Fra lokalt til nasjonalt utbrudd av Pseudomonas aeruginosa

Utbrudd som rammer flere sykehus, krever god koordinering. Folkehelseinstituttets rolle i dette arbeidet bør styrkes, og vi trenger bedre systemer for utbruddsovervåking, rask tilgang til genteknologiske verktøy samt metoder for mikrobiologiske undersøkelser av miljø og utstyr.Outbreaks affecting several hospitals require good coordination. The Norwegian Institute of Public Health's role in this work should be strengthened, and we need better systems for monitoring outbreaks, rapid access to genetic engineering tools and techniques for microbiological examinations of equipment and the environment

Infection, inflammation, and risk of venous thromboembolism

Paper IV is not available in Munin. Paper IV: Grimnes, G., Hindberg, K., Davids, M., Nieuwdorp, M., Mollnes, T.E., Brækkan. S.K., … Tichelaar, Y.I.G.V. A Vancomycin-induced shift of the gut microbiome in gram-negative direction increases plasma factor VIII:C levels: Results from a randomized, controlled trial. (Manuscript).SUMMARY Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is the third most common cardiovascular disease after myocardial infarction and stroke. The incidence of VTE is increasing and VTE contributes to a substantial burden of morbidity and mortality. To be able to prevent VTE in vulnerable subjects, there is a need for more knowledge about the pathophysiology and risk factors for VTE. Acute infection and several other inflammatory conditions have been associated with VTE risk in previous studies. The aim of the present thesis was to investigate the association between both short- and long-term inflammation and VTE risk. Further, the aim was to investigate the impact of acute infection on VTE risk in hospitalized patients, and, finally, whether gut microbiome composition was associated with systemic inflammation and coagulation. In Paper I, we used data from the fourth survey of the Tromsø Study, conducted in 1994-95, with follow-up until the end of 2012. Incident and recurrent VTE events were registered and thoroughly validated. Cox proportional hazards regression models were used to calculate hazard ratios for VTE across quartiles of the inflammatory marker neutrophil to lymphocyte ratio (NLR). We found no association between NLR measured at baseline in Tromsø 4 and future risk of incident or recurrent VTE. However, when restricting the follow-up time to the first three years after baseline, those with NLR above the 95th percentile had a 2.4-fold increased risk of VTE. In Papers II and III, we used a case-crossover designed study with the incident VTE cases from Tromsø 4 as the study population. We found that acute infection was a frequent and strong trigger for VTE in hospitalized patients, also after adjustment for potential confounders. Moreover, we found that concomitant infection and immobilization had a synergistic effect on VTE risk. Acute inflammation, assessed by C-reactive protein (CRP), was associated with VTE risk, regardless of the cause of inflammation. The association was slightly attenuated in analyses adjusted for infection and immobilization. In stratified analyses, acute inflammation was associated with VTE risk both in cases with and without infection. In Paper IV, we conducted a randomized, controlled trial in healthy volunteers aged 18-40 years. The intervention group received oral Vancomycin, which induced a gram-negative shift in the gut microbiome composition. Compared to the untreated control group, this change in microbiome composition was accompanied by a significant increase in coagulation factor VIII:C and high sensitivity CRP from baseline to after intervention.SAMMENDRAG Venøs tromboembolisme (VTE), som innbefatter dyp venetrombose og lungeemboli, er den tredje vanligste kardiovaskulære sykdommen etter hjerteinfarkt og slag. Forekomsten av VTE er økende, og sykdommen bidrar til en betydelig sykdomsbyrde og i noen tilfeller også død. Det trengs mer kunnskap om patofysiologi og risikofaktorer for VTE, for å kunne identifisere grupper med høy risiko som kan profitere på forebyggende behandling. Både akutte infeksjoner og andre tilstander preget av inflammasjon har i tidligere studier vært assosiert med økt risiko for VTE. Målet med denne avhandlingen var å undersøke sammenhengen mellom inflammasjon av både kort og lang varighet og risiko for VTE, samt å undersøke sammenhengen mellom akutt infeksjon under sykehusopphold og risiko for VTE. Videre var målet å undersøke om sammensetningen av tarmbakterier påvirker systemisk inflammasjon og koagulasjon. I artikkel I brukte vi data fra den fjerde Tromsøundersøkelsen, som ble gjennomført i 1994-95, og deltakerne ble fulgt med registrering av validerte VTE-tilfeller til utgangen av 2012. Vi brukte overlevelsesanalyse (Cox regresjonsmodeller) for å undersøke sammenhengen mellom nøytrofil-lymfocytt ratio (NLR), som er en inflammasjonsmarkør, og risiko for VTE. Det var ingen sammenheng mellom NLR, inndelt i kvartiler, og risiko for hverken førstegangs eller gjentakende VTE. Når oppfølgingstiden ble satt til de tre første årene etter inklusjon i Tromsø 4, hadde imidlertid de med NLR over 95-percentilen 2.4 ganger økt VTE-risiko. Ved bruk av case-crossover design med VTE-tilfellene fra Tromsø 4 som studiepopulasjon, undersøkte vi sammenhengen mellom akutt infeksjon (artikkel II) og inflammasjon (artikkel III) og risiko for VTE. Akutt infeksjon under sykehusopphold var hyppig forekommende og sterkt assosiert med VTE-risiko, også etter justering for mulige konfunderende faktorer. Samtidig infeksjon og immobilisering hadde synergistisk effekt på VTE-risiko. Akutt inflammasjon under sykehusopphold, målt ved C-reaktivt protein (CRP), var assosiert med VTE-risiko uavhengig av inflammasjonsreaksjonens årsak, og sammenhengen besto etter justering for infeksjon og immobilisering. Artikkel IV beskriver en randomisert, kontrollert studie hvor friske frivillige i alderen 18-40 år ble invitert til å delta. Intervensjonsgruppen fikk Vancomycin kapsler, som førte til en endring i tarmfloraen til økt andel gram-negative bakterier. Sammenlignet med en ubehandlet kontrollgruppe fant vi at intervensjon med Vancomycin førte til en signifikant økning i koagulasjonsfaktor VIII:C og CRP

Infection, inflammation, and risk of venous thromboembolism

SUMMARY Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is the third most common cardiovascular disease after myocardial infarction and stroke. The incidence of VTE is increasing and VTE contributes to a substantial burden of morbidity and mortality. To be able to prevent VTE in vulnerable subjects, there is a need for more knowledge about the pathophysiology and risk factors for VTE. Acute infection and several other inflammatory conditions have been associated with VTE risk in previous studies. The aim of the present thesis was to investigate the association between both short- and long-term inflammation and VTE risk. Further, the aim was to investigate the impact of acute infection on VTE risk in hospitalized patients, and, finally, whether gut microbiome composition was associated with systemic inflammation and coagulation. In Paper I, we used data from the fourth survey of the Tromsø Study, conducted in 1994-95, with follow-up until the end of 2012. Incident and recurrent VTE events were registered and thoroughly validated. Cox proportional hazards regression models were used to calculate hazard ratios for VTE across quartiles of the inflammatory marker neutrophil to lymphocyte ratio (NLR). We found no association between NLR measured at baseline in Tromsø 4 and future risk of incident or recurrent VTE. However, when restricting the follow-up time to the first three years after baseline, those with NLR above the 95th percentile had a 2.4-fold increased risk of VTE. In Papers II and III, we used a case-crossover designed study with the incident VTE cases from Tromsø 4 as the study population. We found that acute infection was a frequent and strong trigger for VTE in hospitalized patients, also after adjustment for potential confounders. Moreover, we found that concomitant infection and immobilization had a synergistic effect on VTE risk. Acute inflammation, assessed by C-reactive protein (CRP), was associated with VTE risk, regardless of the cause of inflammation. The association was slightly attenuated in analyses adjusted for infection and immobilization. In stratified analyses, acute inflammation was associated with VTE risk both in cases with and without infection. In Paper IV, we conducted a randomized, controlled trial in healthy volunteers aged 18-40 years. The intervention group received oral Vancomycin, which induced a gram-negative shift in the gut microbiome composition. Compared to the untreated control group, this change in microbiome composition was accompanied by a significant increase in coagulation factor VIII:C and high sensitivity CRP from baseline to after intervention

Acute infection as a trigger for incident venous thromboembolism: Results from a population- based case- crossover study

Background: A bidirectional relation exists between acute infection and immobilization, and both are triggers for venous thromboembolism (VTE). To what extent the association between infection and VTE‐risk is explained by immobilization is unknown. Aims: To investigate the impact of hospitalization with acute infection on the VTE‐risk in patients with and without concomitant immobilization, and to explore the differential impact of respiratory‐ (RTI) and urinary‐ (UTI) tract infections on the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods: We conducted a case‐crossover study of VTE‐patients (n = 707) recruited from a general population. Hospitalizations and VTE‐triggers were registered during the 90 days before a VTE (hazard period) and in four preceding 90‐day control periods. Conditional logistic regression was used to estimate odds ratios (ORs) for VTE according to triggers. Results: Acute infection was registered in 267 (37.8%) of the hazard periods and in 107 (3.8%) of the control periods, corresponding to a high VTE‐risk after infection (OR 24.2, 95% CI 17.2‐34.0), that was attenuated to 15‐fold increased after adjustment for immobilization. The risk was 20‐fold increased after infection without concomitant immobilization, 73‐fold increased after immobilization without infection, and 141‐fold increased with the two combined. The risk of PE was apparently higher after RTIs (OR 48.3, 95% CI 19.4‐120.0) than UTIs (OR 12.6, 95% CI 6.4‐24.7), but diminished in sensitivity analyses excluding uncertain RTI diagnoses. Conclusions: Our findings suggest that hospitalization with infection is a strong VTE‐trigger also in non‐immobilized patients. Infection and immobilization had a synergistic effect on the VTE‐risk

C-reactive protein and risk of venous thromboembolism: Results from a population-based case-crossover study

Long-term, low-grade inflammation does not seem to be a risk factor for venous thromboembolism. The impact of acute inflammation, regardless of cause, on risk of venous thromboembolism is scarcely studied. We aimed to investigate the impact of acute inflammation, assessed by C-reactive protein, on short-term risk of venous thromboembolism. We conducted a case-crossover study of patients with venous thromboembolism (n=707) recruited from a general population. Information on triggers and C-reactive protein levels were retrieved from hospital records during the 90 days before the event (hazard period) and in four preceding 90 day control periods. Conditional logistic regression was used to obtain β coefficients for change in natural log (ln) transformed C-reactive protein from control to hazard periods and to determine corresponding odds ratios for venous thromboembolism. Median C-reactive protein was 107 mg/L in the hazard period, and ranged from 7 mg/L to 16 mg/L in the control periods. The level of C-reactive protein was 58% (95% CI 39-77%) higher in the hazard period than in the control periods. A one-unit increase in ln-C-reactive protein was associated with increased risk of venous thromboembolism (OR 1.79, 95% CI 1.48-2.16). The risk estimates were only slightly attenuated after adjustment for immobilization and infection. In stratified analyses, ln-C-reactive protein was associated with increased risk of venous thromboembolism in cases with (OR 1.55, 95% CI 1.01-2.38) and without infection (OR 1.77, 95% CI 1.22-2.57). In conclusion, we found that acute inflammation, assessed by C-reactive protein, was a trigger for venous thromboembolism

Myocardial infarction as a transient risk factor for incident venous thromboembolism: Results from a population-based case-crossover study

Patients with myocardial infarction (MI) are at increased short-term risk of venous thromboembolism (VTE). The mechanisms behind this association are unclear. We aimed to investigate the impact of acute MI as a transient risk factor for incident VTE while taking other concomitant VTE risk factors into account. We conducted a case–crossover study of VTE patients (n = 707) recruited from the fourth survey of the Tromsø Study. VTE risk factors and hospitalizations were registered during the 90-day period preceding the VTE diagnosis (hazard period) and in four 90-day control periods. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE according to acute MI and after adjustment for other risk factors. Additionally, we applied a mediation analysis to quantify how much the known transient risk factors account for the observed effect of MI on VTE risk. MI was recorded in 13 (1.8%) of the hazard periods and in 6 (0.2%) of the control periods, which yielded a crude OR of 11.9 (95% CI: 3.9–36.7). Adjustment for immobilization and infection yielded an OR of 2.7 (95% CI: 0.6–11.2). The OR was attenuated to 2.6 (95% CI: 0.6–11.9) after further adjustment for major surgery, trauma, red blood cell transfusion, and central venous catheterization. Approximately 60% of the association between MI and VTE was mediated through infection and immobilization. In conclusion, our findings suggest that the increased VTE risk after MI may to a large extent be explained by concomitant conditions related to MI, particularly infections and immobilization

The Role of Stroke as a Trigger for Incident Venous Thromboembolism: Results from a Population-based Case-Crossover Study

Stroke is associated with a short-term increased risk of subsequent venous thromboembolism (VTE). It is unclear to what extent this association is mediated by strokerelated complications that are potential triggers for VTE, such as immobilization and infection. We aimed to investigate the role of acute stroke as a trigger for incident VTE while taking other concomitant VTE triggers into account. We conducted a populationbased case-crossover study with 707 VTE patients. Triggers were registered during the 90 days before a VTE event (hazard period) and in four preceding 90-day control periods. Conditional logistic regression was used to estimate odds ratios with 95% confidence intervals (CIs) for VTE according to triggers. Stroke was registered in 30 of the 707 (4.2%) hazard periods and in 6 of the 2,828 (0.2%) control periods, resulting in a high risk of VTE, with odds ratios of 20.0 (95% CI: 8.3–48.1). After adjustments for immobilization and infection, odds ratios for VTE conferred by stroke were attenuated to 6.0 (95% CI: 1.6–22.1), and further to 4.0 (95% CI: 1.1–14.2) when other triggers (major surgery, red blood cell transfusion, trauma, and central venous catheter) were added to the regression model. A mediation analysis revealed that 67.8% of the total effect of stroke on VTE risk could be mediated through immobilization and infection. Analyses restricted to ischemic stroke yielded similar results. In conclusion, acute stroke was a trigger for VTE, and the association between stroke and VTE risk appeared to be largely mediated by immobilization and infection

Impact of a Vancomycin-Induced Shift of the Gut Microbiome in a Gram-Negative Direction on Plasma Factor VIII:C Levels: Results from a Randomized Controlled Trial

Rationale - Inflammation is present in several conditions associated with risk of venous thromboembolism. The gut microbiome might be a source of systemic inflammation and activation of coagulation, by translocation of lipopolysaccharides from gram-negative bacteria to the systemic circulation. Objective - To investigate whether a vancomycin-induced shift of the gut microbiome in a gram-negative direction influences systemic inflammation and plasma factor (F) VIII procoagulant activity (FVIII:C). Methods and Results - We performed a randomized controlled trial including 43 healthy volunteers aged 19 to 37 years. Twenty-one were randomized to 7 days of oral vancomycin intake and 22 served as controls. Feces and blood were sampled at baseline, the day after the end of intervention, and 3 weeks after intervention. Gut microbiome composition was assessed by amplicon sequencing. FVIII:C was measured using an activated partial thromboplastin time-based assay, cytokines were measured using multiplex technology, complement activation was measured using the enzyme-linked immunosorbent assay, and high-sensitivity C-reactive protein (CRP) was measured by an immunoturbidimetric assay. Vancomycin intake reduced gut microbiome diversity and increased the abundance of gram-negative bacteria. Change in FVIII:C in the intervention group was +4 IU/dL versus −6 IU/dL (p = 0.01) in the control group. A similar change was observed for log-transformed CRP (+0.21 mg/dL vs. −0.25 mg/dL, p = 0.04). The cytokines and complement activation markers remained similar in the two groups. Conclusion - The found slight increases in FVIII:C and CRP levels might support the hypothesis that a vancomycin-induced gram-negative shift in the gut microbiome could induce increased systemic inflammation and thereby a procoagulant state