Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne bunyavirus, causes mild-to-moderate infection to critical illness or even death in human patients. The effect of virus variations on virulence and related clinical significance is unclear. We prospectively recruited SFTSV-infected patients in a hotspot region of SFTS endemic in China from 2011 to 2020, sequenced whole genome of SFTSV, and assessed the association of virus genomic variants with clinical data, viremia, and inflammatory response. We identified seven viral clades (I-VII) based on phylogenetic characterization of 805 SFTSV genome sequences. A significantly increased case fatality rate (32.9%) was revealed in one unique clade (IV) that possesses a specific co-mutation pattern, compared to other three common clades (I, 16.7%; II, 13.8%; and III, 11.8%). The phenotype-genotype association (hazard ratios ranged 1.327-2.916) was confirmed by multivariate regression adjusting age, sex, and hospitalization delay. We revealed a pronounced inflammation response featured by more production of CXCL9, IL-10, IL-6, IP-10, M-CSF, and IL-1β, in clade IV, which was also related to severe complications. We observed enhanced cytokine expression from clade IV inoculated PBMCs and infected mice. Moreover, the neutralization activity of convalescent serum from patients infected with one specified clade was remarkably reduced to other viral clades. Together, our findings revealed a significant association between one specific viral clade and SFTS fatality, highlighting the need for molecular surveillance for highly lethal strains in endemic regions and unravelled the importance of evaluating cross-clade effect in development of vaccines and therapeutics.

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Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with a high case fatality rate. Few studies have been performed on bacterial or fungal coinfections or the effect of antibiotic therapy. A retrospective, observational study was performed to assess the prevalence of bacterial and fungal coinfections in patients hospitalized for SFTSV infection. The most commonly involved microorganisms and the effect of antimicrobial therapy were determined by the site and source of infection. A total of 1201 patients hospitalized with SFTSV infection were included; 359 (29.9%) had microbiologically confirmed infections, comprised of 292 with community-acquired infections (CAIs) and 67 with healthcare-associated infections (HAIs). Death was independently associated with HAIs, with a more significant effect than that observed for CAIs. For bacterial infections, only those acquired in hospitals were associated with fatal outcomes, while fungal infection, whether acquired in hospital or community, was related to an increased risk of fatal outcomes. The infections in the respiratory tract and bloodstream were associated with a higher risk of death than that in the urinary tract. Both antibiotic and antifungal treatments were associated with improved survival for CAIs, while for HAIs, only antibiotic therapy was related to improved survival, and no effect from antifungal therapy was observed. Early administration of

Objectives: Tick-borne rickettsiae are increasingly recognized to cause human infections; however, a complete clinical spectrum is lacking. Thus, surveillance study was conducted among forest rangers with tick bites to describe the clinical manifestations. Methods: One hundred fifty-nine blood samples were obtained from individuals bitten by ticks and 780 tick samples collected in the same endemic region were examined for the presence of Rickettsia. Serum samples were tested for IgM and IgG antibodies against R. heilongjiangensis. Results: Twenty-five (15.7%) individuals were shown to be infected with 5 Rickettsia species, including 14 Candidatus Rickettsia tarasevichiae (CRT), 8 R. raoultii, 1 R. felis, 1 R. heilongjiangensis, and 1 R. massiliae. Five individuals (1 CRT, 1 R. heilongjiangensis, and 3 R. raoultii) had mild illnesses; the other 20 individuals were asymptomatic. CRT was present in 38.4% (274/713) of I. persulcatus and 6.4% (3/47) of Hae. concinna. R. raoultii was demonstrated in 30.0% (6/20) of D. silvarum and 14.9% (7/17) of Hae. concinna. R. heilongjiangensis was detected in 9.5% (2/21) of D. silvarum and 0.3% (2/713) of I. persulcatus. Conclusions: The clinical manifestations of these rickettsioses were non-specific and differed from traditional features, thus supporting the necessity of wider investigations involving individuals with tick bites to develop an early differential diagnosis.