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Objectives: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Gue?rin (BCG) vaccine may provide non-specific protection against respiratory infections through enhancement of trained immunity. We investigated the impact of BCG vaccination on HCW absenteeism during the COVID-19 pandemic. Methods: HCWs exposed to COVID-19 patients in nine Dutch hospitals were randomized to BCG vaccine or placebo in a 1:1 ratio, and followed for one year using a mobile phone application. The primary endpoint was the self-reported number of days of unplanned absenteeism for any reason. Secondary endpoints included documented COVID-19, acute respiratory symptoms or fever. This was an investigator-funded study, registered at ClinicalTrials.gov (NCT03987919). Results: In March/April 2020, 1511 HCWs were enrolled. The median duration of follow-up was 357 person-days (interquartile range [IQR], 351 to 361). Unplanned absenteeism for any reason was observed in 2.8% of planned working days in the BCG group and 2.7% in the placebo group (adjusted relative risk 0.94; 95% credible interval, 0.78-1.15). Cumulative incidences of documented COVID-19 were 14.2% in the BCG and 15.2% in the placebo group (adjusted hazard ratio (aHR) 0.94; 95% confidence interval (CI), 0.72-1.24). First episodes of self-reported acute respiratory symptoms or fever occurred in 490 (66.2%) and 443 (60.2%) participants, respectively (aHR: 1.13; 95% CI, 0.99-1.28). Thirty-one serious adverse events were reported (13 after BCG, 18 after placebo), none considered related to study medication.Conclusions: During the COVID-19 pandemic, BCG-vaccination of HCW exposed to COVID-19 patients did not reduce unplanned absenteeism nor documented COVID-19. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

Contains fulltext : 293489.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities. METHODS: Community-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events. RESULTS: A total of 6112 participants with a median age of 69 years (interquartile range, 65-74) and median of 2 (interquartile range, 1-3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95% CI, 0.87-1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95% CI, 0.46-1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95% CI, 0.35-1.43), of which 11 deaths (35%) were COVID-19-related: six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95% CI, 0.66-1.28). DISCUSSION: BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs. 01 juni 2023

BackgroundBacillus Calmette-Guerin (BCG) vaccination has been hypothesised to reduce SARS-CoV-2 infection, severity, and/or duration via trained immunity induction.MethodsHealthcare workers (HCWs) in 9 Dutch hospitals were randomised to BCG or placebo vaccination (1:1) in March/April 2020 and followed for one year. They reported daily symptoms, SARS-CoV-2 test results, and healthcare-seeking behaviour via a smartphone application, and donated blood for SARS-CoV-2 serology at two time points.Results1,511 HCWs were randomised and 1,309 analysed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio=0.95; 95% confidence interval 0.76-1.21; p=0.732). Only three participants required hospitalisation for COVID-19. The proportions of participants with asymptomatic, mild, or mild-to-moderate infections, and the mean infection durations, did not differ between randomisation groups. Unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes either. The percentage of participants with seroconversion (7.8% versus 2.8%; p=0.006) and mean anti-S1 antibody concentration (13.1 versus 4.3 IU/ml; p=0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months post-vaccination.ConclusionsBCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (on a scale from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection.

Background: A delay in admission to the intensive care unit (ICU) of patients with community-acquired pneumonia (CAP) has been associated with an increased mortality. Decisions regarding interventions and eligibility for immune modulatory therapy are often made at the time of admission to the ICU. The primary aim of this study was to compare the host immune response measured upon ICU admission in CAP patients admitted immediately from the emergency department (direct ICU admission) with those who were transferred within 72 h after admission to the general ward (delayed ICU admission)., Methods: Sixteen host response biomarkers providing insight in pathophysiological mechanisms implicated in sepsis and blood leukocyte transcriptomes were analysed in patients with CAP upon ICU admission in two tertiary hospitals in the Netherlands., Results: Of 530 ICU admissions with CAP, 387 (73.0%) were directly admitted and 143 (27.0%) had a delayed admission. Patients with a delayed ICU admission were more often immunocompromised (35.0 versus 21.2%, P = .002) and had more malignancies (23.1 versus 13.4%, P = .011). Shock was more present in patients who were admitted to the ICU directly (46.6 versus 33.6%, P = .010). Delayed ICU admission was not associated with an increased hospital mortality risk (hazard ratio 1.25, 95% CI 0.89-1.78, P = .20). The plasma levels of biomarkers (n = 297) reflecting systemic inflammation, endothelial cell activation and coagulation activation were largely similar between groups, with exception of C-reactive protein, soluble intercellular adhesion molecule-1 and angiopoietin-1, which were more aberrant in delayed admissions compared to direct ICU admissions. Blood leukocyte transcriptomes (n = 132) of patients with a delayed ICU admission showed blunted innate and adaptive immune response signalling when compared with direct ICU admissions, as well as decreased gene expression associated with tissue repair and extracellular matrix remodelling pathways. Conclusions: Blood leukocytes of CAP patients with delayed ICU admission show evidence of a more immune suppressive phenotype upon ICU admission when compared with blood leukocytes from patients directly transferred to the ICU., peer-reviewed

Objective:Automated surveillance methods increasingly replace or support conventional (manual) surveillance; the latter is labor intensive and vulnerable to subjective interpretation. We sought to validate 2 previously developed semiautomated surveillance algorithms to identify deep surgical site infections (SSIs) in patients undergoing colorectal surgeries in Dutch hospitals.Design:Multicenter retrospective cohort study.Methods:From 4 hospitals, we selected colorectal surgery patients between 2018 and 2019 based on procedure codes, and we extracted routine care data from electronic health records. Per hospital, a classification model and a regression model were applied independently to classify patients into low- or high probability of having developed deep SSI. High-probability patients need manual SSI confirmation; low-probability records are classified as no deep SSI. Sensitivity, positive predictive value (PPV), and workload reduction were calculated compared to conventional surveillance.Results:In total, 672 colorectal surgery patients were included, of whom 28 (4.1%) developed deep SSI. Both surveillance models achieved good performance. After adaptation to clinical practice, the classification model had 100% sensitivity and PPV ranged from 11.1% to 45.8% between hospitals. The regression model had 100% sensitivity and 9.0%–14.9% PPV. With both models, Conclusions:In this independent external validation, both surveillance models performed well. The classification model is preferred above the regression model because of source-data availability and less complex data-management requirements. The next step is implementation in infection prevention practices and workflow processes.

BackgroundGram-positive and Gram-negative bacteria are the most common causative pathogens in community-acquired pneumonia (CAP) on the intensive care unit (ICU). The aim of this study was to determine whether the host immune response differs between Gram-positive and Gram-negative CAP upon ICU admission.Methods16 host response biomarkers providing insight into pathophysiological mechanisms implicated in sepsis and blood leukocyte transcriptomes were analysed in patients with CAP upon ICU admission in two tertiary hospitals in the Netherlands.Results309 patients with CAP with a definite or probable likelihood (determined by predefined criteria) were included. A causative pathogen was determined in 74.4% of admissions. Patients admitted with Gram-positive CAP (n=90) were not different from those admitted with Gram-negative CAP (n=75) regarding demographics, chronic comorbidities, severity of disease and mortality. Host response biomarkers reflective of systemic inflammation, coagulation activation and endothelial cell function, as well as blood leukocyte transcriptomes, were largely similar between Gram-positive and Gram-negative CAP. Blood leukocyte transcriptomes were also similar in Gram-positive and Gram-negative CAP in two independent validation cohorts. On a pathogen-specific level, Streptococcus pneumoniae and Escherichia coli induced the most distinct host immune response.ConclusionOutcome and host response are similar in critically ill patients with CAP due to Gram-positive bacteria compared with Gram-negative bacteria.

Background Colistin is an antibiotic that targets the LPS molecules present in the membranes of Gram-negative bacteria. It is used as a last-resort drug to treat infections with MDR strains. Colistin is also used in selective decontamination of the digestive tract (SDD), a prophylactic therapy used in patients hospitalized in ICUs to selectively eradicate opportunistic pathogens in the oropharyngeal and gut microbiota. Objectives To unravel the mechanisms of acquired colistin resistance in Gram-negative opportunistic pathogens obtained from SDD-treated patients. Results Routine surveillance of 428 SDD-treated patients resulted in 13 strains with acquired colistin resistance (Escherichia coli, n = 9; Klebsiella aerogenes, n = 3; Enterobacter asburiae, n = 1) from 5 patients. Genome sequence analysis showed that these isolates represented multiple distinct colistin-resistant clones but that colistin-resistant strains within the same patient were clonally related. We identified previously described mechanisms that lead to colistin resistance, i.e. a G53 substitution in the response regulator PmrA/BasR and the acquisition of the mobile colistin resistance gene mcr-1.1, but we also observed novel variants of basR with an 18 bp deletion and a G19E substitution in the sensor histidine kinase BasS. We experimentally confirmed that these variants contribute to reduced colistin susceptibility. In a single patient, we observed that colistin resistance in a single E. coli clone evolved through two unique variants in basRS. Conclusions We show that prophylactic use of colistin during SDD can select for colistin resistance in species that are not intrinsically colistin resistant. This highlights the importance of continued surveillance for strains with acquired colistin resistance in patients treated with SDD.

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled “a randomized embedded multifactorial adaptive platform.” The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas. Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Pulmonary embolism (PE) occurs in one-third of critically-ill COVID-19 patients. Although prior studies identified several pathways contributing to thrombogenicity, it is unknown whether this is COVID-19-specific or also occurs in ARDS patients with another infection.To compare pathway activity among patients having COVID-19 with PE (C19PE+), COVID-19 without PE (C19PE-), and influenza-associated ARDS (IAA) using a targeted proteomics approach.We exploited an existing biorepository containing daily plasma samples to carefully match C19PE+ cases to C19PE- and IAA controls on mechanical ventilation duration, PEEP, FiO2, and cardiovascular-SOFA (n = 15 per group). Biomarkers representing various thrombosis pathways were measured using proximity extension- and ELISA-assays. Summed z-scores of individual biomarkers were used to represent total pathway activity.We observed no relevant between-group differences among 22 biomarkers associated with activation of endothelium, platelets, complement, coagulation, fibrinolysis or inflammation, except sIL-1RT2 and sST2, which were lower in C19PE- than IAA (log2-Foldchange -0.67, p = .022 and -1.78, p = .022, respectively). However, total pathway analysis indicated increased activation of endothelium (z-score 0.2 [-0.3-1.03] vs. 0.98 [-2.5--0.3], p = .027), platelets (1.0 [-1.3-3.0] vs. -3.3 [-4.1--0.6], p = .023) and coagulation (0.8 [-0.5-2.0] vs. -1.0 [-1.6-1.0], p = .023) in COVID-19 patients (C19PE+/C19PE- groups combined) compared to IAA.We observed only minor differences between matched C19PE+, C19PE-, and IAA patients, which suggests individual biomarkers mostly reflect disease severity. However, analysis of total pathway activity suggested upregulation of some distinct processes in COVID-19 could be etiologically related to increased PE-risk.

Background: Current guidelines on the management of infective endocarditis (IE) recommend follow-up blood cultures (FUBCs) to identify persistent bacteraemia, as this has prognostic value and guides treatment decisions. While persistent bacteraemia frequently occurs in Staphylococcus aureus bacteraemia and IE, its prevalence and impact in non-staphylococcal IE is largely unknown. We determined prevalence and prognostic value of persistent bacteraemia in non-staphylococcal IE. Methods: We conducted a retrospective analysis of all patients diagnosed with definite non-staphylococcal endocarditis according to the modified Duke Criteria in two university hospital endocarditis registries We determined the prevalence and prognostic value of persistent bacteraemia. Results: Of the included 159 patients 70 (44%) had prosthetic valve endocarditis (PVE). A median number of two [IQR 1–3] FUBCs were taken during the first week, with 134/159 (84%) having at least one FUBC in the first four days. Seven patients (4,4%) had persistent bacteraemia 48 h after start of antibiotic treatment: 5/70 patients (7.1%) with PVE and 2/89 (2.2%) with native valve endocarditis. Among 97 patients with streptococcal IE, nine patients with HACEK IE and six patients with Cutibacterium IE, no persistent bacteraemia was observed. Enterococcus faecalis was the causative microorganism in five patients with persistent bacteraemia, the other two had non-HACEK Gram-negative endocarditis. Conclusion: Persistent bacteraemia in non-staphylococcal endocarditis was rare. It was more frequently observed in PVE and was restricted to more resilient microorganisms such as enterococci and non-HACEK Gram-negative bacteria. Routine collection of FUBCs in patients with streptococcal endocarditis has a low yield and may require re-evaluation.

BACKGROUNDThe objective is to determine the impact of the Bacillus Calmette-Guérin (BCG) vaccine compared to placebo or no vaccine on COVID-19 infections and hospitalisations in healthcare workers. We are using a living and prospective approach to Individual-Participant-Data (IPD) meta-analysis of ongoing studies based on the Anytime Live and Leading Interim (ALL-IN) meta-analysis statistical methodology.METHODSPlanned and ongoing randomised controlled trials were identified from trial registries and by snowballing (final elicitation: Oct 3 2022). The methodology was specified prospectively – with no trial results available – for trial inclusion as well as statistical analysis. Inclusion decisions were made collaboratively based on a risk-of-bias assessment by an external protocol review committee (Cochrane risk-of-bias tool adjusted for use on protocols), expected homogeneity in treatment effect, and agreement with the predetermined event definitions. The co-primary endpoints were incidence of COVID-19 infection and COVID-19-related hospital admission. Accumulating IPD from included trials was analysed sequentially using the exacte-value logrank test (at level α = 0.5% for infections and level α = 4.5% for hospitalisations) and anytime-valid 95%-confidence intervals (CIs) for the hazard ratio (HR) for a predetermined fixed-effects approach to meta-analysis (no measures of statistical heterogeneity). Infections were included if demonstrated by PCR tests, antigen tests or suggestive lung CTs. Participants were censored at date of first COVID-19-specific vaccination and two-stage analyses were performed in calendar time, with a stratification factor per trial.RESULTSSix trials were included in the primary analysis with 4 433 participants in total. Thee-values showed no evidence of a favourable effect of minimal clinically relevance (HR < 0.8) in comparison to the null (HR = 1) for COVID-19 infections, nor for COVID-19 hospitalisations (HR < 0.7 vs HR = 1). COVID-19 infection was observed in 251 participants receiving BCG and 244 participants not receiving BCG, HR 1.02 (anytime-valid 95%-CI 0.78-1.35). COVID-19 hospitalisations were observed in 13 participants receiving BCG and 7 not receiving BCG, resulting in an uninformative estimate (HR 1.88; anytime-valid 95%-CI 0.26-13.40).DISCUSSIONIt is highly unlikely that BCG has a clinically relevant effect on COVID-19 infections in healthcare workers. With only limited observations, no conclusion could be drawn for COVID-19 related hospitalisation. Due to the nature of ALL-IN meta-analysis, emerging data from new trials can be included without violating type-I error rates or interval coverage. We intend to keep this meta-analysis alive and up-to-date, as more trials report. For COVID-19 related hospitalisations, we do not expect enough future observations for a meaningful analysis. For BCG-mediated protection against COVID-19 infections, on the other hand, more observations could lead to a more precise estimate that concludes the meta-analysis for futility, meaning that the current interval excludes the HR of 0.8 predetermined as effect size of minimal clinical relevance.OTHERNo external funding. Preregistered at PROSPERO: CRD42021213069.

OBJECTIVES Rotavirus vaccination has 87% to 100% effectiveness against severe rotavirus acute gastroenteritis (AGE) in healthy infants in high-income countries. Little is known whether infants with medical risk conditions (MRCs) are equally protected and if the vaccine is equally well tolerated. We conducted a quasi-experimental prospective multicenter before-after cohort study to assess the vaccine effectiveness (VE) and safety profile of the human rotavirus vaccine (HRV) among MRC infants that required prolonged or frequent postnatal care. METHODS The Netherlands has no national rotavirus immunization program, but HRV was implemented in routine care for MRC infants in 13 Dutch hospitals. Participants in the before and after cohort, HRV unvaccinated and vaccinated, respectively, were followed for occurrence of (rotavirus) AGE. VE of at least 1 dose was estimated by using time-to-event analysis for severe rotavirus AGE. Vaccine-related serious adverse event (AEs) after HRV were retrieved systematically from medical charts. Solicited AEs after vaccinations were prospectively collected and compared between vaccination time points with or without HRV. RESULTS In total, 1482 high-risk infants with MRC were enrolled, including 631 in the before and 851 in the after cohorts; 1302 infants were premature (88.3%), 447 were small for gestational age (30.2%), and 251 had at least 1 congenital disorder (17.0%). VE against severe rotavirus AGE was 30% (95% confidence interval [CI]: −36% to 65%). Overall, the observed number of rotavirus hospitalizations was low and not significantly different between the cohorts (2 and 2, respectively). The rate of vaccine-related serious AE was 0.24 per 100 vaccine doses. The adjusted risk ratio for any AE after HRV vaccination compared with other routine vaccinations was 1.09 (95% CI: 1.05 to 1.12) for concomitant administration and 0.91 (95% CI: 0.81 to 0.99) for single HRV administration. Gastrointestinal AEs were 10% more frequent after HRV. CONCLUSIONS In contrast to previous findings among healthy term infants, in routine use, HRV offered limited protection to vulnerable medical risk infants. HRV is generally well tolerated in this group in single administration, but when coadministered with routine vaccines, it is associated with higher risk of (mostly gastrointestinal) AE. Our study highlights the importance of studying vaccine performance in subgroups of medically vulnerable infants.

OBJECTIVE: In the Democratic Republic of Congo and other low-resource countries, community-acquired pathogens are increasingly resistant to most locally available antibiotics. To guide efforts to optimize antibiotic use to limit antibiotic resistance, we quantified healthcare provider-specific and community-wide antibiotic use. METHODS: From household surveys, we estimated monthly healthcare visit rates by provider. From healthcare visit exit surveys, we estimated prevalence, defined daily doses, and access/watch/reserve distribution of antibiotic use by provider. Combining both, we estimated community-wide antibiotic use rates. RESULTS: Of 88.7 (95% CI 81.9-95.4) healthcare visits per 1000 person-months (n = 31221), visits to private clinics (31.0, 95% CI 30.0-32.0) and primary health centres (25.5, 95% CI 24.6-26.4) were most frequent. Antibiotics were used during 64.3% (95% CI 55.2-73.5%, 162/224) of visits to private clinics, 51.1% (95% CI 45.1-57.2%, 245/469) to health centres, and 48.8% (95% CI 44.4-53.2%, 344/454) to medicine stores. Antibiotic defined daily doses per 1000 inhabitants per day varied between 1.75 (95% CI 1.02-2.39) in rural Kimpese and 10.2 (95% CI 6.00-15.4) in (peri) urban Kisantu, mostly explained by differences in healthcare utilisation (respectively 27.8 versus 105 visits per 1000 person-months), in particular of private clinics (1.23 versus 38.6 visits) where antibiotic use is more frequent. The fraction of Watch antibiotics was 30.3% (95% CI 24.6-35.9%) in private clinics, 25.6% (95% CI 20.2-31.1%) in medicine stores, and 25.1% (95% CI 19.0-31.2%) in health centres. Treatment durations

Background: A prolonged prothrombin time (PT) is a common feature in sepsis indicating consumptive coagulopathy., Objectives: To determine the association between a prolonged PT and aberrations in other host response mechanisms in sepsis., Methods: Patients admitted to the intensive care unit with sepsis were divided in quartiles according to the highest PT value measured within 24 h after admission. The host response was evaluated by measuring 19 plasma biomarkers reflecting pathways implicated in sepsis pathogenesis and by blood leukocyte gene expression profiling., Measurements and main results: Of 1524 admissions for sepsis, 386 (25.3%) involved patients with a normal PT (≤12.7 s); the remaining quartiles entailed 379 (24.9%) patients with a slightly prolonged PT (12.8 ≤ PT ≤ 15.0 s), 383 (25.1%) with an intermediately prolonged PT (15.1 ≤ PT ≤ 17.2 s), and 376 (24.7%) with an extremely prolonged PT (≥17.3 s). While patients with an extremely prolonged PT showed an increased crude mortality up to 1 year after admission, none of the prolonged PT groups was independently associated with 30-day adjusted mortality. Comparison of the host response between patients with a normal PT or an extremely prolonged PT matched for baseline characteristics including severity of disease showed that an extremely prolonged PT was associated with impaired anticoagulant mechanisms, a more disturbed endothelial barrier integrity and increased systemic inflammation, and blood leukocyte transcriptomes indicating more prominent metabolic reprogramming and protein catabolism., Conclusion: A prolonged PT is associated with stronger anomalies in pathways implicated in the pathogenesis of sepsis, suggesting that activation of coagulation impacts other host response mechanisms., peer-reviewed

Background: Prospective identification of patients at high risk of nosocomial pneumonia may improve clinical trial feasibility and foster antibacterial development. Clinical criteria prospectively identified patients at highest risk of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in the United States (US). Whether these findings are applicable in a European population is unknown. Methods: Adults considered high risk for pneumonia (treatment with ventilation or high levels of supplemental oxygen) in the intensive care units of seven European hospitals were prospectively enrolled. We estimated the proportion of high-risk patients developing HABP/VABP, defined according to US Food and Drug Administration (FDA) guidance, and the subset potentially eligible for antibacterial trial enrollment. We compared patient characteristics, exposures, and HABP/VABP incidence in European and US cohorts. Findings: Of 888 high-risk patients enrolled between June 12 and December 27, 2017, 211/888 (24%) were treated for possible pneumonia and 150/888 (17%) met the FDA definition for HABP/VABP. A higher proportion of European high-risk patients treated for possible pneumonia met the HABP/VABP definition (150/211 [71%] versus 537/1464 [37%] in US, p

Background: Additional safe and effective vaccines are needed to control the COVID-19 pandemic. Methods: HERALD is an ongoing phase 2b/3 randomised, observer-blinded, placebo-controlled clinical trial in ten countries in Europe and Latin America. SARS-CoV-2 naive adults were randomised 1:1 to receive two doses of CVnCoV mRNA vaccine candidate or placebo 28 days apart. Primary efficacy analysis included symptomatic COVID-19 more than 14 days after second dose. Solicited adverse events (AEs) were assessed in phase 2b participants and unsolicited AEs in all participants. The study is registered at ClinicalTrials.gov (NCT04652102). Findings: Between 11 December 2020 and 12 April 2021, 39 680 participants were randomised and 39 529 received CVnCoV (19 783) or placebo (19 746). Overall VE was 48·2% (95% CI: 31·0–61·4; 83/12 851 vs. 145/12 221 in CVnCoV and placebo recipients, respectively). Overall VE against moderate-to-severe COVID-19 was 70·7% (95% CI: 42·5–86·1; 12/12 851 vs. 37/12 211, respectively). In participants aged 18–60 years VE was 52·5% (95% CI: 36·2–64·8; 71/11 532 vs. 136/11 031, respectively). Too few cases occurred in participants aged ≥61 years (CVnCoV: 12, placebo: 9) precluding VE evaluation. Wild type SARS-CoV-2 was detected in 7/204 (3%) sequenced cases, with 14 variants being responsible for the other cases. Solicited adverse events, mostly systemic, were more common in CVnCoV recipients; 542/2002 CVnCoV recipients and 61/1980 placebo recipients reported grade 3 events. Unsolicited serious AEs were reported for 82/19 746 CVnCoV recipients and 66/19 746 placebo recipients; 8 and 2 SAEs, respectively were considered related to vaccination. Fatal SAEs were reported for 8 and 6 CVnCoV and placebo recipients. Interpretation: CVnCoV is efficacious in the prevention of COVID-19 of any severity and has an acceptable safety profile. Trial Registration: Study number: ClinicalTrials.gov Identifier: NCT04652102. Funding: This trial was funded by the German Federal Ministry of Education and Research (grant 01KI20703), and CureVac AG. Declaration of Interest: MB declares institutional funding from CureVac during the conduct of this study, from Janssen Vaccines, molecular partners, and Merck outside of the submitted work, and consulting fees from Janssen Vaccines. EJLDB, and MFMR, TO and XSL declare institutional funding from CureVac during the conduct of this study. LE, and LG declare institutional funding from CureVac during the conduct of this study and outside of the submitted work. CFL declares institutional funding from CureVac during the conduct of this study, and outside of the submitted work, and is a member of WHO Covid-19 Vaccine Effectiveness Working Group and WHO Product Development for Vaccines Advisory Committee (PDVAC). CL declares institutional funding from CureVac during the conduct of this study, and is a member of the of German Society of Infection board. ILR declares institutional funding from CureVac during the conduct of this study and from J &J, and OSE Immunotherapeutics outside of the submitted work. PGK declares institutional funding from CureVac during the conduct of this study, and is a member of the scientific advisory board for the HERALD clinical trial. VVRH declares institutional funding from CureVac during the conduct of this study, and speakers fees from Gilead outside of the submitted work. HJ declares consultant fees from CureVac, is the Medical Responsible Person for the HERALD clinical trial, and is co-chair of DSMB for the HERALD clinical trial. AK and PM are employed by CureVac, and hold stock options. OSK declares consultant fees from CureVac during the conduct of this study, and is a member of the DSMB for a CVnCoV phase 1 trial. TV declares consultant fees from CureVac during the conduct of this study, and consultant fees from CureVac, AstraZeneca, Pfizer, Johnson&Johnson, and Moderna outside of the submitted work. LO is employed by CureVac, and holds stock options, and is the holder of a pending patent. The other authors declare no competing interests. Ethical Approval: The trial protocol and amendments have been approved by the appropriate independent ethics committee or institutional review board at each study centre

The role of school-based contacts in the epidemiology of SARS-CoV-2 is incompletely understood. We use an age-structured transmission model fitted to age-specific seroprevalence and hospital admission data to assess the effects of school-based measures at different time points during the COVID-19 pandemic in the Netherlands. Our analyses suggest that the impact of measures reducing school-based contacts depends on the remaining opportunities to reduce non-school-based contacts. If opportunities to reduce the effective reproduction number (Re) with non-school-based measures are exhausted or undesired and Re is still close to 1, the additional benefit of school-based measures may be considerable, particularly among older school children. As two examples, we demonstrate that keeping schools closed after the summer holidays in 2020, in the absence of other measures, would not have prevented the second pandemic wave in autumn 2020 but closing schools in November 2020 could have reduced Re below 1, with unchanged non-school-based contacts., The role of school-based contacts in the epidemiology of SARS-CoV-2 is incompletely understood. Here, the authors use an age-structured transmission model fitted to age-specific seroprevalence and hospital admission data to assess the effects of school-based measures during the COVID-19 pandemic in the Netherlands.

PRAISE network: Maaike S. M. van Mourik, Stephanie M.van Rooden, Mohamed Abbas, Olov Aspevall, Pascal Astagneau, Marc J. M. Bonten, Elena Carrara, Aina Gomila-Grange, Sabine C. de Greeff , Sophie Gubbels, Wendy Harrison, Hilary Humphreys, Anders Johansson, Mayke B. G. Koek, Brian Kristensen, Alain Lepape, Jean-Christophe Lucet, Siddharth Mookerjee, Pontus Naucler, Zaira R. Palacios-Baena, Elisabeth Presterl, Miquel Pujol, Jacqui Reilly, Christopher Roberts, Evelina Tacconelli, Daniel Teixeira, Thomas Tängdén, John Karlsson Valik, Michael Behnke, PetraGastmeier., [Introduction] Healthcare-associated infections (HAI) are a major public health concern. Monitoring of HAI rates, with feedback, is a core component of infection prevention and control programmes. Digitalization of healthcare data has created novel opportunities for automating the HAI surveillance process to varying degrees. However, methods are not standardized and vary widely between different healthcare facilities. Most current automated surveillance (AS) systems have been confined to local settings, and practical guidance on how to implement large-scale AS is needed., [Methods] This document was written by a task force formed in March 2019 within the PRAISE network (Providing a Roadmap for Automated Infection Surveillance in Europe), gathering experts in HAI surveillance from ten European countries., [Results] The document provides an overview of the key e-health aspects of implementing an AS system of HAI in a clinical environment to support both the infection prevention and control team and information technology (IT) departments. The focus is on understanding the basic principles of storage and structure of healthcare data, as well as the general organization of IT infrastructure in surveillance networks and participating healthcare facilities. The fundamentals of data standardization, interoperability and algorithms in relation to HAI surveillance are covered. Finally, technical aspects and practical examples of accessing, storing and sharing healthcare data within a HAI surveillance network, as well as maintenance and quality control of such a system, are discussed., [Conclusions] With the guidance given in this document, along with the PRAISE roadmap and governance documents, readers will find comprehensive support to implement large-scale AS in a surveillance network., This network has been supported under the 7th transnational call within the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), Network Call on Surveillance (2018) and was thereby funded by ZonMw (grant 549007001). This project also received support from the COMBACTE MAGNET EPI-Net project funded by the Innovative Medicines Initiative Joint Undertaking under grant agreement 115523 | 115620 | 115737 | 777362, resources of which are composed of financial contribution from the European Union Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. J.K.V. was supported by grants from Region Stockholm and Vinnova.

BackgroundRT-qPCR is the reference test for identification of active SARS-CoV-2 infection, but is associated with diagnostic delay. Antigen detection assays can generate results within 20 minutes and outside of laboratory settings. Yet, their diagnostic test performance in real life settings has not been determined.MethodsThe diagnostic value of the Panbio™ COVID-19 Ag Rapid Test (Abbott), was determined in comparison to RT-qPCR (Seegene Allplex) in community-dwelling mildly symptomatic subjects in a medium (Utrecht, the Netherlands) and high endemic area (Aruba), using two concurrently obtained nasopharyngeal swabs.Findings1367 and 208 subjects were enrolled in Utrecht and Aruba, respectively. SARS-CoV-2 prevalence, based on RT-qPCR, was 10.2% (n=139) and 30.3% (n=63) in Utrecht and Aruba respectively. Specificity of the Panbio™ COVID-19 Ag Rapid Test was 100% (95%CI: 99.7-100%) in both settings. Test sensitivity was 72.6% (95%CI: 64.5-79.9%) in the Netherlands and 81.0% (95% CI: 69.0–89.8%) in Aruba. Probability of false negative results was associated with RT-qPCR Ct-values, but not with duration of symptoms. Restricting RT-qPCR test positivity to Ct-values InterpretationIn community-dwelling subjects with mild respiratory symptoms the Panbio™ COVID-19 Ag Rapid Test had 100% specificity, and a sensitivity above 95% for nasopharyngeal samples when using Ct values FundingUMCU and LABHOH, Aruba

BackgroundLymphocytopenia is frequent in critically ill patients and has been associated with an increased risk of nosocomial infections and death in the ICU. Immunotherapies to promote recovery of lymphocyte counts have therefore been proposed. However, it is unknown if lymphocytopenia is a direct cause of ICU-acquired infections and death, or merely a marker of disease severity. We set out to study the prevalence, temporal evolution, and clinical correlates of lymphocytopenia in ICU patients, and estimate the attributable risk of lymphocytopenia in ICU-acquired infections.MethodsWe assessed the association between persistent lymphocytopenia (absolute lymphocyte counts ResultsAmong 2302 patients admitted to a Dutch tertiary ICU having sepsis, trauma, or major surgery between 2011 and 2018, persistent lymphocytopenia was observed in 980 (42.6%) subjects. Lymphocyte counts remained relatively stable during early ICU admission, and the median duration of lymphocytopenia was 3 (IQR 1-6) days among exposed patients. ICU-acquired infections occurred in 239 (18.1%) patients without and 214 (21.8%) patients with persistent lymphocytopenia (p=0.03). However, in multivariable survival analysis persistent lymphocytopenia was not associated with infection occurrence, either directly (adjusted cause-specific HR 1.08, 95% CI, 0.90–1.31) or indirectly (subdistribution HR 1.09, 95% CI, 0.91–1.32). Sensitivity analyses did not alter these findings.ConclusionPersistent lymphocytopenia was not associated with a higher incidence rate of nosocomial infections in critically ill patients. This challenges the rationale for using absolute lymphocyte counts as a therapeutic target to prevent ICU-acquired infections.

Colistin is an antibiotic that targets the lipopolysaccharides present in the membranes of Gram-negative bacteria. It is used as last-resort drug to treat infections with multidrug-resistant strains. Colistin is also used in selective decontamination of the digestive tract (SDD), a prophylactic therapy used in patients hospitalised in intensive care units (ICUs) to selectively eradicate opportunistic pathogens in the oropharyngeal and gut microbiota. In this study, we aimed to unravel the mechanisms of acquired colistin resistance in Gram-negative opportunistic pathogens obtained from SDD-treated patients.Routine surveillance of 428 SDD-treated patients resulted in thirteen strains with acquired colistin resistance (Escherichia coli n=9; Klebsiella aerogenes, n=3; Enterobacter asburiae, n=1) from five patients. Genome sequence analysis showed that these isolates represented multiple distinct colistin-resistant clones, but that within the same patients, colistin-resistant strains were clonally related. We identified previously described mechanisms that lead to colistin resistance, i.e. a G53 substitution in the response regulator PmrA/BasR, and the acquisition of the mobile colistin resistance gene mcr-1.1, but we also observed novel variants of basR with an 18-bp deletion, and a G19E substitution in the sensor histidine kinase BasS. We experimentally confirmed these variants to contribute to reduced colistin susceptibility. In a single patient, we observed that colistin resistance in a single E. coli clone evolved through two unique variants in basRS.We show that prophylactic use of colistin during SDD can select for colistin resistance in species that are not intrinsically colistin-resistant. This highlights the importance of continued surveillance for the emergence of colistin resistance in patients treated with SDD.

ObjectiveTo review and critically appraise published and preprint reports of models that aim to predict either (i) presence of existing COVID-19 infection, (ii) future complications in individuals already diagnosed with COVID-19, or (iii) models to identify individuals at high risk for COVID-19 in the general population.DesignRapid systematic review and critical appraisal of prediction models for diagnosis or prognosis of COVID-19 infection.Data sourcesPubMed, EMBASE via Ovid, Arxiv, medRxiv and bioRxiv until 24thMarch 2020.Study selectionStudies that developed or validated a multivariable COVID-19 related prediction model. Two authors independently screened titles, abstracts and full text.Data extractionData from included studies were extracted independently by at least two authors based on the CHARMS checklist, and risk of bias was assessed using PROBAST. Data were extracted on various domains including the participants, predictors, outcomes, data analysis, and prediction model performance.Results2696 titles were screened. Of these, 27 studies describing 31 prediction models were included for data extraction and critical appraisal. We identified three models to predict hospital admission from pneumonia and other events (as a proxy for covid-19 pneumonia) in the general population; 18 diagnostic models to detect COVID-19 infection in symptomatic individuals (13 of which were machine learning utilising computed tomography (CT) results); and ten prognostic models for predicting mortality risk, progression to a severe state, or length of hospital stay. Only one of these studies used data on COVID-19 cases outside of China. Most reported predictors of presence of COVID-19 in suspected patients included age, body temperature, and signs and symptoms. Most reported predictors of severe prognosis in infected patients included age, sex, features derived from CT, C-reactive protein, lactic dehydrogenase, and lymphocyte count.Estimated C-index estimates for the prediction models ranged from 0.73 to 0.81 in those for the general population (reported for all 3 general population models), from 0.81 to > 0.99 in those for diagnosis (reported for 13 of the 18 diagnostic models), and from 0.85 to 0.98 in those for prognosis (reported for 6 of the 10 prognostic models). All studies were rated at high risk of bias, mostly because of non-representative selection of control patients, exclusion of patients who had not experienced the event of interest by the end of the study, and poor statistical analysis, including high risk of model overfitting. Reporting quality varied substantially between studies. A description of the study population and intended use of the models was absent in almost all reports, and calibration of predictions was rarely assessed.ConclusionCOVID-19 related prediction models are quickly entering the academic literature, to support medical decision making at a time where this is urgently needed. Our review indicates proposed models are poorly reported and at high risk of bias. Thus, their reported performance is likely optimistic and using them to support medical decision making is not advised. We call for immediate sharing of the individual participant data from COVID-19 studies to support collaborative efforts in building more rigorously developed prediction models and validating (evaluating) existing models. The aforementioned predictors identified in multiple included studies could be considered as candidate predictors for new models. We also stress the need to follow methodological guidance when developing and validating prediction models, as unreliable predictions may cause more harm than benefit when used to guide clinical decisions. Finally, studies should adhere to the TRIPOD statement to facilitate validating, appraising, advocating and clinically using the reported models.Systematic review registration protocolosf.io/ehc47/,registration: osf.io/wy245Summary boxesWhat is already known on this topic-The sharp recent increase in COVID-19 infections has put a strain on healthcare systems worldwide, necessitating efficient early detection, diagnosis of patients suspected of the infection and prognostication of COVID-19 confirmed cases.-Viral nucleic acid testing and chest CT are standard methods for diagnosing COVID-19, but are time-consuming.-Earlier reports suggest that the elderly, patients with comorbidity (COPD, cardiovascular disease, hypertension), and patients presenting with dyspnoea are vulnerable to more severe morbidity and mortality after COVID-19 infection.What this study adds-We identified three models to predict hospital admission from pneumonia and other events (as a proxy for COVID-19 pneumonia) in the general population.-We identified 18 diagnostic models for COVID-19 detection in symptomatic patients.-13 of these were machine learning models based on CT images.-We identified ten prognostic models for COVID-19 infected patients, of which six aimed to predict mortality risk in confirmed or suspected COVID-19 patients, two aimed to predict progression to a severe or critical state, and two aimed to predict a hospital stay of more than 10 days from admission.-Included studies were poorly reported compromising their subsequent appraisal, and recommendation for use in daily practice. All studies were appraised at high risk of bias, raising concern that the models may be flawed and perform poorly when applied in practice, such that their predictions may be unreliable.

BackgroundKnowledge on the molecular epidemiology of Escherichia coli causing E. coli bacteremia (ECB) in the Netherlands is mostly based on extended-spectrum beta-lactamase-producing E. coli (ESBL-Ec). We determined differences in clonality and resistance and virulence gene (VG) content between non-ESBL-producing E. coli (non-ESBL-Ec) and ESBL-Ec blood isolates with different epidemiological characteristics.Materials/methodsA random selection of non-ESBL-Ec isolates as well as all available ESBL-Ec blood isolates was obtained from two Dutch hospitals between 2014 and 2016. Whole genome sequencing was performed to infer sequence types (STs), serotypes, acquired antibiotic resistance genes and VG scores, based on presence of 49 predefined putative pathogenic VG.ResultsST73 was most prevalent among the 212 non-ESBL-Ec (N=26, 12.3%) and ST131 among the 69 ESBL-Ec (N=30, 43.5%). Prevalence of ST131 among non-ESBL-Ec was 10.4% (N=22, P value < 0.001 compared to ESBL-Ec). O25:H4 was the most common serotype in both non-ESBL-Ec and ESBL-Ec. Median acquired resistance gene counts were 1 (IQR 1 – 6) and 7 (IQR 4 – 9) for non-ESBL-Ec and ESBL-Ec, respectively (P value < 0.001). Among non-ESBL-Ec, acquired resistance gene count was highest among blood isolates from a primary gastro-intestinal focus (median 4, IQR 1 – 8). Median VG scores were 13 (IQR 9 – 20) and 12 (IQR 8 – 14) for non-ESBL-Ec and ESBL-Ec, respectively (P value = 0.002). VG scores among non-ESBL-Ec from a primary urinary focus (median 15, IQR 11 – 21) were higher compared to non-ESBL-Ec from a primary gastro-intestinal (median 10, IQR 6 – 13) or hepatic-biliary focus (median 11, IQR 5 – 18) (P values = 0.007 and 0.036, respectively). VG content varied between different E. coli STs.ConclusionsNon-ESBL-Ec and ESBL-Ec blood isolates from two Dutch hospitals differed in clonal distribution, resistance gene and VG content. Also, resistance gene and VG content differed between non-ESBL-Ec from different primary foci of ECB.

The human body produces a vast variety of circulating immunoglobulins (Igs) to recognize and combat pathogens and other non-self molecular components. In human plasma the most abundant class of Igs is the immunoglobulin G subclass I (IgG1) 1. Through somatic recombination and hypermutation, our bodies can theoretically produce several billions of distinct IgG1 variants 2,3. The theoretically available IgG1 repertoire thereby far exceeds the physical number of memory B cells available 4. The theoretical possibilities are highly suggestive of a vastly complex IgG1 plasma repertoire, but here we show that in all studied individuals, this repertoire is dominated by only a few dozens of clones. Our data indicate that each person’s IgG1 repertoire is distinctly unique, representing a personalized barcode. We sequentially measured IgG1 repertoires of critically ill individuals with hospital-acquired sepsis, revealing the occurrence and disappearance of specific IgG1 clones during the evolution of the disease. We demonstrate here that 1) personalized IgG1 profiling by LC-MS is feasible, 2) each person exhibits a unique serological IgG1 repertoire, 3) this repertoire adapts to changes in physiology, and 4) that individual plasma IgG clones can be de novo sequenced by integrative protein-centric and peptide-centric proteomic approaches. We foresee that the presented mass spectrometric approach will accommodate more rapid development of monoclonal antibody treatments, immediately assessing fully human, matured, and optimized molecules. The potential of repertoires from disease survivors can then be used to prevent disease excesses, as was demonstrated for Ebola 5-7, and is the hope for the current COVID-19 pandemic.

BackgroundObservational studies have demonstrated that de-escalation of antimicrobial therapy is independently associated with lower mortality. This most probably results from confounding by indication. Reaching clinical stability is associated with the decision to de-escalate and with survival. However, studies rarely adjust for this confounder. We quantified the potential confounding effect of clinical stability on the estimated impact of de-escalation on mortality in patients with community-acquired pneumonia.MethodsData were used from the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA). The primary outcome was 30-day mortality. We performed Cox proportional-hazards regression with de-escalation as time-dependent variable and adjusted for baseline characteristics using propensity scores. The potential impact of unmeasured confounding was quantified through simulating a variable representing clinical stability on day three, using data on prevalence and associations with mortality from the literature.ResultsOf 1,536 included patients, 257 (16.7%) were de-escalated, 123 (8.0%) were escalated and in 1156 (75.3%) the antibiotic spectrum remained unchanged. The adjusted hazard ratio of de-escalation for 30-day mortality (compared to patients with unchanged coverage), without adjustment for clinical stability, was 0.36 (95%CI: 0.18-0.73). If 90% to 100% of de-escalated patients were clinically stable on day three, the fully adjusted hazard ratio would be 0.53 (95%CI: 0.26-1.08) to 0.90 (95%CI: 0.42-1.91), respectively. The simulated confounder was substantially stronger than any of the baseline confounders in our dataset.ConclusionsWith plausible, literature-based assumptions, clinical stability is a very strong confounder for the effects of de-escalation. Quantification of effects of de-escalation on patient outcomes without proper adjustment for clinical stability results in strong negative bias. As a result, the safety of de-escalation remains to be determined.

Rationale: Myocardial injury, as reflected by elevated cardiac troponin levels in plasma, is common in patients with community-acquired pneumonia (CAP), but its temporal dynamics and etiology remain unknown. Objectives: Our aim was to determine the incidence of troponin release in patients with CAP and identify risk factors that may point to underlying etiologic mechanisms. Methods: We included consecutive patients admitted with severe CAP to two intensive care units in the Netherlands between 2011 and 2015. High-sensitivity cardiac troponin I was measured daily during the first week. We used multivariable linear regression to identify variables associated with troponin release on admission, and we used mixed-effects regression to model the daily rise and fall of troponin levels over time. Results: Of 200 eligible patients, 179 were included, yielding 792 observation days. A total of 152 (85%) patients developed raised troponin levels greater than 26 ng/L. Baseline factors independently associated with troponin release included coronary artery disease (176% increase; 95% confidence interval [CI], 11–589), smoking (248% increase; 95% CI, 33–809), and higher Acute Physiology and Chronic Health Evaluation IV score (2% increase; 95% CI, 0.8–3.3), whereas Staphylococcus aureus as a causative pathogen was protective (70% reduction; 95% CI, 18–89). Time-dependent risk factors independently associated with daily increase in troponin concentrations included reduced platelet count (2.3% increase; 95% CI, 0.6–4), tachycardia (1.5% increase; 95% CI, 0.1–2.9), hypotension (6.2% increase; 95% CI, 2.1–10.6), dobutamine use (44% increase; 95% CI, 12–85), prothrombin time (8.2% increase; 95% CI, 0.2–16.9), white cell count (1.7% increase; 95% CI, 0–3.5), and fever (22.7% increase; 95% CI, 0.1–49.6). Conclusions: Cardiac injury develops in a majority of patients with severe CAP. Myocardial oxygen supply–demand mismatch and activated inflammation/coagulation are associated with this injury.

Background: The R-GNOSIS (Resistance in Gram-Negative Organisms: Studying Intervention Strategies) WP3 study was the first multicenter randomized clinical trial systematically investigating fecal microbiota transplantation (FMT) for intestinal decolonization of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) or carbapenemase-producing Enterobacteriaceae (CPE). Here, we characterized the temporal dynamics of fecal microbiota changes in a sub-cohort of the R-GNOSIS WP3 participants before and after antibiotics/FMT using whole metagenome shotgun sequencing. Methods: We sequenced fecal DNA obtained from 16 ESBL-E/CPE carriers having received oral colistin/neomycin followed by FMT and their corresponding seven donors. Ten treatment-na&iuml, ve controls from the same trial were included. Fecal samples were collected at baseline (V0), after antibiotics but before FMT (V2) and three times after FMT (V3, V4 and V5). Results: Antibiotic treatment transiently decreased species richness and diversity and increased the abundance of antibiotic resistance determinants (ARDs). Bifidobacterium species, together with butyrate- and propionate-producing species from Lachnospiraceae and Ruminococcaceae families were significantly enriched in post-FMT microbiota of treated carriers. After FMT, the proportion of Enterobacteriaceae was lower compared to baseline but without statistical significance. Conclusions: Combined antibiotic and FMT treatment resulted in enrichment of species that are likely to limit the gut colonization by ESBL-E/CPE.

Background The gut microbiota is a reservoir of opportunistic pathogens that can cause life-threatening infections in critically ill patients during their stay in an intensive care unit (ICU). To suppress gut colonization with opportunistic pathogens, a prophylactic antibiotic regimen, termed “selective decontamination of the digestive tract” (SDD), is used in some countries where it improves clinical outcome in ICU patients. Yet, the impact of ICU hospitalization and SDD on the gut microbiota remains largely unknown. Here, we characterize the composition of the gut microbiota and its antimicrobial resistance genes (“the resistome”) of ICU patients during SDD and of healthy subjects. Results From ten patients that were acutely admitted to the ICU, 30 fecal samples were collected during ICU stay. Additionally, feces were collected from five of these patients after transfer to a medium-care ward and cessation of SDD. Feces from ten healthy subjects were collected twice, with a 1-year interval. Gut microbiota and resistome composition were determined using 16S rRNA gene phylogenetic profiling and nanolitre-scale quantitative PCRs. The microbiota of the ICU patients differed from the microbiota of healthy subjects and was characterized by lower microbial diversity, decreased levels of Escherichia coli and of anaerobic Gram-positive, butyrate-producing bacteria of the Clostridium clusters IV and XIVa, and an increased abundance of Bacteroidetes and enterococci. Four resistance genes (aac(6′)-Ii, ermC, qacA, tetQ), providing resistance to aminoglycosides, macrolides, disinfectants, and tetracyclines, respectively, were significantly more abundant among ICU patients than in healthy subjects, while a chloramphenicol resistance gene (catA) and a tetracycline resistance gene (tetW) were more abundant in healthy subjects. Conclusions The gut microbiota of SDD-treated ICU patients deviated strongly from the gut microbiota of healthy subjects. The negative effects on the resistome were limited to selection for four resistance genes. While it was not possible to disentangle the effects of SDD from confounding variables in the patient cohort, our data suggest that the risks associated with ICU hospitalization and SDD on selection for antibiotic resistance are limited. However, we found evidence indicating that recolonization of the gut by antibiotic-resistant bacteria may occur upon ICU discharge and cessation of SDD. Electronic supplementary material The online version of this article (doi:10.1186/s40168-017-0309-z) contains supplementary material, which is available to authorized users.

BackgroundMyocardial injury, as reflected by elevated cardiac troponin levels in plasma, is common in patients with community-acquired pneumonia (CAP), but its temporal dynamics and etiology remain unknown. Our aim was to determine the incidence of troponin release in patients with CAP and identify risk factors which may point to underlying etiologic mechanisms.MethodsWe included consecutive patients admitted with severe CAP to two intensive care units in the Netherlands between 2011 and 2015. High-sensitivity cardiac troponin I was measured daily during the first week. We used multivariable linear regression to identify variables associated with troponin release on admission, and mixed-effects regression to model the daily rise and fall of troponin levels over time.ResultsAmong 200 eligible patients, 179 were included, yielding 792 observation days. A total of 152 (85%) patients developed raised troponin levels >26 ng/L. Baseline factors independently associated with troponin release included coronary artery disease (160% increase, 95% CI 7–529), smoking (304% increase, 95% CI 59-924), and higher APACHE IV score (2% increase, 95% CI 0.7-3.3), whereasStaphylococcus aureusas a causative pathogen was protective (67% reduction, 95% CI 9-88). Time-dependent risk factors independently associated with daily increase in troponin concentrations included reduced platelet count (1.7% increase, 95% CI 0.1-3.4), tachycardia (1.6% increase, 95% CI 0.3-3), hypotension (5.1% increase, 95% CI 1-9.4) and dobutamine use (38.4% increase 95% CI 8.8-76).ConclusionsCardiac injury develops in a majority of patients with severe CAP. Myocardial oxygen supply-demand mismatch and activated coagulation are potential causes of this injury.

Background: Sepsis is frequently complicated by the release of cardiac troponin, but the clinical significance of this myocardial injury remains unclear. We studied the associations between troponin release during sepsis and 1-year outcomes. Methods and Results: We enrolled consecutive patients with sepsis in 2 Dutch intensive care units between 2011 and 2013. Subjects with a clinically apparent cause of troponin release were excluded. High-sensitivity cardiac troponin I (hs-cTnI) concentration in plasma was measured daily during the first 4 intensive care unit days, and multivariable Cox regression analysis was used to model its association with 1-year mortality while adjusting for confounding. In addition, we studied cardiovascular morbidity occurring during the first year after hospital discharge. Among 1258 patients presenting with sepsis, 1124 (89%) were eligible for study inclusion. Hs-cTnI concentrations were elevated in 673 (60%) subjects on day 1, and 755 (67%) ever had elevated levels in the first 4 days. Cox regression analysis revealed that high hs-cTnI concentrations were associated with increased death rates during the first 14 days (adjusted hazard ratio, 1.72; 95% confidence interval, 1.14–2.59 and hazard ratio, 1.70; 95% confidence interval, 1.10–2.62 for hs-cTnI concentrations of 100–500 and >500 ng/L, respectively) but not thereafter. Furthermore, elevated hs-cTnI levels were associated with the development of cardiovascular disease among 200 hospital survivors who were analyzed for this end point (adjusted subdistribution hazard ratio, 1.25; 95% confidence interval, 1.04–1.50). Conclusions: Myocardial injury occurs in the majority of patients with sepsis and is independently associated with early—but not late—mortality, as well as postdischarge cardiovascular morbidity.

Background The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) assessed vaccine-type community-acquired pneumonia (VT-CAP) and vaccine-type invasive pneumococcal disease (VT-IPD) prevention with 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ⩾65 years. We report vaccine efficacy (VE) of PCV13 for the remaining 23 exploratory endpoints and serotype distributions for pneumococcal CAP and IPD. Methods This was a parallel-group, randomised, placebo-controlled, double-blind trial comparing single-dose PCV13 with placebo. Exploratory CAP endpoints included first episode of confirmed non-VT (NVT) pneumococcal CAP; all confirmed episodes of NVT pneumococcal CAP, pneumococcal CAP, nonbacteraemic/noninvasive (NB/NI) VT pneumococcal CAP, and NB/NI pneumococcal CAP; and first and all episodes of culture-confirmed VT pneumococcal CAP, culture-confirmed pneumococcal CAP, culture-confirmed NVT pneumococcal CAP, probable VT pneumococcal CAP, probable NVT pneumococcal CAP, and probable and possible pneumococcal CAP. Exploratory IPD endpoints included all episodes of VT-IPD and IPD, and first and all episodes of NVT-IPD. The per-protocol and modified intent-to-treat (mITT) populations were evaluated. Results In total, 84,496 participants were enrolled. Eight of 23 exploratory CAP and IPD endpoints were statistically significant in both populations. In the per-protocol population, these included VE of 29% for all episodes of confirmed pneumococcal CAP, 43% for all NB/NI episodes of VT pneumococcal CAP, 52% for all episodes of culture-confirmed pneumococcal CAP, and 53% for all episodes of IPD. Comparable VE estimates were observed in the mITT population. The most common VT serotypes were 1 (10 first episodes of confirmed pneumococcal CAP; 2 first episodes of IPD) and 7F (22; 7) among PCV13 and placebo recipients, respectively. Conclusions The results of this analysis yielded statistically significant PCV13 VE for all episodes of confirmed pneumococcal CAP (including NB/NI and culture-confirmed episodes) and for all episodes of IPD in adults aged ⩾65 years. These findings are consistent with the primary efficacy analysis. ClinicalTrials.gov identifier: NCT00744263 .

BackgroundCritically ill patients hospitalized in an Intensive Care Unit (ICU) are at increased risk of acquiring potentially life-threatening infections with opportunistic pathogens. The gut microbiota of ICU patients forms an important reservoir for these infectious agents. To suppress gut colonization with opportunistic pathogens, a prophylactic antibiotic regimen, termed ‘Selective decontamination of the digestive tract’ (SDD), may be used. SDD has previously been shown to improve clinical outcome in ICU patients, but the impact of ICU hospitalization and SDD on the gut microbiota remains largely unknown. Here, we characterize the composition of the gut microbiota and its antimicrobial resistance genes (‘the resistome’) of ICU patients during SDD.ResultsDuring ICU-stay, 30 fecal samples of ten patients were collected. Additionally, feces were collected from five of these patients after transfer to a medium-care ward and cessation of SDD. As a control group, feces from ten healthy subjects were collected twice, with a one-year interval. Gut microbiota and resistome composition were determined using 16S rRNA phylogenetic profiling and nanolitre-scale quantitative PCRs.The microbiota of the ICU patients differed from the microbiota of healthy subjects and was characterized by low microbial diversity, decreased levels of E. coli and of anaerobic Gram-positive, butyrate-producing bacteria of the Clostridium clusters IV and XIVa, and an increased abundance of Bacteroidetes and enterococci. Four resistance genes (aac(6′)-Ii, ermC, qacA, tetQ), providing resistance to aminoglycosides, macrolides, disinfectants and tetracyclines respectively, were significantly more abundant among ICU patients than in healthy subjects, while a chloramphenicol resistance gene (catA) and a tetracycline resistance gene (tetW) were more abundant in healthy subjects.ConclusionsThe microbiota and resistome of ICU patients and healthy subjects were noticeably different, but importantly, levels of E. coli remained low during ICU hospitalization, presumably due to SDD therapy. Selection for four antibiotic resistance genes was observed, but none of these are of particular concern as they do not contribute to clinically relevant resistance. Our data support the ecological safety of SDD, at least in settings with low levels of circulating antibiotic resistance.

Background The Community Acquired Pneumonia immunization Trial in Adults (CAPiTA) was conducted to evaluate 13-valent pneumococcal conjugate vaccine (PCV13) for the prevention of vaccine-type community-acquired pneumonia (VT-CAP) and vaccine-type invasive pneumococcal disease (VT-IPD) in adults aged ⩾65 years. Plotting the cumulative number of episodes against time from vaccination demonstrated that efficacy was evident soon after vaccination and persisted throughout the duration of the study. This post hoc analysis was performed to quantify the persistence of vaccine efficacy (VE) of PCV13. Methods This was a parallel-group, randomized, placebo-controlled, double-blind trial. Subjects were enrolled between September 15, 2008 and January 30, 2010 at 101 sites in the Netherlands and randomized 1:1 to receive a single dose of PCV13 or placebo. The observed accumulation of episodes for VT-CAP, nonbacteremic/noninvasive VT-CAP (NB/NI-VT-CAP), and VT-IPD over the course of the study after vaccination was assessed. Post hoc time-to-event analyses of primary and secondary endpoints were performed. VE behavior over time was derived and effects of treatment, time, and time by treatment interactions were estimated. Results A total of 84,496 individuals were enrolled (PCV13, n = 42,240; placebo, n = 42,256). Cases of VT-CAP, NB/NI-VT-CAP, and VT-IPD were greater among placebo recipients compared with PCV13 recipients throughout the postvaccination observation period with a periodic rise in cases in the placebo group that was consistent with varied exposure and ensuing disease over time. There was a significant difference in disease-free survival among PCV13 recipients compared with placebo recipients for VT-CAP (log-rank test P = 0.0005), NB/NI VT-CAP ( P = 0.0051), and VT-IPD ( P = 0.0004). VE ranged from 42.9% to 50.0% for VT-CAP, 36.2% to 48.5% for NB/NI-VT-CAP, and 66.7% to 75.0% for VT-IPD. Conclusions The results of this post hoc analysis of the persistence of PCV13 VE in adults ⩾65 years, indicate that PCV13 was protective over the 5-year duration of the study, with no waning of efficacy observed. ClinicalTrials.gov identifier NCT00744263

A systematic review was performed to determine the effectiveness of different approaches for eradicating methicillin-resistant Staphylococcus aureus carriage. Twenty-three clinical trials were selected that evaluated oral antibiotics (7 trials), topically applied antibiotics (12 trials), or both (4 trials). Because of clinical heterogeneity, quantitative analysis of all studies was deemed to be inappropriate, and exploratory subgroup analyses were performed for studies with similar study populations, methods, and targeted bacteria. The estimated pooled relative risk of treatment failure 1 week after short-term nasal mupirocin treatment, compared with placebo, was 0.10 (range, 0.07–0.14). There was low heterogeneity between study outcomes, and effects were similar for patients and healthy subjects, as well as in studies that included only methicillin-susceptible S. aureus carriers or both methicillin-susceptible S. aureus and methicillin-resistant S. aureus carriers. The development of drug resistance during treatment was reported in 1% and 9% of patients receiving mupirocin and oral antibiotics, respectively. Short-term nasal application of mupirocin is the most effective treatment for eradicating methicillin-resistant S. aureus carriage, with an estimated success of rate of 90% 1 week after treatment and ∼60% after a longer follow-up period. Colonization is an important step in the pathogenesis of Staphylococcus aureus infection and is instrumental in the nosocomial epidemiology of these bacteria. Approximately 20% of the general population is persistently colonized with S. aureus, most frequently in the anterior nares, although other body sites, such as the perineum and throat, may also be colonized. Another 30% of the general population is intermittently colonized, and the remaining 50% appear not to be susceptible, for unknown reasons, to S. aureus carriage [1]. Methicillin-resistant S. aureus (MRSA) has become endemic in health care institutions worldwide, with up to 70% of invasive S. aureus infections having resistance [2–5], and most patients who develop drug-resistant S. aureus infection will have been colonized prior to infection. The half-life of MRSA carriage has been reported to be as long as 40 months in individuals who do not receive treatment [6].

Background The 13-valent pneumococcal conjugate-vaccine (PCV13) was effective in preventing vaccine-type Community-Acquired Pneumonia (VT-CAP) and Invasive Pneumococcal Disease (VT-IPD) in elderly subjects, but vaccine efficacy (VE) in patients with comorbidities at time of vaccination is unknown. Methods This is a post hoc analysis of the CAPiTA study, a double blind, randomized controlled trial with 84,496 immunocompetent participants aged ⩾65 years, receiving PCV13 or placebo vaccination. Presence of diabetes mellitus (DM), heart disease, respiratory disease, liver disease, asplenia, and smoking at the time of immunization was verified on medical records in 139 subjects developing the primary endpoint of VT-CAP. Presence of DM and respiratory disease based on International Classification of Primary Care (ICPC) coding was also determined in 40,427 subjects. Findings In the 139 subjects developing VT-CAP, DM caused significant effect modification (p-value 0.002), yielding VE of 89.5% (95%CI, 65.5–96.8) and 24.7% (95%CI, −10.4 to 48.7) for those with and without DM, respectively. Comparable effect modification (p-value 0.020) was found in the 40,427 subjects with and without ICPC-based classification of DM with VE of 85.6% (95%CI, 36.7–96.7) and of 7.0% (95%CI, −58.5 to 45.5) respectively. Effect modification through respiratory disease was not statistically significant, although the point estimate of VE was lower for those with respiratory disease in both analyses. There was no evidence of effect modification in subjects stratified by heart disease, smoking, and presence of any comorbidity. Conclusions Among immunocompetent elderly, VE of PCV13 was modified by DM with higher VE among subjects with DM. Significant effect modification was not observed for subjects with heart disease, respiratory disease, smoking, or presence of any comorbidity. CAPiTA trial registration number: www.ClinicalTrials.gov ; trial number NCT00744263 .

Competing events are common in medical research. Ignoring them in the statistical analysis can easily lead to flawed results and conclusions. This article uses a real dataset and a simple simulation to show how standard analysis fails and how such data should be analysed

Objective Automated surveillance of healthcare-associated infections can improve efficiency and reliability of surveillance. The aim was to validate and update a previously developed multivariable prediction model for the detection of drain-related meningitis (DRM). Design Retrospective cohort study using traditional surveillance by infection control professionals as reference standard. Patients Patients receiving an external cerebrospinal fluid drain, either ventricular (EVD) or lumbar (ELD) in a tertiary medical care center. Children, patients with simultaneous drains

Year in review in Intensive Care Medicine 2010 : III. ARDS and ALI, mechanical ventilation, noninvasive ventilation, weaning, endotracheal intubation, lung ultrasound and paediatrics