapy of albendazole plus praziquantel.

Five patients with spinal osseous CE were treated with albendazole plus praziquantel plus nitazoxanide. Nitazoxanide has shown to be active in vitro and in vivo against E . multilocularis and E . granulosus . Yet, its possible effectiveness seems to be better when it is given in combination with other antiparasitic drugs reporting best results for nitazoxanide in combination with albendazole [ 34 – 36 ]. Our data on osseous CE and disseminated CE have been published elsewhere. We found that the combination of nitazoxanide with albendazole +/- praziquantel is effective for disseminated CE involving soft tissue, muscle or viscera. However, this combination therapy was not effective for chronic and extensive osseous lesions [ 37 ].

Patients with osseous CE require long-term follow-up for potential recurrence and possible complications or sequels associated with surgery or antiparasitic therapy [ 10 ]. Because a curative therapy is rarely feasible, follow-up is lifelong. In our series, the average duration of follow-up exceeded 20 years, and during that time nearly 93% of patients relapsed. Surveillance must be based on clinical data and radiology. As recurrence cannot be confirmed by serology, it is not used for follow-up [ 4 ]. The most common sequels reported in our series were medullary syndrome and severe pain in spinal CE. In pelvic CE, limb amputations and other severe functional disabilities were described. In patients with rib CE and femur CE, the most frequent sequel was severe pain. This is consistent with the literature, where persistent pain, fractures, paraplegia in spine CE or even death due to progression of the disease have been reported as frequent sequels and complications of osseous CE [ 10 ].

A strength of this study is that it includes patients with long-term follow-up. This offers a global vision of the evolution of osseous CE over time. However, the low incidence of osseous CE and the heterogeneity of cyst sites make it difficult to establish a diagnostic or therapeutic protocol based on our results. One possible limitation of this series is that it may provide information only about those most complicated cases of osseous CE, which are more frequently refereed to reference units.

This article reports experience with the management of osseous CE in a referral unit of tropical and parasitic diseases in Spain. Fortunately, the incidence of osseous CE is low, but its diagnosis and management is highly challenging. Diagnosis must be based on a combination of indicators based on clinical symptoms, radiological findings and serological results. In most cases, osseous CE must be considered a chronic disease, since complete surgical resection is unlikely and antiparasitic drugs are rarely curative. The absence of protocols for the management of this disease and its low prevalence force physicians to approach the disease on a case-by-case basis. Additionally, osseous CE requires long-term follow-up for recurrence and possible sequels.

Supporting information

S1 table. locations of osseous cystic echinococcosis based on a single or multiple bones affected..

https://doi.org/10.1371/journal.pntd.0007006.s001

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Textbook of Parasitic Zoonoses pp 353–368 Cite as

Echinococcosis

  • Subhash Chandra Parija 4 &
  • S. Pramodhini 5 , 6  
  • First Online: 25 September 2022

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Part of the Microbial Zoonoses book series (MZ)

Echinococcosis, denotes a parasitic zoonosis disease caused by both the adult and larval stages of the tapeworm of the genus Echinococcus . Most commonly, Echinococcusgranulosus causes cystic echinococcosis in humans with the other members like Echinococcusmultilocularis , Echinococcusvogeli and Echinococcusoligarthrus inflicting with alveolar and neotropicalechinococcosis, respectively. Cystic echinococcosis is worldwide in distribution. The life cycle of E. granulosus commonly involves sheep as the intermediate host and dogs as the definitive host. Humans are an accidental intermediate host, they acquire the infection by ingestion of the food, water contaminated by the eggs or by direct contact with the animals. Echinococcosis treatment is often complicated which requires extensive surgery and prolonged drug therapy. Alveolar echinococcosis, caused by E. multilocularis , is characterized by metastatic spread of infections with unprecedented outcomes. Neotropicalechinococcosis caused by the other two species ( E. vogeli (polycystic) and unicysticechinococcosis Echinococcusoligarthrus is an emerging infection. Preventive measures include deworming of dogs, the definitive hosts and in addition to it, slaughterhouse hygiene and public education should be done to combat cystic echinococcosis.

  • Hydatid disease
  • Alveolar echinococcosis
  • Neotropicalechinococcosis

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Department of Microbiology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India

Abhijit Chaudhury

A 43-year-old woman presented with acute onset of severe right upper quadrant abdominal pain of 7 days duration. The patient complained of severe cough associated with haemoptysis, wheezing, fever and malaise. History of loose stools and weight loss was also elicited. She gave a history of close contact with dogs. Her serological assay showed positivity for hydatid cyst antibody (IgG). On chest X-ray, a lesion was noted in the inferior right lobe of the lung with calcified shell and her abdominal CT demonstrated multiple cysts in the liver, which confirms the presence of multi-organ echinococcosis.

What are the suggestive clues from the clinical history?

What are the serological assays available?

What could be the species involved?

How would you proceed for the definitive diagnosis?

Research Questions

Preventive measures in the control of infection transmission are the major hindrance due to the role of wild animals in the life cycle of this parasite which is more often influenced by climatic changes and landscape.

Another major challenging issue in near future is developing a safe and effective vaccine by defining an optimum target in the definitive host to interrupt the transmission cycle of Echinococcus .

Newer drug discovery to overcome the limited efficacy of current drugs.

Transcriptomic and genetic deciphering of the complex life cycle events.

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Parija, S.C., Pramodhini, S. (2022). Echinococcosis. In: Parija, S.C., Chaudhury, A. (eds) Textbook of Parasitic Zoonoses. Microbial Zoonoses. Springer, Singapore. https://doi.org/10.1007/978-981-16-7204-0_33

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Montclair SCM Student Team Celebrates Rich Diversity of Campus in Month-Long Campaign for National Case Study Competition

Posted in: School of Communication and Media News

Students holding up flags from around the world, while smiling and standing and sitting in two rows.

A team of Montclair State School of Communication & Media students have created Montclair Culturs , a month-long campaign designed to educate, celebrate, and spotlight the diverse and rich cultural stories of our campus community. This effort is part of the prestigious national Bateman Case Study Competition, hosted by the Public Relations Student Society of America (PRSSA), whereby student teams must design, implement, and measure a public relations campaign to support the goals of a real-world client. 

This year’s client is Culturs , a global lifestyle network that enhances community and fosters human connection between cross-cultural populations including racially and culturally blended individuals. The missing “e” in Culturs represents the often-hidden diversities of these populations. 

The team conducted extensive research to discover the insights that were then used to plan and execute the robust on and offline campaign.  Their findings highlighted that more than half of students who identify as multi-ethnic have felt out of place or not fully belonging to one culture; and that 60% of respondents felt their culture was represented on campus but didn’t feel fully seen or heard.  

A team of six students and faculty sitting in two rows, smiling and dressed professionally.

The Montclair Culturs campaign set out to establish an inclusive community that celebrates cultural diversity through engaging conversations and shared learning experiences, fostering a deeper understanding and appreciation of multiculturalism.

Anchored by a robust Instagram account, the campaign featured the following initiatives:

  • The Melting Pot Meals :  a collaborative digital and printed cookbook featuring Montclair students sharing cultural dishes from around the world and the significance of these recipes.
  • Cultur-ella: Inspired by Coachella, the team hosted a festival celebrating the cultures of Montclair State through dance, music, and art. The more than 300 attendees made cultural bracelets, danced alongside the LASO dance troupe, Montclair West African Drumming, and influencer Jerseyy Joe, and also learned about the many cultural organizations on campus including Daughta Speaks, the Dominican Student Organization (DSO), the Korean Culture and Language Association (KCLA), the Latin American Student Organization(LASO), the Mexican-American Student Association (MASA), and the Veteran and Military Resource office.
  • Cultural Print: More than 500 people took the pledge to embrace cultural diversity and shared their personal cultural print on our world map representing their heritage and ethnicities.
  • Living in Full Color: An Intimate Conversation on Culture:   a curated conversation with NBC and Telemundo, Montclair faculty and students on multiculturalism and 21st-century diversity.  Kicked off by Provost Junius Gonzales and hosted by Associate Provost for Hispanic Initiatives and International Programs Katia Paz Goldfarb, the event featured WNBC reporter Checkey Beckford and Telemundo 47’s Ashley Chaparro, Yessi Hernandez and Alexa Rodriguez.  

A group of nine people in two rows, dressed professionally. Two are kneeling in the front and seven are standing behind them.

The Montclair Culturs campaign was developed by five SCM students: Riana Cafaro (’24), Gabriella Castillo (’24), Diana Ochoa (’24), Kaylee Seitz (’25) and Gina-Marie Zoccoli (’25). Professor Mary Scott served as the faculty advisor for the third consecutive year and SVP Communications at United Entertainment Group Heter Myers served as the industry advisor.  

The team will conclude the campaign on March 5 th and create a submission for the national judging panel.

Watch CBS News

Attorneys for Trump, Fani Willis spar at final hearing over removing district attorney from Trump Georgia case

By Melissa Quinn, Jared Eggleston

Updated on: March 1, 2024 / 5:04 PM EST / CBS News

Atlanta  — Whether Fulton County District of Attorney Fani Willis should be removed from the  Georgia election interference case  against former President Donald Trump and his co-defendants is now up to the Fulton County judge overseeing the matter, who said he would make a decision within the next two weeks.

At the three-hour proceeding before Superior Court Judge Scott McAfee, attorneys for each side presented legal arguments for and against disqualifying Willis from the case over her romantic relationship with special prosecutor Nathan Wade.

It capped a series of extraordinary hearings following allegations from Michael Roman , a GOP operative charged along with Trump, that Willis and Wade had an "improper" romantic relationship, and that the district attorney financially benefited from it. Trump and seven others joined Roman's effort to disqualify Willis, Wade and her office from prosecuting the racketeering case against them, and are seeking to have the charges against them dismissed.

Prosecutors and defense attorneys gathered in the Atlanta courtroom to present their closing arguments to McAfee. Wade was attendance for the entirety of the hearing, while Willis sat at the prosecution's table to watch Adam Abbate, who works in her office, give his presentation.

The judge did not issue a decision from the bench, saying he has several legal issues to sort through and factual determinations to make before issuing a ruling.

Fulton County District Attorney Fani Willis looks on during a hearing on March 1, 2024, in Atlanta.

"If this court allows this kind of behavior to go on and allows DAs across the state by its order to engage in these kinds of activities, the entire public confidence in the system will be shot and the integrity of the system will be undermined," said John Merchant, a defense attorney representing Roman who opened the arguments for the defendants.

Abbate said there has been "absolutely no evidence that the district attorney has benefited at all," or would benefit in the future, from the prosecution of the case.

Roman claimed that the relationship between Wade and Willis began before she hired him as special prosecutor in the case against Trump in early November 2021. The two admitted in a court filing that they did have a personal relationship, but said it started in 2022.

Both Willis and Wade testified during evidentiary hearings  last month and divulged personal details about their relationship, financial affairs and travels to places like Napa Valley, Belize and Aruba. During several hours on the witness stand, Willis forcefully defended herself from accusations she acted improperly and financially benefited from Wade's hiring.

Defense attorneys claimed that Wade paid for hotel rooms, cruises and getaways, though both prosecutors said they split the costs associated with their travels and that Willis often reimbursed Wade in cash. To demonstrate that Willis typically used cash to cover expenses, on Tuesday prosecutors filed an affidavit from Stan Brody, who worked at a winery in Napa that she and Wade visited last year . Brody asserted that Willis paid $400 in cash for two bottles of wine and a tasting.

The district attorney had accused Ashleigh Merchant, Roman's attorney, of spreading lies and "salacious" rumors.

"You've been intrusive into people's personal lives," Willis said during her testimony Feb. 16. "You're confused. You think I'm on trial. These people are on trial for trying to steal an election in 2020. I'm not on trial, no matter how hard you try to put me on trial."

Friday's hearing

Fulton County Superior Judge Scott McAfee presides during final arguments in the District Attorney Fani Willis disqualification hearing at the Fulton County Courthouse on March 1, 2024, in Atlanta.

Defense attorneys representing Trump and his co-defendants were given 90 minutes to make their arguments for why Willis and Wade should be disqualified. Abbate, the prosecutor, had the same amount of time to present the district attorney's case. 

During his presentation, John Merchant accused Willis of developing a financial interest in the case in violation of the rules of professional conduct, which "created the appearance of unfairness by setting a prosecutorial relationship with her boyfriend that she had been dating for two years, according to the testimony."

Though Wade and Willis testified that they split expenses related to their trips, John Merchant said Willis received a benefit of roughly $9,200 that cannot be accounted for. He accused the district attorney of "intentionally" crafting a scheme to benefit Wade.

"She put her boyfriend in the spot, paid him and them reaped the benefits from it," John Merchant said. "She created the system and then didn't tell anyone about it."

He said that if McAfee finds that Wade and Willis' relationship began in 2019 — roughly two years before his appointment as special prosecutor — and Wade's hiring was improper, it undermines the indictment charging Trump and his co-defendants. 

Attorney John Merchant looks on during a hearing in Fulton County Courthouse on March 1, 2024 in Atlanta.

Both Steve Sadow, who is representing Trump, and Craig Gillen, another defense lawyer, accused Willis of engaging in misconduct when she delivered a speech at a church in January, shortly after the allegations about her relationship with Wade were made public. Though Willis did not mention Wade by name, she defended his qualifications and suggested that racism was behind the claims. 

Gillen and Sadow said the speech was designed to prejudice potential jurors against the defendants.

"She chose to inject race into the minds of the listeners, and virtually everybody in this community and literally everyone in this country has reviewed and analyzed that speech that she made in a premeditated way," Gillen said.

Sadow argued that Willis and Wade have the strongest motive to lie about the start of their relationship.

"Who has the best motive of anyone to lie? They do. Who has the most at stake to lie? They do. Who wants to stay on this case, for whatever the financial reason may be? They do," he said.

Citing records from Wade's cellphone that were obtained by the defense, defense attorney Richard Rice suggested they communicated extensively throughout 2021.

"I don't even think lovestruck teenagers communicate that much," he said.

Rice also told McAfee that the two "have some difficulty expressing the truth when it comes to their relationship and these cases." Wade, he claimed, lied in filings submitted in his divorce proceedings. He accused Willis of falsely certifying on ethics forms that she had not received gifts worth more than $100.

"It defies imagination that she could somehow forget about all these trips, all these dinners, all these day trips," Rice said.

Harry MacDougald, who is representing former Justice Department official Jeffrey Clark, claimed that Willis and Wade have made the Fulton County District Attorney's Office "a global laughing stock because of their conduct." 

Abbate argued that the defense fell short of meeting the standard required to disqualify Willis and accused the opposing side of making "material misrepresentations." He called testimony from Robin Yeartie, a former longtime friend of Willis, "at best inconsistent," and said the defendants misstated the law about what is required for the district attorney and her office to be removed from the case.

No evidence was produced during the earlier evidentiary hearings that showed the defendants' constitutional rights were affected by Wade and Willis' relationship, Abbate said. He reiterated that their romantic relationship began in March 2022, and said Willis repaid Wade for her share of their travel and trips.

McAfee, though, said it is no longer "speculation and conjecture" that there was a personal relationship between the prosecutors, and that money changed hands. "Where the ledger stands" may still be an open question, the judge said.

But Abbate said it is still unproven that Willis benefited financially from the relationship, and he accused defense attorneys of attempting to "harass and embarrass" her by invoking a tax lien unrelated to the proceedings.

The relationship timeline

The timeline surrounding Willis and Wade's relationship has emerged as a crucial issue in the effort to kick the district attorney and her office off the case. Yeartie claimed the relationship with Wade pre-dated his appointment on Nov. 1, 2021. Yeartie testified that she witnessed the couple being affectionate with one another.

State of Georgia v. Donald John Trump, in Atlanta

Defense attorneys also questioned Terrence Bradley, Wade's former law partner and divorce attorney, about his communications with Wade and text messages he exchanged with Ashleigh Merchant about the relationship between the two prosecutors before she filed a motion exposing their private dealings.

After asserting attorney-client privilege while testifying twice last month, Bradley was called back to the stand at a hearing Wednesday. He said he had been "speculating" when he told Ashleigh Merchant in a message that the relationship between Wade and Willis started before Wade's hiring. Bradley repeatedly said he had no direct knowledge of when it began.

Prosecutors sought to discredit both Bradley and Yeartie. They revealed during the evidentiary hearing last month that Bradley left the firm he shared with Wade following an accusation of sexual assault. Bradley forcefully denied the allegation, and said earlier this week that he has not spoken to Wade in more than a year.

Lawyers with the district attorney's office also said Yeartie left her job there on poor terms after she was told she could either resign or be terminated. Willis testified last month that she has not spoken with Yeartie for more than a year, and said she "betrayed" their friendship.

Abbate continued working to undermine Bradley and Yeartie's credibility during his closing arguments, calling them both "disgruntled."

Bradley in particular, he said, was "vengeful" and a "speculator" who had reason to lie about Willis and Wade's relationship because he has "disdain" toward his former law partner after he was expelled from their law firm following the sexual assault allegation.

The controversy over Willis' romantic relationship with Wade has cast a shadow over the prosecution involving Trump and derailed the case for several weeks. Trump and his allies face charges over alleged efforts to overturn the results of the 2020 presidential election in Georgia. Several original co-defendants have taken plea deals, while the remaining defendants have all pleaded not guilty . 

Heading into Friday's hearing, there were lingering disputes over evidence that both sides have sought to admit. Defense attorneys want McAfee to admit Wade's cellphone data as evidence, claiming it shows he was in the vicinity of a condo Willis rented from Yeartie in Hapeville, south of Atlanta, at least three dozen times in 2021. They said testimony about location data from Wade's phone show that he was near Willis' condo late at night and into the early morning hours in the months before he was tapped as special prosecutor.

Prosecutors have also said Brody, who worked at the Napa winery that Wade and Willis visited, is available to testify Friday if the court declines to accept his affidavit.

McAfee said at the start of the hearing that he was ready to hear the legal argument regarding what prosecutors and defense attorneys have already presented and said he may be able to make a decision without the cellphone records and testimony from Brody. The judge did not rule out further proceedings for admitting the additional information.

Melissa Quinn is a politics reporter for CBSNews.com. She has written for outlets including the Washington Examiner, Daily Signal and Alexandria Times. Melissa covers U.S. politics, with a focus on the Supreme Court and federal courts.

More from CBS News

Read the Supreme Court's opinion in the Trump ballot eligibility case

Trump, special counsel at odds in Florida over future of documents case

Allen Weisselberg, former Trump Organization CFO, pleads guilty to perjury

Poll: Voters remember Trump's economy as good, boosting Trump to lead over Biden

IMAGES

  1. (PDF) The Medical Treatment of Echinococcosis

    case study of echinococcosis

  2. Overview on Echinococcosis

    case study of echinococcosis

  3. Overview of Case Reports of Rare Echinococcosis Cyst Localizations

    case study of echinococcosis

  4. Cystic echinococcosis in a child

    case study of echinococcosis

  5. Echinococcosis of the liver

    case study of echinococcosis

  6. Echinococcosis

    case study of echinococcosis

VIDEO

  1. XXIX World Congress on Echinococcosis in Bishkek, Kyrgyzstan 1

  2. Echinococcosis Part 2

  3. Alveolar Echinococcosis🤔Echinococcus multilocularis👍Parasite 👍Parasitology👌🔬✅

  4. Echinococcus granulosus (Hydatid disease)

  5. Class echinoidea

  6. parasitology lec 9

COMMENTS

  1. Acute Echinococcosis: a Case Report

    We report the case of a 69-year-old man with acute pulmonary echinococcosis. A computed tomographic scan of the thorax revealed the presence of multiple nodules in both lungs, and laboratory tests showed eosinophilia and the presence of antibodies against Echinococcus granulosus.Therapy with albendazole led to resolution of the pulmonary nodules and a normalization of the white cell count.

  2. Osseous cystic echinococcosis: A case series study at a referral unit

    Several studies have shown that Echinococcosis present an increasing risk to public health and can be regarded as an emerging or re-emerging disease . In CE, the lifecycle of the parasite involves two hosts: a) the definitive host-generally dogs, although other carnivores such as wolves, dingoes, hyenas can also host this parasite.

  3. Pulmonary cystic echinococcosis: A case report from tertiary care

    Human echinococcosis is caused by larval forms (metacestodes) of the tapeworm of the genus Echinococcus. Human infection is acquired from ingestion of the parasite eggs from infected animals. Echinococcus granulosus causes cystic echinococcosis in humans. This relatively benign parasitic disease is characterized by slowly growing cysts most ...

  4. CDC

    This was a case of echinococcosis. Diagnostic morphologic features shown included: presence of protoscoleces, which are easily identifiable by the refractile hooklets ... Images presented in the dpdx case studies are from specimens submitted for diagnosis or archiving. On rare occasions, clinical histories given may be partly fictitious.

  5. Twenty-six years of involvement with cystic echinococcosis: a case

    The current case study demonstrates the importance of a suitable surgical approach, adequate intraoperative prophylaxis to prevent cyst rupture, and prolonged complete paraplegia. Spinal hydatidosis, a zoonotic disease caused by infection with Echinococcus spp. larvae, is rare, but its treatment remains a significant medical challenge.

  6. Echinococcosis

    In the case of cystic echinococcosis preventive measures also include, deworming dogs, slaughterhouse hygiene, and public education. ... The study assessed the prevalence of the disease among rural populations in the three countries. In the Americas, a cystic echinococcosis control manual was produced by the Pan American Health Organization ...

  7. Past and present of diagnosis of echinococcosis: A review (1999-2021)

    In this systematic review, we describe diagnosis, and the species (human, canids, livestock, and small rodents) affected by cystic (CE) and alveolar echinococcosis (AE). From 1999 to 2021, we searched the online directory through PubMed, SCOPUS, Web of Science, and google scholar. Among the 37,700 records found in the online databases, 187 ...

  8. A young woman from an

    Cystic echinococcosis is a zoonotic infection caused by Echinococcus granulosus. This case report shows the difficulty in differential diagnosis in a patient with highly suspected hydatid disease. A 29-year-old Chinese woman presented with progressive abdominal distension. Imaging results revealed a large multicystic tumor with typical features of hydatid disease.

  9. Echinococcosis

    Echinococcosis is a near-cosmopolitan zoonosis caused by adult or larval stages of cestodes belonging to the genus Echinococcus (family Taenlldae). The two major species of medical and public health importance are Echinococcus granulosus and Echinococcus multilocularis, which cause cystic echinococcosis and alveolar echinococcosls, respectively.Both are serious and severe diseases, the latter ...

  10. Giant isolated hydatid lung cyst: two case reports

    Background Echinococcosis is a parasitic disease caused by Echinococcus granulosus and causes cystic lesions in the liver and lungs commonly. It is endemic in many parts of the world, and though humans are incidental hosts of the parasite, the disease can have severe consequences. Case presentation We present two patients from pastoralist (Maasai) communities in rural Tanzania with long ...

  11. A One-Health evaluation of the burden of cystic echinococcosis and its

    The study area corresponded to the administrative territory of the Veneto region and CE was chosen as a case study, in consideration of its emerging nature in the area. ... Retrospective study of human cystic echinococcosis in Italy based on the analysis of hospital discharge records between 2001 and 2012. Acta Trop., 140 (2014), ...

  12. Source attribution of human echinococcosis: A systematic review ...

    Author summary Echinococcus granulosus and E. multilocularis are zoonotic parasites that cause human cystic (CE) and alveolar (AE) echinococcosis, respectively: both diseases resulting in a substantial burden of disease. They are transmitted to humans via wild or domestic caniid definitive hosts. This study aimed at finding and evaluating the source attribution of echinococcosis and provides ...

  13. Cerebral echinococcosis: Case report and literature review

    Echinococcosis is a zoonosis caused by the larval form of the cestode Echinococcus granulosus. The cerebral affectation in the human is uncommon; only in 1-2% cases is observed encephalic involvement. This condition occurs mainly in the pediatric population and it is characterized by the presence of single and unilocular cysts.

  14. A Case-Study of the Molecular Diagnosis of Echinococcus ...

    Echinococcus multilocularis is a parasite species of zoonotic importance which can be fatal to humans and causes Alveolar Echinococcosis (AE). This report describes the development of a cyst from the liver of a wild boar and molecular confirmation of its identification. The cyst material was obtaine …

  15. Echinococcosis: Advances in the 21st Century

    Early studies showed that E. granulosus sensu lato-specific circulating antigens, positive in 75% sera of antibody-negative CE patients, were associated with the growth dynamics and activity of cysts ... Rheumatoid arthritis, alveolar echinococcosis, and rituximab: a case report. Joint Bone Spine 79:325-327. doi: 10.1016/j.jbspin.2011.10.014.

  16. Dog Ownership and Risk for Alveolar Echinococcosis, Germany

    For this case-control study, we recruited patients with alveolar echinococcosis from the National Echinococcosis Registry Germany and recruited healthy volunteers from veterinary and veterinary medical facilities listed in the Veterinary Online Directory Germany (Figures 1, 2).We conducted a written survey of case-patients and controls during January 2019-February 2020 by using a ...

  17. Confirmed Autochthonous Case of Human Alveolar Echinococcosis, Italy

    The main human echinococcal infections are caused by Echinococcus granulosus sensu lato, which causes cystic echinococcosis (CE), and E. multilocularis, which causes alveolar echinococcosis (AE).The parasites have different life cycles and cause different diseases ().E. granulosus s.l./CE is endemic worldwide in livestock-raising areas, including Italy, and accounts for most human echinococcal ...

  18. CDC

    Echinococcosis is a parasitic disease caused by infection with tiny tapeworms of the genus Echinocococcus. Echinococcosis is classified as either cystic echinococcosis or alveolar echinococcosis. Cystic echinocccosis (CE), also known as hydatid disease, is caused by infection with the larval stage of Echinococcus granulosus, a ~2-7 millimeter ...

  19. An innovative strategy for deworming dogs in Mediterranean areas highly

    Study design. The strategies described in the present study are part of the project ECHINO-SAFE-MED "New sustainable tools and innovative actions to control cystic ECHINOcoccosis in sheep farms in the MEDiterranean area: improvement of diagnosis and SAFEty in response to climatic changes" (supported by PRIMA-Partnership for research and innovation in the Mediterranean area), which aims to ...

  20. Dynamics of echinococcosis transmission among multiple species and a

    Echinococcosis transmission is principally maintained in IHs-DHs-EEs cycle with accidental infection in human [1].It includes three key elements: (1) the jth DH is infected at rate b ij in case of consuming the viscera of ith IH with parasite, and then evacuates eggs X at rate w j; (2) the ith IH is infected at rate β r,i via ingesting EEs, and then the cysts in its organ will enlarge ...

  21. Osseous cystic echinococcosis: A case series study at a referral unit

    Author summary Echinococcosis occurs in humans as a result of infection by a cestodes of the genus Echinococcus. One of the species, E. granulosus, causes cystic echinococcosis (CE) in humans worldwide. In the lifecycle there is a definitive host (generally dogs) which host this parasites at the small bowel. From there, ground is shed with the eggs of the parasite through feces and the ...

  22. Echinococcosis

    Introduction. Echinococcosis denotes an infection caused by both the adult and larval forms of the tapeworms belonging to the genus Echinococcus . The cestode inhabits the small intestine of carnivores, which are the definitive hosts. Echinococcus granulosus , Echinococcus multilocularis , Echinococcus oligarthus and Echinococcus vogeli are the ...

  23. Dynamics of echinococcosis transmission among ...

    DOI: 10.1016/J.CHAOS.2019.06.032 Corpus ID: 198450465; Dynamics of echinococcosis transmission among multiple species and a case study in Xinjiang, China @article{Zhu2019DynamicsOE, title={Dynamics of echinococcosis transmission among multiple species and a case study in Xinjiang, China}, author={Guanghu Zhu and Sixing Chen and Benyun Shi and Hongjun Qiu and Shang Xia}, journal={Chaos ...

  24. Montclair SCM Student Team Celebrates Rich Diversity Of Campus In Month

    A team of Montclair State School of Communication & Media students have created Montclair Culturs, a month-long campaign designed to educate, celebrate, and spotlight the diverse and rich cultural stories of our campus community. This effort is part of the prestigious national Bateman Case Study Competition, hosted by the Public Relations Student Society of America […]

  25. Seeking Savannah Spurlock Part 1: A Bluegrass Beat Case Study

    In this special episode of Bluegrass Beat, Richmond Police Sgt. Kelli Fraze reflects on the early days of the case that threw Kentucky into the spotlight and spanned three counties. Fraze, who was one of the case's lead investigators, also talks about the first steps taken, lessons learned, gaining information from technology and more.

  26. Dynamics of echinococcosis transmission among multiple species and a

    The present study provides useful information to improve the understanding of echinococcosis transmission and further help control the disease. Introduction Echinococcosis is a zoonotic parasitic disease caused by infection with tiny tapeworms of the genus Echinococcus, which occurs in two main forms in humans: cystic echinococcosis (CE) and ...

  27. Watch Live: Fani Willis hearing underway over removing her from Trump

    A Georgia judge is hearing closing arguments over removing Fulton County District Attorney Fani Willis from the case against former President Donald Trump and others.

  28. Sustainability

    The scope of this article is to study and propose optimized electricity production plants powered by renewable energy sources, in the frame of energy transition in non-interconnected, rural monasteries. Energy transition, namely, the transition from fossil fuels to renewables and rational use of energy, constitutes a major component of sustainability. In particular, monasteries constitute a ...