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Global prevalence of 4 neglected foodborne trematodes targeted for control by WHO: A scoping review to highlight the gaps [1]
['Rachel Tidman', 'Department Of Control Of Neglected Tropical Diseases', 'World Health Organization', 'Geneva', 'World Organisation For Animal Health', 'Paris', 'Kaushi S. T. Kanankege', 'College Of Veterinary Medicine', 'University Of Minnesota', 'Saint Paul']
Date: 2023-03
This review presents an up-to-date synthesis on the quantitative and qualitative evidence available for the 4 FBTs. The data show a large gap between what is being estimated and what is being reported. Although progress has been made with control programmes in several endemic areas, sustained effort is needed to improve surveillance data on FBTs and identify endemic and high-risk areas for environmental exposures, through a One Health approach, to achieve the 2030 goals of FBT prevention.
One hundred and fifteen studies reporting data on any of the 4 FBTs of focus (Fasciola spp., Paragonimus spp., Clonorchis sp., and Opisthorchis spp.) were included in the final selection. Opisthorchiasis was the most commonly reported and researched FBT, with recorded study prevalence ranging from 0.66% to 88.7% in Asia, and this was the highest FBT prevalence overall. The highest recorded study prevalence for clonorchiasis was 59.6%, reported in Asia. Fascioliasis was reported in all regions, with the highest prevalence of 24.77% reported in the Americas. The least data was available on paragonimiasis, with the highest reported study prevalence of 14.9% in Africa. WHO Global Health Observatory data indicated 93/224 (42%) countries reported at least 1 FBT and 26 countries are likely co-endemic to 2 or more FBTs. However, only 3 countries had conducted prevalence estimates for multiple FBTs in the published literature between 2010 to 2020. Despite differing epidemiology, there were overlapping risk factors for all FBTs in all geographical areas, including proximity to rural and agricultural environments; consumption of raw contaminated food; and limited water, hygiene, and sanitation. Mass drug administration and increased awareness and health education were commonly reported preventive factors for all FBTs. FBTs were primarily diagnosed using faecal parasitological testing. Triclabendazole was the most reported treatment for fascioliasis, while praziquantel was the primary treatment for paragonimiasis, clonorchiasis, and opisthorchiasis. Low sensitivity of diagnostic tests as well as reinfection due to continued high-risk food consumption habits were common factors.
Funding: This work was supported by the World Health Organization. The World Health Organization approved the final manuscript before publication and thus their permission was required before the decision to publish. All authors were WHO employees when the study was designed, thus the WHO did have an input into the study design, analysis, preparation of the manuscript and decision to publish.
Considering these FBTs are confined to areas where the intermediate host species inhabit and the specific cultural or food habits of people leading to exposure to the pathogens, identifying the FBTs in relation to the geographical area is important. Furthermore, knowledge on co-endemicity of multiple FBTs in certain countries may inform planning campaigns of preventive chemotherapy against more than 1 FBT simultaneously, which could improve the cost-effectiveness of these campaigns [ 2 , 11 , 13 – 15 ]. Therefore, the overarching objective of this review is to bring together available data on reporting, prevalence, risk factors, prevention, testing, and treatment of the FBTs while identifying the potential for co-endemicity and data gaps at the country level.
FBTs are targeted for control as part of the WHO NTD road map 2021–2030, with mapping and surveillance and advocacy, capacity, and awareness building identified as critical actions required to reach the 2030 targets. A core component of this road map is the promotion of integrated One Health approaches in the development and implementation of NTD prevention and control programmes. Such One Health initiatives have already been implemented in several endemic areas, and while these initiatives have highlighted the complexity of FBT epidemiology and control, promising outcomes have been demonstrated which can be used as an example in other areas.
Fasciola hepatica is globally distributed, with F. gigantica distribution restricted to Africa and Asia. Infection sources are diverse and include contaminated food and water [ 4 – 6 ]. Fascioliasis most commonly results in inflammation of the bile ducts, gallbladder, and liver, resulting in liver fibrosis [ 5 , 6 ], but adult trematodes can also occur in the eyes and central nervous system, resulting in severe neurological and ocular symptoms [ 7 ]. Infection with Paragonimus spp. is acquired through the consumption of undercooked crab or crayfish and is found in Africa, Asia, and Latin America [ 4 , 5 ]. Adult flukes lodge in the lung tissue of the final host and can result in a chronic cough with bloody sputum, chest pain, and dyspnoea [ 5 , 6 ]. Ectopic infection in the brain is uncommon and may result in headaches, convulsions, and cerebral haemorrhages [ 5 , 6 ]. Clonorchis sinensis and Opisthorchis viverrini are largely confined to Asia, with infection acquired via the consumption of undercooked fish [ 5 , 6 ]. These parasites are classified as carcinogenic, as adult flukes can lodge in the bile ducts of the liver, causing inflammation of tissues and resulting in cholangiocarcinoma, a fatal bile duct cancer [ 5 , 6 ]. Infection with Opisthorchis felineus may result in acute abdominal pain due to gallbladder obstruction, and there is evidence that this is also carcinogenic [ 8 ].
The cluster of selected foodborne trematodes (FBTs) listed by the World Health Organization (WHO) consists of 4 genera of trematodes (Fasciola spp., Paragonimus spp., Clonorchis sp., and Opisthorchis spp.) [ 1 ] Despite the prominent public health impacts of the FBTs, they remain listed as neglected tropical diseases (NTDs) by WHO. FBTs, like other NTDs, impact the most impoverished populations and lack the surveillance systems and tools to adequately ascertain their true burden [ 2 , 3 ]. FBTs are zoonotic diseases, with a complex lifecycle involving a primary intermediate snail host, and a secondary intermediate host for all except Fasciola spp. (crustaceans for Paragonimus spp., freshwater fish for Clonorchis sp. and Opisthorchis spp.), with humans becoming infected via the consumption of contaminated food [ 2 ].
Reported “Presence only” data from the WHO Global Health Observatory were mapped using Adobe Illustrator CS5, version 15.1.0 on WHO official template of world map, to represent the combinations of FBTs reported to the WHO Global Health Observatory. Countries that had reported more than 2 FBTs were considered to have potential for geographical co-endemicity. WHO records were compared with the records extracted through the review process to identify countries that has conducted epidemiological studies on the FBTs bteween 2010 and 2020 even if the records were not submitted to WHO.
We extracted qualitative data related to the risk and preventive factors associated with FBTs and grouped them into the following categories: environmental and sociocultural risk factors for infection, preventive measures, diagnostic methods and challenges, and treatment methods and challenges from each record. Qualitative data that were extracted included all risk and preventive factors that were discussed in each record and not only those which were the focus of the study.
Prevalence data at national level were scarce; therefore, prevalence studies of smaller spatial areas were recorded for the purpose of this review. Where multiple records were available for a specific country and parasite, the minimum and maximum prevalence were recorded. The full list of countries with WHO data and the selected studies and prevalence reported are included in Table A in S1 Supplementary material .
Records were initially screened based on title and abstract and were excluded if the abstract focused on an animal population and did not identify a human population of interest, and if the abstract did not mention 1 of the 4 trematode species of interest (Fasciola spp., Paragonimus spp., Clonorchis sp., and Opisthorchis spp.). Records were retained for full-text review if they identified a human population of interest and identified 1 or more of the 4 FBTs of interest. Full-text articles were evaluated for inclusion, and a second reviewer was consulted where there was ambiguity. Records were excluded if there was no prevalence or incidence recorded for a human population, for 1 or more of the 4 FBTs of interest. Records were also excluded if they did not specify the geographical area where data was collected, or if no diagnostic method was identified for determining prevalence. While the focus was on prevalence, 2 publications reported an incidence rate, and these records were included to highlight the presence of O. felineus captured in the literature. Extracted data included: parasite species and subspecies, geographical location, reported prevalence, time frame of study, diagnostic methods used, diagnostic challenges, treatments used, treatment challenges, environmental risk factors, sociocultural risk factors, and preventive factors.
An initial broad-based search of PubMed, IRIS, Web of Science, Science Direct, and Cochrane electronic databases was performed using a combination of search terms, including each FBT and the terms “burden,” “prevalence,” “incidence,” and “cases.” A complete list of the specific search terms used can be found in Box A in S1 Supplementary material . No language restrictions were set, although all search terms were in English. All references published from January 2010 through February 2020 were included in the review. Additional records were identified through a snowballing approach, whereby the bibliographies of full text articles included from the initial literature search were screened, and any reference published after 2010 was reviewed using the same inclusion/exclusion criteria.
Treatment consisted of praziquantel, using a single dose of 40 mg/kg [ 62 , 64 , 65 , 67 , 75 , 80 , 99 , 102 , 117 , 127 ], with 1 record reporting 25 mg/kg for 3 doses over a single day [ 70 ]. Limited awareness about the severity of opisthorchiasis, community complacency driven by the belief that symptoms were mild and an effective treatment was available, and deeply rooted cultural food habits contributed to frequent reinfection in endemic communities [ 59 , 62 , 67 , 71 , 73 , 74 , 100 , 106 ]. It was also noted that repeated cycles of reinfection and treatment with praziquantel could result in drug resistance and potentially increase the risk of cholangiocarcinoma [ 77 ].
Similar to the other FBTs reported, diagnosis of opisthorchiasis was primarily based on the detection of eggs from faecal samples with microscopy, as this was a low cost and non-invasive method [ 54 , 56 , 59 , 67 , 99 ]. However, this had limited diagnostic sensitivity and specificity, required skill parasitologists for diagnosis, and it was difficult to differentiate opisthorchiid eggs from other small intestinal flukes [ 54 , 63 , 67 , 80 , 99 , 103 , 105 , 106 ]. Additional smears from multiple stool samples were reported to improve sensitivity [ 99 , 100 , 103 , 105 , 106 ].
River basins were reported risk areas for the transmission of Opisthorchis species, as these environments supported both the snail and fish intermediate hosts [ 37 , 60 ]. Similarly, areas of higher rainfall and rural, lowland villages with surrounding land that was dominated by high water content (wetlands, paddies, streams, ponds, and lakes) were reported to have high prevalence of O. viverrini due to the suitable environments for intermediate hosts [ 60 , 99 , 103 ]. The development of water resources for aquaculture and irrigation may have contributed to the high prevalence found in northeast Thailand [ 60 ]. Higher altitude areas were reported to have a lower risk of opisthorchiasis, although this was likely related to accessibility to freshwater fish and the difference of cultural food preferences [ 99 ].
25 mg/kg every 5 h for 3 doses was the reported praziquantel dose regime by 4 records [ 92 , 116 , 117 , 129 ], with another record reporting a single treatment of 40 mg/kg [ 118 ]. Poor compliance with taking the second and third dose of praziquantel was identified as a possible factor for low cure rates in some communities [ 84 ]. Repeated mass or selective treatment every 6 to 12 months was recommended for reducing prevalence and reinfection in heavily endemic areas [ 8 , 115 , 119 ].
Serological methods such as ELISA improved the sensitivity, but had poor specificity and were unable to detect early phases of infection [ 87 ]. Cross-reactivity with other parasites could also result in additional false-positive results [ 87 , 111 ]. However, while the ELISA method was recommended to be an auxiliary method to faecal microscopy for the diagnosis of individuals, ELISA methods were noted as being a potential option for large-scale screening to monitor community prevalence [ 87 ].
Diagnosis by faecal parasitological methods were commonly reported, using either formalin-ether concentration technique (FECT) or the Kato–Katz thick smear method [ 122 ]. Such methods were widely used as they were simple, non-invasive, rapid, inexpensive, and were able to determine both the diagnosis and the intensity of infection [ 84 , 90 , 91 ]. However, microscopy methods could result in false negative results, particularly in light infections, and there were challenges in differentiating C. sinensis from other minute intestinal flukes [ 85 , 87 , 92 , 117 ]. Increasing the size of the faecal sample, repeating egg counts, and increasing the number of slides improved the sensitivity but also increased time and labour costs and was not always acceptable to communities [ 87 ].
Reported diagnostic methods included examination of sputum and faeces for eggs, serological diagnosis, and intradermal testing. Serological methods were reported as a more sensitive diagnostic tool in both the African and the Southeast Asia regions, as ova were expectorated or shed intermittently in sputum and faeces, respectively [ 19 , 52 ]. Although positive serological results could include past infections and cross-reactions, it was considered a reliable diagnostic method [ 111 ]. Collection of multiple sputum samples increased diagnostic sensitivity of microscopy methods, with a record from the Philippines recommending 2 sputum samples to allow same day diagnosis, thereby improving patient compliance and reducing costs of diagnostics compared to samples collected over multiple days [ 97 ]. The same record recommended the collection of an early morning sputum sample followed by a spot sample, as the early morning sample improved sensitivity [ 97 ].
The Three Gorges Reservoir area of China was reported to be area of high paragonimiasis endemicity, with hilly and forested areas, and natural bodies of water that sustain populations of both the intermediate snail host and intermediate freshwater crab host [ 93 ]. Mountainous areas of Vietnam were reported endemic and provided suitable habitats for intermediate mountainous crab hosts [ 128 ], while hyperendemic foci of paragonimiasis were identified in rural, remote hilly, and forested areas of northeastern India where populations had poor access to health care [ 53 ].
Treatment with triclabendazole was the most reported treatment for fascioliasis, although challenges to treatment included drug resistance, adverse drug reactions, and difficulty in obtaining the medication [ 18 , 20 , 29 , 33 , 34 , 47 , 81 ]. Four records reported the dosing regimen used for treatment, with 3 records using a single dose of 10 mg/kg [ 23 , 34 , 47 ] and the third record using 10 mg/kg per day for 2 days [ 81 ]. One record from Tanzania reported the use of nitazoxanide in areas with limited supply of triclabendazole, noting that not all patients were cleared with this treatment [ 18 ]. Another record reported the use of nitazoxanide in Mexico, noting its potential as an alternative to triclabendazole in countries where triclabendazole is not registered or where triclabendazole resistance is found [ 26 ].
The Eastern Mediterranean Region was the only region where serological diagnostic methods were more frequently used than faecal coprological tests and were considered more sensitive [ 40 , 48 , 49 ]. However, serological testing was unable to determine between past and current infections, and the possibility of cross-reactivity with other parasites could result in false positives [ 20 , 21 , 31 , 48 , 124 ]. These challenges meant that serological testing did not necessarily equate to true active cases and could overestimate Fasciola prevalence [ 31 , 45 , 124 ].
Faecal parasitological tests were considered simple, cheap, and rapid for diagnosis and mass screening of populations. However, frequently identified challenges to faecal coprological tests included the low sensitivity of these tests due to low egg burdens, intermittent egg shedding, or acute infections, resulting in possible false negatives and underestimation of prevalence [ 19 – 21 , 26 , 28 – 30 , 32 – 34 , 47 , 77 , 81 ]. Increasing the number of faecal samples collected and increasing the number of slides examined from each sample were both identified as options to improve the sensitivity of these methods, but required further resources, had a lower compliance from patients, and faced logistical challenges with collection in remote areas [ 40 , 41 , 51 ].
Countries reporting co-endemicity of FBTs to WHO included: (i) 16 countries reporting fascioliasis and paragonimiasis; (ii) 3 countries reporting fascioliasis, paragonimiasis, and clonorchiasis (China, Japan, and the Republic of Korea); and (iii) 7 countries reported all 4 FBTs (Cambodia, Lao People’s Democratic Republic, India, the Philippines, Russian Federation, Thailand, and Viet Nam) ( Fig 2 ). Except for the United Republic of Tanzania and Kazakhstan, all countries that were included in the scoping review process also reported to WHO for at least 1 of the 4 FBTs during the 2010 to 2019 period. However, among these 26 countries with co-endemicity, only 3 countries (China, Republic of Korea, and Viet Nam) had conducted prevalence estimates for multiple FBTs in the published literature between 2010 and 2020.
Among the 224 countries and territories reporting data to the WHO Global Health Observatory from 2010 to 2019, 93/224 (42%) countries reported at least 1 of the 4 FBTs (i.e., 131/224 (58%) did not report any), and 2019 was the last available year of data as the process of reporting and validation of NTD surveillance data to WHO entails approximately 1-year lag in data availability. Fascioliasis was reported in 75/224 (33%), paragonimiasis in 44/224 (20%), clonorchiasis in 10/224 (4%), and opisthorchiasis in 7/224 (3%) countries. Among the reporting countries, 26 were co-endemic to 2 or more FBTs.
Discussion
There was a mismatch between the data that are reported to WHO and that which are reported in the literature reviewed, with the data captured in this review representing 25 countries despite 93 countries reporting FBT “presence only” data to WHO between 2010 and 2019. Similarly, although 26 countries reported ≥ 2 FBTs to WHO, only 3 countries in this review conducted studies for multiple FBTs (Fasciola, Paragonimus, Clonorchis in China; Paragonimus and Clonorchis in Republic of Korea; all FBTs in Viet Nam). This mismatch of data highlights the limited availability of reliable data in some regions and challenges in reporting FBTs and the need for more research in many geographical areas. Additional countries were identified during the screening process of records that reported clinical cases of FBTs, without reporting prevalence, further enforcing the need to instal surveillance and mapping where cases are reported.
Although the geographical distribution of each FBT discussed in this review reflects what has previously been reported, there were differences in reported prevalences. The highest FBT study prevalence was reported for O. viverrini in Lao People’s Democratic Republic. This is consistent with the reported high prevalence of 37.02% by Furst and colleagues; however, the records in our review identified study prevalences as high as 88.7% in some areas [6,100]. While this could be due to increasing cases or improved surveillance resulting in increased case detection, the prevalences depicted in this review are based on very limited data and are unlikely to reflect true national prevalence. The highest fascioliasis study prevalence identified in this review was in the Region of the Americas, consistent with previous literature [132]. A high study prevalence was also identified in the United Republic of Tanzania, despite no reporting of FBTs to WHO in this time period [18]. The highest recorded study prevalence of paragonimiasis was also reported in the African Region, in Cameroon [18]. The available data on FBTs in Africa is limited, and the reports of high prevalences for both fascioliasis and paragonimiasis support an urgent need for research to better understand the epidemiology and burden of FBTs in this region.
Several limitations exist with our method of reporting prevalence. Although no language restrictions were set, all search terms were in English, potentially resulting in the exclusion of records from areas that have a high burden of FBTs, including Latin America and the Russian Federation. This bias is most notable with the absence of records for F. Hepatica in the Americas, despite the well-documented hyperendemic areas in this region [132]. Due to the limited availability of national prevalence data, we instead extracted the study prevalence from each record, using the mean study prevalence when multiple prevalences were recorded. However, as study size and methodology varied greatly between records, and there was a wide range of study prevalences reported even between geographically close areas with similar risk factors, this data cannot be used to reliably estimate national prevalence.
Nevertheless, the data gaps recognised here demonstrate the need for continued improvement of mapping and surveillance to confirm focal points of disease that should be targeted for public health interventions. While disease burden can be estimated within assumptions and available data [6], the limited knowledge available on FBTs in many areas highlights the need for more research and the promotion of successful frameworks, guidelines, and control programmes for surveillance and reporting of FBTs. For example, initiatives in highly endemic fascioliasis areas of Bolivia [133–139], Peru [22,140], Argentina [141], Egypt [142], Pakistan [143] and Vietnam [144], and highly endemic opisthorchiasis areas of Thailand [145–147] have included experimental studies and field surveys to assess transmission and infection sources, field evaluation of diagnostic tools, passive and active surveillance, mass chemotherapy, and the promotion of health awareness among a wide variety of stakeholders. Comprehensive education programmes aimed at community leaders and schoolchildren have been implemented in China [148] and the Republic of Korea [116] to complement mass screening and MDA for clonorchiasis, and reduce transmission and infection risk, and studies in the Philippines have explored the integration of paragonimiasis surveillance and control with tuberculosis control to improve finding and treatment of cases [97,149,150]. These efforts have helped to improve surveillance and case detection [22,135], map FBT endemic areas [140], understand and reduce transmission and infection risk [138,139,147], lower FBT prevalence in humans and intermediate hosts [116,147], and helped to prioritise where resources should be most effectively used in control programmes [135,136,139]. Such initiatives could help inform future studies in other endemic areas to identify within country variation of the endemic areas and delineate treatment strategies according to the level of geographical co-endemicity.
Several themes were highlighted from the qualitative data extracted from the literature; however; as these data reflect what each record discussed and were not necessarily supported by strong epidemiological data, the trends identified in this review may not align with the true epidemiological situation in communities. In addition to this, as our search strategy focused on human prevalence studies, prevalence studies of other species were not captured, and the extracted qualitative data does not take into account the evidence provided in many valuable epidemiological or transmission risk studies available. This is a significant limitation in our review of qualitative data, and a more comprehensive review focusing on such qualitative data, and prevalence in intermediate and reservoir hosts should be considered to capture these aspects. The inclusion of robust epidemiological data in future prevalence studies would also be valuable to support ongoing surveillance and targeted prevention and treatment programmes.
Despite the epidemiological differences between FBTs, there was significant overlap in the geographical and sociocultural factors that promoted infection and sustained transmission for each FBT. Rural and agricultural communities with appropriate aquatic environments provided a suitable ecological niche for intermediate snail hosts, and secondary fish and crustacean hosts, and also promoted activities that increased the risk of exposure to FBTs (poor sanitation, high-risk food consumption, contact with livestock). Identifying communities that meet these risk criteria can help predict distribution at non-surveyed locations, inform disease surveillance, and help target control programmes against multiple FBTs [99]. However, the interplay of these factors is complex, and endemic and non-endemic villages often coexist within close proximity despite meeting the same risk criteria [80]. The wide range of study prevalences identified in this review, even between geographically close areas with similar risk factors, highlights the need for local health systems to be strengthened and engaged in order for FBTs to be prioritised and dealt with by local health authorities [97,104]. Improved screening is needed to confirm these focal areas of endemicity and co-endemicity. As recognised by previous studies, this review also highlighted the logistical and diagnostic challenges of available methods and the need for an efficient and accurate diagnostic methods to improve surveillance [18]. Although MDA and improved community awareness were frequently discussed as preventive factors for FBT infection, this review highlighted that even in communities that received regular treatment with anthelmintics and were aware of the risks of infection, there continued to be ongoing community transmission and reinfection [80,128,131]. Communities with strong cultural dietary habits and poor sanitation will continue to have a high risk of exposure to infection [17,58]. High infection rates in untreated domestic reservoir species will contribute to ongoing transmission, as well as resulting in veterinary and economic impacts in communities that are dependent on agriculture for their livelihoods [2,17,25,64,105].
One Health approaches are needed to reduce environmental contamination, improve access to clean water and adequate sanitation, and address the role of reservoir hosts in FBT transmission [81,104,105]. One Health is defined as an “integrated, unifying approach that aims to sustainably balance and optimise the health of people, animals, and ecosystems,” and is core to the NTD road map [151,152]. However, while the concept of One Health is becoming more familiar, there is still significant work to be done to promote a consistent understanding across sectors and finding practical ways to operationalise One Health in disease prevention and control programmes. One Health approaches need to address more than the zoonotic pathway of disease transmission, but should also promote coordinated resource allocation and planning, and explore opportunities for treatment implementation to be integrated with that of other diseases and protocols. Implementing such approaches, at both local and national levels, are integral to effectively and sustainably reducing the burden of FBTs. These approaches should further be integrated into Universal Health Care programmes to ensure equitable implementation of the road map for NTD control by 2030 [153]. Examples of successfully implemented One Health approaches have been demonstrated in several areas, including Fascioliasis endemic areas of Northern Bolivian Altiplano and Opisthorchiasis endemic areas of Khon Kaen Province in Thailand, and such examples can provide a framework that can help build similar One Health programmes in other endemic areas.
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