| 1. |
- Asfaw Idosa, Berhane, 1977-
(författare)
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Inflammasome polymorphisms and the Inflammatory Response to Bacterial Infections
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- NLRP3 inflammasome; a key component of the innate immune system, can be activated by a number of pathogens and other threats of the body. Activation of the NLRP3 inflammasome triggers caspase-1 mediated maturationof IL-1β and IL-18. Polymorphisms Q705K and C10X are two gene variants of the NLRP3 inflammasome that combined or per se have been associated with higher risk and severity of chronic inflammation and excessive production of IL-1β. Host genetic factors have been found an important determinants of susceptibility of infectious diseases and disease outcome. The aims of this thesis were to investigate the association between polymorphisms Q705K and C10X with bacterial infections and the inflammatory response, moreover to determine the inflammasome activation state in healthy carriers of these polymorphisms. The data of the thesis show higher levels of IL-1β and IL-33 in healthy carriers of combined polymorphisms of Q705K and C10X as compared to non-carrier controls. This may provide individuals with combined polymorphisms a more robust innate immune response against pathogens, but could also lead to the onset of chronic inflammation, and excessive inflammation during acute infection. In addition, individuals with C10X polymorphism per se showed association with the presence of bacteremia as compared withhealthy blood donors. No association was found in severely ill patients with negative blood culture bottle. In addition, the results show that LOS of N. meningitidis is responsible for the priming and activating steps of the inflammasome. The non-LOS components were found to contribute to the priming step. A higher inflammatory response to N. meningitidis was found in individuals who were non-carriers of the polymorphisms than individuals with the Q705K and C10X per se or combined regardless of the strain of bacteria. Taken together, the gene variations of the NLRP3 inflammasome are of importance in explaining inter-individual variation in susceptibility to infectious diseases.
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| 2. |
- Månsson, Emeli, 1978-
(författare)
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Molecular epidemiology of Staphylococcus epidermidis in prosthetic joint infections
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Staphylococcus epidermidis is ubiquitous in the human microbiota, but also an important pathogen in healthcare-associated infections, such as prosthetic joint infections (PJIs). In this thesis, aspects of the molecular epidemiology of S. epidermidis in PJIs were investigated with the aim of improving our understanding of the pre- and perioperative measures required to reduce the incidence of S. epidermidis PJIs.In Paper I, S. epidermidis retrieved from air sampling in the operating field during arthroplasty was characterized by multilocus sequence typing and antibiotic susceptibility testing. No isolates belonging to sequence types (STs) 2 and 215, previously associated with PJIs, were found in the air of the operating field. During air sampling, several Staphylococcus pettenkoferi isolates were identified, and as a spin-off of Paper I, the genomic relatedness of these isolates to S. pettenkoferi isolates from blood cultures was described in Paper II.In Paper III, genetic traits distinguishing S. epidermidis isolated from PJIs were determined using genome-wide association study accounting for population effects after whole-genome sequencing (WGS) of a population- based 10-year collection of S. epidermidis isolates from PJIs and of nasal isolates retrieved from patients scheduled for arthroplasty. Genes associated with antimicrobial agents used for prophylaxis in arthroplasty, i.e., beta-lactam antibiotics, aminoglycosides, and chlorhexidine, were associated with PJI origin. S. epidermidis from PJIs were dominated by the ST2a, ST2b, ST5, and ST215 lineages.In Paper IV, selective agar plates were used to investigate colonization with methicillin resistant S. epidermidis (MRSE) in patients scheduled for arthroplasty. MRSE were further characterized by WGS. A subset of patients was found to harbour PJI-associated S. epidermidis lineages in their microbiota before hospitalization, but no isolates belonging to the ST2a lineage nor any rifampicin-resistant isolates were retrieved.
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| 3. |
- Sahlberg Bang, Charlotte, 1967-
(författare)
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Carbon monoxide and nitric oxide as antimicrobial agents : focus on ESBL-producing uropathogenic E.coli
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Urinary tract infections (UTI) are common in humans and most often caused by uropathogenic Escherichia coli (E. coli). Extended-spectrum beta-lactamase (ESBL)-producing E. coli are increasing worldwide and they are frequently multidrug-resistant with limited treatment options. The overall aim of this thesis was to study the role of the host-derived factors nitric oxide (NO) and carbon monoxide (CO) as antimicrobial agents against ESBL-producing uropathogenic strains of E. coli (UPEC).The NO-donor DETA/NO caused a temporary growth inhibition in ESBL-producing UPEC. The antibacterial effect of DETA/NO was improved when DETA/NO was combined with miconazole, a pharmacological inhibitor of NO-protective mechanisms. Combination treatment with DETA/NO, miconazole and polymyxin B nonapeptid prolonged the bacteriostatic effect in the majority of examined isolates. The CO-donor CORM-2 showed a pronounced antibacterial effect in ESBL-producing UPEC with a fast bactericidal effect. Moreover, CORM-2 was shown to reduce the bacterial viability of ESBL-producing UPEC grown under biofilm-like conditions and to decrease the bacterial colonization of human bladder epithelial cells. A microarray analysis was performed to define transcriptomic targets of CORM-2 after a single exposure and after repeated exposure to CORM-2. Many processes were affected by CORM-2, including a downregulation in energy metabolism and biosynthesis pathways and upregulation of the SOS response and DNA repair. Repeated exposure to CORM-2 did not change the gene expression patterns or fold changes and the growth inhibitory response to CORM-2 was not altered after repeated exposure.In conclusion, NO- and CO-donors have antibacterial effects against ESBL-producing UPEC and may be interesting candidates for development of new antibiotics to treat UTI caused by multidrug-resistant uropathogens.
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| 4. |
- Rasmussen, Gunlög, 1973-
(författare)
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Staphylococcus aureus bacteremia, molecular epidemiology and host immune response
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Staphylococcus aureus is a major pathogen responsible for a considerable disease burden worldwide. It may cause a wide array of infections, from superficial skin infections to invasive bacteremia and complications such as infective endocarditis (IE) and osteomyelitis. This thesis aimed to investigate aspects of the molecular epidemiology of S. aureus and host immune response in relation to disease manifestation, severity, and over time during S. aureus bacteremia (SAB).Genotypic characteristics in isolates causing colonization, bacteremia, and bacteremia with IE were studied. The S. aureus population was genetically diverse and certain clones with their set of often lineage-specific virulence genes were associated with invasive disease. Characterization of the long-term molecular epidemiology of MSSA bacteremia showed an increased prevalence of CC5 and CC15, while CC8, CC25 and CC30 declined. Antibiotic resistance pattern was favorable and unaffected.Further, different aspects of host immune response were explored in patients with SAB during the acute phase of bacteremia. When investigating the NLRP3 inflammasome signaling, induced caspase-1 activity was found, with a great inter-individual variation between patients, and subsequent release of IL-18, indicating inflammasome activity. Finally, the dynamics of MHC class II related genes HLA-DRA and CD74 were analyzed as markers of immunosuppression. Patients with complicated SAB had significantly lower HLA-DRA expression than patients with uncomplicated bacteremia, demonstrating an association between complicated SAB and impaired immune function.In conclusion, the S. aureus genotype, as well as host factors reflected by inter-individual variations in inflammasome signaling and immune function, may all contribute to disease manifestation and outcome during SAB. An ability to measure the immune response early and continuously during the hospital stay and course of bacteremia could offer a way to tailor patient management and treatment in an individualized way.
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| 5. |
- Tevell, Staffan, 1975-
(författare)
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Staphylococcal prosthetic joint infections : similar, but still different
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Staphylococci constitute a major part of our commensal flora but are also the most common bacteria causing prosthetic joint infections (PJIs), a dreaded complication of arthroplasty surgery. However, not all staphylococci are the same. The virulent Staphylococcus aureus has the ability to cause severe disease such as bacteremia and infective endocarditis in previously healthy people, while the coagulase-negative staphylococci Staphylococcus epidermidis and Staphylococcus capitis rarely act as pathogens unless the patient is immunocompromised or has an implanted medical device, such as a prosthetic joint. This thesis accordingly explores similarities and differences between these three staphylococci in PJIs.S. capitis can cause early postinterventional and chronic PJIs, a finding that has not previously been described. Furthermore, its nosocomial NRCS-A outbreak sublineage, recently observed in neonatal intensive care units, is also present in adult PJIs. When comparing nasal and PJI isolates, the patterns differed between staphylococcal species. In S. capitis, the commensal and infecting strains were separated phylogenetically, while they clustered together for S. aureus. This may indicate diverse reservoirs and acquisition routes in PJIs caused by different staphylococcal species.Outcomes in early postinterventional PJIs were similar in S. capitis and S. aureus infections, with 70–80% achieving clinical cure. In S. aureus infections, no virulence genes were significantly associated with outcome. Although multidrug resistance (MDR) was rare in S. aureus, inability to use biofilm-active antibiotics was a risk factor for failure. However, in S. epidermidis and in the NRCS-A sublineage of S. capitis, MDR and glycopeptide heteroresistance were widespread, highlighting the challenge of antibiotic resistance in the treatment of PJIs.
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| 6. |
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| 7. |
- Wistrand, Camilla, 1970-
(författare)
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Swedish operating room nurses preventive interventions to reduce bacterial growth, surgical site infections, and increase comfort in patients undergoing surgery
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Surgical site infection is a major postoperative complication that causes patient suffering and is costly for society. The general aim of this thesis was to test and describe interventions performed by operating room (OR) nurses to prevent bacterial growth in surgical patients, with the intent to prevent surgical site infections (SSIs) whilst increase patients comfort.In studies I and II, 220 pacemaker patients were tested to compare pre-heated skin disinfection with room-temperature skin disinfection regard-ing bacterial growth, skin temperature and patient experience. Preheated skin disinfection was not less effective compared to room-temperature skin disinfection in reducing bacterial growth after skin disinfection and there were no differences regarding SSIs three month postoperatively. Preheated skin disinfection reduces skin heat loss and was perceived as more pleas-ant compared to room-temperature skin disinfection.In study III, 12 OR nurses were examined regarding bacterial growth on their hands and at the sterile glove cuff end after surgical hand disinfec-tion and again after wearing sterile surgical gloves during surgery. They were compared with a control group of 13 non-health care workers. OR nurses’ hands had higher amounts of bacterial growth at two of three culture sites after surgical hand disinfection compared with the control group, and the bacterial growth increased in both groups with time during surgery. There seems to be a risk of bacterial growth at the glove cuff end during surgery, involving the same type of bacteria as isolated from the hands.In study IV, 890 OR nurses answered an online questionnaire describ-ing OR nurses interventions guided by national guidelines to reduce SSIs, such as preparation of the patient skin, patient temperature, and OR ma-terials used. The proportion of the OR nurses who complied with the national guidelines preventive interventions was high: skin disinfection solution (93.5%), drapes (97.4%) and gowns (83.8%), and double gloves (73%). However, when guidelines were lacking the interventions differed.
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| 8. |
- Cajander, Sara, 1980-
(författare)
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Dynamics of Human Leukocyte Antigen-D Related expression in bacteremic sepsis
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Monocytic human leukocyte antigen-D related (mHLA-DR) expression determined by flow cytometry has been suggested as a biomarker of sepsisinduced immunosuppression.In order to facilitate use of HLA-DR in clinical practice, a quantitative real-time PCR technique measuring HLA-DR at the transcription level was developed and evalutated. Levels of HLA-DR mRNA correlated to mHLADR expression and were robustly measured, with high reproducibility, during the course of infection. Dynamics of mHLA-DR expression was studied during the first weeks of bloodstream infection (BSI) and was found to be dependent on the bacterial etiology of BSI. Moreover, mHLA-DR was shown to be inversely related to markers of inflammation. In patients with unfavourable outcome, sustained high C-reactive protein level and high neutrophil count were demonstrated along with low mHLA-DR expression and low lymphocyte count. This supports the theory of sustained inflammation in sepsis-induced immunosuppression. The association between mHLA-DR and bacterial etiology may be linked to the clinical trajectory via differences in ability to cause intractable infection. Staphylococcus aureus was the dominating etiology among cases with unfavourable outcome. With focus on patients with S. aureus BSI, those with complicated S. aureus BSI were found to have lower HLA-DR mRNA expression during the first week than those with uncomplicated S. aureus BSI. If these results can be confirmed in a larger cohort, HLA-DR measurement could possibly become an additional tool for early identification of patients who require further investigation to clear infectious foci and achieve source control.In conclusion, PCR-based measurement of HLA-DR is a promising method for measurements of the immune state in BSI, but needs further evaluation in the intensive care unit setting to define the predictive and prognostic value for deleterious immunosuppression. The etiology of infection should be taken into consideration in future studies of translational immunology in sepsis.
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| 9. |
- Luhr, Robert, et al.
(författare)
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Trends in sepsis mortality over time in randomised sepsis trials : a systematic literature review and meta-analysis of mortality in the control arm, 2002-2016
- 2019
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Ingår i: Critical Care. - : BMC. - 1364-8535 .- 1466-609X. ; 23
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Forskningsöversikt (refereegranskat)abstract
- Background: Epidemiologic data have shown an increasing incidence and declining mortality rate in sepsis. However, confounding effects due to differences in disease classification might have contributed to these trends.To assess if a declining mortality over time could be supported by data derived from high-quality prospective studies, we performed a meta-analysis using data from randomised controlled trials (RCTs) on sepsis. The primary aim was to assess whether the mortality in sepsis trials has changed over time. The secondary aim was to investigate how many of the included trials could show efficacy of the studied intervention regarding 28-day mortality.Methods: We searched PubMed for RCTs enrolling patients with severe sepsis and septic shock, published between 2002 and 2016. The included trials were assessed for quality and sorted by date of first inclusion. A meta-analysis was performed to synthesise data from the individual sepsis trials.Results: Of 418 eligible articles, 44 RCTs on sepsis were included in the analysis, enrolling 13,315 patients in the usual care arm between 1991 and 2013. In this time period, mortality decreased by 0.42% annually (p=0.04) to give a total decline of 9.24%. In subgroup analyses with adjustments for APACHE II, SAPS II and SOFA scores, the observed time trend was not significant (p=0.45, 0.23 and 0.98 respectively). Only four of the included trials showed any efficacy with regard to mortality.Conclusions: Data from RCTs show a declining trend in 28-day mortality in severe sepsis and septic shock patients during the years from 1991 to 2013. However, when controlling for severity at study inclusion, there was no significant change in mortality over time. The number of trials presenting new treatment options was low.Trial registration: PROSPERO CRD42018091100. Registered 27 August 2018.
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| 10. |
- Thunberg, Ulrica, 1967-, et al.
(författare)
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Anti-Staphylococcal humoral immune response in patients with chronic rhinosinusitis
- 2019
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Ingår i: Rhinology Online. - : European Rhinologic Society. - 2589-5613. ; 2, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- Background: Staphylococcus aureus (S. aureus) can behave both as a harmless commensal and as a pathogen. Its significance in the pathogenesis of chronic rhinosinusitis (CRS) is not yet fully understood. This study aimed to determine serum antibody re-sponses to specific staphylococcal antigens in patients with CRS and healthy controls, and to investigate the correlation between specific antibody response and severity of symptoms.Methodology: Serum samples from 39 patients with CRS and 56 healthy controls were analysed using a protein microarray to investigate the antibody response to S. aureus specific antigens, with a focus on immunoglobulin G (IgG) directed toward stap-hylococcal components accessible to the immune system. Holm-Bonferroni corrections were applied in all analyses. Information about growth of S. aureus in nares and maxillary sinus was taken from a previous study based on the same individuals. Clinical symptoms were assessed using a scoring system.Results: IgG antibody levels toward staphylococcal TSST-1 and LukF-PV were significantly higher in the CRS patient group com-pared to healthy controls, and levels of anti-TSST-1 antibodies were significantly higher in the CRS patient group with S. aureus in maxillary sinus than in controls. There were no correlations between the severity of symptoms and levels of serum anti-staphylo-coccal IgG antibody levels for LukF-PV and TSST-1.Conclusions: TSST-1 and LukF-PV could be interesting markers for future studies of the pathogenesis of CRS.
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