Factors associated with susceptibility to and outcome of bacteraemia with reference to Staphylococcus aureus, Streptococcus pneumoniae, B-haemolytic streptococcus and Escherichia coli bacteraemias

Uutta tietoa bakteeriperäisen verenmyrkytyksen taudinkuvaan ja ennusteeseen liittyvistä tekijöistä Bakteremialla eli bakteeriperäisellä verenmyrkytyksellä tarkoitetaan bakteerilajin lisääntymistä verenkierrossa, ja kyseessä on melko yleinen esimerkiksi keuhkokuumetta tai virtsatieinfektiota komplisoiva sairaus. Taudin oirekuva vaihtelee yksilöittäin lieväoireisesta infektiosairaudesta vaikeaan verenkiertoelimistön häiriötilaan, monielinvaurioon ja kuolemaan. Eri bakteereiden tiedetään aiheuttavan keskimäärin eri vaikeusasteisia taudinkuvia, mutta tästä huolimatta usein samankin bakteerilajin aiheuttama verenmyrkytys on taudinkuvaltaan eri yksilöillä erilainen. Tähän mennessä on tunnistettu huonoon ennusteeseen liittyviä yksilöön liittyviä tekijöitä, joita ovat esimerkiksi syöpäsairaudet, muut krooniset sairaudet, ja korkea ikä. Sensijaan elintapojen merkityksestä verenmyrkytyspotilaan tai ylipäänsä infektiopotilaan ennusteeseen on rajallisesti tietoa. Vaikka bakteeriperäisen verenmyrkytyksen hoitomenetelmät ovat kehittyneet viime vuosina, taudinkuvat ovat edelleen huonosti ennustettavia, ja kuolleisuus tautiin on korkea. Tämän tutkimuksen tärkein tavoite on selvittää geneettisten tekijöiden ja elintapojen merkitystä bakteremiapotilaiden ennusteeseen, sekä selvittää bakteremiariskiin liittyviä geneettisiä tekijöitä. Tutkimuksessa etsitään bakteremian taudinkulkuun vaikuttavia tekijöitä, jotta hoito voidaan jatkossa suunnata paremmin. Väitöstutkimus perustui etenevästi kerättyyn potilasjoukkoon Tampereen yliopistollisessa sairaalassa hoidetuista aikuisista verenmyrkytyspotilaista. Lihavuus ja tupakointi olivat verenmyrkytyspotilaiden itsenäisiä kuoleman vaaratekijöitä. Tupakointi myös lisäsi grampositiivisen bakteerin aiheuttaman verenmyrkytyksen riskiä potilailla, jotka kantoivat luonnollisen immuunijärjestelmän säätelyyn osallistuvan mannoosia sitovan lektiinigeenin (MBL2-geenin) eksonialueella varianttialleelia eli perinnöllisen rakennevaihtelun läpikäynyttä vaihtoehtoista geenialuetta. Tutkimuksessa saatiin viitteitä verisuonten typpioksidisynteesiin osallistuvan geenin (eNOS) eksonialueen polymorfismin eli monimuotoisuuden osallisuudesta verenmyrkytyspotilaiden verenpainevasteen säätelyyn ja siitä, että gramnegatiivisten ja grampositiivisten bakteerien aiheuttamat verenmyrkytykset eroavat verenpaineen säätelymekanismien osalta toisistaan. Väitöstyö osoitti aminohappopilkkomiseen osallistuvan indoliamiini 2,3-dioksigenaasi (IDO) entsyymin korkean pitoisuuden liittyvän selkeästi verenmyrkytyspotilaiden kuolemanriskiin. IDO-välitteiset mekanismit vaikuttavat tutkimuksen perusteella keskeisiltä vaikean verenmyrkytyksen taudinkehityksessä ja tämän tapahtumaketjujen salpaaminen voi jatkossa tarjota lisää hoidollisia mahdollisuuksia. Väitöstutkimus viittaa siihen, että yksilöiden väliset erot sairastumisherkkyydessä bakteeriperäiseen verenmyrkytykseen selittyvät osittain geeni-ympäristövuorovaikutussuhteilla ja elintavoilla on merkitystä verenmyrkytyspotilaiden ennusteen kannalta. Verenpainevasteen säätelyyn osallistuvien geenien monimuotoisuus voi selittää osaltaan verenmyrkytyspotilaiden erilaisia verenpainevasteita aiheuttajabekteerista riippuvaisesti ja näiden geenien roolia taudinkuvaan ja ennusteeseen tulee jatkossa selvittää suurissa väestöpohjaisissa tutkimuksissa. Koska korkea IDO-entsyymin pitoisuus ennusti verenmyrkytyspotilaiden kuolleisuutta, jatkossa on tärkeää selvittää IDO-entsyymin rooli verenmyrkytykseen liittyvässä immuunijärjestelmän lamaantumisessa eli immunoparalyysissä, koska nykykäsityksen mukaan juuri immunoparalyysillä on tärkeä rooli vaikeasta taudista kärsivillä potilailla.Bacteraemia and sepsis are major causes of mortality worldwide. Individual subjects seem to have different risks of developing bacteraemia and sepsis, individual organ failures and death. Despite novel options in the treatment of sepsis, the course of disease in individuals remains unpredicted and the mortality rate high. The lack of knowledge of sepsis pathogenesis and the heterogeneity of patients with bacteraemia and sepsis make risk stratification difficult. The main purpose of this study was to elucidate the role of host genetic factors, living habits, and underlying diseases in bacteraemia outcome, to study the effect of genetic factors on susceptibility to bacteraemia, and to find new approaches in understanding the pathogenesis and prognostication in bacteraemia. This prospective cohort study involved 149 in-hospital patients (79 male and 70 female) with bacteraemia caused by Staphylococcus aureus (S. aureus) (41 patients), Streptococcus pneumoniae (Str. pneumoniae) (42 patients), ß-haemolytic streptococcus (ß-hml str.) (23 patients) and Escherichia coli (E. coli) (43 patients) recruited in Tampere University Hospital during the years 1999-2004. Nineteen (12.8%) bacteraemic patients died. Mannose-binding lectin (MBL) insufficiency caused by point mutations in the MBL2 gene has been associated with increased susceptibility to infections, but the data are controversial. To study the effect of MBL2 polymorphisms on susceptibility to and the clinical course of bacteraemia, 145 patients with bacteraemia and 400 controls were examined. In study I, MBL2 structural polymorphisms at codons 52, 54 and 57, and promoter region polymorphisms at position -221 were determined. No difference in MBL2 genotype frequencies was detected between bacteraemic patients and controls, and MBL2 genotype had no independent effect on mortality. However, smoking proved a significant risk factor for gram-positive (S. aureus, Str. pneumoniae or ß-hml. str.) bacteraemia among carriers of the variant O allele, while it had no effect on those homozygous for the A allele. Nitric oxide (NO) is a crucial element in the pathogenesis of sepsis. Endothelial nitric oxide synthase (eNOS) is a key regulator of vascular NO production. The eNOS gene polymorphism at position 894 (G>T, Glu298Asp), resulting in the T allele, has been studied in the context of vascular diseases, but its role in sepsis is unclear. In study II, the polymorphism of the eNOS gene, G894T, was genotyped in patients with bacteraemia. Carriage of the T allele was associated with hypotension and severe disease in patients suffering from E. coli bacteraemia, but not in bacteraemia caused by a gram-positive organism. The Glu298Asp polymorphism had no effect on case fatality. In study III, the major underlying conditions associated with case fatality in bacteraemia were studied. Obesity (body mass index (BMI ≥30)) and smoking were independently associated with case fatality in a multivariate model adjusted for the effect of potential confounders. The median BMI was significantly higher among those who died compared to survivors (33 vs. 26, p=0.003) Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan catabolism, may play a critical role in various inflammatory disorders. IDO degrades tryptophan (trp) to its metabolite kynurenine (kyn), constituting a suppressor of T-cells. However, the precise role of IDO in different disease processes is largely unknown. In study IV, serum tryptophan and kynurenine concentrations were determined by high-performance-liquid chromatography (HPLC) in bacteraemic patients. The kyn/trp ratio, reflecting the activity of the IDO enzyme, was calculated. Maximum IDO activity 1-4 days after blood culture was significantly higher in nonsurvivors compared to survivors. High IDO activity remained an independent predictor of case fatality in the multivariate model. In summary, this study showed that obese patients and smokers had significantly higher case fatality rates in bacteraemia compared to their normal-weight and non-smoking counterparts. Smoking also increased the risk of gram-positive bacteraemia in patients carrying the MBL2 gene structural variant O allele, this constituting a novel example of gene-environment interaction. Carriage of the eNOS gene T allele at nucleotide position 894 was associated with hypotension in patients with E. coli bacteraemia. A high kyn/trp ratio, reflecting IDO activity was strongly associated with case fatality in patients with bacteraemia. The present findings provide evidence of fundamental differences between gram-negative and gram-positive sepsis and interindividual differences in predisposition to bacteraemia relating to genetic and smoking interactions, and of lifestyle effects on outcome. The contribution of the eNOS gene, a gene regulating vascular tone, on disease severity in bacteraemia is shown. IDO may constitute a novel key to the understanding of sepsis pathogenesis

Major risk factors for Streptococcus dysgalactiae subsp. equisimilis bacteremia : a population-based study

Background: Streptococcus dysgalactiae subspecies equisimilis is a human pathogen causing severe invasive infections. Detailed information on S. dysgalactiae subsp. equisimilis bacteremia and especially of predisposing factors are lacking. The purpose of the study is to investigate the risk factors of S. dysgalactiae subsp. equisimilis bacteremia compared to the general population in Finland. Methods: We retrospectively reviewed all patients older than 18 years with S. dysgalactiae subsp. equisimilis bacteremia in the Pirkanmaa health district from August 2015 to July 2018. The risk factors for S. dysgalactiae subsp. equisimilis bacteremia were investigated with respect to the normal population in Finland using the Finhealth study data provided by the Finnish institute for health and welfare. The study group was matched with the Finhealth study by age and sex. Results: Altogether 230 cases of S. dysgalactiae subsp. equisimilis bacteremia were detected. The medical records of 217 episodes of S. dysgalactiae subsp. equisimilis bacteremia (involving 211 patients) were available for analysis. Obesity was a statistically significant risk factor for S. dysgalactiae subsp. equisimilis bacteremia (Odds Ratio 2.96 [95% CI 2.22–3.96]). Diabetes and coronary artery disease were also associated with an increased risk of S. dysgalactiae subsp. equisimilis bacteremia (OR 4.82 [95% CI 3.62–6.42]) and (OR 3.03 [95% CI 2.18–4.19]). Conclusions: We found obesity, diabetes, and coronary artery disease to be associated with an increased risk for S. dysgalactiae subsp. equisimilis bacteremia. These results provide an increased understanding of risk factors for S. dysgalactiae subsp. equisimilis bacteremia.publishedVersionPeer reviewe

High Cell-Free DNA Predicts Fatal Outcome among Staphylococcus aureus Bacteraemia Patients with Intensive Care Unit Treatment

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Fungemia and other Fungal Infections Associated with Use of Saccharomyces boulardii Probiotic Supplements

Because of widespread use of probiotics, their safety must be guaranteed. We assessed use of Saccharomyces boulardii probiotic yeast from medical records for patients who had Saccharomyces fungemia or other clinical Saccharomyces culture findings. We evaluated all Saccharomyces sp. findings at 5 university hospitals in Finland during 2009-2018. We found 46 patients who had Saccharomyces fungemia; at least 20 (43%) were using S. boulardii probiotic. Compared with a control group that had bacteremia or candidemia, the odds ratio for use of an S. boulardii probiotic was 14 (95% CI 4-44). Of 1,153 nonblood culture findings, the history for 125 patients was checked; at least 24 (19%) were using the probiotic (odds ratio 10, 95% CI 3-32). This study adds to published fungemia cases linked to use of S. boulardii probiotic and sheds light on the scale of nonblood Saccharomyces culture findings that are also linked to use of this probiotic.Peer reviewe

Plasma Levels of Soluble Urokinase-Type Plasminogen Activator Receptor Associate with the Clinical Severity of Acute Puumala Hantavirus Infection

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Fatal Outcome in Bacteremia is Characterized by High Plasma Cell Free DNA Concentration and Apoptotic DNA Fragmentation: A Prospective Cohort Study

INTRODUCTION: Recent studies have shown that apoptosis plays a critical role in the pathogenesis of sepsis. High plasma cell free DNA (cf-DNA) concentrations have been shown to be associated with sepsis outcome. The origin of cf-DNA is unclear. METHODS: Total plasma cf-DNA was quantified directly in plasma and the amplifiable cf-DNA assessed using quantitative PCR in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, ß-hemolytic streptococcae or Escherichia coli. The quality of cf-DNA was analyzed with a DNA Chip assay performed on 8 survivors and 8 nonsurvivors. Values were measured on days 1-4 after positive blood culture, on day 5-17 and on recovery. RESULTS: The maximum cf-DNA values on days 1-4 (n = 132) were markedly higher in nonsurvivors compared to survivors (2.03 vs 1.26 ug/ml, p<0.001) and the AUCROC in the prediction of case fatality was 0.81 (95% CI 0.69-0.94). cf-DNA at a cut-off level of 1.52 ug/ml showed 83% sensitivity and 79% specificity for fatal disease. High cf-DNA (>1.52 ug/ml) remained an independent risk factor for case fatality in a logistic regression model. Qualitative analysis of cf-DNA showed that cf-DNA displayed a predominating low-molecular-weight cf-DNA band (150-200 bp) in nonsurvivors, corresponding to the size of the apoptotic nucleosomal DNA. cf-DNA concentration showed a significant positive correlation with visually graded apoptotic band intensity (R = 0.822, p<0.001). CONCLUSIONS: Plasma cf-DNA concentration proved to be a specific independent prognostic biomarker in bacteremia. cf-DNA displayed a predominating low-molecular-weight cf-DNA band in nonsurvivors corresponding to the size of apoptotic nucleosomal DNA

Population-Based Assessment of Contact Tracing Operations for Coronavirus Disease 2019 in Pirkanmaa Hospital District, Finland

Background: The coronavirus disease 2019 (COVID-19) epidemic overwhelmed local contact tracing (CT) efforts in many countries. In Finland, severe acute respiratory syndrome coronavirus 2 incidence and mortality were among the lowest in Europe during 2020-2021. We evaluated CT efficiency, effectiveness, and transmission settings. Methods: Polymerase chain reaction (PCR) test-positive COVID-19 cases and high-risk contacts in the population-based CT database of Pirkanmaa Hospital District (population 540 000) during June 2020-May 2021 were interviewed. Results: Altogether 353 926 PCR tests yielded 4739 (1.3%) confirmed cases (average 14-day case notification rate, 34 per 100 000 population); about 99% of confirmed cases and high-risk contacts were reached by a CT team. Of 26 881 high-risk contacts who were placed in quarantine, 2275 subsequently tested positive (48% of new cases), 825 (17%) had been in quarantine ≥48 hours before symptoms, and 3469 (77%) of locally acquired cases were part of transmission chains with an identified setting. The highest secondary attack rates were seen in households (31%), healthcare patients (18%), and private functions (10%). Among the 311 hospitalized patients, COVID-19 diagnosis or exposure was known in 273 (88%) before emergency room admission (identified patients). Healthcare workers had the highest proportion of work-related infections (159 cases [35%]). The source of infection was classifiable in 65% and was most commonly a coworker (64 cases [62%]). Conclusions: Our data demonstrate the role of effective testing and CT implementation during the cluster phase of COVID-19 spread. Although half of newly diagnosed cases were already in quarantine, targeted public health measures were needed to control transmission. CT effectiveness during widespread community transmission should be assessed.publishedVersionPeer reviewe

Shopping Detail Information and Home Freezer Sampling Confirmed the Role of Commercial, Modified-Atmosphere Packaged Meatballs as a Vehicle for Listeriosis in Finland

In November 2016, an elderly patient was diagnosed with Listeria monocytogenes bacteremia in Finland. Grocery store loyalty card records and microbiological investigation of foods found in the home fridge and freezer of the patient revealed commercial, modified-atmosphere packaged meatballs as the source of the infection. Investigation of the meatball production plant revealed that the floor drain samples were contaminated with the same L. monocytogenes strain as those isolated from the patient and meatballs. Ready-to-eat meatballs were likely contaminated after heat treatment from the production environment before packaging. Long-term cold storage, modified-atmosphere conditions, and the absence of competing bacteria presumably enhanced the growth of L. monocytogenes. We recommend that collection of shopping details and home fridge and freezer sampling should be part of surveillance of all cases of L. monocytogenes infections to complement information obtained from in-depth interviews.Peer reviewe

Fungemia and Other Fungal Infections Associated with Use of Saccharomyces boulardii Probiotic Supplements

Because of widespread use of probiotics, their safety must be guaranteed. We assessed use of Saccharomyces boulardii probiotic yeast from medical records for patients who had Saccharomyces fungemia or other clinical Saccharomyces culture findings. We evaluated all Saccharomyces sp. findings at 5 university hospitals in Finland during 2009–2018. We found 46 patients who had Saccharomyces fungemia; at least 20 (43%) were using S. boulardii probiotic. Compared with a control group that had bacteremia or candidemia, the odds ratio for use of an S. boulardii probiotic was 14 (95% CI 4–44). Of 1,153 nonblood culture findings, the history for 125 patients was checked; at least 24 (19%) were using the probiotic (odds ratio 10, 95% CI 3–32). This study adds to published fungemia cases linked to use of S. boulardii probiotic and sheds light on the scale of nonblood Saccharomyces culture findings that are also linked to use of this probiotic.</p