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BackgroundFluid overload is associated with excess mortality in septic shock. Current approaches to reduce fluid overload include restrictive administration of fluid or active removal of accumulated fluid. However, evidence on active fluid removal is scarce. The aim of this study is to assess the efficacy and feasibility of an early de-resuscitation protocol in patients with septic shock. MethodsAll patients admitted to the intensive care unit (ICU) with a septic shock are screened, and eligible patients will be randomised in a 1:1 ratio to intervention or standard of care. Intervention: Fluid management will be performed according to the REDUCE protocol, where resuscitation fluid will be restricted to patients showing signs of poor tissue perfusion. After the lactate has peaked, the patient is deemed stable and assessed for active de-resuscitation (signs of fluid overload). The primary objective of this study is the proportion of patients with a negative cumulative fluid balance at day 3 after ICU. Secondary objectives are cumulative fluid balances throughout the ICU stay, number of patients with fluid overload, feasibility and safety outcomes and patient-centred outcomes. The primary outcome will be assessed by a logistic regression model adjusting for the stratification variables (trial site and chronic renal failure) in the intention-to-treat population. Ethics and disseminationThe study was approved by the respective ethical committees (No 2020–02197). The results of the REDUCE trial will be published in an international peer-reviewed medical journal regardless of the results. Trial registration numberClinicalTrials.gov, NCT04931485. …

IntroductionFebrile infants 90 days and younger are at risk of invasive bacterial infections (bacteraemia and meningitis) and urinary tract infections. Together this is previously termed serious bacterial infection with an incidence of approximately 10–20%. The National Institute for Health and Care Excellence guidance advocates a cautious approach with most infants requiring septic screening, parenteral broad-spectrum antibiotics and hospital admission. Internationally, variations exist in the approach to febrile infants, with European and North American guidance advocating a tailored approach based on clinical features and biomarker testing. None of the available international clinical decision aids (CDAs) has been validated in the UK and Irish cohorts. The aim of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study is to prospectively validate a range of CDAs in a UK and Irish population including CDAs that use procalcitonin testing. Methods and analysisThe FIDO Study is a prospective multicentre mixed-methods cohort study conducted in UK and Irish hospitals. All infants aged 90 days and younger presenting with fever or history of fever (≥38°C) are eligible for inclusion. Infants will receive standard emergency clinical care without delay. Clinical data and blood samples will be collected, and consent will be obtained at the earliest appropriate opportunity using research without prior consent methodology. The performance and cost-effectiveness of CDAs will be assessed. An embedded qualitative study will explore clinician and caregiver views on different approaches to care and perceptions of risk. Ethics and disseminationThis study was reviewed and approved by the Office for Research Ethics Committees Northern Ireland-Health and Social Care Research Ethics Committee B, Public Benefit and Privacy Panel for Health and Social Care Scotland, and Children’s Health Ireland Research and Ethics Committee Ireland. The results of this study will be presented at academic conferences and in peer-reviewed publications. Trial registration numberNCT05259683. …

Abstract Background Dialister pneumosintes is an anaerobic, Gram negative bacillus, found in the human oral cavity and associated with periodontitis. It has also been isolated from gastric mucosa and stool samples. Recent case reports implicate D. pneumosintes in local infection such as dental root canals, sinusitis, Lemierres syndrome and brain abscesses, as well as distal infections of the liver and lung through haematogenous spread. Case presentation We present a novel case of aortic graft infection and aortoenteric fistula (AEF) in a 75 year old Caucasian male, associated with D. pneumosintes bacteraemia. Microbiological evaluation of septic emboli in the lower limbs revealed other gastrointestinal flora. This suggests either AEF leading to graft infection and subsequent distal emboli and bacteraemia, or a dental origin of infection which seeded to the graft, resulting in AEF and systemic infection. To our knowledge this is the first report of D. pneumosintes associated aortic graft infection. The patient underwent surgical explantation, oversew of the aorta and placement of extra-anatomical bypass graft in conjunction with antimicrobial therapy, making a good recovery with discharge home after a 35-day hospital admission. Conclusion We report a case of Dialister pneumosintes bacteraemia associated with aortic graft infection. To our knowledge, vascular graft-associated infection with D. pneumosintes has not been reported before. …

Abstract Background The gastrointestinal tract contains a massive microbiota, and targeting the gut could be a potential intervention for sepsis. However, the interaction between sepsis and the intestinal microbiota is defined as an “incompletely understood bidirectional relationship”. Methods This retrospective observational cohort study investigated the fecal microbiota of sepsis patients admitted to the Department of Critical Care Medicine of the Central Hospital of Wuhan, China, from May 2019 to January 2020. 14 septic patients were divided into the non-severe group and the severe group according to the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Herein, fecal samples were serially collected on admission, the third, fourth, and fifth days, and ICU discharge. The fecal microbiota was analyzed by 16S rRNA gene sequencing and its correlation with clinical parameters was evaluated. Results Bacteroidetes, Firmicutes, and Proteobacteria were dominant phyla at ICU admission, and fecal biodiversity was not significantly different between the non-severe group (APACHE II  15). However, the diversity of the gut microbiota was significantly lower at ICU discharge than that at ICU admission with the extension of treatment time. Further significant difference flora analysis (LEfSe) showed that the genera Veillonella and Ruminococcus were the most discriminant biomarkers at ICU admission in non-severe and severe patients, respectively, while Enterococcus was the most discriminant biomarker at ICU discharge in all septic patients. Of note, liver function tests, including ALT, AST, TBIL, and DBIL correlated with the prevalence of various bacterial genera. Conclusions The diversity of the gut microbiota in patients with sepsis decreases dramatically during ICU stay, and there are distinct dynamic changes in gut microbiota among patients with different severity in sepsis. …

Abstract Background The course of monkeypox can be severe. Our aim was to retrospectively compare the risk of hospital admission, the need for ventilation, sepsis, pneumonitis and death between the recent outbreak and historical outbreaks. Materials and Methods Cases of monkeypox were retrieved from the TriNetX database and assigned to either cohort I (recent outbreak between May 1st and September 16th, 2022) and cohort II (historical outbreaks before May 1st, 2022). After matching for age distribution, statistical analysis was performed. Results Of 640 patients with monkeypox 81 subjects per cohort remained after matching (mean age±standard deviation = 36.1±18.3 years). Within 56 days after diagnosis 10 patients per cohort were hospitalized (12.4%) and/or developed sepsis (12.4%). The risk of ventilation and pneumonitis were significantly lower among cohort I compared with cohort II (0 vs. 10 cases; risk difference = 12.4%; p = 0.001; Log-Rank test). No cases of death were recorded. Conclusion Even though monkeypox provides a risk of severe courses, the infection is self-limiting in most cases. Unlike past outbreaks, the risk of ventilation and pneumonitis may be relatively low among recent outbreaks. …

Volume 14, Issue 1, December 2023 .

Volume 14, Issue 1, December 2023 .

Abstract Background Several studies suggested pancreatic stone protein (PSP) as a promising biomarker to predict mortality among patients with severe infection. The objective of the study was to evaluate the performance of PSP in predicting intensive care unit (ICU) mortality and infection severity among critically ill adults admitted to the hospital for infection. Methods A systematic search across Cochrane Central Register of Controlled Trials and MEDLINE databases (1966 to February 2022) for studies on PSP published in English using ‘pancreatic stone protein’, ‘PSP’, ‘regenerative protein’, ‘lithostatin’ combined with ‘infection’ and ‘sepsis’ found 46 records. The search was restricted to the five trials that measured PSP using the enzyme-linked immunosorbent assay technique (ELISA). We used Bayesian hierarchical regression models for pooled estimates and to predict mortality or disease severity using PSP, C-Reactive Protein (CRP) and procalcitonin (PCT) as main predictor. We used statistical discriminative measures, such as the area under the receiver operating characteristic curve (AUC) and classification plots. Results Among the 678 patients included, the pooled ICU mortality was 17.8% (95% prediction interval 4.1% to 54.6%) with a between-study heterogeneity (I-squared 87%). PSP was strongly associated with ICU mortality (OR = 2.7, 95% credible interval (CrI) [1.3–6.0] per one standard deviation increase; age, gender and sepsis severity adjusted OR = 1.5, 95% CrI [0.98–2.8]). The AUC was 0.69 for PSP 95% confidence interval (CI) [0.64–0.74], 0.61 [0.56–0.66] for PCT and 0.52 [0.47–0.57] for CRP. The sensitivity was 0.96, 0.52, 0.30 for risk thresholds 0.1, 0.2 and 0.3; respective false positive rate values were 0.84, 0.25, 0.10. Conclusions We found that PSP showed a very good discriminative ability for both investigated study endpoints ICU mortality and infection severity; better in comparison to CRP, similar to PCT. Combinations of biomarkers did not improve their predictive ability. …

Abstract Purpose Timely and accurate data on the epidemiology of sepsis are essential to inform policy decisions and research priorities. We aimed to investigate the validity of inpatient administrative health data (IAHD) for surveillance and quality assurance of sepsis care. Methods We conducted a retrospective validation study in a disproportional stratified random sample of 10,334 inpatient cases of age ≥ 15 years treated in 2015–2017 in ten German hospitals. The accuracy of coding of sepsis and risk factors for mortality in IAHD was assessed compared to reference standard diagnoses obtained by a chart review. Hospital-level risk-adjusted mortality of sepsis as calculated from IAHD information was compared to mortality calculated from chart review information. Results ICD-coding of sepsis in IAHD showed high positive predictive value (76.9–85.7% depending on sepsis definition), but low sensitivity (26.8–38%), which led to an underestimation of sepsis incidence (1.4% vs. 3.3% for severe sepsis-1). Not naming sepsis in the chart was strongly associated with under-coding of sepsis. The frequency of correctly naming sepsis and ICD-coding of sepsis varied strongly between hospitals (range of sensitivity of naming: 29–71.7%, of ICD-diagnosis: 10.7–58.5%). Risk-adjusted mortality of sepsis per hospital calculated from coding in IAHD showed no substantial correlation to reference standard risk-adjusted mortality (r = 0.09). Conclusion Due to the under-coding of sepsis in IAHD, previous epidemiological studies underestimated the burden of sepsis in Germany. There is a large variability between hospitals in accuracy of diagnosing and coding of sepsis. Therefore, IAHD alone is not suited to assess quality of sepsis care. …

Abstract Background Dialister pneumosintes is an anaerobic, Gram negative bacillus, found in the human oral cavity and associated with periodontitis. It has also been isolated from gastric mucosa and stool samples. Recent case reports implicate D. pneumosintes in local infection such as dental root canals, sinusitis, Lemierres syndrome and brain abscesses, as well as distal infections of the liver and lung through haematogenous spread. Case presentation We present a novel case of aortic graft infection and aortoenteric fistula (AEF) in a 75 year old Caucasian male, associated with D. pneumosintes bacteraemia. Microbiological evaluation of septic emboli in the lower limbs revealed other gastrointestinal flora. This suggests either AEF leading to graft infection and subsequent distal emboli and bacteraemia, or a dental origin of infection which seeded to the graft, resulting in AEF and systemic infection. To our knowledge this is the first report of D. pneumosintes associated aortic graft infection. The patient underwent surgical explantation, oversew of the aorta and placement of extra-anatomical bypass graft in conjunction with antimicrobial therapy, making a good recovery with discharge home after a 35-day hospital admission. Conclusion We report a case of Dialister pneumosintes bacteraemia associated with aortic graft infection. To our knowledge, vascular graft-associated infection with D. pneumosintes has not been reported before. …

Abstract Background The gastrointestinal tract contains a massive microbiota, and targeting the gut could be a potential intervention for sepsis. However, the interaction between sepsis and the intestinal microbiota is defined as an “incompletely understood bidirectional relationship”. Methods This retrospective observational cohort study investigated the fecal microbiota of sepsis patients admitted to the Department of Critical Care Medicine of the Central Hospital of Wuhan, China, from May 2019 to January 2020. 14 septic patients were divided into the non-severe group and the severe group according to the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Herein, fecal samples were serially collected on admission, the third, fourth, and fifth days, and ICU discharge. The fecal microbiota was analyzed by 16S rRNA gene sequencing and its correlation with clinical parameters was evaluated. Results Bacteroidetes, Firmicutes, and Proteobacteria were dominant phyla at ICU admission, and fecal biodiversity was not significantly different between the non-severe group (APACHE II  15). However, the diversity of the gut microbiota was significantly lower at ICU discharge than that at ICU admission with the extension of treatment time. Further significant difference flora analysis (LEfSe) showed that the genera Veillonella and Ruminococcus were the most discriminant biomarkers at ICU admission in non-severe and severe patients, respectively, while Enterococcus was the most discriminant biomarker at ICU discharge in all septic patients. Of note, liver function tests, including ALT, AST, TBIL, and DBIL correlated with the prevalence of various bacterial genera. Conclusions The diversity of the gut microbiota in patients with sepsis decreases dramatically during ICU stay, and there are distinct dynamic changes in gut microbiota among patients with different severity in sepsis. …

Abstract Background The course of monkeypox can be severe. Our aim was to retrospectively compare the risk of hospital admission, the need for ventilation, sepsis, pneumonitis and death between the recent outbreak and historical outbreaks. Materials and Methods Cases of monkeypox were retrieved from the TriNetX database and assigned to either cohort I (recent outbreak between May 1st and September 16th, 2022) and cohort II (historical outbreaks before May 1st, 2022). After matching for age distribution, statistical analysis was performed. Results Of 640 patients with monkeypox 81 subjects per cohort remained after matching (mean age±standard deviation = 36.1±18.3 years). Within 56 days after diagnosis 10 patients per cohort were hospitalized (12.4%) and/or developed sepsis (12.4%). The risk of ventilation and pneumonitis were significantly lower among cohort I compared with cohort II (0 vs. 10 cases; risk difference = 12.4%; p = 0.001; Log-Rank test). No cases of death were recorded. Conclusion Even though monkeypox provides a risk of severe courses, the infection is self-limiting in most cases. Unlike past outbreaks, the risk of ventilation and pneumonitis may be relatively low among recent outbreaks. …

Abstract Background Several studies suggested pancreatic stone protein (PSP) as a promising biomarker to predict mortality among patients with severe infection. The objective of the study was to evaluate the performance of PSP in predicting intensive care unit (ICU) mortality and infection severity among critically ill adults admitted to the hospital for infection. Methods A systematic search across Cochrane Central Register of Controlled Trials and MEDLINE databases (1966 to February 2022) for studies on PSP published in English using ‘pancreatic stone protein’, ‘PSP’, ‘regenerative protein’, ‘lithostatin’ combined with ‘infection’ and ‘sepsis’ found 46 records. The search was restricted to the five trials that measured PSP using the enzyme-linked immunosorbent assay technique (ELISA). We used Bayesian hierarchical regression models for pooled estimates and to predict mortality or disease severity using PSP, C-Reactive Protein (CRP) and procalcitonin (PCT) as main predictor. We used statistical discriminative measures, such as the area under the receiver operating characteristic curve (AUC) and classification plots. Results Among the 678 patients included, the pooled ICU mortality was 17.8% (95% prediction interval 4.1% to 54.6%) with a between-study heterogeneity (I-squared 87%). PSP was strongly associated with ICU mortality (OR = 2.7, 95% credible interval (CrI) [1.3–6.0] per one standard deviation increase; age, gender and sepsis severity adjusted OR = 1.5, 95% CrI [0.98–2.8]). The AUC was 0.69 for PSP 95% confidence interval (CI) [0.64–0.74], 0.61 [0.56–0.66] for PCT and 0.52 [0.47–0.57] for CRP. The sensitivity was 0.96, 0.52, 0.30 for risk thresholds 0.1, 0.2 and 0.3; respective false positive rate values were 0.84, 0.25, 0.10. Conclusions We found that PSP showed a very good discriminative ability for both investigated study endpoints ICU mortality and infection severity; better in comparison to CRP, similar to PCT. Combinations of biomarkers did not improve their predictive ability. …

IntroductionSepsis is one of the most common risk factors for acute respiratory distress syndrome (ARDS). Neutrophil elastase (NE) is believed to be an important mediator of ARDS. When sepsis occurs, a large number of inflammatory factors are activated and released, which makes neutrophils migrate into the lung, eventually leading to the occurrence of ARDS. Sivelestat sodium is an NE inhibitor that can inhibit the inflammatory reaction during systemic inflammatory response syndrome and alleviate lung injury. Therefore, we hypothesise that intravenous sivelestat sodium may prevent the occurrence of ARDS in patients with sepsis. Methods and analysisThis is a prospective, investigator-initiated, double-blind, adaptive, multicentre, randomised, controlled clinical trial with an adaptive ‘sample size re-estimation’ design. Patients meeting the inclusion criteria who were transferred into the intensive care unit will be randomly assigned to receive sivelestat sodium or placebo for up to 7 days. The primary outcome is the development of ARDS within 7 days after randomisation. A total of 238 patients will be recruited based on a 15% decrease in the incidence of ARDS in the intervention group in this study. A predefined interim analysis will be performed to ensure that the calculation is reasonable after reaching 50% (120) of the planned sample size. Ethics and disseminationThe study protocol was approved by the Ethics Committee of ZhongDa Hospital affiliated to Southeast University (identifier: Clinical Ethical Approval No. 2021ZDSYLL153-P03). Results will be submitted for publication in peer-reviewed journals and presented at relevant conferences and meetings. Trial registration numberNCT04973670. …

Objectives: Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct “high-risk” patients not captured by prior LCA classifications. Design: Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar’s test and then tested the correlation between IL-18 and LCA biomarkers using Pearson’s exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup. Setting: Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients. Subjects: Six hundred eighty-three patients in SAILS and 511 patients in HARP-2. Interventions: None. Measurements and Main Results: We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17–0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8–6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2–3.8; p = 0.009). Conclusions: Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts.

Objectives: To identify cytokine signature clusters in patients with septic shock. Design: Prospective observational cohort study. Setting: Single academic center in the United States. Patients: Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support. Interventions: None. Measurements and Main Results: One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t1) and 24 hours later (t2). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t2–t1), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1–3: 11% vs 31%; odds ratio [OR], 3.56 [1.10–14.23] vs 54% OR, 9.23 [2.89–37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t1 or t2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance. Conclusions: Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.

Infection and Immunity, Ahead of Print.

ObjectiveSepsis remains a high cause of death, particularly in immunocompromised patients with cancer. The study was to develop a model to predict hospital mortality of septic patients with cancer in intensive care unit (ICU). DesignRetrospective observational study. SettingMedical Information Mart for Intensive Care IV (MIMIC IV) and eICU Collaborative Research Database (eICU-CRD). ParticipantsA total of 3796 patients in MIMIC IV and 549 patients in eICU-CRD were included. Primary outcome measuresThe model was developed based on MIMIC IV. The internal validation and external validation were based on MIMIC IV and eICU-CRD, respectively. Candidate factors were processed with the least absolute shrinkage and selection operator regression and cross-validation. Hospital mortality was predicted by the multivariable logistical regression and visualised by the nomogram. The model was assessed by the area under the curve (AUC), calibration curve and decision curve analysis curve. ResultsThe model exhibited favourable discrimination (AUC: 0.726 (95% CI: 0.709 to 0.744) and 0.756 (95% CI: 0.712 to 0.801)) in the internal and external validation sets, respectively, and better calibration capacity than Acute Physiology and Chronic Health Evaluation IV in external validation. ConclusionsDespite that the predicted model was based on a retrospective study, it may also be helpful to predict the hospital morality of patients with solid cancer and sepsis. …

Abstract Purpose Timely and accurate data on the epidemiology of sepsis are essential to inform policy decisions and research priorities. We aimed to investigate the validity of inpatient administrative health data (IAHD) for surveillance and quality assurance of sepsis care. Methods We conducted a retrospective validation study in a disproportional stratified random sample of 10,334 inpatient cases of age ≥ 15 years treated in 2015–2017 in ten German hospitals. The accuracy of coding of sepsis and risk factors for mortality in IAHD was assessed compared to reference standard diagnoses obtained by a chart review. Hospital-level risk-adjusted mortality of sepsis as calculated from IAHD information was compared to mortality calculated from chart review information. Results ICD-coding of sepsis in IAHD showed high positive predictive value (76.9–85.7% depending on sepsis definition), but low sensitivity (26.8–38%), which led to an underestimation of sepsis incidence (1.4% vs. 3.3% for severe sepsis-1). Not naming sepsis in the chart was strongly associated with under-coding of sepsis. The frequency of correctly naming sepsis and ICD-coding of sepsis varied strongly between hospitals (range of sensitivity of naming: 29–71.7%, of ICD-diagnosis: 10.7–58.5%). Risk-adjusted mortality of sepsis per hospital calculated from coding in IAHD showed no substantial correlation to reference standard risk-adjusted mortality (r = 0.09). Conclusion Due to the under-coding of sepsis in IAHD, previous epidemiological studies underestimated the burden of sepsis in Germany. There is a large variability between hospitals in accuracy of diagnosing and coding of sepsis. Therefore, IAHD alone is not suited to assess quality of sepsis care. …

ObjectiveTo determine if the introduction of an emergency department (ED) sepsis screening tool and management bundle affects antibiotic prescribing and use. DesignMulticentre, cohort, before-and-after study design. SettingThree tertiary hospitals in Queensland, Australia (median bed size 543, range 520–742). ParticipantsAdult patients, presenting to the ED with symptoms and signs suggestive of sepsis who had blood cultures collected. These participants were further assessed and stratified as having septic shock, sepsis or infection alone, using Sepsis-3 definitions. The study dates were 1 July 2017–31 March 2020. InterventionThe breakthrough series collaborative ‘Could this be Sepsis?’ Programme, aimed at embedding a sepsis screening tool and treatment bundle with weighted-incidence syndromic combined antibiogram-derived antibiotic guidelines in EDs. Main outcome measuresThe primary outcome was the rate of empirical prescriptions adherent to antibiotic guidelines during the ED encounter. Secondary outcomes included the empirical prescriptions considered appropriate, effective antibiotics administered within 3 hours and assessment of harm measures. ResultsOf 2591 eligible patients, 721 were randomly selected: 241 in the baseline phase and 480 in the post-intervention phase. The rates of guideline adherence were 54.0% and 59.5%, respectively (adjusted OR (aOR) 1.41 (95% CI 1.00, 1.98)). As compared with baseline, there was an increase in the rates of appropriate antibiotic prescription after bundle implementation (69.9% vs 57.1%, aOR 1.92 (95% CI 1.37, 2.68)). There were no differences between the baseline and post-intervention groups with respect to time to effective antibiotics, adverse effects or ED rates of broad-spectrum antibiotic use. Conclusion and relevanceThe use of an ED sepsis screening tool and management bundle was associated with an improvement in the rates of appropriate antibiotic prescription without evidence of adverse effects. …

Abstract Purpose To determine whether a novel intervention improves the adherence to guideline-based preventive measures in asplenic patients at risk of post-splenectomy sepsis (PSS). Methods We used a prospective controlled, two-armed historical control group design to compare a novel, health action process approach (HAPA)-based telephonic intervention involving both patients and their general practitioners to usual care. Eligible patients were identified in cooperation with the insurance provider AOK Baden-Wuerttemberg, Germany. Patients with anatomic asplenia (n = 106) were prospectively enrolled and compared to a historical control group (n = 113). Comparisons were done using a propensity-score-based overlap-weighting model. Adherence to preventive measures was quantified by the study-specific ‘Preventing PSS score’ (PrePSS score) which includes pneumococcal and meningococcal vaccination status, the availability of a stand-by antibiotic and a medical alert card. Results At six months after the intervention, we estimated an effect of 3.96 (95% CI 3.68–4.24) points on the PrePSS score scale (range 0–10) with mean PrePSS scores of 3.73 and 7.70 in control and intervention group, respectively. Substantial improvement was seen in all subcategories of the PrePSS score with the highest absolute gains in the availability of stand-by antibiotics. We graded the degree of participation by the general practitioner (no contact, short contact, full intervention) and noted that the observed effect was only marginally influenced by the degree of physician participation. Conclusions Patients who had received the intervention exhibited a significantly higher adherence to guideline-based preventive measures compared to the control group. These data suggest that widespread adoption of this pragmatic intervention may improve management of asplenic patients. Health insurance provider-initiated identification of at-risk patients combined with a patient-focused intervention may serve as a blueprint for a wide range of other preventive efforts leading to patient empowerment and ultimately to better adherence to standards of care. …

American Journal of Respiratory and Critical Care Medicine, Volume 208, Issue 5, Page 513-515, September 1, 2023.

American Journal of Respiratory and Critical Care Medicine, Volume 208, Issue 5, Page 570-578, September 1, 2023.

American Journal of Respiratory and Critical Care Medicine, Volume 208, Issue 5, Page 616-618, September 1, 2023.

American Journal of Respiratory and Critical Care Medicine, Volume 208, Issue 5, Page 628-630, September 1, 2023.

Abstract Purpose To determine whether a novel intervention improves the adherence to guideline-based preventive measures in asplenic patients at risk of post-splenectomy sepsis (PSS). Methods We used a prospective controlled, two-armed historical control group design to compare a novel, health action process approach (HAPA)-based telephonic intervention involving both patients and their general practitioners to usual care. Eligible patients were identified in cooperation with the insurance provider AOK Baden-Wuerttemberg, Germany. Patients with anatomic asplenia (n = 106) were prospectively enrolled and compared to a historical control group (n = 113). Comparisons were done using a propensity-score-based overlap-weighting model. Adherence to preventive measures was quantified by the study-specific ‘Preventing PSS score’ (PrePSS score) which includes pneumococcal and meningococcal vaccination status, the availability of a stand-by antibiotic and a medical alert card. Results At six months after the intervention, we estimated an effect of 3.96 (95% CI 3.68–4.24) points on the PrePSS score scale (range 0–10) with mean PrePSS scores of 3.73 and 7.70 in control and intervention group, respectively. Substantial improvement was seen in all subcategories of the PrePSS score with the highest absolute gains in the availability of stand-by antibiotics. We graded the degree of participation by the general practitioner (no contact, short contact, full intervention) and noted that the observed effect was only marginally influenced by the degree of physician participation. Conclusions Patients who had received the intervention exhibited a significantly higher adherence to guideline-based preventive measures compared to the control group. These data suggest that widespread adoption of this pragmatic intervention may improve management of asplenic patients. Health insurance provider-initiated identification of at-risk patients combined with a patient-focused intervention may serve as a blueprint for a wide range of other preventive efforts leading to patient empowerment and ultimately to better adherence to standards of care. …

Competing definitions of sepsis have significant clinical implications and impact both medical coding and hospital payment. Although clinicians may prefer Sepsis-2, payer use of Sepsis-3 to validate clinical diagnoses may result in denial of payment or requests to recoup previously paid funds from healthcare providers. The Sepsis-2.5 project was a cooperative effort between a hospital system and a private payer to develop a community-based, literature-supported consensus definition for sepsis characterized by the presence of clinical illness, a source of infection, and evidence of organ dysfunction. This new definition (“Sepsis-2.5”) has been instrumental in resolving provider-payer conflicts in defining clinical sepsis and reimbursing care.

OBJECTIVES: We analyzed whether patients with the International Classification of Diseases, 10th Edition (ICD-10) discharge diagnosis code for sepsis are different in regard to demographics and outcome variables when comparing those with sepsis only to those also diagnosed with COVID-19 or those with a COVID-19 diagnosis alone. DESIGN: Retrospective cohort study. SETTING: Nine hospitals in an academic health system. PATIENTS: Patients with a final ICD-10 discharge diagnostic code for sepsis only, a diagnosis of COVID-19-only, or a final sepsis ICD-10 discharge code + a diagnosis of COVID-19 admitted to the hospital were analyzed for demographic and outcome differences between the cohorts. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 11,395 patients met inclusion criteria: 6,945 patients (60.9%) were ICD-10 sepsis code only, 3,294 patients (28.9%) were COVID-19 diagnosis-only, and 1,153 patients (10.1%) were sepsis ICD-10 code + COVID-19 diagnosis. Comparing sepsis ICD-10 code + COVID-19 diagnosis patients to sepsis ICD-10 code only and COVID-19 diagnosis-only patients, the sepsis ICD-10 code + COVID-19 diagnosis patients were: older (69 [58–78] vs 67 [56–77] vs 64 [51–76] yr), less likely to be female (40.3% vs 46.7% vs 49.5%), more frequently admitted to the ICU (59.3% [684/1,153] vs 54.9% [1,810/3,297] vs 15% [1,042/6,945]), more frequently required ventilatory support (39.3% [453/1,153] vs 31.8% [1,049/3,297] vs 6.0% [417/6,945]), had longer median hospital length of stay (9 [5,16] vs 5 [3,8] vs 7. [4,13] d), and were more likely to die in the hospital (39.2% [452/1,153] vs 22.3% [735/3,297] vs 6.4% [444/6,945]). CONCLUSIONS: During the COVID-19 pandemic the sickest cohort of patients was those receiving an explicit ICD-10 code of sepsis + a COVID-19 diagnosis. A significant percentage of COVID-19 diagnosis-only patients appear to have been under-coded as they received a level of critical care (ICU admission; intubation) suggestive of the presence of acute organ dysfunction during their admission.

AbstractBackgroundPatients with sepsis accompanying with acute lung injury (ALI) usually suffer from increased mortality. Ferroptosis is a vital regulator in sepsis-induced ALI. Exploring the association of ferroptosis and sepsis-induced ALI is crucial for the management of sepsis-induced ALI.MethodsWhole blood was collected from sepsis patients. Mice were treated with caecal ligation and puncture (CLP) for modeling sepsis. Primary murine pulmonary microvascular endothelial cells (PMVECs) were treated with LPS as a cell model. Ferroptosis was evaluated by analyzing levels of iron, MDA, GSH, non-heme iron, ferroportin, ferritin and GPX4. Hematoxylin and eosin and Masson’s trichrome staining were applied to examine lung injury and collagen deposition. Cell apoptosis was analyzed by caspase-3 activity and TUNEL assays. Gene regulatory relationship was verified using RNA pull-down and immunoprecipitation assays.ResultsCircEXOC5 was highly expressed in sepsis patients and CLP-treated mice, of which knockdown alleviated CLP-induced pulmonary inflammation and injury and ferroptosis. CircEXOC5 recruited IGF2BP2 to degrade ATF3 mRNA. The demethylase ALKBH5 was responsible for circEXOC5 upregulation through demethylation. CircEXOC5 silencing significantly improved sepsis-induced ALI and survival rate of mice through ATF3.ConclusionALKBH5-mediated upregulation of circEXOC5 exacerbates sepsis-induced ALI via facilitating ferroptosis through IGF2BP2 recruitment for degrading ATF3 mRNA.

Abstract Background Gram-negative bloodstream infections (GN-BSIs) are a significant clinical challenge. The utility of follow-up blood cultures (FUBCs) in GN-BSIs and their impact on mortality and antibiotic consumption are areas of debate. This study aimed to evaluate the effect of FUBCs on mortality and antibiotic consumption in patients with GN-BSIs. Methods This single-center, retrospective study was conducted in aged > 18 years of patients with GN-BSIs. FUBC was defined as a blood culture performed 2–7 days after the first blood culture. Patients were grouped as FUBC and no FUBC and compared. A 1:1 match analysis was performed between the groups according to the SOFA score. The matched subgroup was compared for mortality risk factors with logistic regression models. The two groups were compared for the duration of effective antibiotic therapy and total antibiotic consumption (days of therapy per 1000 patient days (DOT/1000 PD)). Results FUBC was performed in 564 (69.4%) of 812 patients. Persistent, positive and negative FUBC rates were 7.9%, 14%, and 78%, respectively. The frequency of persistent GN-BSI in patients with appropriate antibiotic therapy was 3.9%. SOFA score (OR:1.33; 95% CI, 1.23–1.44), Charlson comorbidity index score (OR:1.18; 95% CI, 1.08–1.28), hospital-acquired infections (OR:1.93; 95% CI, 1.08–3.46) and carbapenem-resistant GN-BSI (OR: 2.92; 95% CI, 1.72–4.96) were independent risk factors for mortality. No relationship was found between FUBC and mortality (p > 0.05). Duration of effective antibiotic therapy (10(4–16) vs. 15(9–20), p 

IntroductionMaternal and neonatal infections are among the most frequent causes of maternal and neonatal mortality, and current antibiotic strategies have been ineffective in preventing many of these deaths. A randomised clinical trial conducted in a single site in The Gambia showed that treatment with an oral dose of 2 g azithromycin versus placebo for all women in labour reduced certain maternal and neonatal infections. However, it is unknown if this therapy reduces maternal and neonatal sepsis and mortality. In a large, multinational randomised trial, we will evaluate the impact of azithromycin given in labour to improve maternal and newborn outcomes. Methods and analysisThis randomised, placebo-controlled, multicentre clinical trial includes two primary hypotheses, one maternal and one neonatal. The maternal hypothesis is to test whether a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labour will reduce maternal death or sepsis. The neonatal hypothesis will test whether this intervention will reduce intrapartum/neonatal death or sepsis. The intervention is a single, prophylactic intrapartum oral dose of 2 g azithromycin, compared with a single intrapartum oral dose of an identical appearing placebo. A total of 34 000 labouring women from 8 research sites in sub-Saharan Africa, South Asia and Latin America will be randomised with a one-to-one ratio to intervention/placebo. In addition, we will assess antimicrobial resistance in a sample of women and their newborns. Ethics and disseminationThe study protocol has been reviewed and ethics approval obtained from all the relevant ethical review boards at each research site. The results will be disseminated via peer-reviewed journals and national and international scientific forums. Trial registration numberNCT03871491 (https://clinicaltrials.gov/ct2/show/NCT03871491?term=NCT03871491&draw=2&rank=1). …

OBJECTIVES: Impaired nitric oxide (NO) bioavailability may contribute to microvascular dysfunction in sepsis. Excessive plasma NO consumption has been attributed to scavenging by circulating cell-free hemoglobin. This may be a mechanism for NO deficiency in sepsis and critical illness. We hypothesized that plasma NO consumption is high in critically ill patients, particularly those with sepsis, acute respiratory distress syndrome (ARDS), shock, and in hospital nonsurvivors. We further hypothesized that plasma NO consumption is correlated with plasma cell-free hemoglobin concentration. DESIGN: Retrospective cohort study. SETTING: Adult ICUs of an academic medical center. PATIENTS AND SUBJECTS: Three hundred sixty-two critically ill patients and 46 healthy control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma NO consumption was measured using reductive chemiluminescence and cell-free hemoglobin was measured with a colorimetric assay. Mean (95% CI) plasma NO consumption (µM) was higher in critically ill patients versus healthy control subjects (3.9 [3.7–4.1] vs 2.1 [1.8–2.5]), septic versus nonseptic patients (4.1 [3.8–4.3] vs 3.6 [3.3–3.8]), ARDS versus non-ARDS patients (4.4 [4.0–4.9] vs 3.7 [3.6–3.9]), shock vs nonshock patients (4.4 [4.0–4.8] vs 3.6 [3.4–3.8]), and hospital nonsurvivors versus survivors (5.3 [4.4–6.4] vs 3.7 [3.6–3.9]). These relationships remained significant in multivariable analyses. Plasma cell-free hemoglobin was weakly correlated with plasma NO consumption. CONCLUSIONS: Plasma NO consumption is elevated in critically ill patients and independently associated with sepsis, ARDS, shock, and hospital death. These data suggest that excessive intravascular NO scavenging characterizes sepsis and adverse outcomes of critical illness.

Abstract Background Gram-negative bloodstream infections (GN-BSIs) are a significant clinical challenge. The utility of follow-up blood cultures (FUBCs) in GN-BSIs and their impact on mortality and antibiotic consumption are areas of debate. This study aimed to evaluate the effect of FUBCs on mortality and antibiotic consumption in patients with GN-BSIs. Methods This single-center, retrospective study was conducted in aged > 18 years of patients with GN-BSIs. FUBC was defined as a blood culture performed 2–7 days after the first blood culture. Patients were grouped as FUBC and no FUBC and compared. A 1:1 match analysis was performed between the groups according to the SOFA score. The matched subgroup was compared for mortality risk factors with logistic regression models. The two groups were compared for the duration of effective antibiotic therapy and total antibiotic consumption (days of therapy per 1000 patient days (DOT/1000 PD)). Results FUBC was performed in 564 (69.4%) of 812 patients. Persistent, positive and negative FUBC rates were 7.9%, 14%, and 78%, respectively. The frequency of persistent GN-BSI in patients with appropriate antibiotic therapy was 3.9%. SOFA score (OR:1.33; 95% CI, 1.23–1.44), Charlson comorbidity index score (OR:1.18; 95% CI, 1.08–1.28), hospital-acquired infections (OR:1.93; 95% CI, 1.08–3.46) and carbapenem-resistant GN-BSI (OR: 2.92; 95% CI, 1.72–4.96) were independent risk factors for mortality. No relationship was found between FUBC and mortality (p > 0.05). Duration of effective antibiotic therapy (10(4–16) vs. 15(9–20), p 

Abstract Background Hypervirulent Klebsiella pneumoniae (hvKP) is emerging globally and can cause various, severe infections in healthy individuals. However, the clinical manifestations of hvKP infections are nonspecific, and there is no gold standard for differentiating hvKP strains. Our objective was to develop prognostic models for estimating severity of disease and predicting 30-day all-cause mortality in patients with hvKP infections. Methods We enrolled 116 patients diagnosed with hvKP infections and obtained their demographic and clinical data. Taking septic shock and acute respiratory distress syndrome (ARDS) as the primary outcomes for disease severity and 30-day all-cause mortality as the primary outcome for clinical prognosis, we explored the influencing factors and constructed prognostic models. Results The results showed that increased Acute Physiologic and Chronic Health Evaluation (APACHE) II score [odds ratio (OR) = 1.146; 95% confidence interval (CI), 1.059–1.240], decreased albumin (ALB) level (OR = 0.867; 95% CI, 0.758–0.990), diabetes (OR = 9.591; 95% CI, 1.766–52.075) and high procalcitonin (PCT) level (OR = 1.051; 95%CI, 1.005–1.099) were independent risk factors for septic shock. And increased APACHE II score (OR = 1.254; 95% CI, 1.110–1.147), community-acquired pneumonia (CAP) (OR = 11.880; 95% CI, 2.524–55.923), and extrahepatic lesion involved (OR = 14.718; 95% CI, 1.005–215.502) were independent risk factors for ARDS. Prognostic models were constructed for disease severity with these independent risk factors, and the models were significantly correlated with continuous renal replacement therapy (CRRT) duration, vasopressor duration, mechanical ventilator duration and length of ICU stay. The 30-day all-cause mortality rate in our study was 28.4%. Younger age [hazard ratio (HR) = 0.947; 95% CI, 0.923–0.973)], increased APACHE II score (HR = 1.157; 95% CI, 1.110–1.207), and decreased ALB level (HR = 0.924; 95% CI, 0.869–0.983) were the independent risk factors for 30-day all-cause mortality. A prediction model for 30-day mortality was constructed, which had a good validation effect. Conclusions We developed validated models containing routine clinical parameters for estimating disease severity and predicting 30-day mortality in patients with hvKP infections and confirmed their calibration. The models may assist clinicians in assessing disease severity and estimating the 30-day mortality early. …

Abstract Background Invasive extraintestinal pathogenic Escherichia coli disease (IED) can lead to severe outcomes, particularly among older adults. However, the clinical burden of IED in the U.S. has not been well characterized. Methods IED encounters among patients ≥ 60 years old were identified using the PINC AI™ Healthcare Database (10/01/2015–03/31/2020) by either a positive E. coli culture in blood or another normally sterile body site and ≥ 1 sign of systemic inflammatory response syndrome or signs of sepsis, or a positive E. coli culture in urine with urinary tract infection and signs of sepsis. Medical resource utilization, clinical outcomes, and E. coli isolate characteristics were descriptively reported during the first IED encounter and during the following year (observation period). Results Overall, 19,773 patients with IED were included (mean age: 76.8 years; 67.4% female; 78.5% with signs of sepsis). Most encounters involved community-onset IED (94.3%) and required hospitalization (96.5%; mean duration: 6.9 days), with 32.4% of patients being admitted to the intensive care unit (mean duration: 3.7 days). Most E. coli isolates were resistant to ≥ 1 antibiotic category (61.7%) and 34.4% were resistant to ≥ 3 antibiotic categories. Following their first IED encounter, 34.8% of patients were transferred to a skilled nursing/intermediate care facility, whereas 6.8% had died. During the observation period, 36.8% of patients were rehospitalized, 2.4% had IED recurrence, and in-hospital death increased to 10.9%. Conclusions IED is associated with substantial clinical burden at first encounter with considerable long-term consequences. Findings demonstrate the need for increased IED awareness and highlight potential benefits of prevention. …

by Hui Wang, Yulu Fang, Yongtao Jia, Jiajie Tang, Changzheng Dong Enterovirus B (EVB) is a common species of enterovirus, mainly consisting of Echovirus (Echo) and Coxsackievirus B (CVB). The population is generally susceptible to EVB, especially among children. Since the 21st century, EVB has been widely prevalent worldwide, and can cause serious diseases, such as viral meningitis, myocarditis, and neonatal sepsis. By using cryo-electron microscopy, the three-dimensional (3D) structures of EVB and their uncoating receptors (FcRn and CAR) have been determined, laying the foundation for the study of viral pathogenesis and therapeutic antibodies. A limited number of epitopes bound to neutralizing antibodies have also been determined. It is unclear whether additional epitopes are present or whether epitope mutations play a key role in molecular evolutionary history and epidemics, as in influenza and SARS-CoV-2. In the current study, the conformational epitopes of six representative EVB serotypes (E6, E11, E30, CVB1, CVB3 and CVB5) were systematically predicted by bioinformatics-based epitope prediction algorithm. We found that their epitopes were distributed into three clusters, where the VP1 BC loop, C-terminus and VP2 EF loop were the main regions of EVB epitopes. Among them, the VP1 BC loop and VP2 EF loop may be the key epitope regions that determined the use of the uncoating receptors. Further molecular evolution analysis based on the VP1 and genome sequences showed that the VP1 C-terminus and VP2 EF loop, as well as a potential “breathing epitope” VP1 N-terminus, were common mutation hotspot regions, suggesting that the emergence of evolutionary clades was driven by epitope mutations. Finally, footprints showed mutations were located on or near epitopes, while mutations on the receptor binding sites were rare. This suggested that EVB promotes viral epidemics by breaking the immune barrier through epitope mutations, but the mutations avoided the receptor binding sites. The bioinformatics study of EVB epitopes may provide important information for the monitoring and early warning of EVB epidemics and developing therapeutic antibodies.

Studies investigating the pathogenesis of neonatal infections and sepsis have proposed that colonization of the skin and mucosal surfaces (respiratory tract, gastrointestinal tract) are important sources of neonatal infections [1,2]. Early colonization of the infant with potential pathogenic microorganisms from the mother, especially with multi-drug resistant organisms (MDROs), have been shown to lead to durable, long-term colonisation with an increased risk of infections from these organisms [3–5].

AbstractGlucocorticoid (GC) therapy had been strongly recommended for pediatric sepsis (grade 1A). However, the recommendation was changed to grade 2C in 2020 due to weak evidence. About 32.8% pediatric septic patients develops relative adrenal insufficiency (RAI). But whether GC therapy should be determined by RAI status is controversial. This study utilized 21-day-old SF1CreSRBIfl/fl mice as the first pediatric RAI mouse model to assess the pathogenesis of RAI and evaluate GC therapy. RAI mice exhibited substantially higher mortality rate in both cecal ligation and puncture (CLP) and cecal slurry induced sepsis. These mice featured persistent inflammatory responses, and were effectively rescued by GC therapy. RNA-seq analysis revealed persistent inflammatory responses in RAI mice, caused by transcriptional dysregulation of AP-1 and NF-κB, and cytokine-induced secondary inflammatory response. Our findings support a precision medicine approach to guide GC therapy for pediatric patients - use of GC based on the status of RAI.

Publication date: Available online 20 July 2023 Source: Immunity Author(s): Hang Thi Thuy Gander-Bui, Joëlle Schläfli, Johanna Baumgartner, Sabrina Walthert, Vera Genitsch, Geert van Geest, José A. Galván, Carmen Cardozo, Cristina Graham Martinez, Mona Grans, Sabine Muth, Rémy Bruggmann, Hans Christian Probst, Cem Gabay, Stefan Freigang …