key: cord-0697594-4jjg5ic6 authors: Pugliese, Agostino; Beltramo, Tiziana; Torre, Donato title: Emerging and re‐emerging viral infections in Europe date: 2006-08-31 journal: Cell Biochem Funct DOI: 10.1002/cbf.1342 sha: 11d75160da5281fe36b77cc22c187cdeaf6ea06e doc_id: 697594 cord_uid: 4jjg5ic6 Emerging viral infections are becoming a serious problem in Europe in the recent years. This is particularly true for severe acute respiratory syndrome (SARS), West Nile virus (WNV) disease, Toscana virus (TOSV) disease, and potentially for avian influenza virus (H5N1). In contrast, emergence or re‐emergence of severe viral infections, including tick borne encephalitis virus, and viral haemorrhagic fever caused by Hantavirus and dengue virus have been frequently reported in several European countries. Laboratory diagnosis of these viral infections based on viral isolation or detection by immune electron microscopy, immunoassay and polymerase chain reaction (PCR) has dramatically improved in the recent years, and SARS represents a good example of a diagnostic approach to emerging viral infections. Finally, old and new promising agents are in the pipeline of pharmaceutical companies to treat emerging viral infections. However only prevention based on large epidemiological studies, and research and development of new vaccines may be able to control and eventually eradicate these deadly viral infections. Copyright © 2006 John Wiley & Sons, Ltd. Emerging or re-emerging viral infections represent an important problem of public health in the recent years. This phenomenon in part is due either to infective agents' evolution, or to globalisation, and habitat modification. 1 In particular, emergent infective viruses can originate by variation of previously present agents (genetic mutations and/or recombinations) or as a consequence of animal viruses adapting to human hosts. Also, the introduction of new infective agents in a determined area can be significant. 2, 3 Instead, reemergent infections can originate by reactivation of quiescent reservoirs or as a consequence of the reappearance of previously circulating viruses that have spread to other areas. In addition, changes in the behaviour of human population, and in their habitat, as well as migration, deforestation, agricultural evolution or involution, and climate modification may also contribute to the onset and diffusion of new viral infections. 4 Finally, the possibility of covering long distances in a brief time can permit the rapid introduction of infective agents in areas previously unaffected. This may occur directly from person to person or indirectly through arthropod vectors or other carrier animals, and sometimes by means of goods transport 4 (Table 1) . Historically, several severe epidemics, including plague, originated from southeast Asia. 5 Recently this area has produced two types of serious viral-emerging infections: Severe Acute Respiratory Syndrome (SARS), caused by very virulent strains of new Coronaviruses, and aviary influenza (especially produced by the strain A/H5N1). 3, 6, 7 Other emergent viruses, such as the West Nile one, originated from Africa. 8 Rabies is present in many depressed areas but is reemerging in North America and in Europe. Especially, in the latter continent, Lyssavirus infection of bats represents an effective zoonosis that can also affect humans. 9 In the occidental world increase in travel has promoted the importation of some exotic infections such as dengue, hepatitis E, West Nile, and haemorrhagic fevers that are diffused in various areas of Africa and Asia. 10, 11 Also, there has been a recent diffusion of Tick-borne encephalitis virus in south European countries, coming from Euro-Asiatic forests, and in part from the Danube basin. These are issues of serious concern, 12 together with the spread of emergent neurotropic Toscana virus (TOSV) in Mediterranean areas. 13 Preventive strategies for emerging or re-emerging infections are hardly studied by infectivologists and epidemiologists. For prevention and control of these infections, vaccine strategies, chemoprophylaxis (rarely for viral agents), and actions against the vectors have been used, but these measures have sometimes proved to be poorly effective, especially in the absence of a deep control of healthy population. 4 However, an international collaboration on infectious diseases control may often obtain effective results. An example of this action is the success attained, up to now, in the control of the emergent epidemic of SARS. 14 During the spring of 2003 the onset of an unknown respiratory epidemic was noticed in southeast China which previously seemed to be due to emerging parainfluenza viruses but was subsequently demonstrated to be caused by new Coronavirus types (two types and several strains). 15 Because of severe respiratory involvement in this syndrome (bronchopneumonia and bronchiolitis) 16 which can also produce enteric manifestations and hepatic dysfunctions, the virus was named SARS. 17 Indeed, the Italian physician Dr Carlo Urbani had announced the new emergent epidemic in February 2003, but unfortunately he died from this infection. During a medical Congress in Hong Kong where physicians from different parts of the world had gathered, some of the participants were infected by the SARS coronavirus and then the epidemic spread to various parts of the world, especially in Toronto (Canada). 18, 19 By the end of June 2003, when the epidemic seemed to recede, the number of cases announced in the world were more than 8000, with a total mortality index of 10-15%. However, the mortality reached 50% in people aged over 65 years. 20 Transmission of the SARS virus is from person-toperson, but it also propagated indirectly through excreta and stagnant water. Moreover, some animals, such as civet cats, ferrets, bandits eye, badgers, and perhaps bats, may constitute reservoirs of the infection. [21] [22] [23] The incubation period is about 2-7 days, 20 but at present, the percentage of possible asymtomatic or paucisymptomatic infections is unknown, as is also the amount of clinical manifestations not followed by lung involvement. Additionally, the percentage of patients evolving in irreversible fibrosis is also unknown. 24 For critical patients with acute respiratory distress, mechanical ventilation is required. 19 Several antiviral therapies have been proposed, but at present only treatment with interferon 25 or with hyperimmune globulins seems to be effective. 26 Use of anti-sense oligonucleotides does not appear to be useful. However, a suggestive therapeutic perspective is that of blocking the renin-angiotensin pathway. In fact, angiotensin-converting enzyme 2 (ACE2) seems to be a possible receptor of the causative virus. 27 Laboratory diagnosis of SARS can be made using direct methods such as isolation and polymerase chain reaction (PCR), and indirect ones such as neutralisation, ELISA, indirect immunofluorescence and immunochromatographic tests that may also be employed for IgM demonstration. [28] [29] [30] As previously noted, fortunately, world collaboration in respiratory infection control has, at least up to now, averted the hazard-one SARS. In Europe, only 20 suspected cases have been found, and half of them were really infected. In particular, five were found in France (two really affected) 31 and three in Germany (two developed SARS). 32 In Italy, four imported probable cases were identified. 33 In consequence, SARS viral infection constitutes a threat in Europe as well. Table 2 summarises clinical manifestations of the main emergent and re-emergent viral respiratory infections. At present, there is more concern regarding the spread of avian influenza in humans. [34] [35] Influenza viruses have caused serious epidemics and pandemics in humans (involvement of the whole world), beginning from times when viral etiology was Table 1 . Factors contributing to emergent and re-emergent viral infections in Europe unknown. The most serious was the pandemic of 1918 (type A/H1N1) that caused more deaths than those produced by the First World War, and it re-emerged from Russia during an epidemic in 1977. 36 More recently, influenza pandemics of Asian origin, occurred, respectively, in 1957 (A/H2N2) and 1968 (A/H3N2), and were also notable for their spread and severity. 36, 37 Moreover, some avian type A influenza strains are considered to be emergent viruses with serious impact on human health, but fortunately its direct transmission to man, and especially from person to person, represents an uncommon possibility. 38, 39 However, recently a 11-year-old Thai girl, infected with H5N1 avian virus, seems to have directly transmitted the infection to her mother, who died together with the daughter, and to an aunt who survived. 40 41 As previously noted, the original A/H5N1 strain and similar strains subsequently spread in Asia, during the winter of 2003-2004, especially in Vietnam, Thailand, and China with a higher number of human deaths (over 70%). In fact, the H5N1 avian influenza virus that originated in ducks, progressively showed increase of pathogenicity for animals and a possible greater hazard for men. 41, 42 Recently in Thailand, strains with a fixed mutation in M2 causing amantadine resistance were found. 42 Another emerging influenza virus strain of concern is A/H9N2 noticed in North America and in Asia is carried by turkeys and migratory ducks, and in Korea by chickens. This virus may easily combine with H5N1 virus and produce new dangerous strains. 43 Besides A/H7N3, another emergent chicken virus had been isolated in British Columbian (Canadian) poultry farms. 44 This virus spread in Italy also. During winterspring 2003 strain H7N7 caused a poultry epidemic in the Netherlands that also affected several farmers and members of their family, but generally with a nonsevere illness (about 450 persons). Often, conjunctivitis was the only clinical manifestation. 45 Oseltamivir and a specific vaccine employed together as appropriate veterinary interventions stopped the epidemic. Table 3 reports the most important episodes of avian viruses spread in European countries. As previously mentioned, avian influenza viruses could transfer cross-species to reach humans, however, with a low probability of direct transfer. Moreover, there is a possibility of human infection by these strains through an intermediate passage through large mammalian species, such as pigs, or a recombination of avian strains with human influenza viruses, circulating at the same time. 39, 52 Moreover, in the case of avian influenza, it is important to differentiate the strains into low pathogenicity (LP) and high pathogenicity (HP). 53 In addition, H5N1 genotype Z that originated in southeast China and spread to some parts of the world and which is a HP strain, showed emergence of resistance to adamantanes, and recently to oseltamivir also. Consequently, many studies are underway exploring the use of various vaccines in different countries. 53 A brief incubation period of 1-3 days precedes respiratory manifestations of common influenza, and the illness duration in uncomplicated cases is about 5-7 days. 54 However, bacterial complication of the lower respiratory tract, such as bronchitis and/or pneumonia, can seriously worsen the course of influenza, more frequently in debilitated and in old age persons. Viral pneumonia or neurologic and myocardial complications have been rarely reported. [55] [56] [57] [58] In humans, avian influenza that can take a longer incubation period (7 days or longer) is generally more serious with frequent cases of pneumonia and acute respiratory distress syndrome (ARDS). In addition, conjunctivitis, gastrointestinal manifestations, hepatic, and renal impairment are also likely to occur. 59, 60 Diagnosis of influenza can be made not only by viral isolation, PCR techniques, or serologic tests such as haemoagglutination-inhibition and ELISA, but also by employing new biosensor markers. 41, 61 A very high and efficient level of sanitary surveillance may prevent the unlucky event of influenza epidemics, especially the onset of dangerous emergent strains. In fact, population protection against influenza is possible with vaccine prophylaxis and with antiviral agents such as neuraminidase inhibitors and amantadine derivates. 62 Antiviral drugs, especially the neuraminidase inhibitor, oseltamivir, may also be successfully employed for treatment of influenza, if the treatment is started early. 63 However, pharmacologic resistance is also possible. 64 68 Moreover, experimental vaccines are being studied, using either attenuated or adenovirus vector modifications, for nasal and epicutaneous administration. 69 Information about influenza epidemiology and prophylaxis can be provided by the Influenza Branch website of Division of Viral and Rickettsial Diseases-CDC, Atlanta, USA: http://www.cdc.gov/ incidod/diseases/flu/fluvirus.htm. It is interesting to draw attention to the recently identified new human Metapneumovirus indicated as HMPV (Paramyxoviridae family, Pneumovirinae subfamily) that seriously affects children and persons over 65 years of age in Europe, North America, Australia, and Asia. 70 This virus is similar to Respiratory Syncytial Virus (RSV) and is responsible for bronchiolitis and pneumonia. As previously noted, this emergent virus is particularly dangerous in infants, old people, immunocompromised patients and also in those affected by chronic respiratory diseases. 70 Finally, re-emergence of Enteroviruses, such as Coxsackie virus responsible for Bornholm disease, is also possible in Europe, as it occurred recently in Japan. 71 Moreover, a similar phenomenon happened in the case of Coxsackievirus A16 and Enterovirus 71, responsible for ''Hand, foot, and mouth disease'' in children 72, 73 and sometimes also for pulmonary infections. [74] [75] [76] A new antiviral, Pleconaril, shows promise for enteroviruses infection. 74 Similarly, adenoviruses can have re-emergent behaviour in parts of Europe, especially, type 4 re-emerged in USA. 77 HAEMORRHAGIC FEVERS Crimean-Congo haemorrhagic fever (CCHF) is a severe zoonosis endemic in Africa, in the middle east, and central and southwestern Asia 78 and is reemergent in different European areas. This has occurred especially in the southern provinces of Russia, in Bulgaria, Greece, Kosovo, in some provinces of former Yugoslavia, in Albania, and also in some parts of Hungary, France, Portugal, [78] [79] [80] and in Spain. 81 The transmission of different strains of the etiologic viral agent (an arbovirus belonging to Nairovirus genus, Bunyaviridae family) is caused either by some Tick specie bites, especially belonging to Hyalomma genus, or by transcutaneous or respiratory routes, and perhaps by ingestion of infected raw milk. More rarely, the virus is transmitted by a nosocomial pathway. 78 CCHF was first recognised among farmers of the Crimean Peninsula in 1940. 82 After an incubation period of 2-7 days, the infection is characterised by high fever, headache, dizziness, nausea, vomiting, diarrhoea, hepatic, and pulmonary involvement, neuropsychiatric, and cardiovascular disorders. Severe haemorrhagic manifestations, preceded by petecchial rash and ecchymosis, may cause death in about 30% of patients. 82 At present molecular tests are used for the diagnosis (direct methods), and particularly useful is the employment of real-time reverse transcription-polymerase chain reaction (RT-PCR). ELISA tests are generally employed for serologic detection. 78, 82 Presently, there is no specific therapy for this viral infection although immunotherapy and ribavirin have been used with varying degrees of success. 82 Support therapy is generally employed, and vaccines that are rarely available have also been proposed for prophylaxis. 78 Among tick-borne flaviviruses causing human haemorrhagic fevers, Omsk disease agent can be considered to be a Russian re-emergent virus. In fact, at the end of 1940 it was first isolated in a rural region of the Omsk district in Siberia. From that time, it has reappeared at different periods. In some small regions of Siberia, it was transmitted to humans by muskrats through tick bites of Dermacentor spp. 78, [83] [84] [85] Omsk haemorrhagic fever is similar in clinical manifestations to Kyasanur Forest disease and Saudi Arabia Alkhurma virus infection, all responsible for haemorrhagic fevers and sometimes for neurologic disorders as well. 84 Biphasic behaviour of the infection may be present in 30-50% of the cases with appearance in the second stage of haemorrhagic manifestations. Fortunately, the prognosis is generally good; however, a mortality of 0.5-3% has been reported. 78, 86 Hantavirus genus (family Bunyaviridae) represents one of the main emergent, re-emergent viral groups responsible for haemorrhagic fever in Europe. 87, 88 The name is derived from the Han River basin where the infection was first identified in 1978. At present, different serotypes, grouped in Hantavirus genus, have been described in Asia, America, and Europe, having Arvicoline rodents as reservoir that can transmit the infection to humans through their excretions. 89 These viruses spread worldwide and are responsible for fever with renal and/or pulmonary syndromes. 90 95 and Denmark (Saaremaa and Puumala). 96 In Greece the Dobrava type is predominant, carried by the rodent Apodemus flavicollis. 91 Puumala virus (also affecting sheep and transmitted by Clethrinomys glareolus) predominates in northern Sweden, 97 in Scandinavia, 94 and in Balkans. 93 Dobrava and Puumala spread especially in Croatia, Serbia, Bosnia, Herzegovina, and Montenegro 98,99 as well as in Slovakia, 100 and, in general, in eastern and central Europe. 101 In addition, in Germany, about 600 cases of Hantavirus disease, caused mainly by Puumala, and also by Dobrava viruses, were found during the period 2001-2003, mainly in the Baden-Wurttemberg regions. 102 Also, cases were found in Spain 103 and especially in western Russia, where Hantaviruses are widely spread by different rodents. 91, 94 In Europe, the infection is generally transmitted, in addition to the Apodemus species, by the bank vole. 101 After an incubation period of 2-3 weeks, different manifestations occur, depending on the viral type involved. 98 In particular, Dobrava often shows haemorrhagic manifestations, Puumala and Saaremaa are more commonly associated with epidemic nephropathy. 101 Minor symptoms are headache, gastrointestinal manifestations, and vertigo. 101 Table 4 summarises the clinical manifestations of haemorrhagic fevers. Diagnosis of Hantavirus is performed by immunofluorescence, ELISA, and Western blot tests (IgM detection is also possible). Typing is obtained by employing neutralisation assays or RT-PCR and sequencing techniques. 98, 101, 102 Whereas Puumala virus is more antigenically distinct from other Hantaviruses, Dobrava, and Saaremaa are genetically and antigenically strongly correlated. 101 Consequently, cross reactions are also possible in serologic detection. 101, 102 In this context, Sin Nombre virus (Hantavirus) deserves a special mention. It is responsible for the cardiopulmonary syndrome, first recognised in 1993 in the southwestern region of USA. The first cases were reported in Europe in 2002. 104 Finally, we recall Dengue viruses that caused a severe epidemic of haemorrhagic fever during 1927-1928 in Greece, with 1200 deaths (type 1 and 2) 105 and some cases of fever with arthralgia in the Mediterranean area. At present, in Europe, dengue virus is responsible for infections only in travelers from endemic regions. These cases are generally not severe and lack haemorrhagic manifestations. 85 Tick Ixodes that transmits TBEV in European climates completes its development cycle in 3 years. In particular the infection is transmissible even in the nymph phase. 108 TBEV is present in different variants or subtypes, 78 among them the two main are Sofin (eastern subtype) and Neudorfl (western subtype). The former, responsible for more severe infection, and also known as Spring-Summer Russian Encephalitis, is diffused particularly in Russia, Czech Republic, Austria, Poland, Hungary, and former Yugoslavia. The latter, responsible for a less aggressive form, called Central European Encephalitis, is diffused particularly in this geographic area, but has spread also to Austrian border regions (Italy and former Yugoslavia). In the recent years, the virus reached some Italian regions, for example, northeast and central Italy, 109 and has also been reported in Piedmont (northwest region). 110 Moreover, TBEV (strain Neudorfl) has been reported in Denmark, 111 in Scandinavia, 112 and in Greece. 113 TBEV, in addition to tick bites, is also transmitted by unpasteurized milk and infected aerosols. 78 Its incubation period ranges from 1 to 2 weeks. 78 In Poland, during 1993-2002, 1996 cases of TBE were reported (Kondrusik et al., 2004) 114 and in Russia, over 10 000 cases a year; about 3000 cases are possible in the rest of Europe. 12, 86 Biphasic behaviour has been observed when the central nervous system (CNS) is involved. In Germany, during 1991-2000, 1500 patients were diagnosed for symptomatic infection of TBEV; neurologic manifestations were described in 47% of the cases (42% with meningoencephalitis and 11% with meningoencephalomyelitis) ( Table 5) . The mortality was about 1%, but a higher percentage of neurologic sequelae was signalled. 115 More severe is the Russian type disease (Spring-summer encephalitis) with mortality also above 20% in patients with neurologic implication. 12, 86, 116 Diagnosis of TBE can be performed by viral isolation and neutralisation tests (with hazard), or by using classical serologic tests, including complement fixation and enzyme immunoassay (EIA) for IgM research, 117 and more recently by higher specific rE-3D enzyme-linked immunosorbent assay (rE-D3 ELISA) and Western tests. The rE-D3 ELISA permits a differential diagnosis with respect to other tick borne zoonosis. 118 Also, in recent years real-time RT-PCR for detection and quantitation of TBEV RNA that also permits the strain differentiation has been used. 119 Because of increasing risk for TBE infection, vaccination is suggested for subjects living or working in areas infested by ticks. 115 TBE-related viruses are also sporadically present in Europe, such as Louping ill, Langat, and Powassan. Sporadic presence in Europe also occurs for haemorrhagic fever viruses partially related to the TBE complex, such as Omsk haemorrhagic fever, Kyasanur Forest disease and Alkhurma agents that occasionally may cause encephalitis. 12, 86 West Nile fever is a mosquito-transmitted viral infection, emergent and subsequently re-emergent in Europe from the first half of the 1960s, particularly in Western Mediterranean areas and southern Russia. 120 Recently, the infection reached Germany, Denmark, and Scandinavia, with increased incidence of encephalitic diseases. 35, 121 WNV may cause fever and sometimes encephalitis in large mammals, especially in horses and also in humans. 120, 122, 123 Reservoirs are wild (often migratory) and domestic birds; mosquito vectors (generally belonging to Culex genus) may also act as reservoirs. In fact, transovaric transmission of the infection is also possible. 124 Extravectorial infection in animals 125 and even by blood transfusion in humans, 126 or consequent to organ transplants have been reported. 127, 128 The virus was first isolated in Africa (West Nile District of Uganda, 1937) and originally produced a prevalently febrile disease and acquired neurotropism during the second half of the 20th century. 129 It seems that the death of Alexander the Great in Babylon at the age of 32 was the result of a serious febrile disease, in reality he was affected by WNV encephalitis. 130 During 1999, the virus reached northeastern United States, New York City, and subsequently also the West Coast of USA, and Canada. 129, 131 A peculiar characteristic of West Nile epidemic in the USA and in Europe was the involvement of urban areas where the virus was transmitted by the house mosquito, Culex pipiens. 129 In particular, in USA the infection is associated with fatal diseases of crows, so demonstrating an evolution of the agent virulence; 129,132 moreover, since 1999 the infection has affected thousands of subjects. 133 The highest incidence was during 2003 with 9000 cases and 200 deaths. 128 Moreover in USA, Canada, and Mexico the total cases reported from 2002 to October 2004 reached 16 000. 134 However, during 2005, in North America a decrease in the number of cases was observed and a mean seropositivity from 2 to 5% was detected in the population. 135 The particular aggressiveness of West Nile infection is correlated with the fact that the viral strains, already previously present in Asia, recently underwent an incidence and virulence increase in their diffusion to western areas. 136 In particular, in Europe, we recall the important epidemics in Romania and in Russia, especially in the Volgograd region. In the first case the virus circulated in the southern regions from the 1960s or earlier. However, an unexpected epidemic broke out in Bucharest during the summer of 1996 (393 hospitalized cases and 17 deaths). Moreover, a novel introduction of WNV occurred during 1997-2000 with 39 human cases. 137 In Russia, the epidemic occurred in July-October 1999 in the Volgograd Region with more than 800 cases of symptomatic infection and 84 cases of meningoencephalitis (40 fatal) . 138 In addition in France, an equine epizootic epidemic was described in the Camargue in 2000, and six human cases were detected in the French Mediterranean coast. 139 Neurologic manifestations of West Nile disease that occurs in temperate areas during mosquito seasons may present an aseptic meningitis, meningoencephalitis, encephalitis, or encephalomyelitis accompanied by ophthalmologic manifestations (Table 5) . Moreover, both the central and peripheral nervous systems may be involved. Flaccid paralysis is one of the most frequent sequelae, and no specific therapy exists for this infection. 131, 133 However, in humans, 80% of infections are asymptomatic, about 20% of the infections are present as an influenza-like disease whereas less than 1% of infections may cause disorders of CNS, with a mortality rate of 15%. 140 Promising experimental results have been obtained with interferon a and specific immunoglobulins' administrations. 128 A high degree of relative lymphopenia at the onset, elevation of serum ferritin, and advanced age of affected persons may predict an unfavourable evolution. For laboratory diagnosis, an ELISA test using the recombinant antigen (preM/E,) can be easily employed to detect IgM and IgG against WNV. 141 At present vaccines, attenuated or recombinant or chimeric ones, are available only for animals. 142 In fact, 150 bird species and 30 mammalian species are susceptible to WNV. In particular, some species of birds and lemurs, hamsters, and frogs may be a reservoir of the virus. 142 TOSV is a neurotropic arbovirus first isolated in Tuscany during the early 1980s by Professor Paola Verani of the Italian Istituto Superiore di Sanità. This infective agent belongs to the Sandfly fever group viruses (genus Phlebovirus, family Bunyaviridae) that are transmitted by Phlebotomus vectors. TOSV is diffused in the Mediterranean basin (especially Italy, Portugal, Spain, France, and Cyprus) and may cause aseptic meningitis, meningoencephalitis and encephalitis [143] [144] [145] [146] [147] [148] (Table 5) . Laboratory diagnosis is made by PCR techniques and immunoenzymatic tests. 144, 145, 149 The latter permits the detection of IgG and IgM subclass in sera and cerebrospinal fluid. 146 Other sandfly fever viruses, diffused in some areas of continental Africa, in middle east, and central Asia, differ from TOSV by not being endowed with neurotropism. 150 Thayna, together with Batai and Inkoo viruses, can be considered to be an emergent arbovirus (Bunyavirus genus, Bunyaviridae family). These viruses are correlated with California encephalitis subgroup and have been sporadically identified in Europe, especially in southern Russia, 151, 152 Germany, Czech Republic, and Netherlands (prevalently Thayna), 153 in Balkans, 154 and rarely in other regions of southern Europe. In particular, in the Czech Republic, seroprevalence for Tahyna virus in an area affected by flood was 16% in 2002. 155 These viruses are transmitted by various mosquito species, and their incidence increase at times of flood events. 154, 155 Monitoring of vectors and their rate of infection is useful for prophylactic measures, as for other arbovirus infections. 154 In addition, non-poliomyelitic neurotropic enteroviruses can behave, from time to time, as emerging/ re-emerging viruses. From May to September 2000, an outbreak of aseptic meningitis caused by some Enterovirus strains occurred in Belgium. In particular, there was a high prevalence of Echovirus 13 (23.8% of cases), previously considered a rare serotype. 156 Moreover, encephalitis caused by Enterovirus 71 was recently described in Germany. 157 Finally, neurologic manifestations caused by ECHO 30, ECHO 6, and Coxsackievirus A16 were reported in Scandinavia, 158 and by ECHO 30 in France. 159 Emergent and re-emergent viral infections are historically a major and crucial concern for biologists, epidemiologists, infectivologists, and veterinarians. Today's globalised and interconnected world enhances several social, political, and economic factors allowing viral pathogens rapid and easy access to new environments and populations. Over the past decade, new viral agents have spread at an alarming rate, including Hantavirus, Metapneumovirus, and Coronavirus that causes SARS. In addition, previously recognised viral infections such as WNV disease and Rift valley fever have emerged in new continents. The modification in reservoir host environment and adaptation of viral agents to new hosts are the main causes of pattern modification of these infections in the world. Figure 1 summarises the main emergent and re-emergent viral infections in Europe. The lessons that we have learned from emergent and re-emergent infections in Europe may be based summarised by the four crucial features: (i) global surveillance with alert systems to monitor outbreaks and epidemics early; (ii) prevention by use of old and new vaccines; (iii) employment of scarce antiviral drugs for treatment and prevention of emergent and reemergent viral infections; and (iv) awareness of change of environment, viral agents (mutations), and adoption of public health measures. Only a strict approach to these crucial points in future will be able to control and greatly reduce the emergence, and particularly re-emergence, of severe and deadly viral infections. 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Dengue-fever Increase in imported dengue Ixodes ricinus, transmitted diseases and reservoirs Seroprevalence of tick-borne infections in forestry rangers from northeastern Italy Seroprevalence study of Tick Borne Encephalitis, Borrelia burgdorferi, Dengue and Toscana virus in Turin Province Survey in tickborne infections in Denmark Characterization of human tick-borne encephalitis virus from Sweden Tickborne encephalitis Tick-borne encephalitis (TBE) cases in Bialostocki and Podlaski regions in 1993-2002 years Tick-borne encephalitis (TBE) in Germany and clinical course of the disease Life flavivirus vaccines: reasons for caution Tick borne zoonosis: selected clinical and diagnostic aspects Use of recombinant E protein domain III-based enzyme-linked immunosorbent assays for differentiation of tick-borne encephalitis serocomplex flaviviruses from mosquito-borne flaviviruses Development of a quantitative realtime RT-PCR assay with internal control for the laboratory detection of tick borne encephalitis virus (TBEV) RNA Nile fever-a reemerging mosquito-borne viral disease in Europe Death from the Nile crosses the Atlantic: the West Nile Fever story West Nile virus in the western hemisphere Clinical and neuropathological features of West Nile virus equine encephalomyelitis in Italy West Nile virus in birds and mammals Transmission of arboviruses without involvement of arthropod vectors Transfusion transmission of West Nile virus: a merging of historical and contemporary perspectives West Nile virus infection in a renal transplant recipient West Nile virus: pathogenesis and therapeutic options West Nile virus: Uganda Alexander the Great and West Nile virus encephalitis Neurological manifestations of West Nile virus infection Differential virulence of West Nile strains for American crows Differential diagnosis of west Nile encephalitis West Nile virus, an emerging arbovirus West Nile virus up to West Nile virus and other zoonotic viruses in Russia: examples of emerging-reemerging situations Epidemic West Nile encephalitis in Romania: waiting for history to repeat itself Outbreak of West Nile virus infection, Volgograd region West Nile virus: in France again, in humans and horses West Nile virus encephalitis Performance of immunoglobulin G (IgG) and IGM enzymelinked immunosorbent assays using a West Nile virus recombinant antigen (preM/E) for detection of West Nile virus-and other flavivirus-specific antibodies West Nile virus in the vertebrate world Symptomatic infections by Toscana virus in the Modena province in the triennium A Mediterranean arbovirus: the Toscana virus Serological survey of Toscana virus infections in a high-risk population in Italy Meningitis caused by Toscana virus during a summer stay in Italy Acute meningitis due to Toscana virus infection among patients from both the Spanish Mediterranean region and the region of Madrid Toscana virus and acute meningitis Detection and identification of Toscana and other phleboviruses by RT-nested-PCR assays with degenerated primers Epidemiological, clinical and laboratory aspects of sandfly fever Molecular characterization of California serogroup viruses isolated in Russia Specific markers for the detection of circulating of Tahyna, Inko and Batai viruses (Bunyaviridae, Bunyavirus) in humans, mosquitoes, ticks and cattle of the Ul'ianovsk region Isolation of Tahyna virus from mosquitoes in 2 different European natural foci Antibodies against mosquito-born viruses in human population of an area of Central Bohemia affected by the flood of Mosquito-borne viruses Molecular typing and epidemiology of enteroviruses identified from an outbreak of aseptic meningitis in Belgium during the summer of Molecular characterization of an Enterovirus 71 causing neurological disease in Germany Enterovirus infections diagnosed in middle Norway during the period 1992-2001 Prospective investigation of a large outbreak of meningitis due to Echovirus 30 during summer This work was supported by Italian Ministry of Public Education, University and Scientific Research.