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One Health Scoping Review of the Epidemiology of Human Fascioliasis across Africa for the Period 2000–2022

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Submitted:

23 April 2024

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25 April 2024

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Abstract
(1)Background: Fascioliasis is considered a neglected tropical disease affecting an estimated 17 million people in more than 70 countries worldwide. The highest prevalence of human fascioliasis is found in regions where livestock farming and consumption of raw or undercooked freshwater plants are common, such as parts of Africa, Asia, Europe, and Latin America. It is responsible for over 90,000 disability-adjusted years of life due to associated abdominal complications. We conducted a study to investigate the prevalence of human fascioliasis through a systematic review and meta-analysis of all available literature in Sun-Saharan Africa.(2). Methods: We screened a total of 126 publications using pubmed online search engine databases; Web of Science and CAB for articles published within a 20-year period between 2000 and 2022. We used a comprehensive search method using a combination of terms, parasite and disease names. The initial search resulted in a screening of articles by title, abstracts and full texts. The relevant information on the prevalence of human fascioliasis in Africa was extracted. Of the 126 publications, 33 articles were selected for meta-analysis. The essential information required was extracted from these documents and determined through statistical analysis in Microsoft Excel for calculating the prevalence of human fascioliasis in sub-Saharan Africa. The variance of each study was assessed using a bimodal distribution and heterogeneity assessment using a I2 index. Analysis was performed using random effects models.(3)Results: A total of 271 articles were searched through the database search and 33 articles were eligible studies that provided qualitative information on the prevalence of human fascioliasis in Africa. These make up 12.17% (n=33). The pooled prevalence estimates for human fascioliasis are 0.032% (IVhet PPE: 0.032% (95%CI 1.4-6.53). The highest prevalence rate was observed in Egypt with a prevalence of 100%. The prevalence of human fascioliasis is very high in some sub-Saharan countries, partly due to neglect of diagnostics, demonstrating the bias of available information for decision-making in human fascioliasis across Africa, given the spatial presence, scarcity and incompleteness are region.(4)Conclusions: The prevalence of Human fascioliasis is very high in some Sub-Saharan Countries partly due to neglect in diagnostics. This presents how highly focal with spatial occurrences, scarcity and patchy the available information for decision making is on Human fascioliasis across the Sub-Saharan African region.
Keywords: 
Subject: Public Health and Healthcare  -   Other

The Scoping Review and Analysis Has Observed the Following Strengths and Limitations

The rigorous and comprehensiveness search methodology of existing studies provided large datasets for standardized statistical pool analysis where a robust conclusion was drawn.
The review highlighted the current burden of fascioliasis in humans in Africa.
There is increased generalizability as datasets were derived from a collection of multiple African countries and longer identification of trends over time (2000-2022). This increased the statistical power and reduced bias.
There shortcomings to this review by the impossibility of disaggregating the datasets relating to sample sizes, diagnostic methods, data scarcity from African Countries, heterogeneity due to environmental, cultural and socioeconomic factors of the disease that affect drawing conclusions.

Introduction

Fascioliasis is a parasitic zoonosis caused by liver flukes of the genus Fasciola that infects both humans and ruminants worldwide [1,2,3]. Human fascioliasis infection causes significant liver obstruction and biliary inflammation in affected patients [1,2,3]. The disease occurs in travelers and immigrants from endemic areas and in sporadic outbreaks due to environmental or social changes. Worldwide, over 17 million people are infected and 180 million are at risk of infection, from over 70 countries including Europe, Asia, Africa, Oceania and the Americas worldwide [1,2,3]. The global burden is underestimated due to the lack of reliable diagnostic tools and monitoring systems as well as low awareness and recognition among health professionals and the general public [4,5,6]. This parasite has a complex life cycle involving an intermediate host of the family Lymnaeidae [1,2,3], an aquatic freshwater plant that acts as a carrier, and a mammalian host like Sheep, goats, cattle and humans [1,2,3]. The infection is responsible for the development of symptoms such as urticaria, eosinophilia and malaise and can also lead to chronic diseases in humans and ruminants [1,2,3]. Human fascioliasis infections are becoming a neglected zoonotic disease across Africa [1,2,3] and are responsible for over 90,000 disability adjusted life years (DALYS) lost associated abdominal complications [1,2,3].
The prevalence of human fascioliasis infections has been reported in over 17 African countries, including Algeria [7], Angola [7], Cape Verde Islands [7], Chad, Egypt, Ethiopia, Djibouti [7], Ghana [7], Libya [8], 1998), Morocco [8], Nigeria, Senegal [9], South Africa [10], Swaziland [10], Tunisia [11], the United Republic Tanzania [12] and Zimbabwe [13] in Africa [1,2,3], which negatively affects the good health of the human and animal population [14].The Epidemiology of fascioliasis depends on the intermediate host snails of the family Lymnaeidae. Diagnosis relies on a number of techniques; using the standard sedimentation method of stool samples for egg concentration, followed by microscopy [15], coproantigen testing using stool samples [16] and antibody detection in blood serum using ELISA [17,18], meat inspections [19] through morphological identification of the adult Fasciola parasites with F.gigantica with a typical, leaf-shaped, dorsoventrally flattened, longer, narrower body of 28–52mm, while F. hepatica is significantly shorter at 12–29mm [20,21]. PCR-based tools provide the best molecular markers for diagnosing and distinguishing the two types of Fasciola infections [22,23,24] in Lymnaeid Snails [25].
The prevention and control of fascioliasis in both animals and humans depends heavily on the use of antiheminthic, with the following approved for regular deworming of animals: triclabendazole, closantel or nitroxynil and the use of triclabendazole in both chronic and acute forms of human infections [26,27]. In addition, health education campaigns aimed at empowering farmers to practice animal hygiene and ensure regular deworming are crucial, alongside established surveillance systems to detect, monitor and report outbreaks. Freshwater snails of the Lymnaeid group play an important role in the maintenance and transmission of fascioliasis [25,28], which has a significant economic impact [29] and biomedical burden [13] worldwide, especially in bovine fascioliasis [30,31]. The transmission potentials are favored by the local tolerance of Lymnaeid snails [32], which therefore requires a precise localization of their epidemiological distribution and identification, which is crucial to combat the infections.
In animals, the infection tends to show a notable reduction in milk production as well as weak reproductive rates [33] with significant associated costs of treatment and meat condemnation, which represent a very large economic loss to the farmer [34,35,36]. While human infections are reported as symptomatic, more non-specific symptoms such as fever, abdominal pain, diarrhea and nausea are reported in individuals during the acute or chronic form of the infections [37,38]. Many studies have documented the prevalence of the infection in domestic and wild populations throughout Africa [39]. However, there is little data on its prevalence in humans across the African region.

Methods and Methods

This study aimed to investigate the prevalence of human fascioliasis through a systematic review and meta-analysis of all available literature in the African region during 2000-2022. The primary outcome of the systematic review and meta-analysis should be available datasets on the prevalence of human fascioliasis in Africa. Secondary outcomes included reviewing available diagnostic methods to estimate the prevalence of infections across the African region.
Information sources and searching approach: A systematic review was performed with the objective of mapping out all the relevant literature needed for the study on Human fascioliasis and intermediate vector snails across Africa. All the publications relevant over 20 year period between 2000-2022were searched using the databases from pubmed, web of science and CAB. The study conducted an online search using the following words “fascioliasis,” “human fascioliasis,” “zoonosis,” “Fasciola liverfluke,” “Fasciola hepatica,” “Fasciola gigantic,” “human fascioliasis epidemiology,” “human fascioliasis distribution,” “research trends in “human fascioliasis,” and “fascioliasis outbreaks in Africa”
Study Materials and Eligibility: All the datasets required for this review were generated from the various databases and later merged into a single one. This helped remove and eliminate duplicate downloads from the records. The reviews were sorted by title and abstract. All articles that focused on non-human fascioliasis and Lymnaeid datasets will be removed from the analysis. The full texts of the remaining study texts follow the admission criteria. The following criteria were used to exclude the reviewed studies:
Reporting parasites other than F.gigantica or F.hepatica across Africa.
Duplicate datasets were removed from the analysis.
All of these followed the PRISMA guideline for reporting systematic and meta-analysis reviews as previously described [40].
Data processing and quality assessments: All retrieved articles were classified based on the following characteristics: study period, population, prevalence, diagnostics used, observed outcomes, and risk factors associated with human fascioliasis. While species identified in the Lymnaeid snails are included in the study, the numbers infected with Fasciola infections are checked. This study also considered article publication years for impact factor and index citations. All records were entered into preformatted tables. The study also conducted quality assessments for all population-based human fascioliasis surveys using the Prevalence Critical Appraisal Tool [41].
Summary measures and synthesis of results: The study examined a total of 126 publications. All populations based on the studies were screened for a descriptive analysis of the populations infected with human fascioliasis to determine the proportion of infected individuals. The magnitude of significance associations was determined using Wilson’s score at 95%CI for subjects infected with fascioliasis. We performed chi-square tests to determine associations between risk factors for fascioliasis infections in humans and their presence. Odds ratios and associated Wilsons score at 95%CI were also determined.

Results

A total of 271 articles were searched through the database search. An additional 10 records were identified from other sources and 33 articles were eligible studies that provided qualitative information on the prevalence of human fascioliasis in Africa (Figure 1). After duplicate records were deleted from the system database, a total of 85 records were retained and subjected to a further verification process. At this point, we determined that 26 datasets were ineligible based on the exclusion criteria and were excluded from the final qualitative review and analysis. The final database contained a total of 33 articles that were considered for further synthesis. In total, a total of 33 (n=33) articles were included for full review in the systematic and meta-analytic review of human fascioliasis. Of 26 (n=26) studies, 78.8% were from Egypt, seven were from Nigeria (n=07), which 21.2%, while a single study was conducted in the remaining countries where studies on human fascioliasis were conducted including Angola (n=01), Ethiopia (n=01), Ghana (n=01), South Africa (n=01), Tanzania (n=01) and Tunisia (n=01).
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Figure 1. Showing PRISMA Flow of Study Selection. Studies were assessed using a 10-point Quality Index scorecard (Qi). Results were rated on a scale of 1-4 as low, 5-6 as moderate and 7-10 as high. The final analysis revealed that 9 studies from Egypt (n=06), Nigeria (n=02) and Tunisia (n=01) were rated as high. The majority (n=20) of studies from Egypt (n=14), Nigeria (n=02), South Africa (n=03) were rated as low and thirteen from Angola (n=01) were rated as moderate. Egypt (n=06), Ethiopia (n=01), Ghana (n=01), Nigeria (n=01) and Tanzania (n=01).
Figure 1. Showing PRISMA Flow of Study Selection. Studies were assessed using a 10-point Quality Index scorecard (Qi). Results were rated on a scale of 1-4 as low, 5-6 as moderate and 7-10 as high. The final analysis revealed that 9 studies from Egypt (n=06), Nigeria (n=02) and Tunisia (n=01) were rated as high. The majority (n=20) of studies from Egypt (n=14), Nigeria (n=02), South Africa (n=03) were rated as low and thirteen from Angola (n=01) were rated as moderate. Egypt (n=06), Ethiopia (n=01), Ghana (n=01), Nigeria (n=01) and Tanzania (n=01).
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Table 1. Showing characteristics of the Studies included in the Qi Analysis on human Fascioliasis across Africa 2000-2022.
Table 1. Showing characteristics of the Studies included in the Qi Analysis on human Fascioliasis across Africa 2000-2022.
Author Name Sample Size & (%) Country Year Article type %Qi Evaluation Citation
Abaver et al.,2012 480(1.04) Nigeria 2012 Clinical Reviews 50.0 low [42]
Abo-Madyan et al.,2004 1,019(1.67) Egypt 2004 clinical trial 50.0 low [43]
Abou-Basha et al.,2000 2,492(4.45) Egypt 2000 Clinical Reviews 40.0 low [44]
Adarosy et al.,2013a 1,868(0,59) Egypt 2013 clinical trial 30.0 low [45]
Adarosy et al.,2013b 1,868(1.07) Egypt 2013 clinical trial 30.0 low [45]
Adarosy et al.,2013c 1,868(0.75) Egypt 2013 clinical trial 30.0 low [45]
Arinola et al.,2015 349(0.29) Nigeria 2015 Impact Evaluation 37.5 high [46]
Black et al. 2013a 3(33.33) South Africa 2013 Case report article 30.0 low [47]
Black et al.,2013b 3(66.67) South Africa 2013 Case report article 30.0 low [47]
Curtale et al.,2000 8,854(2.88) Egypt 2000 Parasitological Reviews 62.5 moderate [48]
Curtale et al.,2003 1,331(5.41) Egypt 2003 Crossectional Survey 80.0 low [49]
de Alegría et al.,2017 372(0.27) Angola 2017 Crossectional Survey 100.0 moderate [50]
El Shazly et al.,2006 3,180(4.78) Egypt 2006 Parasitological Survey 12.5 high [51]
El-Karaksy et al.,2018 4,475(0.85) Egypt 2018 Clinical Reviews 37.5 high [52]
el-Shazly et al.,2001 605(52.56) Egypt 2001 clinical trial 37.5 moderate [53]
El-Shazly et al.,2002a 1,000(8.20) Egypt 2002 Serological Evaluation 50.0 moderate [54]
El-Shazly et al.,2002b 6(33.33) Egypt 2002 Rectal Biospy 50.0 moderate [55]
el-Shazly et al.,2006 1,000(0.40) Egypt 2006 Clinical Reviews 37.5 low [54]
El-Shazly et al.,2009 3,000(3.27) Egypt 2009 Clinical Reviews 33.3 low [53]
Esteban et al.,2003 678(19.03) Egypt 2003 Clinical Reviews 70.0 low [56]
Fawzi et al.,2004 575(2.43) Egypt 2004 Public Health Reviews 55.6 moderate [57]
Fawzi et al.,2004 575 Egypt 2004 Crossectional Survey 50.0 high [57]
Fentie et al.,2013 520(3.27) Ethiopia 2013 Crossectional Survey 90.0 moderate [58]
Hammami et al.,2007 30(6.67) Tunisia 2007 Crossectional Survey 25.0 high [59]
Ihesiulor et al.,2013 570(0.88) Nigeria 2013 Parasitological Reviews 37.5 moderate [60]
Ijagbone et al.,2006 533(0.56) Nigeria 2006 Parasitological Survey 44.4 moderate [61]
Keiser et al.,2011 1,215(3.37) Egypt 2011 clinical trial 62.5 moderate [62]
Lukambagire et al.,2015 1,460(20.89) Tanzania 2015 Crossectional Survey 55.6 moderate [12]
Mas-Coma.2004 7,071(6.84) Africa 2004 research article 30.0 low [39]
Mekky et al.,2015a 23(8.70) Egypt 2015 research article 25.0 low [63]
Mekky et al.,2015b 23(100) Egypt 2015 research article 80.0 high [63]
Mekky et al.,2015c 23(100) Egypt 2015 research article 80.0 high [63]
Mekky et al.,2015d 23(65.22) Egypt 2015 research article 80.0 high [63]
Mekky et al.,2015e 23(13.04) Egypt 2015 research article 37.5 low [63]
Mekky et al.,2015f 23(13.04) Egypt 2015 research article 37.5 low [63]
Na’acha et al.,2017 438(0.46) Nigeria 2017 Crossectional Survey 50.0 high [64]
Nxasana et al.,2013 162(0.62) South Africa 2013 Crossectional Survey 87.5 low [65]
Okaka et al.,2000 6,430(2.32) Nigeria 2000 Public Health Reviews 25.0 moderate [66]
Osman et al.,2011 6,214(2.29) Egypt 2011 Impact Evaluation 62.5 low [67]
Periago et al.,2021 6,657(1.44) Egypt 2021 Crossectional Survey 12.5 high [68]
Shitta et al.,2017 254(33.07) Nigeria 2017 Crossectional Survey 50.0 low [69]
Soliman,2008 3,000(3.0) Egypt 2008 research article 30.0 low [70]
Squire et al.,2018 95(1.05) Ghana 2018 Parasitological Survey 50.0 moderate [71]
The pooled prevalence estimates (PPE) for human fascioliasis were 0.032% and the inverse variance quasi likelihood based alternative pooled prevalence estimates (IVhet PPE) at 0.032% (95% CI 1.4-5.3) and the statistic meta-analysis of prevalence worthwhile or worthless (I2) estimated at 98.7% (95% CI; 98.548-98.859) with Chi2, p=0.000.
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Figure 2. Showing Forest Plot for PPE Analysis for Human Fascioliasis in Africa for period 2000-2022.
Figure 2. Showing Forest Plot for PPE Analysis for Human Fascioliasis in Africa for period 2000-2022.
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Figure 3. Showing Funnel plot of the double arcsine transformed prevalence estimates of for Human Fascioliasis in Africa for period 2000-2022.
Figure 3. Showing Funnel plot of the double arcsine transformed prevalence estimates of for Human Fascioliasis in Africa for period 2000-2022.
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Discussions

Human fascioliasis is a parasitic disease caused by the liver fluke Fasciola hepatica or Fasciola gigantica. The disease affects people in over 70 countries worldwide, with an estimated 2.4 million people infected worldwide. In Africa, fascioliasis occurs primarily in areas where livestock grazing is common, such as the Nile Valley, the Ethiopian Highlands, and South Africa. The epidemiology of human fascioliasis in Africa is influenced by several environmental, ecological and climatic factors that influence the growth, development and survival of the parasite and its intermediate host. The disease has been shown to be a major plant-borne zoonosis in the high-altitude Andean rural regions of Bolivia and Peru [72], in the northern provinces of Iran bordering the Caspian Sea [73,74], Nile Delta region of Egypt [75] and Central provinces of Vietnam [76].
The results of our analysis and review suggest that several epidemiological studies on the transmission of human fascioliasis have been conducted in Africa [7,77]. This adds to the growing evidence that human fascioliasis infections are becoming a problem Across Africa as described in Egypt [70,72,78], Ethiopia [79,80,81], South Africa [47], Tanzania [82], Angola [83], Nigeria [7,84], Senegal [7], Ghana [7,85], Morocco [7,8], Algeria [7,86] and Tunisia [7,79,87]. This increase trend of infections and spread across African region could be due to a shift in consumption of raw vegetables and raw or partially cooked liver [88] and also the presence of available intermediate hosts of snails. The analysis further indicates that the trend of human fascioliasis in Africa varies depending on local conditions and transmission patterns; this has been observed to spread across the African region with significant adaptations by the intermediate Vector snails as previously described [89,90]. The transmission of the disease is primarily zoonotic, with people becoming infected through consumption of contaminated watercress or other vegetables [79].
Our analysis and reviews have further pointed that transmission is predominantly described as zoonotic and anthroponotic [79,91]. The overall trend analysis across Africa indicateda generally low and stable transition between 2-5 publication reported on Human Fascioliasis from 2000-2012 and a significant swift upto 10 publications from 2012-2015 and steady drop to 2 publications in 2021. For example, in Egypt over twenty six publications on human fascioliasis reported and Nigeria with seven on human fascioliasis reportedpublications which correspond to the Fascioliasis outbreaks.The epidemiology is also influenced by socioeconomic factors and public health interventions. Indeed our analysis revealed that Poverty, poor sanitation and lack of access to clean water is major driver to increased risk of infection with the parasite across all observed countries with reported cases [7,39].
One Health epidemiological underpinning for this scoping review in Africa: This study has highlighted epidemiological setting categorization into rural, urban, or rural-urban that drives the emergent zoonosis [92]. The people from the low- to middle-income countries are more likely to suffer from fascioliasis whereas those residents from developed countries are likely to become infected if they feed on imported infested vegetable plants that evade quarantine measures [92,93]. Similar observation have been reported in this scoping review especially during field trips to endemic countries, city dwellers were at high risk of infection due to fascioliasis [93,94]. The human feeding and dietary habits are also another cause to weary especially when the source of food and water consumed are linked to marsh vegetations with open and free range animal husbandry practices [94], this scoping review has highlighted this an important epidemiological factor of human fascioliasis. The unregulated and uncontrolled supplies of vegetable products (such as carrots, cucumbers, cabbage, onions, tomatoes, spinach, etc.) to markets coupled with drinking contaminated water and fruit drinks/juices made from local plants make humans vulnerable to infection as previously documented [94].
One Health Concept of the Fascioliasis Prevention and Control in Africa: One Health approach recognizes the interconnections between human health, animal health, and the environment, emphasizing the need for collaborative efforts across disciplines to address complex health issues like fascioliasis [95,96].The diagnosis relies on a number of techniques; with the standard sedimentation method of faecal samples for eggs concentration followed by microscopy [15], coproantigen tests using feacal samples [16] and antibody detections in blood serum by ELISA [17,18], Meat inspections [19] by morphological identifications of the adult Fasciola parasites with Fasciola hepatica with a typical leafy shaped dorso-ventrally flattened longer-narrower body measuring 28-52mm whilst Fasciola hepatica shorter measuring 12-29mm [20,21]. PCR based tools provide the best molecular markers for diagnosing and differentiating the two species of Fasciola infections [22,23,24] in Lymnaeid snails [25]. The prevention and control of Fascioliasis in both animal and human populations relies heavily on the use of antiheminthic drugs with the following approved for regular deworming of animals: triclabendazole, closantel or nitroxynil and use of triclabendazole in both chronic and acute forms of human infections [26,27]. Additionally, health education campaigns geared at equipping farmers to practice animal hygiene and ensure regular deworming alongside established surveillance systems to detect, monitor and report outbreaks are key and vital.
Observed theoretical Gap: Fascioliasis is an emerging neglected zoonotic disease [13,97] affecting the health and wellbeing of humans and animals [97,98]. The burden of the infection is not well defined with studies showing geographical expansion of the disease in human-animal population due to climate change [99,100,101,102]. This is likely to be uncovered through increase awareness and continued surveillance systems [103]. There is need for research in new adjuvants/therapeutic agents to tackle the challenges of emerging resistance to triclabendazole treatment. Future research into genomics and molecular biology could be a fruitful area of investigations to bridge the theoretical gap in treatments.
Observed methodological Gap: There are studies that have assessed the global linkage of climate change [97] and annual prevalence of Fasciolasis at 0.45% (95%CL: 0.35-0.56) [104]. Other studies by [105] were able to highlight the significant role played by bibliometric document visualization and analysis where reporting steady increases in publications which corresponds to the Fascioliasis outbreaks between 1913 to 2021 although there was a sharp increase reported between 1965 to 1985 that explains the deadly outbreak in Britain and Europe at the time [105].These findings are similar to trends observed in our analysis reported here. There is lack of a standardized diagnostic tool as many diagnostics are reportedly used in different scenarios ranging from microscopy, serological tests and ELISA each with varying degrees of sensitivities and specificities. There are challenges in the differential assessments of acute versus chronic infections as well as differentiating a symptomatic and subclinical form of the disease which are missed during the surveys [106]. There are gaps in the reliability of data collection systems that incorrectly capture and report data often siloed to veterinary level reporting.

Conclusion

In summary, the epidemiology of human fascioliasis in Africa is complex and influenced by various factors. A better understanding of the epidemiology of the disease is critical to developing effective control strategies and reducing the burden of disease in affected communities. Mass administrations of drugs, improved sanitation, and health education programs have been effective in reducing the prevalence of human fascioliasis in some countries. However, sustained efforts are needed to control the disease in areas where it remains a public health problem. The results suggest that the burden of disease is underestimated due to a number of factors; Lack of reliable diagnostic tools, adequate surveillance systems, lack of denominator for cases tracked, low awareness and recognition among health professionals and the general public. This requires increased multispectral collaboration using a One Health approach.
Fascioliasis has emerged as an important foodborne disease with human and zoonotic importance. Climate change together with emerging drug resistance and development of new parasite strains through hybridization are becoming serious threats and challenges likely to impact and potentially change the climate driven epidemiology of Fascioliasis disease in years to come. Therefore, its prudent that researchers must double the synergies towards research and innovations to develop promising vaccines that will be the margin bullet to provide the maximum required protection to livestock and humans.

Author Contributions

MA: EMT,MBM, DM,SN,PV,LM, MP, TM, KC, Conceptualized and designed the study, MA, EMT,MBM, DM, SN,PV,LM, MP, TM, KC, SM, MJC, ASS and BV, MA, EMT,MBM, DM, SN,PV,LM, MP, TM, collected the data, prepared it and proposed an analysis plan and interpreted the results. MA, EMT,MBM, DM, SN, PV and LM wrote the first drafted the manuscript. All the authors read, revised and approved the final manuscript.

Funding

This manuscript is part of PhD write up and the PhD study received financial support from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 101000365.

Institutional Review Board Statement

Data used in the current study were generated from already published articles and followed the guidelines for systematic review and meta-analysis guideline and appropriate acknowledgements to authorship cited.

Informed Consent Statement

Not applicable

Data Availability Statement

The datasets generated and analyzed during the review are available and attached. Further details are on satisfactory request.

Acknowledgments

The authors thank for their contribution to this manuscript. We also acknowledge the contribution of all authors whose work citations provided us with a solid basis for these systematic reviews and analyzes of the manuscript. This scholarship received financial support from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 101000365.

Conflicts of Interest

The authors declare that there are no conflicts of interest in the authorship of this publication.

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