Strengthening preparedness for (re-) emerging arboviruses in Europe
Authors: L. Sigfrid, I. Eckerle, A. Papa, P. Horby, M. Koopmans, C. Reusken
Journal: Clinical Microbiology and Infection (2018)

This theme issue draws attention to arboviral diseases: arboviruses (arthropod-borne viruses) are predominantly transmitted between vertebrate hosts by arthropod vectors, such as ticks, mosquitoes and sand-flies. Although arboviral infections are not the most common diagnosis in clinical and clinical microbiology practices in most of Europe, events of the past years raise the question: is Europe prepared to deal with expansions or outbreaks of arboviruses? Globally, the burden of arboviral disease is huge, with more than 100 million cases, 100 000s of deaths, and an unknown number of chronic complications [[1]Gould E.A. Solomon T. Pathogenic flaviviruses.The Lancet. 2008; 371: 500-509Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar]. An important observation is that the geographic distribution of arboviral diseases has undergone quite dramatic changes in past decades, with recent global and regional expansion of e.g. West Nile virus (WNV), chikungunya virus (CHIKV), dengue virus (DENV) and Zika virus (ZIKV), with associated travel-imported cases in Europe. Zika virus, a previously known but not well studied arbovirus, gained attention in 2015 when the Brazilian Ministry of Health alerted the world to an increase in congenital anomalies and neurological disease, thought to be linked to a large ZIKV outbreak across naïve areas in South and Central America. Since then a link between ZIKV and severe neurological complications has been established, and sexual and transfusion related transmission has been documented [2Baud D. Gubler D.J. Schaub B. Lanteri M.C. Musso D. An update on Zika virus infection.Lancet. 2017; 390: 2099-2109Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar, 3Musso D. Baud D. Gubler D.J. Zika virus: what do we know?.Clin Microbiol Infect. 2016; 22: 494-496Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 4Moreira J. Peixoto T.M. Siqueira A.M. Lamas C.C. Sexually acquired Zika virus: a systematic review.Clin Microbiol Infect. 2017; 23: 296-305Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar]. The ZIKV outbreak resulted in a large number of travel-imported cases globally and highlighted the need to strengthen preparedness to (re-) emerging epidemics globally, to enable earlier detection of outbreaks and implementation of rapid clinical research responses. How do these global epidemics affect Europe? Europe already hosts a range of endemic arboviruses of clinical significance, with tick-borne encephalitis virus and Crimean-Congo haemorrhagic fever virus (CCHFV) arguably of most relevance and Toscana virus emerging as a leading cause of aseptic meningitis in regions of southern Europe [5Papa A. Emerging arboviral human diseases in Southern Europe.J Med Virol. 2017; 89: 1315-1322Crossref PubMed Scopus (19) Google Scholar, 6Cleton N. Koopmans M. Reimering J. Godeke G. Reusken C. Come fly with me Review of clinically important arboviruses for global travelers..J Clin Virol. 2012; Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 7Charrel R.N. Gallian P. Navarro-Mari J.M. Nicoletti L. Papa A. Sanchez-Seco M.P. et al.Emergence of Toscana virus in Europe.Emerging Infect Dis. 2005; 11: 1657-1663Crossref PubMed Scopus (223) Google Scholar]. In addition, concomitant with the global expansion of WNV, endemic circulation of WNV is now established in parts of Europe, and CHIKV has sparked recent outbreaks in Italy and France [6Cleton N. Koopmans M. Reimering J. Godeke G. Reusken C. Come fly with me Review of clinically important arboviruses for global travelers..J Clin Virol. 2012; Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 8ECDC Clusters of autochthonous chikungunya cases in Italy - rapid risk assessment.2017Google Scholar]. These examples demonstrate the difficulty in predicting the fate of arbovirus incursions: whereas in the Americas WNV expanded over the course of a few years, the human arbovirus disease outbreaks in Europe have so far remained relatively localized. While it is tempting to explain this by climate conditions, this does not explain the widespread veterinary arboviral disease outbreaks caused by blue tongue virus and Schmallenberg virus that has occurred in Northern Europe [9Wernike K. Conraths F. Zanella G. Granzow H. Gache K. Schirrmeier H. et al.Schmallenberg virus—Two years of experiences.Prev Vet Med. 2014; 116: 423-434Crossref PubMed Scopus (68) Google Scholar, 10Jacquot M. Nomikou K. Palmarini M. Mertens P. Biek R. Bluetongue virus spread in Europe is a consequence of climatic, landscape and vertebrate host factors as revealed by phylogeographic inference.Proc Biol Sci. 1864; 2017: 284Google Scholar]. An important question therefore is how to be prepared for arboviral diseases in the European context. The increasing reports of non-vector transmission, such as sexual transmission of ZIKV [2Baud D. Gubler D.J. Schaub B. Lanteri M.C. Musso D. An update on Zika virus infection.Lancet. 2017; 390: 2099-2109Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar, 4Moreira J. Peixoto T.M. Siqueira A.M. Lamas C.C. Sexually acquired Zika virus: a systematic review.Clin Microbiol Infect. 2017; 23: 296-305Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar] and the risk of blood transfusion transmission for many arboviruses [6Cleton N. Koopmans M. Reimering J. Godeke G. Reusken C. Come fly with me Review of clinically important arboviruses for global travelers..J Clin Virol. 2012; Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 11Musso D. Gould E. Lanteri M.C. Documentation of transfusion-transmitted arbovirus infections in endemic areas.Transfusion. 2016; 56: 3143-3144Crossref PubMed Scopus (5) Google Scholar] emphasize the need for early pathogen detection to prevent the risk of onward transmission. While non-vector transmission from body fluids has been reported for several arboviruses, with 27 different viruses detected in human semen [12Salam A.P. Horby P.W. The breadth of viruses in human semen.Emerg Infect Dis. 2017; 23: 1922-1924Crossref PubMed Scopus (107) Google Scholar, 13Musso D. Richard V. Teissier A. Stone M. Lanteri M.C. Latoni G. et al.Detection of Zika virus RNA in semen of asymptomatic blood donors.Clin Microbiol Infect. 2017; 23 (1001.e1–e3)Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar] and the risk of nosocomial transmission of CCHFV well documented [14Aradaib I.E. Erickson B.R. Mustafa M.E. Khristova M.L. Saeed N.S. Elageb R.M. et al.Nosocomial outbreak of Crimean-Congo hemorrhagic fever, Sudan.Emerging Infect Dis J. 2010; 16: 837Crossref PubMed Scopus (83) Google Scholar, 15Gürbüz Y. Sencan I. Oztürk B. Tütüncü E. A case of nosocomial transmission of Crimean–Congo hemorrhagic fever from patient to patient.Int J Infect Dis. 2009; 13: e105-e107Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 16Elata A.T. Karsany M.S. Elageb R.M. Hussain M.A. Eltom K.H. Elbashir M.I. et al.A nosocomial transmission of crimean-Congo hemorrhagic fever to an attending physician in north kordufan, Sudan.Virol J. 2011; 8: 303Crossref PubMed Scopus (39) Google Scholar], there is still limited evidence on the risk of transmission from different body fluids for most arboviruses. The recent CHIKV outbreak in Italy prompted ECDC to issue pre-cautionary guidance to member states on screening of blood products and blood donation deferrals [[8]ECDC Clusters of autochthonous chikungunya cases in Italy - rapid risk assessment.2017Google Scholar], despite limited evidence, highlighting the need for further research on effective and appropriate control policies. Travel medicine aside, in regions with known endemic arboviral presence, or at risk for incursions, front line staff, including clinicians and virologists, play a key role in the early identification of human cases and outbreaks. The identification of arboviruses is however complex. Arbovirus infections can present with a range of non-specific, overlapping syndromes [[17]Cleton N.B. Reusken C.B.E.M. Wagenaar J.F.P. van der Vaart E.E. Reimerink J. van der Eijk A.A. et al.Syndromic approach to arboviral diagnostics for global travelers as a basis for infectious disease surveillance.PLOS Neglected Trop Dis. 2015; 9e0004073Crossref PubMed Scopus (17) Google Scholar]. This is further complicated by complex diagnostics, with serological cross-reactivity between related arboviruses. Moreover, the documented high proportion of mild or asymptomatic cases, can also contribute to delays in identification of outbreaks. Using a syndromic approach together with detailed patient history and vaccination status, coupled with an understanding of seasonality and current epidemiology can help guide differential diagnosis [[17]Cleton N.B. Reusken C.B.E.M. Wagenaar J.F.P. van der Vaart E.E. Reimerink J. van der Eijk A.A. et al.Syndromic approach to arboviral diagnostics for global travelers as a basis for infectious disease surveillance.PLOS Neglected Trop Dis. 2015; 9e0004073Crossref PubMed Scopus (17) Google Scholar]. This theme issue aims to raise awareness of the changing epidemiology and increasing threat of arboviruses in Europe, with the objective of strengthening preparedness and response to the detection of cases and outbreaks. The issue comprises three reviews related to the ESCMID Postgraduate education course “Preparing for (Re-) Emerging Arbovirus Infections in Europe” which was held in 2016 and 2017 and is planned again for 2018. The first review by Sigfrid et al, presents an update on epidemiology, risk factors, syndromic presentation and treatment of arboviruses of clinical significance to Europe [[18]Sigfrid L. Reusken C. Eckerle I. Nussenblatt V. Lipworth S. Messina J. et al.Preparing clinicians for (re-)emerging arbovirus infectious diseases in Europe.Clin Microbiol Infect. 2018; 24: 229-239Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. This paper also presents models predicting further expansion of Ae. aegypti, Ae.albopictus and CCHFV in Europe. The second review by Reusken et al, is focused on European laboratory preparedness and response capacity [[19]Reusken C.B. Ieven M. Sigfrid L. Eckerle I. Koopmans M. Laboratory preparedness and response with a focus on arboviruses in Europe.Clin Microbiol Infect. 2018; 24: 221-228Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. This review illustrates the needs for laboratory preparedness especially to endemic and (re)-emerging arboviruses. It identifies the components and barriers of such preparedness and discusses the laboratory preparedness in the broader context of the current and widening landscape of international research, clinical and laboratory preparedness networks. The third review by Eckerle et al, aims to raise awareness and strengthen preparedness among clinicians by presenting a series of case-reports of travel-imported arboviruses, with differential diagnostics, presenting at secondary care across three European countries [[20]Eckerle I. Briciu V.T. Ergönül Ö. Lupşe M. Papa A. Radulescu A. Emerging souvenirs—clinical presentation of the returning traveller with imported arbovirus infections in Europe.Clin Microbiol Infect. 2018; 24: 240-245Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. Strengthening clinical preparedness is the mission of the EU funded Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE). PREPARE was set up in 2014, with a mission to strengthen clinical preparedness and facilitate early identification and rapid clinical research responses to (re-) emerging infectious diseases with epidemic potential across Europe. To achieve this, PREPARE partners are strengthening networks of primary and secondary care sites, identifying regulatory barriers to rapid clinical responses, and developing syndromic research tools and frameworks for rapid clinical research responses. For diagnostic guidance, PREPARE clinical researchers collaborate with laboratory experts involved in laboratory preparedness activities, which for arboviruses is the EVD-LabNet network. The protocols and tools are tested through pan-European studies designed to enrol patients presenting with syndromes of severe infectious diseases with epidemic potential, including those caused by arboviruses. PREPARE is a model for a network of coordinated, regional preparedness hubs to facilitate harmonised, rapid research responses to infectious disease outbreaks globally. The authors declare no conflicts of interest. This work forms part of the PREPARE (Platform for European Preparedness against (re-)emerging epidemics funded by the European Commission under grant number 602525.