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Background: Tularemia is a re-emerging disease in Sweden, frequently affecting working-age individuals and often resulting in prolonged recovery times. The disease-related economic impact has not previously been investigated outside bioterrorism scenarios. In this study we assess the economic burden associated with endemic tularemia in Sweden.  

Method: Data on primary care visits, hospital admissions, and sick leaves were collected from participants with serology-confirmed tularemia through questionnaires and electronic medical records in Northern Sweden from 2011 to 2021. The dataset was enhanced with national cost-of-care data for tularemia in primary and specialist care from NordDRG (Diagnosis Related Group; 2021-2023), and sickness benefit data from the Social Insurance Agency (2011-2023). Total direct and indirect costs were estimated by integrating these data sources and adjusted for inflation to 2025 levels. Average salary and labor productivity (Gross Domestic Product [GDP] per person employed) was assumed.

Results: Among participants (n=294), the mean age was 52 years; 68.1% were employed or job-seeking, with 71.3% of these reporting sick leave during illness. Healthcare costs were primarily driven by general practitioner visits (mean 1.74 visits; 5,125 SEK per participant [p.p.]) and hospital admissions (15.6% of participants; mean 4.7 days; 11,268 SEK p.p.) with relatively low complexity (mean DRG weight 0.8), while antibiotic treatment and diagnostics were less costly (figure 1). Indirect costs included sick pay (≤14 days; 70.0%; 4,106 SEK p.p.), sickness benefit (>14 days; 30.0%; 5,835 SEK p.p.), and lost GDP-based productivity, and made up 75.7% of total costs (78,503 SEK p.p.).

A mean of 394 (range 87-1,048) tularemia cases per year were reported to the Swedish Public Health Agency between 2011-2023. The estimated annual societal cost of human tularemia infection was 30.9 million SEK (range 6.8-82.3 million SEK). 

Conclusion: Tularemia imposes a significant socioeconomic burden on society primarily through morbidity and prolonged recovery. Regional outbreaks could have detrimental effects on local economy and public services. Further evaluation of the cost-effectiveness of primary and secondary preventive measures is required. 

Introduction: For a majority of tularemia patients, serology is the basis for the diagnosis. The aim of this study was to perform an analysis of the samples analyzed at a Swedish reference laboratory for the presence of Francisella tularensis-specific antibody levels in sera from individuals with suspected tularemia. Annual and monthly variations of the total number of samples and proportions of positive samples were analyzed, as well as the influence of age and gender.

Methods: We performed a retrospective analysis of the presence of F. tularensis-specific antibodies in serological samples from patients with suspected tularemia analyzed during the period 2010 - 2022 at the University Hospital of Umeå in Sweden, a national reference laboratory, by use of various statistical methods. In total, some 15,100 serum samples had been analyzed for the presence of IgG and IgM antibodies by ELISA during the 13-year period.

Results: Overall, there were higher number of samples with IgG positive or borderline titers, 2,522 and 921, respectively, than with IgM positive or borderline titers, 1,802 and 409, respectively. Repeated samples were obtained from some 1,930 individuals and approximately a third of the cases, which were initially seronegative, had seroconverted when resampled. Peak number of monthly samples were recorded in August and September, > 3,000. Annual numbers varied greatly and peak numbers were observed in 2015 and 2019, 1,832 and 2,250, respectively, whereas some other years the numbers were 700 – 800. There was also much variation in the annual and monthly percentages of positive samples and they varied between less than 10% to greater than 20%. The highest percentages of positive samples were recorded in September and October. IgG and IgM titers declined with age and these differences were highly significant for IgG titers, with decreasing average titers for each 20-year interval.

Discussion: Collectively, the data demonstrate the marked annual and seasonal variations in tularemia sampling occurring in Sweden. Also, the proportion of positive samples increased during months and years with peak number of samples. Another notable finding was that average antibody titers decreased with increased age.

Background: Tularaemia is a geographically widespread disease affecting animals and humans. In Sweden, transmission patterns are complex, occurring mainly through mosquito vectors. We investigated human exposure and whether passive tularaemia surveillance (reported by the public) of deceased wild hares could be used to temporally and geographically predict outbreaks among humans. 

Methods: A survey was sent to the 830 cases of reported tularaemia in Norrbotten county, Sweden, between 2011-2021; and 313/415 (75.4%) respondents with laboratory-evidence of tularaemia were included. Geographic data from human infections in 2019 (n=54) and 2020 (n=77) was compared to data on deceased forest hares from the Swedish Veterinary Agency, matched by year and region.

Results: Respondents (n=313) rarely reported direct exposure to hares (8,6%) and/or other rodents (3.8%) during the 2-weeks prior to illness; while recreational activities (forest hiking 61.6%; mushroom/berry-picking 24.0%; fishing 11.5%; and hunting 3.8%) were more common. Peak incidence of reported deceased hares in 2019 and 2020 (n=84 and n=66; 11/15 [73.3%] and 19/21 [90.4%] PCR-positive for tularaemia, respectively) corresponded to peak incidence of symptom onset of human cases (median difference +6 days [2019] and -2 days [2020]; p=0.066 and p=0.695, respectively). Distribution of reported hares corresponded with municipalities with highest incidence of human tularaemia and location of self-reported suspected infection (Figure 1). Most reported their location of infection to be within their residential municipality (n=92/106, 86.8%).

Conclusion: Passive surveillance of tularaemia using deceased hares correlates with symptom onset in humans and could predict geographical outbreaks in the community. Surveillance of other affected/reservoir species should be considered. 

Background: Tularemia is an important re-emerging disease with a multimodal transmission-pattern. Treatment outcomes of current recommended antibiotic regimens (including ciprofloxacin and doxycycline) remain unclear. In this retrospective cohort study, we report clinical, laboratory, geographical, and treatment outcomes of laboratory-confirmed tularemia cases over an 11-year period in Northern Sweden.

Methods: Data from reported tularemia cases (aged >10 years at time of study) in Norrbotten county between 2011-2021 were collected through review of electronic medical records and participant questionnaires; with 415 out of 784 accepting participation (52.9%). Of these, 327 were laboratory-confirmed cases (serology and/or PCR). A multivariable logistic regression model was used to investigate variables associated with re-treatment.

Results: Median age of participants was 54 years (IQR 41.5-65) and 49.2% were female. While ulceroglandular tularemia was the predominant form (n=215, 65.7%), there were several cases of pulmonary tularemia (n=40; 12.2%). Inflammatory markers were largely non-specific, with monocytosis frequently observed (n=36/75; 48%). Tularemia was often misdiagnosed upon presentation (n=158, 48.3%), with 65 (19.9%) receiving initial inappropriate antibiotics, and 102 (31.2%) re-treated. Persistent lymphadenopathy was infrequent (n=22, 6.7%), with 10 undergoing surgical interventions. In multivariable analysis of variables associated with re-treatment, we highlight differences in time until receiving appropriate antibiotics (8 [IQR 3.25-20.75] vs. 7 [IQR 4-11.25] days; adjusted p=0.076), and doxycycline-based treatment regimen (vs. ciprofloxacin; adjusted p=0.084), although not significant after correction for multiple comparisons.

Conclusion: We comprehensively summarize clinical, laboratory, and treatment outcomes of type B tularemia. Targeting tularemia requires clinical awareness, early diagnosis and timely commencement of treatment for an appropriate duration.

Francisella tularensis is the etiological agent of the potentially severe infection tularemia. An existing F: tularensis vaccine, the live vaccine strain (LVS), has been used to protect at-risk personnel, but it is not licensed in any country and it has limited efficacy. Therefore, there is a need of a new, efficacious vaccine. The aim of the study was to perform a detailed analysis of the characteristics of the human immune response to F. tularensis, since this will generate crucial knowledge required to develop new vaccine candidates. Nine individuals were administered the LVS vaccine and peripheral blood mononuclear cells (PBMC) were collected before and at four time points up to one year after vaccination. The properties of the PBMC were characterized by flow cytometry analysis of surface markers and intracellular cytokine staining. In addition, the cytokine content of supernatants from F. tularensis-infected PBMC cultures was determined and the protective properties of the supernatants investigated by adding them to cultures with infected monocyte-derived macrophages (MDM). Unlike before vaccination, PBMC collected at all four time points after vaccination demonstrated F. tularensis-specific cell proliferation, cytokine secretion and cytokine-expressing memory cells. A majority of 17 cytokines were secreted at higher levels by PBMC collected at all time points after vaccination than before vaccination. A discriminative analysis based on IFN-γ and IL-13 secretion correctly classified samples obtained before and after vaccination. Increased expression of IFN-γ, IL-2, and MIP-1β were observed at all time points after vaccination vs. before vaccination and the most significant changes occurred among the CD4 transient memory, CD8 effector memory, and CD8 transient memory T-cell populations. Growth restriction of the highly virulent F. tularensis strain SCHU S4 in MDM was conferred by supernatants and protection correlated to levels of IFN-γ, IL-2, TNF, and IL-17. The findings demonstrate that F. tularensis vaccination induces long-term T-cell reactivity, including T_EM and T_TM cell populations. Individual cytokine levels correlated with the degree of protection conferred by the supernatants. Identification of such memory T cells and effector mechanisms provide an improved understanding of the protective mechanisms against F. tularensis. mechanisms against F. tularensis.

Serological analysis is the predominant method used to diagnose tularemia, a zoonotic disease caused by the highly virulent bacterium F. tularensis. We determined F. tularensis-specific IgM and IgG antibody titers by an LPS-based ELISA assay on five occasions one to twelve months after onset of ulceroglandular tularemia in 19 individuals. Peak IgM antibody titers were observed at the one-month time point and peak IgG antibody titers at the two-month time point. Both IgG and IgM antibody levels declined linearly thereafter with rather similar kinetics. Compared to the average one-month antibody titers, average IgG titers were not significantly lower before the 12-month time point and IgM titers before the 4-month time point. All, but one average titer, were significantly increased compared to the cut-off of the assay. Average IgG and IgM titers were significantly lower for the group = 69 years old compared to the group < 69 years. Collectively, the data demonstrate a persistence of F. tularensis-specific IgM and IgG antibody titers for at least 12 months after ulceroglandular tularemia. Thus, low, but significantly elevated F. tularensis-specific antibody titers are of limited diagnostic value since they are not indicative of ongoing tularemia.

Interpretation of serological findings in suspected Lyme borreliosis (LB) is challenging and IgM reactivities may have low predictive value. Therefore, if used indiscriminately, there is a risk for incorrect diagnosis of LB. To evaluate the usefulness of IgM titer determination, we performed a study of the prevalence of Borrelia-specific antibodies in serological samples from patients with suspected LB analyzed during the period 2010 - 2021 at the University Hospital of Umeå in Sweden. In total, 19,335 samples had been analyzed for the presence of IgG and IgM antibodies. Overall, there were higher percentages of IgM positive or borderline titers, 1,847 (9.6%) and 905 (4.7%), respectively, than IgG positive or borderline titers, 959 (5.0%) and 406 (2.1%), respectively. Peak number of samples were recorded 2012 - 2013, exceeding 1,800, whereas there were around 1,200 during 2020 - 2021. The peak number of positive IgG and/or positive IgM samples were observed during the period 2015 - 2017 with close to, or above 400, and concomitantly, the proportion of IgG positive samples increased markedly. For IgG positive samples, the increase followed a positive linear time trend (P< 0.001). Peak monthly numbers were observed during August, September, and October. This seasonal increase was significant for the IgG positive group (P< 0.05), but not for the IgM positive/IgG negative group. Repeated samples were obtained from 3,188 individuals and of the initial samples 2,817 were (88%) IgG negative and 2,315 (72%) were IgM negative and of these, 130 (4%) showed IgG seroconversion and 300 (9%) IgM seroconversion. Collectively, the data demonstrate that IgG and/or IgM positive samples represented a minority of all samples, even when repeated sampling had occurred, and IgM positive samples were much more common than IgG positive samples. Thus, the accuracy of the clinical suspicion was low and this will lead to a low predictive value of the analysis, in particular of IgM. These findings question the use of IgM titer determination as a routine analysis.

The Hsp100 family member ClpB is a protein disaggregase which solubilizes and reactivates stress-induced protein aggregates in cooperation with the DnaK/Hsp70 chaperone system. In the pathogenic bacterium Francisella tularensis, ClpB is involved in type VI secretion system (T6SS) disassembly through depolymerization of the IglA-IglB sheath. This leads to recycling and reassembly of T6SS components and this process is essential for the virulence of the bacterium. Here we report the backbone chemical shift assignments and 15N relaxation-based backbone dynamics of the N-terminal substrate-binding domain of ClpB (1-156).

The α-pore-forming toxins (α-PFTs) from pathogenic bacteria damage host cell membranes by pore formation. We demonstrate a remarkable, hitherto unknown mechanism by an α-PFT protein from Vibrio cholerae. As part of the MakA/B/E tripartite toxin, MakA is involved in membrane pore formation similar to other α-PFTs. In contrast, MakA in isolation induces tube-like structures in acidic endosomal compartments of epithelial cells in vitro. The present study unravels the dynamics of tubular growth, which occurs in a pH-, lipid-, and concentration-dependent manner. Within acidified organelle lumens or when incubated with cells in acidic media, MakA forms oligomers and remodels membranes into high-curvature tubes leading to loss of membrane integrity. A 3.7 Å cryo-electron microscopy structure of MakA filaments reveals a unique protein-lipid superstructure. MakA forms a pinecone-like spiral with a central cavity and a thin annular lipid bilayer embedded between the MakA transmembrane helices in its active α-PFT conformation. Our study provides insights into a novel tubulation mechanism of an α-PFT protein and a new mode of action by a secreted bacterial toxin.