Doxycycline responding illnesses in returning travellers with undifferentiated non-malaria fever: a European multicentre prospective cohort study

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 center dot 5%) were finally diagnosed with DRI. Only 57 (53 center dot 8%) of the 106 DRI infections were diagnosed by the standard of care. The main causes of DRI were: 55 (51 center dot 9%) Rickettsia spp., 16 (15 center dot 1%) C. burnetii; 15 (14 center dot 2%) Bartonella spp.; 13 (12 center dot 3%) Leptospira spp. and 10 (9 center dot 5%) A. phagocytophilum. The only predictive factor associated with DRI was presenting an eschar (aOR 39 center dot 52, 95%CI 4 center dot 85-322 center dot 18). Features of dengue such as retro-orbital pain (aOR 0 center dot 40, 95%CI 0 center dot 21-0 center dot 76) and neutropenia (aOR 0 center dot 41, 95%CI 0 center dot 21-0 center dot 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.