Emergent Sand Fly-Borne Phleboviruses in the Balkan Region
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HISTORICAL REVIEW Emergent Sand Fly–Borne Phleboviruses in the Balkan Region Nazli Ayhan, Remi N. Charrel Sand fly–borne phleboviruses are associated with febrile is included in the Sandfly fever Naples virus species. Like- diseases and nervous system infections in the Mediter- wise, Sicilian virus was renamed sandfly fever Sicilian virus ranean basin. Sandfly fever was first reported in the Bal- (SFSV), which is still a tentative species. SFSV and SFNV kan Peninsula at the end of the 19th century. Since then, are both responsible for sandfly fever, a self-limiting but accumulating data show that the Balkan Peninsula, as a incapacitating febrile illness. Toscana virus (TOSV), dis- transboundary region between Asia and Europe, plays a covered in 1971, was incriminated as causing central and major role in the emergence of vectorborne diseases in Europe. To provide an inclusive approach, we collected peripheral nervous system infections in 1983 (8,9). TOSV published data on phleboviruses in the Balkan countries can cause aseptic meningitis and meningoencephalitis (9– and used them to evaluate the impact of these pathogens 12), as well as a number of other manifestations affecting from virologic, epidemiologic, and public health perspec- the central and peripheral nervous system. These viruses are tives. Recent findings show a high diversity of phlebo- transmitted via bites of Phlebotomus spp. sand flies. viruses belonging to 3 species or serocomplexes circu- Data concerning the geographic distribution of SFSV, lating heavily in the Balkans. Focusing on undisputable SFNV, and TOSV have drastically increased during the human pathogens, we found direct and indirect labora- past 2 decades, resulting in a more accurate cartography of tory documentation for Toscana virus, Sandfly fever Sicil- their presence in the Mediterranean basin, the Middle East, ian virus, and Adria virus. These data demonstrate that and central Asia (12–16). the Balkans are a hotspot for phleboviruses transmitted The Balkan Peninsula is a principal region for sand- by sand flies. fly fever. It is located in southeastern Europe, and consists of Slovenia, Croatia, Bosnia-Herzegovina, the Republic of hleboviruses (genus Phlebovirus, family Phenuiviri- Macedonia, Albania, Bulgaria, Greece, Montenegro, Ro- Pdae, order Bunyavirales) are 80–120 nm in length mania, Serbia, and Kosovo. The Balkan region is composed and display helical symmetry. Their genome consists of 3 of 3 very different natural entities: the Adriatic littoral in segmented negative-sense single-stranded RNA: the large the southwest, the Pannonian plain in the northeast, and a segment encodes the viral RNA polymerase (RdRp), the broad expanse of mountainous regions in between. The first medium segment encodes envelope glycoproteins (Gn and record of sandfly fever originated in Bosnia-Herzegovina Gc), and the small segment encodes nucleocapsid protein at the end of the 19th century (online Technical Appen- (N) and nonstructural protein (NS) (1,2). The segmented dix Table, http://wwwnc.cdc.gov/EID/article/24/12/17- nature of the genome allows recombination and reassort- 1626-Techapp1.pdf). During World War I and World War ment to occur with the potential to generate new viruses II, sandfly fever affected great numbers of soldiers in the with distinct ancestors (3,4). Segment reassortment in Bu- region (17,18) (online Technical Appendix Table). In ad- nyavirales has been reported with increasing frequency, dition to historical data, recent reports show the activity especially in the genus Orthobunyavirus (5). Specifically, of several novel viruses with severe human infections. We reassortant viruses have been described in both Candiru reviewed all the published data for sand fly–borne phlebo- and Rift Valley fever species (5,6). viruses in the Balkan Peninsula to provide a comprehensive Two sand fly–borne phleboviruses in the Old World view of the current situation and of the public health effect were historically associated with cases of sandfly fever: on humans and vertebrate animals in the region. Sicilian virus and Naples virus (7). Later, Naples virus was renamed sandfly fever Naples virus (SFNV), which Methods We searched global web-based resources (PubMed [www. Author affiliations: Unité des Virus Emergents, Marseille, France ncbi.nlm.nih.gov/pubmed], Google Scholar [https://schol- (N. Ayhan, R.N. Charrel); University of Florida, Gainesville, ar.google.com/], and Web of Science [https://isiknowl- Florida, USA (R.N. Charrel) edge.com]) to collect all the sand fly–borne phlebovirus DOI: https://doi.org/10.3201/eid2412.171626 data from the Balkan region. In addition, we investigated 2324 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 12, December 2018 Sand Fly–Borne Phleboviruses in the Balkan Region libraries and other national resources to identify books During World War II, sandfly fever affected great and conference reports that are not accessible on web- numbers of foreign soldiers in all Mediterranean region based resources. We used the keywords “sand fly,” and Balkan countries during the summer seasons, when “Phlebovirus,” “Bunyaviridae,” “Phenuiviridae,” “sand sand fly activity peaks 17( ). The disease was called phle- fly fever,” “pappataci fever,” “three-day fever,” “sand- botomus fever, pappataci fever, or three-day fever. In fly fever,” “Toscana virus,” “Sicilian virus,” “Naples 1937, a massive outbreak occurred in Athens, Greece virus,” “SFSV,” and “SFNV” matched with “Balkan,” (online Technical Appendix Table). After World War II, “Balkan Peninsula,” “Yugoslavia,” “Slovenia,” “Croa- sandfly fever epidemics were recorded in Belgrade, Ser- tia,” “Bosnia-Herzegovina,” “Macedonia,” “Republic of bia, affecting thousands of persons and then expanding Macedonia,” “Former Yugoslav Republic of Macedonia,” into other regions of the Balkans (27) (online Technical “FYROM,” “RoM,” “Albania,” “Bulgaria,” “Greece,” Appendix Table). Although these articles could be the “Montenegro,” “Romania,” “Moldova,” “Serbia,” and first record of sandfly fever based on clinical and epide- “Kosovo” for the research. After gathering all the data, we miologic grounds, there is no scientific evidence to dem- discarded the irrelevant publications. We put the collected onstrate whether the disease described in the articles was data in order based on country, year, and the phlebovirus sandfly fever caused by phlebovirus. species complex. The seminal seroprevalence study using a neutral- We obtained all the accessible virus sequences from ization assay, by Tesh et al. in 1976, showed that SFNV Balkan countries from GenBank. We aligned 589 nt partial and SFSV had circulated and were likely to continue to nucleoprotein sequences and analyzed them with MEGA infect human populations in the tested regions (online software version 6 (https://www.megasoftware.net/). We Technical Appendix Table). Also in 1976, Gligić et al. constructed a phylogenetic tree using the neighbor-joining isolated a strain of SFNV (Yug Bogdanovac virus strain method (Figure 1) and tested the robustness of each node Yu 8/76) from P. perfiliewi sand flies in the Dobrič re- by 1,000 bootstrap replicates. gion of Serbia. Other strains of SFNV and SFSV were also isolated in Serbia from P. pappatasi sand flies, but Results no accessible sequence data are available (24). At the We collected 51 published articles: 2 articles from Alba- time of isolation, SFNV and SFSV identification was nia, 7 from Bosnia-Herzegovina, 11 from Croatia, 17 from done using mouse hyperimmune ascitis fluid for neutral- Greece, 5 from Kosovo, 1 from Republic of Macedonia, ization assays and acetone sucrose antigens for comple- and 7 from Serbia (online Technical Appendix Table). One ment fixation tests. SFNV strain YU-8-76 is available in reference from Bulgaria was not available (online Techni- the Yale University catalog, now stored at the University cal Appendix Table). We found no published data from of Texas Medical Branch at Galveston. Partial sequence Montenegro and Romania. Most of the references included of this strain has been determined and confirmed the data concerning seroprevalence studies conducted in hu- strain as belonging to the Sandfly fever Naples virusspe - mans or animals (online Technical Appendix Table). Sev- cies (28,29). eral articles reported results about either virus characteriza- In 1985, Corfou virus, closely related to but distinct tion or case reports/outbreak investigations (19–25) (online from SFSV, was isolated from P. neglectus sand flies col- Technical Appendix Table). lected in the island of Corfou, Greece (online Technical Appendix Table). Corfou and SFSV can be distinguished Historical Data on Phleboviruses in the Balkans only by neutralization assays, unlike other serologic assays Alois Pick made a clinical description of sandfly fever in (ELISA, hemagglutination inhibition [HI], indirect immu- Bosnia-Herzegovina military barracks from foreign sol- nofluorescence [IIF], complement fixation [CF]). Several diers at the end of the 19th century (Online Technical Ap- studies have confirmed the presence of antibodies against pendix Table ). Pick, an Austro-Hungarian military doctor both SFNV and SFSV in several areas of the Balkans (20) working in Trebinje (Herzegovina), characterized the syn- (online Technical Appendix Table). drome observed in cases of sandfly fever (26). Sandfly fe- ver was observed both in local populations and in visitors, Toscana Virus in the Balkan Region specifically foreign soldiers. In 1904, Taussig