The authors have declared that no competing interests exist.
Contributed to the manuscript and approved the final version: AC AP CSO RMR MSL GLT BB.
Scientific literature on cystic echinococcosis (CE) reporting data on risk factors is limited and to the best of our knowledge, no global evaluation of human CE risk factors has to date been performed. This systematic review (SR) summarizes available data on statistically relevant potential risk factors (PRFs) associated with human CE.
Database searches identified 1,367 papers, of which thirty-seven were eligible for inclusion. Of these, eight and twenty-nine were case-control and cross-sectional studies, respectively. Among the eligible papers, twenty-one were included in the meta-analyses. Pooled odds ratio (OR) were used as a measure of effect and separately analysed for the two study designs. PRFs derived from case-control studies that were significantly associated with higher odds of outcome were “dog free to roam” (OR 5.23; 95% CI 2.45–11.14), “feeding dogs with viscera” (OR 4.69; 95% CI 3.02–7.29), “slaughter at home” (OR 4.67; 95% CI 2.02–10.78) or at “slaughterhouses” (OR 2.7; 95% CI 1.15–6.3), “dog ownership” (OR 3.54; 95% CI 1.27–9.85), “living in rural areas” (OR 1.83; 95% CI 1.16–2.9) and “low income” (OR 1.68; 95% CI 1.02–2.76). Statistically significant PRFs from cross-sectional studies with higher odds of outcome were “age >16 years” (OR 6.08; 95% CI 4.05–9.13), “living in rural areas” (OR 2.26; 95% CI 1.41–3.61), “being female” (OR 1.38; 95% CI 1.06–1.8) and “dog ownership” (OR 1.37; 95% CI 1.01–1.86).
Living in endemic rural areas, in which free roaming dogs have access to offal and being a dog-owner, seem to be among the most significant PRFs for acquiring this parasitic infection. Results of data analysed here may contribute to our understanding of the PRFs for CE and may potentially be useful in planning community interventions aimed at controlling CE in endemic areas.
Cystic echinococcosis (CE) is a chronic zoonotic disease causing serious global socio-economic losses in human and animal hosts. Two main aspects make it extremely difficult to study risk factors associated with human CE, the parasite’s unknown and apparently long incubation period which may last for several years, and the predominantly fecal-oral transmission route. This systematic review (SR) summarizes findings from relevant publications on this topic and provides a detailed list of potential risk factors (PRFs) associated with CE infection in humans. Free dog roaming, dogs having access to offal, being a dog-owner and slaughtering at home or using inadequately supervised slaughterhouses have all been shown to be highly statistically significant PRFs associated with the perpetuation of the parasite life cycle in endemic areas. The effect of other risk factors identified in this SR can vary between geographically different areas and societies and could reflect socio-cultural determinants of infection.
Cystic echinococcosis (CE), caused by the metacestode stage of the tapeworm
Humans become infected through the ingestion of
The multi-host ecology and genotypic diversity of
The geographical distribution and endemicity of CE differs by country and region and is influenced by different biotic and abiotic factors. Human infection in endemic regions also depends on a number of behavioral and socio-economic variables favoring close contact with parasite eggs [
The poorly understood and apparently long incubation period of this parasitic infection (which in most cases is lifelong), make it difficult to study risk factors associated with human CE. In addition, the fecal-oral route of transmission by direct oral uptake of
The objective of this research was to conduct a systematic review (SR) and meta-analyses of studies evaluating potential risk factors (PRFs) of CE using the Cochrane and PRISMA Group guidelines. This SR summarizes the findings of relevant publications on this topic, synthesizing the PRFs associated with CE infection in humans.
The online search was carried out by combining keywords using Boolean operators AND/OR, “?” and “#”. The question mark (?), when used, expanded the search by looking for words with similar prefixes using more than one letter whereas the hash mark (#) expanded the search by looking for words with similar prefixes using one letter. The strategy developed in PubMed/Medline used queries for papers reporting abstracts on risk factors related to human CE. Thus, the final terms used for the search were “[echinococcus granulosus OR (echinococcus AND granulosus) OR e# granulosus OR cystic echinococcosis OR c# echinococcosis OR hydatidosis OR hydatid disease OR echinococcal] AND [risk factor# OR risk# OR exposure] AND [human# OR people OR person OR man OR men OR women OR woman OR patient# OR case# OR human population]”.
Primary research studies published or in press were considered eligible for inclusion. Other inclusion criteria based on study design were case-control, cross-sectional and cohort studies. Exclusion criteria included review articles, letters, editorials or opinion papers not containing primary data, duplicated data and studies on other echinococcosis causative agents (e.g.
This SR and meta-analysis followed the Cochrane and PRISMA Group guidelines [
The quality of the studies included in this review was evaluated by two independent researchers using the Newcastle-Ottawa Scale (NOS) according to the Cochrane Handbook for Systematic Reviews [
Statistical analysis was performed using the software Review Manager 5.2 (RevMan Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014;
The literature search used in this study identified a total of 1,367 potentially relevant papers. Following an initial screening by title and abstract, 1,061 papers were excluded and 251 were retained for full text analysis (
Of the cross-sectional studies, thirteen used ultrasonography as the reference method for CE detection, whereas only serology or ultrasonography and serology were used in the remaining sixteen papers. Meta-analyses were performed separately on cross-sectional studies reporting ultrasonography as the detection method and case-control studies using imaging techniques (ultrasonography and X-ray), or interventions (surgery and percutaneous techniques). Among the thirty-seven eligible papers, twenty-one (case-control studies n = 8; cross-sectional studies n = 13) were used for the meta-analyses (
When studies were conducted using different diagnostic methods, or performed using different groups of individuals (for example adults versus children) at different time intervals (e.g. in different years or months) they were divided into sub-studies and each sub-study was analysed separately.
Fourteen risk factors were identified from case-control studies and meta-analysis was performed on eight of the included papers. Studies originated from Argentina (n = 1), Egypt (n = 1), Jordan (n = 1), Lebanon (n = 1), Peru (n = 1), Spain (n = 1), Turkey (n = 1) and Yemen (n = 1). These were hospital-based retrospective studies using control groups that were not affected by CE, recruited at hospital level and had similar demographic characteristics as those of the CE patients. Potential risk factors grouped in this meta-analysis were as follows: five were dog related (“dog free to roam”, “feeding dogs with viscera”, “having dog contact”, “dog ownership”, “dog dewormed infrequently or never”), three food- and water-borne related (“eating raw/unwashed vegetables”, “having a kitchen garden”, “drinking tap/piped water”), and six were socio-culturally related (“low income”, “low education”, “herding”, “slaughter at home” or at “slaughterhouses”, and “living in rural areas”). “Low education”, as described in the included sub-studies, was differentiated into primary (or lower) versus secondary education (or higher). The definition of “low-income” was based on direct socio-economic indicators such as receiving social and food aid from the state or indirect indicators such as not having a stone house or a telephone.
Seven PRFs were statistically significant (test for overall effect,
Three PRFs increased the odds of infection but the results were not statistically significant: “dog contact” (OR 3.74; 95% CI 0.41–33.96;
For four PRFs, it was not possible to determine their effect on odds of infection: “dog dewormed infrequently or never” (OR 1.08; 95% CI 0.47–2.49;
PRFs meta-analysed for case-control studies are summarized in
Potential risk factor | Effect model | Odds ratio [95% CI] | Overall effect | N° of sub-studies included |
---|---|---|---|---|
(M-H, Random) | 3.74 [0.41–33.96] | p = 0.24 | 2 | |
(M-H, Fixed) | 1.39 [0.89–2.16] | P = 0.15 | 4 | |
(M-H, Random) | 1.33 [0.80–2.21] | p = 0.27 | 8 | |
(M-H, Fixed) | 1.08 [0.47–2.49] | p = 0.86 | 2 | |
(M-H, Fixed) | 0.79 [0.40–1.56] | P = 0.5 | 4 | |
(M-H, Random) | 0.61 [0.18–2.09] | p = 0.43 | 2 | |
(M-H, Random) | 0.60 [0.05–7.18] | p = 0.68 | 4 |
Bold: significantly increase odds of infection
*: increase odds of infection but not significantly
§: no evidence of impact on infection risk.
Eighteen PRFs were grouped from cross-sectional studies and meta-analysis was performed on thirteen of the twenty-nine included papers which originated from Argentina (n = 2), Canada (n = 1), China (n = 8), China and Mongolia (n = 1), Chile (n = 1), Greece (n = 1), India (n = 1), Iran (n = 5), Jordan (n = 1), Kyrgyzstan (n = 1), Libya (n = 1), Sudan (n = 1), Tunisia (n = 1), Turkey (n = 3) and Uruguay (n = 1). All these cross-sectional studies were community-based ultrasonography surveys. Potential risk factors evaluated in this meta-analysis were: two dog related (“dog ownership”, “feeding dogs with viscera”), five food- and water-borne related (“eating raw/unwashed vegetables”, “drinking well water”, “drinking spring water”, “drinking unboiled water”, “drinking tap/piped water”), two related to working activities (“livestock owner”, “being a farmer”), seven socio-culturally related (“slaughter at home”, “belonging to ethnic group Han”, “low income”, “low education”, “living in rural areas”) and five miscellaneous factors (“age >16 years”, “being female”, having “no knowledge on
Four PRFs were statistically significant (test for overall effect,
Eight PRFs appeared to increase the odds of infection but results were not statistically significant. These were “belonging to ethnic group Han” (OR 2.19; 95% CI 0.66–7.26;
For six PRFs, it was not clear whether they effected odds of infection: “eating raw/unwashed vegetables” (OR 1.13; 95% CI 0.63–2.05;
Potential risk factor | Effect model | Odds ratio [95% CI] | Overall effect | N° of sub-studies included |
---|---|---|---|---|
(M-H, Random) | 3.12 [0.19–51.32] | p = 0.43 | 2 | |
(M-H, Random) | 2.19 [0.66–7.26] | p = 0.2 | 4 | |
(M-H, Random) | 2.18 [0.66–7.22] | p = 0.2 | 3 | |
(M-H, Fixed) | 1.52 [0.88–2.62] | p = 0.13 | 3 | |
(M-H, Fixed) | 1.51 [0.93–2.47] | p = 0.1 | 2 | |
(M-H, Fixed) | 1.45 [0.72–2.91] | p = 0.3 | 2 | |
(M-H, Fixed) | 1.25 [0.89–1.75] | p = 0.2 | 2 | |
(M-H, Fixed) | 1.19 [0.94–1.50] | p = 0.15 | 4 | |
(M-H, Fixed) | 1.13 [0.63–2.05] | p = 0.68 | 2 | |
(M-H, Fixed) | 1.07 [0.63–1.81] | p = 0.8 | 3 | |
(M-H, Fixed) | 0.99 [0.70–1.40] | p = 0.96 | 5 | |
(M-H, Fixed) | 0.80 [0.60–1.06] | p = 0.12 | 2 | |
(M-H, Fixed) | 0.67 [0.43–1.06] | p = 0.08 | 3 | |
(M-H, Random) | 0.23 [0.05–1.07] | p = 0.06 | 2 |
*: increase odds of infection but not significantly
§: no evidence of impact on potential infection risk.
For case-control studies, it was interesting to note that PRFs dealing with the perpetuation of the parasite life cycle between dogs and sheep are among the most statistically significant risk factors highlighted in this SR (test for overall effect,
In blue: possible vertical and horizontal interventions aimed at decreasing or interrupting the transmission of CE to humans.
Potential risk factors increasing the odds of acquiring CE infection but having a weak and non-statistically significant association such as “dog contact” (I2 = 78%), “low education” (I2 = 0) and “herding” (I2 = 62%), demonstrated variable heterogeneity between studies. Contrary to “dog ownership”, for which a strong association was detected, “dog contact” seemed to present a lower probability of exposure to infection. However, socio-cultural factors that influence degree of dog contact such as "low education” and “herding” may represent confounding factors.
For the remaining PRFs such as “dogs dewormed infrequently or never” (I2 = 46%), “eating raw/unwashed vegetables” (I2 = 0), “having a kitchen garden” (I2 = 74%) and “drinking tap/piped water” (I2 = 89%) for which the statistical association was weak and non-significant, the heterogeneity of studies was variable. Results from case-control studies analysed in this SR do not provide significant evidence to indicate that CE is a strictly food- or water-borne disease.
Regarding cross-sectional studies, the identified associations were more difficult to interpret due to the potential selection bias typically introduced by this study design, especially regarding age and gender.
Among the PRFs showing statistically significant evidence of increasing odds of CE infection, the heterogeneity of the studies were quite high for “age >16 years” (I2 = 55%), “living in rural areas” (I2 = 60%), “being female” (I2 = 62%) and “dog ownership” (I2 = 67%). Among potential confounding factors, “age > 16” may be linked to the chronic course of this parasitic disease that may remain asymptomatic for years. In fact, CE can be detected by chance years after the initial infection, for instance because the probability of being examined by ultrasound increases with age. With regards to “being female”, although a potential confounding factor, some activities executed by women in rural endemic areas, such as feeding and handling of dogs, could also reflect a higher exposure to the parasite.
Results regarding the PRFs which increase the odds of infections with a weak and non-significant association such as “belonging to ethnic group Han” (I2 = 87%), “being a farmer” (I2 = 78%), “feeding dogs with viscera” (I2 = 0), “drinking spring water (I2 = 0), “low income” (I2 = 41%) and “low education” (I2 = 82%), the heterogeneity of studies was variable. These PRFs showed no statistically significant association and may be regarded as socio-economic determinants which could potentially influence people’s exposure and vulnerability to non-communicable diseases and may be considered both drivers as well as confounding factors [
The PRFs for which there was no evidence of an impact on CE infection risk and no significant association, mostly demonstrated high variability in heterogeneity of studies such as “eating raw/unwashed vegetables” (I2 = 44%), “drinking tap/piped water” (I2 = 0), “livestock owner” (I2 = 0), “drinking unboiled water” (I2 = 64%), “drinking well water” (I2 = 0%) and having “no knowledge on
Observational studies (such as case-controls and cross-sectional) have intrinsic limits and advantages that should be taken into account during the evaluation of PRFs for acquiring CE. For instance, case-control studies are cost effective and efficient in the study of rare diseases with long latency periods such as CE, but they are particularly prone to selection, recall and observational bias. Moreover, the temporal sequence between exposure and disease may be difficult to determine in these studies [
On the other hand, cross-sectional studies are relatively quick and easy to conduct and are good for descriptive analyses and for generating hypotheses [
It is noteworthy that for certain PRFs, such as “age” and “gender”, a spurious association can be present between a given PRF and CE, as a result of the influence of other confounding variables. For instance, “age” could be considered a confounder because CE is asymptomatic or paucisymptomatic for years, thus the probability of detecting the disease increases with age. Similarly, women are usually numerically more represented during ultrasonography screening than men, which increases the possibility of having a gender selection bias during sampling. In this sense, some of the PRFs reported above may represent potential confounders introducing bias in observational studies. Unfortunately, in the current meta-analysis only aggregated data were available both for case-control and cross-sectional studies, thus the confounding effect on PRFs due to other variables could not be adjusted.
In addition, enforcing a language constraint on the literature search such as that used in this study, may have restricted the retrieval of material published in other languages. However, it is widely perceived that relevant peer reviewed studies are published in English, for example even though Chinese was excluded from the language search, the highest number of retrieved studies used for data extraction and meta-analysis had originated from China (n = 9). Furthermore, a recent study on the effect of language restriction on systematic review-based meta-analyses in conventional medicine found no evidence of bias as a result of language restriction [
This meta-analysis identified a number of PRFs that were statistically associated with higher odds of acquiring CE infection. Although control measures adopted by several countries to interrupt the life cycle of
Several PRFs with relatively high odds ratio reported in this SR may explain how dogs can acquire echinococcosis (e.g., “dog free to roam”, “feeding dogs with viscera”, “slaughter at home) but are not able to elucidate the main pathways of CE transmission to humans. Although these pathways remain unclear, the majority of the PRFs associated with CE are related to dogs which probably represent the most important source of infection for humans [
Results of this SR seem to suggest that the direct or indirect contamination of hands with
In addition, some pathways of transmission identified in this SR can vary between geographically different areas and societies and could reflect socio-cultural determinants of infection, for example “belonging to ethnic group Han”. Additionally, a number of socio-cultural determinants highlighted in this SR, such as “dog dewormed infrequently or never” and having “no knowledge on
Surprisingly, two of the main integrated strategies usually applied in control campaigns against CE (education and dog deworming) showed no clear statistical relationship with human infection in this SR. In fact, with the exception of the Icelandic hydatid campaign, health education for prevention of CE on its own has shown little influence in the reduction of
In general, interventions aimed at mitigating or interrupting the transmission of CE mainly focus on improvement of hygiene at abattoirs, implementing education campaigns and primary health care, deworming of dogs with praziquantel, vaccination of sheep and culling of aged sheep [
Parasitic infections including CE are typically associated with poor and often marginalized communities. Most interventions on CE are tailored to indirectly decrease the burden of CE in humans through vertical interventions in animals [
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We are grateful to Bernadette Abela-Ridder (WHO, Department of Control of Neglected Tropical Diseases, Geneva) for championing the preparation of this manuscript. We are grateful to Rosaria Rosanna Cammarano, Information Specialist (Documentation Centre, Istituto Superiore di Sanità, Rome, Italy) for performing the literature search. Finally, the authors would like to thank Patrizio Pezzotti (Istituto Superiore di Sanità, Rome, Italy) for evaluating our statistical approach. This work was also supported by the European Union Reference Laboratory for Parasites (EURLP).