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Background Identifying the causes of Acute Undifferentiated Febrile Illness (AUFI) is key to improve the management of returning travellers with fever. We evaluated a BioFire®FilmArray® prototype panel of multiplex nucleic acid amplification tests (NAAT) targeting different relevant pathogens in travellers returning with fever. Methods Prospective, multicentre study to evaluate a prototype panel in whole blood samples of adult international travellers presenting with AUFI in three European travel Clinics/Hospitals (November 2017–November 2019). We evaluated 15 target analytes: Plasmodium spp., Plasmodium falciparum, Plasmodium knowlesi, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, chikungunya virus, dengue virus, Zika virus, Anaplasma phagocytophilum, Borrelia spp., Leptospira spp., Orientia tsutsugamushi, Rickettsia spp. and Salmonella spp. Results were compared with composite reference standards (CRSs) for each target infection, including direct methods [smear microscopy, rapid diagnostic test (RDT), reference NAAT and blood cultures] and indirect methods (paired serology). Findings Among 455 travellers with AUFI, 229 target infections were diagnosed; the prototype panel detected 143 (overall sensitivity and specificity of 62.5 and 99.8%, respectively). The panel identified all Plasmodium infections (n = 82). Sensitivity for dengue (n = 71) was 92.9, 80.8 and 68.5% compared with RDT, NAAT and CRS, respectively. Compared with direct methods and CRS, respectively, the prototype panel detected 4/4 and 4/6 chikungunya, 2/2 and 4/29 Leptospira spp., 1/1 and 1/6 O. tsutsugamushi and 2/2 and 2/55 Rickettsia spp., but 0/2 and 0/10 Zika, 0/1 and 0/11 A. phagocytophylum and 0/3 Borrelia spp. diagnosed by serology and only 1/7 Salmonella spp. diagnosed by blood cultures. 77/86 (89.5%) infections not detected by the panel were diagnosed by serology. Interpretation The prototype panel allowed rapid and reliable diagnosis for malaria, dengue and chikungunya. Further improvements are needed to improve its sensitivity for Zika and important travel-related bacterial infections.

Background Diagnosis of undifferentiated non-malaria fevers (NMF) in returning travellers is a great challenge. Currently, there is no consensus about the use of empirical antibiotics in returning travellers with undifferentiated NMF. Although studies in endemic areas showed that a wide range of pathogens implicated in undifferentiated NMF are treatable with doxycycline, the role of doxycycline in returning travellers with fever still has to be explored. Methods Prospective European multicentre cohort study of febrile international travellers (November 2017—November 2019). Immunological and molecular diagnostic techniques for doxycycline responding illnesses (DRI) agents such as Anaplasma phagocytophilum, spotted fever group Rickettsia spp., typhus group Rickettsia spp., Coxiella burnetii, Bartonella spp., Orientia tsutsugamushi, Borrelia miyamotoi, Borrelia recurrentis and Leptospira spp. were systematically performed in all patients with undifferentiated NMF. We estimated the prevalence and predictive factors of DRI in returning travellers with undifferentiated NMF. Results Among 347 travellers with undifferentiated NMF, 106 (30·5%) were finally diagnosed with DRI. Only 57 (53·8%) of the 106 DRI infections were diagnosed by the standard of care. The main causes of DRI were: 55 (51·9%) Rickettsia spp., 16 (15·1%) C. burnetii; 15 (14·2%) Bartonella spp.; 13 (12·3%) Leptospira spp. and 10 (9·5%) A. phagocytophilum. The only predictive factor associated with DRI was presenting an eschar (aOR 39·52, 95%CI 4·85–322·18). Features of dengue such as retro-orbital pain (aOR 0·40, 95%CI 0·21–0·76) and neutropenia (aOR 0·41, 95%CI 0·21–0·79) were negatively associated with DRI. Conclusions Although DRI are responsible for 30% of undifferentiated NMF cases in travellers, those are seldom recognized during the first clinical encounter. Empirical treatment with doxycycline should be considered in returning travellers with undifferentiated fever and negative tests for malaria and dengue, particularly when presenting severe illness, predictive factors for rickettsiosis or no features of dengue.

Background Etiological diagnosis of febrile illnesses in returning travelers is a great challenge, particularly when presenting with no focal symptoms [acute undifferentiated febrile illnesses (AUFI)], but is crucial to guide clinical decisions and public health policies. In this study, we describe the frequencies and predictors of the main causes of fever in travelers. Methods Prospective European multicenter cohort study of febrile international travelers (November 2017–November 2019). A predefined diagnostic algorithm was used ensuring a systematic evaluation of all participants. After ruling out malaria, PCRs and serologies for dengue, chikungunya and Zika viruses were performed in all patients presenting with AUFI ≤ 14 days after return. Clinical suspicion guided further microbiological investigations. Results Among 765 enrolled participants, 310/765 (40.5%) had a clear source of infection (mainly traveler’s diarrhea or respiratory infections), and 455/765 (59.5%) were categorized as AUFI. AUFI presented longer duration of fever (p Conclusions Over 40% of returning travelers with AUFI were diagnosed with malaria or dengue, infections that can be easily diagnosed by rapid diagnostic tests. Arboviruses were the most common cause of AUFI (above malaria) and most cases were diagnosed during Aedes spp. high season. This is particularly relevant for those areas at risk of introduction of these pathogens. Empirical antibiotic regimens including doxycycline or azithromycin should be considered in patients with AUFI, after ruling out malaria and arboviruses.

Background Although tick-borne pathogens have been reported as an important cause of imported fever, the incidence of Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis (HGA), in travellers is unknown. Methods We conducted a prospective cohort study to investigate the aetiologies of fever in returning travellers (November 2017—July 2019). Polymerase chain reaction for msp2 gene amplification and indirect immunofluorescence assay for A. phagocitophilum were performed in all returning travellers with undifferentiated non-malarial fever. Results Among 141 travellers included, 8 patients were diagnosed with probable or confirmed HGA. The overall incidence rate of HGA was 19.9 cases/1000 person—week of travel. The main destination of travel was Asia, accounting for 62.5% patients with HGA. Co-infections were found in 37.5% of patients with HGA. Conclusions Diagnosis of HGA and empirical treatment with doxycycline should be considered in travellers with fever.

The emergence of Zika virus (ZIKV) represents a threat with consequences on maternal and children's health. We aimed to assess the clinical and epidemiological characteristics of pregnant women returning from ZIKV affected areas, and the effects of maternal ZIKV infection on birth outcomes and children's health. This was a hospital-based prospective observational study conducted at the Hospital Clínic of Barcelona and Hospital Sant Joan de Déu, Barcelona, Spain, from January 2016 to February 2020. One hundred and ninety-five pregnant women who had travelled to ZIKV affected areas during pregnancy were recruited. Four women (2.1%) had a confirmed ZIKV infection, 40 women (20.5%) a probable infection, and 151 (77.4%) were negative for ZIKV. Among the ZIKV confirmed cases, a pregnant woman suffered a miscarriage, highly plausible to be associated with ZIKV infection. Brain cysts and microcalcifications were detected in 7% of fetuses or infants from women with confirmed or probable ZIKV infection. Neurodevelopmental delay in the language function was found in 33.3% out of the 21 children evaluated. These findings contribute to the understanding of ZIKV prevalence estimates, and the impact of maternal ZIKV infection on pregnancy outcomes and children's health. Results highlight the importance of long-term surveillance in pregnant travellers and their children. This work was supported by the Government of Spain [grant number PI16/0123, ISCIII-AES Proyectos de Investigación en Salud, 2016]; a predoctoral fellowship from “la Caixa” Foundation (ID 100010434) [fellowship LCF/BQ/ES17/11600006]; the Ministry of Science, Innovation and Universities, Government of Spain through a Ramon y Cajal Grant [RYC-2013-14,512]; RICET, a Tropical Disease Cooperative Research Network in Spain [RD12/0018/0010] cofounded by ISCIII and the Fondo Europeo de Desarrollo Regional (FEDER); the Departament d’Universitats I Recerca de la Generalitat de Catalunya, Spain, AGAUR [grant 2017SGR924]; and ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Sí

Background Dengue virus (DENV) is the most important arbovirus worldwide, causing infections in endemic countries and returning travellers from these areas. Rapid diagnostic tests are needed to improve patient management and monitor local transmission. The detection of DENV non-structural protein 1 (NS1) is a useful tool for the diagnosis, but the currently available methods can be time consuming or lack sensitivity. The objective of our study was to evaluate a new rapid and semi-quantitative microfluidic DENV NS1 immuno-magnetic agglutination assay based on aggregation of magnetic nanoparticles detected by an electronic reader (Virotrack Dengue Acute and Blubox, Blusense diagnostics, Copenhagen, Denmark). Methodology/Principal findings A panel of 135 serum samples from travelers returning from dengue endemic countries was analyzed (74 DENV positive samples including the four DENV serotypes, 26 Zika virus positive samples, 25 chikungunya virus positive samples, 5 malaria positive samples and 5 negative samples). Samples were tested by three different antigen detection methods: SD Dengue NS1 Ag ELISA, SD BIOLINE Dengue Duo and ViroTrack Dengue Acute. The sensitivity observed for SD Dengue NS1 Ag ELISA, ViroTrack Dengue Acute and SD BIOLINE Dengue Duo was 97.2%, 91.1% and 68.1%, respectively. All methods showed high specificity (98.4% for ViroTrack Dengue Acute and 100% for both SD Dengue NS1 Ag ELISA and SD BIOLINE Dengue Duo). SD Dengue NS1 Ag ELISA and ViroTrack Dengue Acute only failed to detect samples positive for DENV-2. Conclusions/Significance ViroTrack Dengue Acute is a sensitive and specific assay for DENV NS1 detection. It provides faster results than the ELISA method and a better performance than the rapid immunochromatographic tests. ViroTrack Dengue Acute could represent a valuable tool for rapid diagnosis of DENV infections in returning travellers from endemic countries., Author summary Dengue virus is a human pathogen that causes millions of infections each year. It can be found in nearly all tropical areas, and people living in those regions and travelers who visit them are at risk of disease. The symptoms may vary from a mild flu-like disease to severe hemorrhagic symptoms. Accurate diagnosis of dengue is important for a better management of the disease and for epidemiological surveillance. Detection of DENV antigen is a useful tool to diagnose DENV infections. However, currently available techniques are not rapid (ELISA assays) or not accurate enough (immunochromatographic tests). Here, we evaluate a new antigen detection technique based on aggregation of magnetic nanoparticles. The method combines a short time to results (12 minutes) with a high diagnostic performance. We therefore conclude that this new technique could be a useful tool for the diagnosis of dengue.

Dengue is the most significant arbovirus worldwide and a public health threat to non-endemic areas in which Aedes vectors are present. Autochthonous dengue transmission has been reported in several European countries in the last decade. Infected travelers from endemic regions arriving to areas colonized by Aedes albopictus in Europe need to be monitored in surveillance and control programs. We aimed to perform molecular characterization of RT-PCR-positive dengue cases detected in Catalonia, northeastern Spain, from 2013 to 2018. The basic demographic information and the geographical regions of importation were also analyzed. One-hundred four dengue cases were studied (103 imported infections and the first autochthonous case in our region). The dengue virus strains detected were serotyped and genotyped using molecular methods, and phylogenetic analyses were conducted. All four dengue serotypes were detected in travelers, including up to 10 different genotypes, reflecting the global circulation of dengue in endemic areas. The primary travel-related case of the 2018 autochthonous transmission was not identified, but the molecular analysis revealed dengue serotype 1, genotype I of Asian origin. Our results highlight the diversity of imported dengue virus strains and the role of molecular epidemiology in supporting arbovirus surveillance programs. This research was partially supported by Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR)-Departament d’Empresa i Coneixement. Generalitat de Catalunya (grant 2017 SGR 794 to M.J.M.), by Instituto de Salud Carlos III-Red de Enfermedades Tropicales, Subprograma Redes Temáticas de Investigación Cooperativa en Salud Plan Estatal de I + D + I 2013–2016-Federación Española de Enfermedades Raras [Una Manera de Hacer Europa] (project RD16CIII/0003/0003 to M.P.S.S.) and by Societat Catalana de Malalties Infeccioses i Microbiologia Clínica (grant Agustí Pumarola 2020 to J.N.-C.). Sí

Dengue has emerged as the most important viral mosquito-borne disease globally. The current risk of dengue outbreaks in Europe appeared with the introduction of the vector Aedes albopictus mosquito in Mediterranean countries. Considering the increasing frequency of dengue epidemics worldwide and the movement of viraemic hosts, it is expected that new autochthonous cases will occur in the future in Europe. Arbovirus surveillance started in Catalonia in 2015 to monitor imported cases and detect possible local arboviral transmission. During 2015, 131 patients with a recent travel history to endemic countries were tested for dengue virus (DENV) and 65 dengue cases were detected. Twenty-eight patients with a febrile illness were viraemic, as demonstrated by a positive real-time RT-PCR test for DENV in serum samples. Entomological investigations around the viraemic cases led to the detection of DENV in a pool of local Ae. albopictus captured in the residency of one case. The sequence of the DENV envelope gene detected in the mosquito pool was identical to that detected in the patient. Our results show how entomological surveillance conducted around viraemic travellers can be effective for early detection of DENV in mosquitoes and thus might help to prevent possible autochthonous transmission.

Dengue has emerged as the most important viral mosquito-borne disease globally. The current risk of dengue outbreaks in Europe appeared with the introduction of the vector Aedes albopictus mosquito in Mediterranean countries. Considering the increasing frequency of dengue epidemics worldwide and the movement of viraemic hosts, it is expected that new autochthonous cases will occur in the future in Europe. Arbovirus surveillance started in Catalonia in 2015 to monitor imported cases and detect possible local arboviral transmission. During 2015, 131 patients with a recent travel history to endemic countries were tested for dengue virus (DENV) and 65 dengue cases were detected. Twenty-eight patients with a febrile illness were viraemic, as demonstrated by a positive real-time RT-PCR test for DENV in serum samples. Entomological investigations around the viraemic cases led to the detection of DENV in a pool of local Ae. albopictus captured in the residency of one case. The sequence of the DENV envelope gene detected in the mosquito pool was identical to that detected in the patient. Our results show how entomological surveillance conducted around viraemic travellers can be effective for early detection of DENV in mosquitoes and thus might help to prevent possible autochthonous transmission. Funding acknowledgment to the CERCA Programme/Generalitat de Catalunya and the Health department of the Generalitat de Catalunya. The study was also partially funded by ISCIII, project RD12/0018/0006 Red de Enfermedades Tropicales, Subprograma RETICS del Plan Estatal de I+D+I 2013-2016 and cofunded by FEDER: Una manera de hacer Europa and by grant 2017 SGR 794 from the Agència de gestió Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) - Departament d’Empresa i Coneixement . Generalitat de Catalunya. The authors are very grateful for the excellent technical contribution of Núria Pujol and Raquel Rivas from CReSA (IRTA). Sí