key: cord-0803387-n3irdy0x authors: Vonesch, Nicoletta; Binazzi, Alessandra; Bonafede, Michela; Melis, Paola; Ruggieri, Anna; Iavicoli, Sergio; Tomao, Paola title: Emerging zoonotic viral infections of occupational health importance date: 2019-03-27 journal: Pathog Dis DOI: 10.1093/femspd/ftz018 sha: f65137c0c8dc11b570fda8d44047edeccf49c297 doc_id: 803387 cord_uid: n3irdy0x Emerging viral infections represent a public health risk pointed out by the spreading of pathogens with potential zoonotic risk. Moreover, the risk of zoonosis has probably been underestimated in occupational settings. A literature review between 2007 and 2018 was performed to identify evidences concerning the epidemiological associations between some emerging viruses and occupational diseases. Observational studies and case-reports were selected and analyzed. West Nile Virus (WNV) disease, Crimean-Congo Hemorrhagic Fever (CCHF) disease and Hepatitis E virus (HEV) infection were included in the review for their potential zoonotic transmission. The most important risk factor for acquiring WNV infection and CCHF infection is the exposure to infected mosquitoes and ticks, respectively; therefore, outdoor workers are at risk of infection. HEV is responsible for epidemics and endemics of acute hepatitis in humans, that can become infected through waterborne, foodborne and zoonotic transmission routes. A total of 10, 34 and 45 eligible studies for WNV, CCHF virus (CCFHV) and HEV, respectively, were analyzed by year, country, study design, risk group and outcomes. The occupational risk groups mainly included farm and agricultural workers, veterinarians, slaughterers, animal handlers, healthcare workers and soldiers. These findings support the need to develop effective interventions to prevent transmission of emerging viruses. It is well known that most infectious diseases in humans originate in animals, and the frequency of such diseases, named zoonoses, has been increasing over time (Belay et al. 2017) . A joint consultation of WHO/FAO/OIE held in 2004 (WHO 2004) defined emerging zoonosis as 'a zoonosis that is newly recognized or newly evolved, or that has occurred previously but shows an increase in incidence or expansion in geographical, host or vector range'. Drivers responsible for the emergence of zoonotic diseases include climate and environmental changes, human behavior, farming and trading practices, vector distribution and characteristics of the pathogens. Many zoonosis emerge from wildlife species, e.g. Severe Acute Respiratory Syndrome Coronavirus raised from bats and transmitted to civets before affecting humans. Examples of zoonotic virus of other origin include West Nile Virus (WNV), Chikungunya virus and Crimean-Congo Hemorrhagic Fever Virus (CCHFV), responsible for diseases with a high impact on public health (Wang and Crameri 2014; Belay et al. 2017) . Hepatitis E virus (HEV) had been considered a sanitation problem in resource limited countries; however, the zoonotic form has emerged in industrialized countries with high seroprevalence, as detected in swine abattoir workers (Ukuli and Mugimba 2017) . Recent epidemiological data on zoonosis are also of concern regarding the occupational medicine. Mitigating the impact of viral emerging zoonotic diseases of occupational health importance is difficult because of several work and economic conditions worldwide, and requires multisectoral collaboration and interdisciplinary partnerships. In fact, control and prevention strategies for most zoonosis are effective according to a One Health approach at the human-animal-ecosystem interface. In this study, a review was carried out to assess and summarize the scientific evidences concerning the epidemiological associations between some emerging viruses and occupational diseases. WNV and CCHFV were included as examples of pathogens responsible for vector-borne infections, transmitted by mosquitoes and ticks, respectively, and both viruses are spreading in Europe and neighboring countries at an increasing rate (Marcantonio et al. 2015) . HEV infection was also included in the review since growing evidences show that zoonotic transmission through contact with infected animals or consumption of contaminated food is responsible for most of the autochthonous cases in industrialized countries (Clemente-Casares et al. 2016) . The purpose was to identify which occupational sector, job, population at risk are more vulnerable to three emerging zoonotic viruses and main clinical outcomes, according to the selected papers, in order to provide evidence for policy makers and stakeholders involved in occupational safety and health. WNV is a neurotropic member of the family Flaviviridae, genus Flavivirus, maintained in enzootic cycles involving several species of birds, which act as amplifying reservoir host, and mosquitoes belonging principally to the Culex pipiens complex, although other species would also support the spread of the virus (Marcantonio et al. 2015) . A study conducted in Italy between 2008 and 2014 detected WNV in three mosquito species belonging to two genera: Culex pipiens s.l., Culex modestus and Ochlerotatus caspius (Mancini et al. 2017 . Humans, horses and other mammals are incidental or dead-end host. First isolated in Uganda in 1937, starting from the 1990s WNV has spread rapidly across all the continents. Climate change (warmer temperature and higher cumulative rainfall) could be one of the drivers that contribute to the changing pattern of transmission of several vector-borne diseases (Riccardo et al. 2018) . Following transmission via mosquito bites, WNV replicates in keratinocytes and in the skin dendritic cells (DCs), Langherans cells (LCs), which then migrates to the local lymphnodes from where the virus disseminate to the kidney, spleen and other visceral organs. In about 1% of all infected patients, the WNV infection evolves to severe neurologic disease, including encephalitis, meningitis, acute flaccid paralysis and death. The virus entry to the central nervous system can be either via blood stream as well as via trans-neural pathways. Infection can also happen by blood transfusion, organ, tissue and cell transplants. According to the above, although most human infections are subclinical, symptoms can vary from a self-limiting fever to severe neurological disease (Ulbert 2011) . It has been demonstrated, by in vitro and in mouse models in vivo, that WNV infection induces innate cell immune response through activation of the toll like receptors (TLR3) and retinoic acid-inducible gene I (RIG-I pathways) and induction of type I interferon (IFN-I) as well as of IFN λ. Type I IFN receptors signaling in astrocytes regulates the permeability of the blood-brain barrier and protects the cerebellum from neuroinvasive infection by WNV. Therefore, the negative regulation of IFN responses, by either host and viral factors, can contribute to the pathogenesis of WNV. In particular, NS1 protein of WNV, secreted upon infection, represses TLR3-induced IFN in mouse and human cells, thus favoring virus spreading in the CNS (Luo and Wang 2018) . CCHFV belongs to the genus Orthonairovirus, family Nairoviridae. Ticks of the genus Hyalomma are considered both main vector and natural reservoir; direct contact with fluids, tissue or blood of infected animals are also considered transmission routes of the infection to humans. CCHFV is maintained and transmitted in a vertical and horizontal transmission cycle involving a variety of wild and domestic animals that act as amplification hosts without showing signs of illness. Despite these animals have been considered reservoirs of the virus, they develop only a transient viremia, while the virus can persist in ticks for their entire lifespan, and can be vertically transmitted to the next generation. Therefore, ticks are considered both vector and reservoir for the virus (Gargili et al. 2017) . Nosocomial transmission may occur through direct contact with human infected blood or body fluids or contaminated medical equipment or supply. First recognized in 1944, human CCHFV infections have been reported in over 30 countries in Asia, Middle East, South-Eastern Europe and Africa. Clinical symptoms usually comprise mild and nonspecific febrile illness; in some cases, severe hemorrhagic disease can develop (Wang and Crameri 2014) . The pathogenesis of CCHFV infection in humans is mainly based on immunopathogenetic mechanisms, mediated by either innate or adaptive immune responses. The RIG-I pathway is an immune sensor of CCHFV RNA. Studies in human patients have shown that TLRs, in particular TLR 7, 8, 9 and 10 polymorphisms correlate with the severity and outcome of the disease in some geographical areas (Turkey) (Hawman and Feldmann 2018) . The virus itself is able to antagonize innate immune signaling through deubiquitinatin and cleavage of proteins involved in innate immunity, such as ISG15, mediated by a specific domain (OTU, ovarian tumor-like deubiquinase domain) in the L segment of CCHFV. With regard to the role of the adaptive immunity responses to CCHFV in human pathogenesis, it is not completely clear, due to the lack of suitable model in vivo. The evidence obtained from the recently developed cynomologus animal model suggested that neither the antibodies titer nor their neutralizing activity seem to correlate to the outcome of CCHFV infection. The role of T cell responses, such as cytolitic activity in hepatic injury and severity of the CCHFV associated haemorragic disease, seems not necessary but needs further studies. Hepatitis E is an acute disease caused by HEV, classified in the family Hepeviridae, genus Orthohepevirus A. Genotypes HEV-1 and HEV-2 are restricted to humans and circulate in endemic area (Asia and Africa) causing outbreaks following the ingestion of contaminated water. In non-endemic areas (industrialized countries), HEV-1 and HEV-2 are linked to travel in endemic areas. In the last 10 years, an increasing number of autochthonous infections, linked to the zoonotic transmission of the genotypes HEV-3 and HEV-4, have been described (Kamar et al. 2017) . There are evidences for the presence of autochthonous cases of HEV infections in Italy since 1980 (Stroffolini et al. 2015) . The virus is transmitted via oral-fecal route, as well as by zoonotic transmission through direct contact with infected animals or food. Swine is the principal reservoir of HEV, mainly belonging to genotypes 3 and 4, with prevalence of anti HEV antibodies ranging from 8% to 93% (Huang et al. 2019) . Other reservoirs are wild board, rabbits, deer, mongooses, yaks and camels, infected with different genotypes (Nan and Zhang 2016) . Vertical transmission from mother to fetuses (Sharma et al. 2017) , and bloodborne transmission of the virus has been reported (Al-Sadeq, Majdalawieh and Nasrallah 2017). The virus probably replicates in extra-hepatic sites, such as intestinal tract, lymphnodes, colon, to reach the hepatocytes where it replicates in cytoplasm and then is released into the bloodstream and bile. The main liver damage by HEV is mediated by T cells and Natural Killer (NK) cells. The virus is shed in the stool (Lhomme et al. 2016) . Hepatitis E is usually a self-limiting illness, in most cases (95%) the infection is asymptomatic, as the HEV is non cytopathic, with mortality rate of 1-2% worldwide (WHO 2018). Sometimes symptoms of acute hepatitis can manifest. HEV infection is associated with a number of extrahepatic manifestations, including kidney and a range of neurological injuries, in particular, Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis/myelitis (Dalton et al. 2016) . During pregnancy, HEV infection can take a fulminant course, resulting in fulminant hepatic failure, membrane rupture, spontaneous abortions and stillbirths. Studies from various developing countries have shown a high incidence of HEV infection in pregnancy, with a fatality rate of up to 30% (Pérez-Gracia, Suay-García and Mateos-Lindemann 2017). Usually mild illness occurs in adult healthy individuals, whereas chronic severe disease occur in immunocompromised patients (transplant recipients, HIV immunocompromised patients) (Kamar et al. 2014) and in pregnant women, in which HEV-1 and HEV-2 are likely to cause serious medical complications including liver failure, increased risk of miscarriage and premature delivery (Khuroo and Kamili 2003) . Chronic HEV infection is defined as detection of HEV RNA in serum or stool for longer than 6 months and is typically associated to the genotype 3 of HEV. It is thus evident that clinical features of HEV infection range from asymptomatic or acute liver failure to chronic infection without clinical symptoms but with increase in liver enzymes. One of the critical point in HEV infection is clinical diagnosis of acute and chronic infection that is achieved by means of serologic and molecular tests, that are often non-specific. Initially an anti-HEV IgM assay is used, whose positivity is confirmed by evidence of rising the IgG titers. Although the IgM appear in the early phase of clinical illness and last for 4 to 5 months in 90% of patients, serology may be negative in a considerable proportion of acutely infected patients. Anti-HEV IgG increase during the convalescent phase but it is not clear how long they persist. HEV RNA can be detected in stool about 1 week before the onset of illness and persists up to 2 weeks thereafter; serum viral RNA can persist up to 4 weeks in those who resolve the acute infection and for years in patients who develop chronic infection. The serological assays are easy to perform and relatively low expensive and several commercial and in-house ELISA assays are available; however, due to the cross-reactivity with other viruses and to the genotype variability of HEV, the sensitivity and specificity as well as performance of the serological tests are low and poor, providing inconclusive results. This is even more complicated in the case of immunosuppressed patients due to their delayed seroconversion upon HEV infection. The detection of HEV RNA by PCR and RT-PCR is therefore needed to confirm serological screening in persistent infection, especially in blood and organ donations (Al-Sadeq et al. 2018 ). The aim of this review is to identify observational studies that show evidence of association between human anti-HEV, anti-WNV and anti-CCHFV antibody seropositivity (IgG and/or IgM) and certain occupational groups at risk of exposure. For this review, we included studies meeting the following eligibility criteria. r Observational studies and case-reports (including crosssectional, seroprevalence, retrospective, case-control and case-report). r Outdoor working population of all ages, sex and ethnic groups. r Well-defined and quantitative information source for the selected etiologic agents: Hepatitis E (HE), West Nile (WN), Crimean-Congo Hemorrhagic Fever (CCHF) viruses. r Outcome measures: seroprevalence of anti-HEV, anti-WNV and anti-CCHFV IgG and/or IgM among occupationally exposed populations. r Studies on humans only. We excluded studies that did not report original results (reviews, letters and comments) or did not provide sufficient data (e.g. lack of information about the number of cases and controls or about the used method). Exploratory studies were not included. Studies were identified by searching electronic database (PubMed, January 2007 to October 2018) and scanning reference lists of articles (from reviews not included). The following Medical Subject Headings (MeSH) terms were used: occupational groups; occupational medicine; industry; occupational diseases; disease; employment; occupational health; occupations; workplace; occupational exposure; workload and work. When building the search syntax, for prompt identification of studies conducted in the occupational setting, we referred to the strings developed precisely for this purpose by Mattioli et al. (Mattioli et al. 2010) The choice of this strategy allows either to assess diseases, which produce only a few articles or to explore scarcely studied disease in more depth, that is the case of the present review on emerging viruses among occupational populations. Two pairs of authors independently screened titles and abstracts of studies obtained by the search strategy. Each potentially relevant study located in the search was obtained in full text and assessed for inclusion independently by the two groups. Measure of inter-reviewer agreement was assessed via Cohen's κ statistics (Landis and Koch 1977) . Disagreements between authors were resolved by consensus. Data were collected from each relevant study. Extracted information included: r source (first author and year of publication); r general study details (citation, study design and year of publication); r setting (country/region considered, study population and job); r exposure measurement details (methodology including diagnostic tools used); r outcome data; r main findings. We reviewed the scientific literature to give an overview of the evidence available from the last 12 years regarding the occupational risk of exposure to three emerging zoonotic viral infections: WNV disease, CCHF disease and Hepatitis E infection. Reports or studies were original papers suitable for inclusion; therefore, full-texts were analyzed and the following information was extracted (as applicable to study): type of study, geographical location, study population (number of cases, patients, control or risk groups), antibody positivity rates of exposed and control subjects, statistical significance comparing risk groups vs. non-risk groups, preventive measures. A total of 71 studies on WNV were collected and examined to determine if the inclusion criteria were met; 55 were discarded because did not meet the criteria. Two articles were reviews, therefore excluded; three studies whose abstracts were not found were also excluded. The full text of the remaining studies were searched and analyzed: one full text was not available, the remaining 10 fully met the inclusion criteria and were included in the systematic review. See flow diagram Fig. 1 (Moher et al. 2009 ). There was a significantly good measure for interreviewer agreement (Cohen's k = 0.860, P < 0.001). Summary data of selected studies are in Table 1 . Of the 10 paper included in our review, 4 were case report studies described in USA, Brazil and South Africa; the remaining were epidemiological studies conducted in Turkey, Italy, Spain and South Africa. We found that main transmission pathways were direct contact with animal's body fluids and indirect contact by infected mosquito bite. The first pathway was described in one veterinarian exposed to infected horse brain while performing an autopsy (Venter and Swanepoel 2010) , and in one laboratorist who acquired the infection after a needlestick injury that exposed her to cell-culture fluid containing WNV strain SPU93/01 (Venter et al. 2009 ). WNV infection acquired by mosquito bite occurred in one security guard (Smith 2016) and in one ranch worker (Vieira et al. 2015) . Both zoonotic transmission pathways were also responsible for infections in farmers, agricultural workers and veterinarians enrolled in the epidemiological studies included in the review, with serologic IgG positivity ranging from 0.9% (Barzon et al. 2009 ) to 20.87% (Karakoç et al. 2013) . A total of 73 studies on CCHFV were identified for inclusion in the review; subsequently 30 were excluded because did not meet the criteria. Reviews and studies based on questionnaires were also excluded, abstract was not found for one study. Full text of the remaining papers were analyzed and 34 totally met the inclusion criteria; therefore, included in the review. See flow diagram Fig. 2 (Moher et al. 2009 ). There was 'moderate measure' for inter-reviewer agreement (Cohen's k = 0.565, P < 0.001). Summary data from selected studies are reported in Table 2 . Of the 34 paper included in our study, 11 were case reports (from Spain, Saudi Arabia, India, Turkey, Iran and Russia), 2 cross-sectional studies (from Greece and Madagascar), 4 retrospective studies (from India and Turkey), 17 epidemiological studies (from Turkey, Afghanistan, Ghana, Tunisia, Greece, South Africa, Iran, Malaysia and Saudi Arabia). CCHFV can follow different pathways while infecting humans: in the selected papers, worker's categories who acquired the virus by direct contact with infected animal's fluids or tissue included slaughterhouse workers with history of being splashed with fluids of animal viscera or of cutting their hands or other parts of the body (Mofleh and Ahmad 2012; Akuffo et al. 2016; Cikman et al. 2016; Wasfi et al. 2016; Mostafavi et al. 2017; Vawda et al. 2018) , and butchers because of contact with infected meat (Mofleh and Ahmad 2012; Mostafavi et al. 2017) . CCHFV seroprevalence among slaughterhouse workers and butchers ranged from 0.51% (Vawda et al. 2018) to 16.49% (Mostafavi et al. 2017) . Vector borne transmission of CCHFV following infected tick bite was found in agricultural and animal husbandry, farmers (Duran et al. 2013; Sisman 2013) and in military personnel deployed in areas where the virus is endemic (Memish et al.2011; Newman et al. 2014; Mostafavi et al. 2017 ). Human to human as well as nosocomial CCHFV transmission may occur through percutaneous or permucosal exposure to blood or body fluids from infected subjects. Health care Workers (HCWs) are at risk for contracting infection during patient care, as reported in papers included in the review (Ergonul et al. 2007; Mardani et al. 2007; Mardani et al. 2009; Naderi et al. 2011; Gozel et al. 2013; Guner et al. 2014; Ozsoy et al. 2015; Leblebicioglu et al. 2016; Yildirmak, Tulek and Bulut 2016; Negredo et al. 2017) . A probable CCHFV transmission occurred in HCWs after aerosol generating medical procedures in Russia (Pshenichnaya and Nenadskaya 2015) . A total of 220 studies regarding HEV were identified for inclusion in the review. Subsequently, 146 studies were discarded because In univariate analysis serologic positivity in the high-risk group was more statistically significant than in the low-risk group (73% versus 56%, P = 0.026). In multivariate analysis, being in an occupational risk group (OR = 2.2, CI 1.02-4.04, P = 0.044) was found to be a risk factor for WNV serologic positivity. did not meet the criteria. Reviews and studies based on questionnaires were also excluded. For three studies the abstracts could not be retrieved and were not considered. The full text of the remaining studies were analyzed and 45 fully met the inclusion criteria and were included in the review. See flow diagram Fig. 3 (Moher et al. 2009 ). There was significantly good measure for inter-reviewer agreement (Cohen's k = 0.825, P < 0.001). Summary data from selected studies are reported in Table 3 . The majority were epidemiological (24) and cross-sectional (15) studies from Africa (Uganda, Nigeria, Madagascar, Ghana and Burkina Faso), Asia (India, China, Korea, Indonesia, Taiwan and Thailand), Europe (Italy, Germany, Portugal, Norway, Finland, France, United Kingdom, Spain and Netherlands), Brazil and Cuba. Three were retrospective studies (from Switzerland, Italy and Spain), two case studies (Australia and Spain) and one casecontrol study (China). In occupational settings zoonotic transmission of HEV implies direct contact with swine, principal reservoir of HEV or other animals (wild boar, deer). Indirect contact in areas where animals live and roam or with objects or surfaces contaminated with HEV stools is also considered a transmission route, as well as contact with pig and slaughterhouse sewage. Articles selected in the review comprised mainly swine workers, including farmers and slaughterers, and veterinarians as occupational categories at risk of exposure to HEV; to a lesser extent food handlers (Appuhamy et al. 2014; Cui et al. 2016 ), workers exposed to wastewater (Tschopp et al. 2009; Albatanony and El-Shafie 2011; Martins et al. 2014 ) and forestry workers (Carpentier et al. 2012; Dremsek et al. 2012) . Seroprevalence data for anti HEV IgG ranged between 2.3% for a group of abattoir workers in Sardinia (Masia et al. 2009 ) and 2.4% among farmers in UK (Meader et al. 2010 ) and 68.5% among pig farmers in Germany (Krumbholz et al. 2014 ) and 76% among butchers in Burkina Faso (Traoré et al. 2015) . Significant risk factors for anti-HEV IgG positivity were age, amount of years of occupational exposure and direct swine contact. Hunting has been considered a possible risk factor for acquiring HEV infection, as reported in a study conducted in 144 hunters from Estonia that revealed the presence of HEV-specific IgG in 4.2% of the samples (Ivanova et al. 2015) . Others found an anti-HEV prevalence significantly higher in Okinawa wild boar hunters (25.3%) than in the residents (male 7.7% and female 4.1%) (P < 0.0001) (Toyoda et al. 2008 ). However, the retrieved studies were not included in this review because we did not consider hunters as an occupational category. Infections continue to represent a global threat to human health. Some emerging viruses with potential zoonotic transmission seem to pose a risk not only for the general population but also for workers in specific settings and activities. WNV, CCHFV and HEV were key topics of our review, which aims to identify possible association between occupational exposure and increasing risk for acquiring these infections. The search of pertinent articles has excluded sources other than PubMed, considered exhaustive for the aim of summarizing current available evidences of occupational risks for the three selected viruses. This is a limit of our study; however, this intends to be a pilot study in the field, suitable for more detailed research in the future. The number of patients with a history of contact with animals or animal blood was significantly higher than that in the control group (P < 0.05). The number of patients with a history of tick bites was higher than that in the control group but the difference was not statistically significant (P > 0.05). Vawda et al. (2018) South Epidemiological study 145 animal husbandry workes; 174 subjects exposed or bitten by ticks, 53 healthy subjects not exposed to livestock or ticks About 12.4% workers IgG positive, 16.7% subjects exposed or bitten by ticks and 9.4% subjects not exposed. Statistically significant difference between prevalence of CCHF in livestock workers or subjects exposed to CCHFV and those unexposed or residing in city (P < 0.05). High seroprevalence in Erzincan, where the disease is endemic. Educational and training programs targeted at high risk group should be developed and implemented. Mohd Shukri et al. CCHF causes severe disease and has a mortality risk of about 10% in Turkey. High-risk groups are working in agriculture and animal husbandry in rural areas, especially those living at an altitude of 600 m or higher, in May, June and July. HCWs also have a higher risk. More patients infected by contact with meat and body fluids died that those whose contact was through animal husbandry or ticks (P = 0.0048). Butchers are routinely exposed to the blood and other body fluids of animals, which suggest exposure to higher doses of the virus. semi-finished products processing workers and 11.85%: less exposed group). Age (40-49 years), working years (3-7 and >7), raw seafood processing workers and semi-finished products processing workers significantly associated with HEV infection. No difference in seroprevalence between exposed and unexposed. Symptoms compatible with hepatitis reported in 10/171 pig exposed. Temmam et al. Madagascar, Cross-sectional study A total of 427 slaughterhouse workers. 14.1% Significantly higher seropositivity for working years <5 (P = 0.03). Egypt, na Cross-sectional study A total of 43 workers at wastewater treatment plants (WWTPs) and 43 not exposed workers. WWTPs workers: 51%; not exposed workers: 30%. Significantly higher seropositivity (P < 0.05) in WWTPs than in not exposed. Adjei et al. (2010) Ghana, 2008 Cross-sectional study A total of 353 were swine exposed (feeding the pigs, cleaning barns, assisting the sows at birth and butchering on the farm). Total 34.84% (19.26% anti-HEV IgG; 15.58% anti-HEV IgM, P < 0.05). Significantly higher seroprevalence (P < 0.001) among swine exposed in the same farm setting for <6 months than >6 months (OR: 8.96; 95% CI: 5.43-14.80). Significantly, higher seroprevalence in subjects with swine contact (13.2-32.8%) compared with that in non-exposed humans (7.7-21.7%). Total 40.5% workers with close swine contact and 27.0% workers without swine contact. Significantly higher seropositivity for age range of 60-70 years and 10-13 working years in pig farms (P = 0.033). Highest anti-HEV rate for swine contact and not keeping animal at home (60.0%). Carpentier et al. Higher seroprevalence in game and fishing keepers and rangers (20.0%) and in silviculturists (24.8%) compared to controls (not statistically significant). Woodcutters at higher risk (37.2%; multivariate analysis: OR: 2.24 (P = 0.003)). Silva et al. (2012 ) Brazil, 2009 Epidemiological study A total of 310 swine exposed and 101 blood donors. Differences in positivity rates of anti-HEV between the 3 groups (P < 0.01). Significantly higher positivity in pig farm than in slaughterhouse workers (P < 0.01), and both significantly higher than general population (P < 0.01). Meader et al. (2010) U n i t e d Kingdom, 1991 Kingdom, , 1995 Kingdom, , 1996 Epidemiological study Full-text articles excluded, (n = 6) -reviews (2) -no full text available (4) Studies included in qualitative synthesis (n = 10) WNV transmission cycles through birds and mosquitoes, and mammals represent dead-end host of the infection, acquired through mosquito bites. The virus is able to amplify or replicate to high titre within birds, usually wetlands birds, which in turn transmit the infection to mosquitoes, primarily belonging to the Culex genus. Mosquitoes can reinfect birds, perpetuating enzootic infection, or can bridge the infection to mammals, humans and horses principally, representing a public health concern (Ahlers and Goodman 2018). Pointing out environmental conditions that favor WNV circulation and transmission to humans is quite difficult, mainly due to the complexity of its biological cycle. Factors contributing to the current epidemiological picture, characterized by an increasing rate of spread in Europe and neighboring countries, are several and include urbanization, variation in land use and climate changes (Marcantonio et al. 2015) . Temporal extension of transmission season may increase the risk of exposure to the infection. In fact, in 2018, early WNV transmission has been observed in Italy and in other countries in South and South Eastern Europe, with a high number of cases (Riccardo et al. 2018) . Moreover, changes in daily work activities caused by increased heat, as longer rest periods in the middle Records identified through database searching (n = 73) of the day and augmented work at dawn and dusk, could correspond to period when vectors are most active, therefore increasing the risk of disease transmission (Vonesch et al. 2016) . Outdoor workers, such as farmers and agricultural workers, may be at increased risk of WNV infection. Furthermore, workers in many other occupations could be at potential risk of exposure to WNV-infected humans and animals, their blood or other fluids and tissues. They comprise laboratory diagnosticians, researchers and technicians, veterinarians, wildlife rehabilitators, wildlife biologists, ornithologists, zoo and aviary curators, healthcare workers, emergency response and public safety personnel (NIOSH 2003 . Few studies on the occupational risk caused by WNV have been performed; in fact, we identified only ten articles eligible for inclusion. The four case reports we included in the review concerned one US security guard who attended an off-site work event (Smith 2016) , one Brazilian ranch worker (Vieira et al. 2015) , one veterinarian and one laboratorist, both in South Africa, (Venter et al. 2009; Venter and Swanepoel 2010) , all affected by the neuroinvasive illness that required hospitalization. In the first two cases, mosquito bites were responsible for the transmission of the virus; the veterinarian and the laboratorist acquired infection by needle stick injuries. The seroprevalence/seroepidemiological studies included in the study showed very low positivity for anti-WNV IgG in Italy and Spain, from 0% (Spataro et al. 2008; Remoli et al. 2018) to 2.8% (Bernabeu-Wittel et al. 2007) , mainly regarding farmers, agricultural workers, veterinarians and foresters. Higher levels were reported in South Africa (7.9% for veterinarians) (van Eeden, Swanepoel and Venter 2014) and Turkey (20.87% for farmers and agricultural workers). In South Africa the virus is an endemic zoonotic agent and occurs where the principal Records identified through database searching (n = 220) Additional records identified through other sources (n = 0) Records after duplicates removed (n = 0) Records screened (n = 220) Full-text articles assessed for eligibility (n = 74) Full-text articles excluded (n = 29) -no full text available (3) -reviews (7) -no sufficient data (e.g. lack of information about occupational exposures, or about seroprevalence in exposed groups) (19) Studies included in qualitative synthesis (n = 45) vector (Culex univittatus) and avian host are present (van Eeden, Swanepoel and Venter 2014). World Health Organization (WHO 2017) as well as experts in Europe are calling for greater awareness of WNV infection, since the number of cases rises because of demographic, environmental and social factors (Holt 2018) . WNV outbreak in animals precede human cases; therefore, an active surveillance system to detect cases in birds and horses is essential to provide early warning for veterinary and human health authorities. In Italy entomological, veterinary and human surveillance systems for WNV infection have been implemented starting from 1998, when the disease was first detected in horses in Tuscany region. Starting from 2008, human cases have been reported in Northeastern Italy, an area now considered endemic for the virus: this is not unexpected since the geographical position of the country favors the distribution of arthropods as possible vectors of human pathogens. The few numbers of studies conducted in Italian workers could be explained by the difficulty in recruiting workers at risk of exposure to the infection, since they are mainly seasonal, often foreigners and cultural and language barriers could limit their participation to the studies (Remoli et al. 2018) . Gloves and other protective clothing should be worn while handling sick animals or their tissues. Physicians should be alerted to detect clinical cases and educational programs raising awareness about the disease and the risk factors should be implemented. Healthcare workers caring for patients with suspected or confirmed WNV infection or handling their specimens, should implement standard infection control precautions; laboratorists should use effective personal protective equipment and apply biosafety measures (WHO 2017). Vaccines are not yet available for humans; treatment is supportive for patients with neuroinvasive disease (WHO 2017) . It should be taken into account that although most WNV infections are subclinical, assessing the occupational risk is important not only for protecting workers' health, but also for providing information on the potential spread of the virus. CCHF is the most widely spread tick-borne viral infection of humans and is endemic in extensive geographical areas comprising many countries in Africa, southeastern Europe, Asia and the Middle East. Human infection can occur either by tick bites, mainly belonging to the genus Hyalomma, or by direct contact with blood or tissues of viremic humans or livestock (Sargianou, Papa 2013) . In recent years, the incidence of CCHFV infection has increased rapidly in countries of the World Health Organization Eastern Mediterranean Region (WHO EMR) and in Central Asia, probably due to a combination of biological, environmental and social factors, and enhanced awareness and diagnostic capability. Weather conditions may influence the timing of activation and densities of ticks, being ectothermic organisms. Migrating birds are sources of blood-meals for immature ticks, contributing to the dispersal of infected vectors and potential emergence of disease foci. Long-distance movement of livestock may also contribute to dispersal of CCHFV-infected ticks (Al-Abri SS et al. 2017; Gargili et al 2017) . In endemic areas, farmers, veterinarians, livestock market workers, abattoir workers and other personnel engaged in activities in contact with animals and/or animal products are considered at risk for acquiring CCHFV infection, as well outdoor workers who could be exposed to infected ticks. Healthcare workers are at risk of exposure to the virus, when nursing infected patients with severe bleeding and hemorrhages without strict barrier procedures. Nosocomial transmission may therefore occur through direct contact with infected blood or body fluids, or through contaminated medical equipment or supply (ECDC 2015) . Case reports attesting CCHFV transmission through direct contact with infected blood or tissue of animals regarded mainly farmers (Yadav et al. 2017 ) and livestock workers (Mardani et al. 2009; Mardani, Namazee 2013) . Traditional slaughtering and butchery performed in some country (Iran) can be considered activities at risk (Fazlalipour et al. 2016) . Most articles sharing this transmission pathway are seroprevalence studies, carried out in Africa, Asia and Europe, and mainly regarding farmers, slaughterers, butchers and veterinarians (Gunes et al. 2009; Sidira et al. 2013; Akuffo et al. 2016; Cikman et al. 2016; Wasfi et al. 2016; Mostafavi et al. 2017; Vawda et al. 2018) . The low seroprevalence for anti-CCHFV IgG antibodies (0.51%) found in South Africa among workers exposed to or in contact with animals seems to suggest that the virus is uncommon in this area (Vawda et al. 2018) . The higher seroprevalence detected in Iran (16.49% among butchers and slaughterhouse workers) could be caused by the minimal use of personal PPE during daily work, as admitted by workers who completed a questionnaire (Mostafavi et al. 2017) . A statistically significant difference between prevalence of CCHFV IgG antibodies in livestock workers and unexposed subjects was found in Turkey. CCHFV is endemic in central and north-eastern Anatolia and southern Black Sea regions of this country and several cases are emerging in other zones (Cikman et al. 2016) . A cross sectional study conducted in Greece showed that an agro-pastoral occupation, contact with sheep and goats, tick bites and increasing age were significantly associated with CCHFV seropositivity. Another cross sectional study performed in Madagascar (Andriamandimby et al. 2011) showed that here the percentage of CCHF infection is very low among at risk professionals because of the lack of ticks of the genera Hyalomma in this country. Four retrospective studies were conducted in India (Mourya et al. 2017) and Turkey (Duran et al. 2013; Guner et al. 2014; Leblebicioglu et al. 2016 ) on patients with a history of occupational exposure, suspected to have CCHFV infection, through a retrospective analysis of clinical and laboratory data. In endemic areas, hemorrhagic manifestations including melena, low platelet count and raised alanine aminotransferase may provide a suspicion of CCHFV infection. In Turkey, people living and actively working in rural areas (including housewives occupied in agriculture and animal husbandry) are particularly subjected to the infection. It was observed that public awareness about CCHFV has decreased the incidence of the disease (Duran et al. 2013) . Nosocomial transmission of CCHFV to HCWs has been reported from different countries. The evidence that HCWs are at risk of exposure to CCHFV while caring infected patients is also supported by most case reports selected for the review (Mardani et al. 2009; Naderi et al. 2011; Celikbas et al. 2014; Ozsoy et al. 2015; Pshenichnaya and Nenadskaya 2015; Yildirmak, Tulek and Bulut 2016; Negredo et al. 2017 ). In the differential diagnosis of subjects with hemorrhagic signs, physicians should consider CCHFV infection if these patients have recently returned from any area where the virus is endemic or prevalent. Of interest the concern regarding transmission of CCHFV via respiratory contact, as supposed by a case report from Russia (Pshenichnaya and Nenadskaya 2015) and one from Turkey (Yildirmak, Tulek and Bulut 2016) , suggesting that airborne precautions could be essential during aerosol generating procedures. High mortality rate has been attested during nosocomial outbreaks; in some cases, ribavirin has been considered an effective treatment for the infection and could be used for postexposure prophylaxis (Celikbas et al. 2014) . In our review, we included seroprevalence studies regarding seropositive HCWs from Turkey (Gozel et al. 2013) , Greece (Maltezou, Maltezos and Papa 2009) and Iran (Mardani et al. 2007 ). Needle-stick injury, interventions for gastrointestinal bleeding, unprotected handling of infected materials, and emergency surgical interventions have been reported as high-risk activities for viral transmission. Military personnel that travel to and work in environments where they could be exposed to endemic or emerging infections, that are not present or prevalent in their native country, can be considered at high risk of contracting CCHFV. We selected 3 articles regarding Afghan National Army recruits (Todd et al. 2016 ) UK military personnel deployed to Afghanistan (Newman et al. 2014) , and military units from Saudi Arabian Provinces. In these groups, seroprevalences were 4.1%, 0% and 0.58%, respectively. CCHFV infection has important public health implication due to the potential of humanto-human transmission; therefore, enhanced surveillance for tick vectors and CCHFV cases is essential. Control and prevention of the infection in ticks and animal is quite difficult since the tick-animal-tick cycle usually goes unnoticed and the infection in animals is usually not apparent. Educational and training programs addressed to workers with potential exposure to the virus aiming at increasing their knowledge, attitude and practice should be developed and implemented as preventive measures. Moreover, the use of approved acaricides on clothing and tick repellent on exposed skin and clothing, and wearing protective clothing are suggested for reducing the risk of tick to human transmission. Wearing gloves and other protective clothing while handling animals or their tissues in areas where CCHFV is endemic could minimize the risk of animal to human transmission (WHO 2013; ECDC 2015) . In healthcare settings, implementation of standard infection control precautions by healthcare workers caring for patients with suspected or confirmed CCHFV infection or handling their specimens, should be recommended. HEV is a major cause of epidemic viral hepatitis in developing countries and of sporadic and cluster cases in industrialized countries. According to the WHO, approximately one-third of the world population has been exposed to HEV, through the ingestion of contaminated water and food or the direct contact with infected animals, and in minor cases by blood-borne transmission (Sinakos et al. 2018) . Serological evidence of prior exposure to the virus has been found in most areas, with higher seroprevalence rates (proportion of people who test positive for IgG antibodies to HEV) in regions with lower standards of sanitation and thus higher risk for transmission. However, presence of these antibodies does not imply presence or increased risk of disease. Traditionally, industrialized countries were considered nonendemic, with most HEV infections in these regions being sporadic and considered to be imported. Nevertheless, in recent years, enhanced surveillance has detected an increasing number of non-travel-associated HEV infections. Genotypes 3 and 4 of HEV are distributed worldwide, have a much wider host range and are considered to be zoonotic: HEV-3 is the principal genotype circulating in commercial swine herds, HEV-4, typical of the Asian continent, is believed to have recently introduced in Europe (Hakze-van der Honing et al. 2011; Monne et al. 2015) . Since the high pathogenicity of genotype 4, other studies should be performed to better understand to which extent this genotype has spread across Europe. The HEV-3 and HEV-4 genotypes circulate also in Europe and they have a high level of nucleotide identity between swine and human strains (Di Bartolo et al. 2012) . In the present review, available studies were carried out in Africa, Asia, Europe and Latin America. Recently, piggish reservoirs and growing evidence of zoonotic transmission of HEV have been reported in these countries, suggesting the possibility of occupational transmission to humans. Exposed groups comprise swine farmers (organized-mixed feed feeders and unorganized-swill feeders), slaughterhouse workers, sewage workers and veterinarians (Bansal et al. 2017) . In this review, an increased risk was found also among food handlers (Appuhamy et al. 2014; Cui et al. 2016 ), workers exposed to wastewater (Tschopp et al. 2009; Albatanony and El-Shafie 2011; Martins et al. 2014 ) and forestry workers (Carpentier et al. 2012; Dremsek et al. 2012) . Seroprevalence results were higher in individuals exposed to swine and/or wild animals, and increased with age and amount of years of occupational exposure. Humans with occupational exposure to wild animals and environmental sources of domestic animal wastes or with unexplained hepatitis showed an increased seroprevalence of anti-HEV antibodies. Poor environmental conditions in farms, occupation and low socioeconomic status might be risk factors in HEV infection. Wild boar stools may be responsible for a further source of HEV infection for people in close contact with the forestry environment. Forestry workers have already been identified to be at risk for HEV infection, as well as woodcutters. The finding of HEV and HEV-related RNA in a rising number of different animal species suggests a possible role for unidentified animal reservoirs, up to now as risk factors associated with HEV seropositivity in humans in areas where HEV is not endemic. Such reservoirs should be further explored by means of suitable diagnostic tools (Carpentier et al. 2012) . The fact that some European countries, such as Germany, have classified Hepatitis E as a notifiable infectious disease for several years and therefore have well defined records, whereas other countries, for example Italy, started in 2008, could explain difference in prevalence found in countries with a similar socioeconomic and health status (Masia et al. 2009 ). Moreover, variations in seropositivity rates reported in studies from around the world, could be ascribed by the use of immunological assays with different sensitivity (Meader et al. 2010) . The usefulness of such data for epidemiological purposes may also be limited due to variable and possible sub-optimal performance of available serological assays, and possible disappearance of the antibody with the passage of time among those exposed to the virus. At population level, transmission of HEV and hepatitis E disease can be reduced by maintaining quality standards for public water reserves and proving appropriate removal systems for human feces. At individual level, infection risk can be diminished by maintaining hygienic habits such as hand washing with safe water, particularly before handling food; preventing consumption of water and/or ice of unknown pureness and adhering to WHO safe food procedures (WHO 2018). Standard biosecurity measures, including regular cleaning and disinfection, should be put in place to limit contamination of swine facilities. A vaccine against HEV, licensed in China in 2011, prevent symptomatic HEV-4 infections, but does not provide sterilising immunity. The vaccine seems to be safe in pregnant women, but the long-term efficacy in immunosuppressed and in subjects with chronic liver disease has to be determined. An important role of the vaccine could be the prevention of HEV outbreaks, e.g. in African refugee camps or other emergency settings (EASL 2018). In the absence of an effective vaccine against HEV, prevention for swine workers, farmers, butchers and veterinarians relies on the implementation of hygiene and individual protection. Raising awareness and improved education about the risk of acquiring HEV and the appropriate precautions may help to prevent the infection. This review provides some evidences of risk for people exposed to emerging viruses in occupational setting. Although the raising number of publications regarding emerging infections, few are related to occupational health. Further studies should therefore be performed to gain more insight into the circulation of viruses in wider geographical area and in working scenarios. Moreover, such studies could contribute to evidence new risk factors for acquiring infections in exposed groups. This will be crucial in the development of effective interventions to prevent transmission of viruses potentially zoonotic. 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