Cystic Echinococcosis in the Early 2020s: History
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Contributor:
Mihai-Octav Hogea
,
Bogdan-Florin Ciomaga
,
Mădălina-Maria Muntean
,
Andrei-Alexandru Muntean
,
Mircea Ioan Popa
,
Gabriela Loredana Popa

Cystic echinococcosis (CE) is a zoonosis caused by metacestodes, the larval stage of Echinococcus granulosus. Although the World Health Organization (WHO) has defined CE as a neglected disease, it is the second most important foodborne parasitic disease, and it remains an important public health issue, considering its zonal endemicity and potential morbidity. The control and prevention of CE is a relevant WHO target, especially from a One Health perspective, as the disease affects not only animals and humans but also the food chain. Since not all countries have a CE surveillance strategy or reporting system and specific management guidelines, recent epidemiological data are relatively scarce, and research concerning the specific geographical distribution of the disease is ongoing. 

  • Cystic echinococcosis (CE)
  • foodborne disease
  • One Health
  • zoonosis

1. Introduction

Echinococcus granulosus is a zoonotic parasite that is responsible for human cystic echinococcosis (CE) [1][2][3]. The infection occurs when hosts ingest Echinococcus eggs, which then develop into the larval (metacestode) stage. Regarding the parasite’s host, canids are the definitive host of the adult-stage parasite [4][5]. The parasite’s metacestode (hydatid) stage thrives in domestic ruminants, such as sheep, cattle, and camels [3]. Transmission from definitive to intermediate hosts occurs via the fecal–oral route. Because humans do not biologically support the parasite’s life cycle, they represent accidental dead-end intermediate hosts [6].
Cystic echinococcosis is diagnosed primarily based on imaging, clinical presentation, and serology. The gold standard for imaging in the diagnosis of abdominal CE is ultrasonography, while computer tomography, magnetic resonance imaging, and conventional radiography can also prove useful in specific circumstances. In this manner, cysts can be classified into categories based on their appearance. To achieve global disease assessment consistency, the World Health Organization Informal Working Group on Echinococcosis (WHO-IWGE) has classified CE cysts into five types and three groups, with CE1 and CE2 reflecting active infection, CE3 being a transitional stage, and CE4 and CE5 representing inactive cysts [1]. Imaging is also used to monitor these patients.
In terms of clinical appearance, the gradual development of the cysts renders patients asymptomatic for an extended period, delaying the diagnosis. Symptoms in humans vary depending on the cysts’ location and size, as well as their number [2][4][7]. Throughout the disease, the liver is the most common location for cysts [4]. Most patients have only one organ affected with a solitary cyst, but in some unfortunate and severe instances, multiple cysts can develop in various viscera [8][9][10][11][12][13], such as the lungs, kidneys, spleen, brain, and bones.
Major antigenic compounds of the hydatid fluid, such as antigen B and antigen 5, can be immuno-assessed. Serum antibodies can be detected using enzyme-linked immunosorbent assay (ELISA), indirect hemagglutination (IHA), and latex agglutination with antigens from the hydatid cyst fluid, with varying sensitivity. ELISA and immunochromatography performed better than IHA as a complementary to the imaging diagnosis [14]. Immunoblotting is usually used in differential diagnosis. As a rule, it is recommended that serology and ultrasonography imaging be used together when performing mass screening [1][15].
The genus Echinococcus (Cestoda: Taeniidae) has undergone multiple taxonomic revisions since the 1960s [16]. In the past, Echinococcus granulosus included up to nine sub-specific genotypes (G1–G9) [2][16][17] or strains that evolve into CE during the metacestode stage. It is currently proposed that the Echinococcus genus be classified into at least nine different species [2][18]. All Echinococcus species that are capable of causing CE in intermediate hosts can be referred to collectively as E. granulosus sensu lato (s.l.), while strains G1–G3, which are closely related, can now be categorized as E. granulosus sensu stricto (s.s.) [16][18][19].

2. Cystic Echinococcosis in the Early 2020s

2.1. Taxonomy

The genus of pathogens defined as Echinococcus has undergone several changes in the past, owing mostly to its transfer to humans from multiple different hosts and the variable morphology of the metacestodes. After its formal classification as Echinococcus, there was some debate as to whether or not the clinical infection with E. granulosus and E. multilocularis was caused by the same pathogen. This issue was resolved when a distinct account of the life cycle of E. multilocularis was provided. Afterwards, the Echinococcus genus was split into four species, with E. oligarthra and E. vogeli joining the two previously listed [18].
E. granulosus seemed to contain a high number of variations, hence its designation as E. granulosus sensu lato. Through studies of molecular epidemiology and geographical data over the course of two decades, it became clear that the genotypes that were enclosed within E. granulosus sensu lato were significantly diverse, and that the genotype taxonomy model was becoming increasingly limited and contradictory [18][20]. The development of mitochondrial DNA sequencing led to the description of 10 genotypes (G1 to G10), a classification that was heavily debated [18][20]. The term E. granulosus sensu lato now includes the E. granulosus sensu stricto genotypes (G1–G3), as well as E. equinus (G4), E. ortleppi (G5), E. intermedius (G6, G7), E. canadensis (G8, G10), and E. felidis [18][20][21][22][23].

2.2. Epidemiology

  • Transmission and Life Cycle.
In terms of transmission, echinococcosis depends on the presence of different hosts within endemic regions, both definitive (domestic dog, lion, etc.) and intermediate (cattle, pig, sheep, etc.). A series of transmission routes have been described, ranging from the fecal–oral route—consumption of contaminated water, unwashed raw produce, and contact with contaminated soil—as well as contact with dogs and livestock (particularly ruminants), either through direct contact or through contact with contaminated fur [6][24][25].
When discussing echinococcosis, it is particularly important to consider that the transmission method varies geographically, depending on host availability, social and cultural customs, awareness of public health, and environmental conditions. Although direct contact with canine hosts has long been suspected as the main source of transmission to humans, the correlation is not compelling. There are endemic regions where the disease’s prevalence and the population of infected dogs are unrelated, or where contact with dogs in the area is kept at a minimum despite their presence. This has led to the conclusion that, while direct contact is not always the cause, the high environmental quantity of Echinococcus eggs contributes to transmission, likely from soil contamination [6][26][27].
  • Epidemiological Data.
Cystic echinococcosis is regionally endemic throughout Europe, North and East Africa, Central Asia, the Middle East, Central and South America, and Australia, particularly in areas with significant animal husbandry and livestock farming [2][24][28]. The WHO estimates an incidence of more than 50 per 100,000 person-years, a prevalence of 5–10% in certain endemic regions, a 20–95% prevalence of CE in slaughtered livestock, as well as an estimated 1 million people currently suffering from this zoonosis [2].

2.3. Current Guidelines

2.3.1. Prevention and Control

In terms of prevention and control, the CDC and WHO recommendations center around preventing exposure and actively treating potential animal hosts that are at risk of coming into contact with infectious material. This can be done by preventing canid access to infected organs and carcasses, controlling the stray dog population, discouraging home slaughter of sheep and cattle, improving sanitation concerning animal slaughter, deworming dogs with praziquantel, and implementing public health programs for rural populations that are most susceptible to this disease. A vaccine for sheep with an E. granulosus recombinant antigen is already in use in Argentina and China [29][30]. The WHO also offers an optimistic estimate that a proper combination of these preventative measures may eliminate CE in as little as 10 years [2][28].
Despite this, data remain scarce, and these estimations may be affected by underreporting. The systematic review mentioned previously offers a different perspective, as the article’s findings suggest that while all CE cases that end in hospitalization and some CE patients who display symptoms are reported, there may be many more instances of echinococcosis patients that are not. This is further compounded by the fact that many countries do not report their findings at a higher institutional level, which means that the overall effect of this disease on human and livestock populations, as well as the overall efficiency of the proposed preventative measures, is likely underestimated [2][24][28].
One such example can be observed in the case of Nigeria. The last study that focused on the prevalence rates of CE was conducted in 1987 and identified a seroprevalence of 0.53% within 176 hospitalized patients [31].

2.3.2. Treatment

Because of its risk of recurrence, the WHO-IWGE recommends that echinococcosis be managed by using a multidisciplinary approach that is similar to that of cancer. The therapeutic and/or prophylactic treatment plan is individualized, taking into account the patient’s clinical characteristics and the experience of the medical and surgical team [1][3][4][10][12][13][23][32][33][34][35][36][37][38][39][40][41]. There are multiple treatment options, and sometimes, a combination of approaches is necessary depending on the location and size of the cysts as well as the presence or absence of complications. Long-term follow-up is also recommended [1].
  • Surgery:
    Surgery was the preferred course of treatment in the past, as it may be curative by the complete removal of the cyst (total cystectomy) [3][28]. Other surgical approaches are sub-total cystectomy and hepatectomy. Total cystectomy avoids cyst opening and therefore prevents recurrence and is the preferred option if possible. Surgery is still used for particular scenarios such as liver cysts that are secondarily infected or cysts that are located in critical areas like the brain, lungs, or kidneys. It is also the elective choice of treatment for large liver cysts, particularly those over 7.5 cm, which are likely to have biliary communication [3]. It is recommended to associate albendazole to prevent relapses.
  • Chemotherapy:
    Over 2000 documented cases [1][3][4][8][12][32][42][43] have been treated with benzimidazoles. The optimal course of treatment includes albendazole (10–15 mg/kg/day or 400 mg q12h) taken after a fatty meal, alone or in association with mebendazole (40–50 mg/kg/day divided into three doses during fat-rich meals) or praziquantel (40 mg/kg once a week), with variable treatment outcomes [1][4][23][42]. Chemotherapy results in cyst disappearance (free from disease) in 10–30% of patients, improvement in 50–70%, and no change in 20–30%. It is generally more effective in younger patients and against specific cyst types. Chemotherapy is indicated in inoperable patients with primary liver echinococcosis, patients with multiple cysts in multiple organs, and in secondary echinococcosis prevention. However, chemotherapy is not recommended for large cysts at risk of rupture, inactive or calcified cysts, compromised patients with severe chronic hepatic diseases, or in early pregnancy. It can be administered before surgery for the safe manipulation of cysts, since it inactivates protoscolices, alters the integrity of cystic membranes, and reduces cyst turgidity [3][28].
    Chemotherapy can be given before surgery, and many regimens have been tested employing both monotherapy and drug associations. These range from treatment with albendazole administrated 1 week before surgery (continued for 2 months after surgery) and 10 mg/kg/day albendazole and 25 mg/kg/day of praziquantel for 1 month prior to surgery to facilitate the safe manipulation of cysts. It inactivates protoscolices, alters the integrity of cyst membranes, and reduces cyst turgidity [3][4][23].
  • Puncture, Aspiration, Injection, and Re-aspiration (PAIR):
    PAIR [11][32][44] is a minimally invasive, ultrasound-guided cyst puncture, followed by the aspiration of cyst fluid, injection of a protoscolicidal substance (preferably 95% ethanol), and re-aspiration of the fluid after a specified time. It is used as a last resort for treating inoperable patients, relapsing instances after surgery, or non-responders to chemotherapy. A modified procedure of PAIR may also be useful as an alternative to surgery for non-complicated CE2 and CE3b cysts. The “modified catheterization technique” (MoCAT) uses sonographic and fluoroscopic guidance to aspirate both the cyst content and the parasitic membranes and to place a catheter for a period of time after the intervention [45]. Even if this method is suitable for a variety of cysts, it should not be used for lung cysts [1][3].
  • “Watch-and-wait” Approach:
    The observation that some CE cysts may spontaneously become inactive leads to the withholding of treatment, as these cysts remain stable over time. The use of albendazole or other treatment options in asymptomatic patients is not recommended on a standard basis [33][46]. However, it may be an option in highly selected cases referred to specialized centers. In 2010, the WHO-IWGE published their recommendation of this approach for uncomplicated, asymptomatic, inactive (CE4-CE5 stages of the WHO-IWGE classification) CE cysts [33][46].

2.4. Projects and Initiatives Related to the WHO Road Map

2.4.1. The HERACLES Project

The “Human Echinococcosis ReseArch in CentraL and Eastern Societies”, commonly known as the HERACLES project, was carried out between 2013 and 2018 [47][48]. The research concentrated on areas in Europe (Spain, Italy, Bulgaria, Romania) and associated countries (Turkey), where the endemic status was either suspected or confirmed by an IR of 1–200 per 100,000 inhabitants [48]. These nations enrolled patients in the European Register of Cystic Echinococcosis (ERCE), supplied parasitic and human samples to the Echino-Biobank, and collaborated on research endeavors pertaining to the molecular epidemiology of [49]. Hence, the ERCE [50] was designed as a prospective, observational, multilingual, multicenter, online clinical registry for patients with probable or proven CE, serving as a crucial part of the HERACLES joint effort.

Objectives and Results

1. Ultrasound screening of CE within the Eastern European population and the ERCE register.
The study approached the subject from two angles: firstly, it used an ultrasound screening protocol to assess the prevalence and burden of CE in underserved rural regions with a substantial sheep farming industry (Bulgaria, Romania, and Turkey); and second, it constructed a comprehensive ERCE database that included Bulgaria, Romania, and Turkey [15][44][47][50][51][52].
One of the project’s triumphs was a cross-sectional ultrasound-based study [15], for which volunteers were recruited from fifty rural towns in Turkey, Bulgaria, and Romania. The communities chosen were located in provinces where the frequency of CE in regional hospitals was comparable to the national average. During the screening period, lesions were detected and categorized using a modified WHO approach. After adjusting for age and gender, the prevalence rates of abdominal CE were determined using direct standardization, with the rural population of each country serving as the reference [15]. A cumulative total of 24,693 individuals were screened; of them, 24,687 underwent ultrasonography examinations. The estimated prevalence of abdominal CE in Bulgaria was 0.41% (0.29–0.58), in Romania, it was 0.41% (0.26–0.65), and in Turkey, it was 0.59% (0.26–1.85) [15][47].
2.
New molecular-based tools for detection, diagnosis, and follow-up of CE.
A key objective was to establish and improve upon a consistent method for the serological identification of CE in both human and animal subjects [47]. A systematic approach was taken to examine the serodiagnosis and serological monitoring of CE. A sample repository was established and connected to databases containing comprehensive clinical and epidemiological data. This ensured the accurate validation of newly identified recombinant antigens and their corresponding antibodies [47][53][54][55][56][57][58].
Initially, the experiment looked at the variables that impact the serological response in individuals with hepatic CE using commercially accessible ELISA and IHA assays that are regularly utilized in parasitology laboratories [59]. It was concluded that the serological responses that are evaluated by these tests are influenced by factors such as the activity, size, and quantity of CE cysts, as well as the time of serum collection relative to the treatment.
The second experiment assessed the diagnostic precision of three commercially accessible rapid diagnostic tests (RDTs) in detecting hepatic CE [60]. One test in particular (the VIRapid test, Vircell, Spain) was demonstrated to perform better when compared to the other evaluated kits; its results were comparable to those of the control test (ELISA). However, it is important to note that all the tests exhibited low sensitivity for inactive cysts [60].
3.
Host–parasite interplay.
The understanding of the underlying molecular pathogenicity mechanisms contributed to the identification of diagnostic and prognostic biomarkers to assist in the care of infected individuals. Additionally, it was critical to determine if the genetic diversity of hosts has led to the observed clinical heterogeneity among study subjects [47][58].
The investigation of haplotypes, genotypes, and species [58] was followed by microRNA arrays [61]. The expression of eight specific microRNAs (let-7g-5p, let-7a-5p, miR-26a-5p, miR-26b-5p, miR-195-5p, miR16-5p, miR-30c-5p, and miR-223-3p) was found to be increased in cases where active cysts were present. It was concluded that host microRNAs play a role in regulating the immune response against E. granulosus and/or in the development of hydatid cysts [61].
The discovery of accessible circulating biomarkers could allow for the creation of a diagnostic test that could considerably improve CE diagnostic rates [47]. The focus was set on exosomes—a type of extracellular vesicle that play a crucial role in intercellular communication, particularly in immune system responses. Following proteomic assays, the proteins were divided into ”true” biomarkers and potential biomarkers that need to be further studied [62]. Research identified the Src family kinases (Src and Lyn) as potential indicators of active CE, based on their presence in distinct plasma pools. An association between TGF-β in active CE and Cdc42 in inactive CE was also identified.
4.
The increasing bioavailability of albendazole and a new enantiomeric drug synthesis.
The primary goals encompassed the synthesis of novel racemic and enantiomeric pure medicines derived from albendazole (ABZ), as well as the evaluation of their efficacy against E. granulosus through in vivo experimentation [47][63][64][65][66]. Salts of compounds with a benzimidazole structure were patented [51] and included in a trial with a murine model [66] and two clinical trials [47][67]. The novel salt formulations of ABZ, ricobendazole (RBZ), and the enantiomer RBZ showed promising results and call for future research. The patent includes more antihelmintic compounds: fenbendazole, triclabendazole, flubendazole, and others [64]. These substances have not undergone comprehensive investigation and provide a backbone for future research endeavors.
5.
Training and dissemination of information.

Correlation with the WHO Road Map

The HERACLES project effectively targets a substantial number of the suggestions that are put forth by the WHO. Noteworthy among these recommendations are:
  • The establishment of an international patient surveillance network for cystic echinococcosis (ERCE);
  • The implementation of screening programs in rural parts of the countries that are at risk, as well as the execution of a study aimed at determining the prevalence rates in these specific regions;
  • Reporting to both national and international authorities tasked with the responsibility to control and prevent infectious diseases, and thereafter engaging in collaborative efforts to formulate recommendations that are targeted at managing the endemic situation;
  • Improving diagnostic techniques by identifying novel biomarkers that can be employed in the molecular diagnosis of CE.

2.4.2. The mEmE Project

Project mEmE (Multi-centre study on Echinococcus multilocularis and Echinococcus granulosus sensu lato in Europe: development and harmonization of diagnostic methods in the food chain), carried out between 2013 and 2018, was a collaborative initiative between multiple international centers. Its primary objective was to address research gaps that were identified by international agencies tasked with the control of zoonotic parasites, specifically E. multilocularis (Em) and E. granulosus sensu lato (Eg s.l.) [68][69][70]. The research was focused on epidemiological and molecular studies to later establish clear guidelines.
The consortium for this project included several countries (Italy, Germany, France, the Netherlands, Poland, Denmark, Portugal, Estonia, and Latvia) and some external partners (Ireland, Switzerland, Norway, and Pakistan) [68]. The approach of the project included a veterinary point of view on the topic, thus reinforcing the need for collaboration between specialists towards the containment of the NTD.

Objectives and Results

1. Standard operating procedures (SOPs) for sampling.
One of the early achievements of the project was the delivery of standard operating procedures (SOPs) for sampling [3][35][71]. The samples that were gathered encompass a wide range of components within the food chain: excrements and digestive systems of the primary carnivorous hosts, vegetables intended for human consumption, and cysts found in the intermediate cattle hosts.
The SOPs have demonstrated significant utility within the project and have the potential to become a standard methodology for sample collection in the years to come.
2.
Validation of multiplex PCRs.
Two methods were chosen for this project [68][70], (1) an assay [72] that used a single-tube multiplex polymerase chain reaction (PCR) method that enables the differentiation of Echinococcus species and genotypes; (2) and another assay [73] that used a single-tube multiplex PCR method to identify eggs of E. granulosus, E. multilocularis, and the Taenia genus by targeting the definitive host.
3.
Sequencing of samples using RSE and NGS.
The method used DNA enrichment techniques with parasite-specific DNA capture probes and magnets to obtain parasite DNA from complex biological materials such as feces or raw vegetables [70][74]. Furthermore, the captured fragments were subjected to high-throughput long- and short-read sequencing technologies to obtain their comprehensive characterization.
4.
The prevalence of Em/Eg in dogs from selected geographical areas [75].
5.
A quantitative assessment of the impact of human CE in Europe.
The mean annual incidence for the period of 1997–2020 was 0.64 per 100,000 individuals across European nations and 0.50 per 100,000 individuals specifically in EU countries [70]. However, certain regions in Europe have been identified as high-endemicity areas for cystic echinococcosis [3][76], with reported cases ranging from 1 to 5 per 100,000 individuals. These areas included Albania (2.25 per 100,000), Bosnia and Herzegovina (1.00 per 100,000), Bulgaria (5.33 per 100,000), Italy (1.21 per 100,000), Moldova (4.65 per 100,000), North Macedonia (1.08 per 100,000), and Romania (2.16 per 100,000).
While exact patterns differed nationally, there was evidence of an overall drop in frequency. Most endemic nations in Southern and Eastern Europe, where the illness had historically exhibited a high prevalence, had documented a decline in the incidence of CE [49][70].
6.
Training and Dissemination of information.

Correlation with WHO Road Map

The mEmE initiative addressed WHO’s appeal to modify the status of CE by employing a range of approaches:
  • The establishment of SOPs on sample collection in cases of CE suspicion, particularly in animals, which has played a significant role in contributing to disease control and prevention efforts;
  • The basis for an epidemiological study within the present context;
  • Confirmation of the efficacy of molecular diagnostic techniques;
  • A wide distribution of project findings, targeting both the general public and experts in human and veterinary disciplines.
One of the most important epidemiological findings was that the geographical focal point (increased incidence rates) was not in Southern or Eastern Europe but rather in the Baltic/Scandinavian area. The need to standardize an operational protocol is heightened, as it plays a critical role in attaining the targets that have been established by the WHO.

This entry is adapted from the peer-reviewed paper 10.3390/tropicalmed9020036

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