Historic methicillin-resistant Staphylococcus aureus: expanding current knowledge using molecular epidemiological characterization of a Swiss legacy collection.

BACKGROUND: Few methicillin-resistant Staphylococcus aureus (MRSA) from the early years of its global emergence have been sequenced. Knowledge about evolutionary factors promoting the success of specific MRSA multi-locus sequence types (MLSTs) remains scarce. We aimed to characterize a legacy MRSA collection isolated from 1965 to 1987 and compare it against publicly available international and local genomes. METHODS: We accessed 451 historic (1965-1987) MRSA isolates stored in the Culture Collection of Switzerland, mostly collected from the Zurich region. We determined phenotypic antimicrobial resistance (AMR) and performed whole genome sequencing (WGS) using Illumina short-read sequencing on all isolates and long-read sequencing on a selection with Oxford Nanopore Technology. For context, we included 103 publicly available international assemblies from 1960 to 1992 and sequenced 1207 modern Swiss MRSA isolates from 2007 to 2022. We analyzed the core genome (cg)MLST and predicted SCCmec cassette types, AMR, and virulence genes. RESULTS: Among the 451 historic Swiss MRSA isolates, we found 17 sequence types (STs) of which 11 have been previously described. Two STs were novel combinations of known loci and six isolates carried previously unsubmitted MLST alleles, representing five new STs (ST7843, ST7844, ST7837, ST7839, and ST7842). Most isolates (83% 376/451) represented ST247-MRSA-I isolated in the 1960s, followed by ST7844 (6% 25/451), a novel single locus variant (SLV) of ST239. Analysis by cgMLST indicated that isolates belonging to ST7844-MRSA-III cluster within the diversity of ST239-MRSA-III. Early MRSA were predominantly from clonal complex (CC)8. From 1980 to the end of the twentieth century, we observed that CC22 and CC5 as well as CC8 were present, both locally and internationally. CONCLUSIONS: The combined analysis of 1761 historic and contemporary MRSA isolates across more than 50 years uncovered novel STs and allowed us a glimpse into the lineage flux between Swiss-German and international MRSA across time.

Factors associated with non-carbapenemase mediated carbapenem resistance of Gram-negative bacteria: a retrospective case-control study.

Infections with carbapenemase-producing Gram-negative bacteria are related to increased morbidity and mortality, yet little is known regarding infections caused by non-beta-lactamase mediated carbapenem-resistant bacteria. Our objective was to identify risk factors for, and the clinical impact of infections caused by carbapenem-resistant carbapenemase-negative Enterobacterales and Pseudomonas aeruginosa. This retrospective matched case-control study was performed at the University Hospital of Basel, Switzerland, in 2016. We focused on other resistance mechanisms by excluding laboratory-confirmed carbapenemase-positive cases. Carbapenem resistance was set as the primary endpoint, and important risk factors were investigated by conditional logistic regression. The clinical impact of carbapenem resistance was estimated using regression models containing the resistance indicator as explanatory factor and adjusting for potential confounders. Seventy-five cases of infections with carbapenem-resistant, carbapenemase-negative bacteria were identified and matched with 75 controls with carbapenem-susceptible infections. The matched data set was well-balanced regarding age, gender, and comorbidity. Duration of prior carbapenem treatment (OR 1.15, [1.01, 1.31]) correlated with resistance to carbapenems. Our study showed that patients with carbapenem-resistant bacteria stayed 1.59 times (CI [0.81, 3.14]) longer in an ICU. The analyzed dataset did not provide evidence for strong clinical implications of resistance to carbapenems or increased mortality. The duration of prior carbapenem treatment seems to be a strong risk factor for the development of carbapenem resistance. The higher risk for a longer ICU stay could be a consequence of a carbapenem resistance. In contrast to carbapenemase-producers, the clinical impact of carbapenamase-negative, carbapenem-resistant strains may be limited. Trial registration: The study design was prospectively approved by the local Ethics Commission on 10.08.2017 (EKNZ BASEC 2017-00222).

Evaluation of the clinical relevance of the Biofire© FilmArray pneumonia panel among hospitalized patients.

PURPOSE: Panel PCR tests provide rapid pathogen identification. However, their diagnostic performance is unclear. We assessed the performance of the Biofire© FilmArray pneumonia (PN)-panel against standard culture in broncho-alveolar lavage (BAL) samples. METHODS: Setting: University Hospital Basel (February 2019 to July 2020), including hospitalized patients with a BAL (± pneumonia). We determined sensitivity and specificity of the PN-panel against standard culture. Using univariate logistic regression, we calculated odds ratios (OR) for pneumonia according to PN-panel and culture status, stratifying by chronic pulmonary disease. We calculated ORs for pneumonia for different pathogens to estimate the clinical relevance. RESULTS: We included 840 adult patients, 60% were males, median age was 68 years, 35% had chronic pulmonary disease, 21% had pneumonia, and 36% had recent antibiotic use. In 1078 BAL samples, bacterial pathogens were detected in 36% and 16% with PN-panel and culture, respectively. The overall sensitivity and specificity of the PN-panel was high, whereas the positive predictive value was low. The OR of pneumonia was 1.1 (95% CI 0.7-1.6) for PN-panel-positive only; 2.6 (95% CI 1.3-5.3) for culture-positive only, and 1.6 (95% CI 1.0-2.4) for PN-panel and culture-positive. The detection rate of Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis in the PN-panel was high but not associated with pneumonia. CONCLUSION: While sensitivity and specificity of PN-panel are high compared to culture, pathogen detection did not correlate well with a pneumonia diagnosis. Patients with culture-positive BAL had the highest OR for pneumonia-thus the impact of the PN-panel on clinical management needs further evaluation in randomized controlled trials.

Identification of microorganisms by a rapid PCR panel from positive blood cultures leads to faster optimal antimicrobial therapy - a before-after study.

BACKGROUND: The BioFire® FilmArray® Blood Culture Identification Panel 1 (BF-FA-BCIP) detects microorganisms with high accuracy in positive blood cultures (BC) - a key step in the management of patients with suspected bacteraemia. We aimed to compare the time to optimal antimicrobial therapy (OAT) for the BF-FA-BCIP vs. standard culture-based identification. METHODS: In this retrospective single-centre study with a before-after design, 386 positive BC cases with identification by BF-FA-BCIP were compared to 414 controls with culture-based identification. The primary endpoint was the time from BC sampling to OAT. Secondary endpoints were time to effective therapy, length of stay, (re-)admission to ICU, in-hospital and 30-day mortality. Outcomes were assessed using Cox proportional hazard models and logistic regressions. RESULTS: Baseline characteristics of included adult inpatients were comparable. Main sources of bacteraemia were urinary tract and intra-abdominal infection (19.2% vs. 22.0% and 16.8% vs. 15.7%, for cases and controls, respectively). Median (95%CI) time to OAT was 25.5 (21.0-31.2) hours with BF-FA-BCIP compared to 45.7 (37.7-51.4) hours with culture-based identification. We observed no significant difference for secondary outcomes. CONCLUSIONS: Rapid microorganism identification by BF-FA-BCIP was associated with a median 20-h earlier initiation of OAT in patients with positive BC. No impact on length of stay and mortality was noted. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04156633, registered on November 5, 2019.

Bacterial genome-wide association study substantiates papGII of Escherichia coli as a major risk factor for urosepsis.

BACKGROUND: Urinary tract infections (UTIs) are among the most common bacterial infections worldwide, often caused by uropathogenic Escherichia coli. Multiple bacterial virulence factors or patient characteristics have been linked separately to progressive, more invasive infections. In this study, we aim to identify pathogen- and patient-specific factors that drive the progression to urosepsis by jointly analysing bacterial and host characteristics. METHODS: We analysed 1076 E. coli strains isolated from 825 clinical cases with UTI and/or bacteraemia by whole-genome sequencing (Illumina). Sequence types (STs) were determined via srst2 and capsule loci via fastKaptive. We compared the isolates from urine and blood to confirm clonality. Furthermore, we performed a bacterial genome-wide association study (bGWAS) (pyseer) using bacteraemia as the primary clinical outcome. Clinical data were collected by an electronic patient chart review. We concurrently analysed the association of the most significant bGWAS hit and important patient characteristics with the clinical endpoint bacteraemia using a generalised linear model (GLM). Finally, we designed qPCR primers and probes to detect papGII-positive E. coli strains and prospectively screened E. coli from urine samples (n = 1657) at two healthcare centres. RESULTS: Our patient cohort had a median age of 75.3 years (range: 18.00-103.1) and was predominantly female (574/825, 69.6%). The bacterial phylogroups B2 (60.6%; 500/825) and D (16.6%; 137/825), which are associated with extraintestinal infections, represent the majority of the strains in our collection, many of which encode a polysaccharide capsule (63.4%; 525/825). The most frequently observed STs were ST131 (12.7%; 105/825), ST69 (11.0%; 91/825), and ST73 (10.2%; 84/825). Of interest, in 12.3% (13/106) of cases, the E. coli pairs in urine and blood were only distantly related. In line with previous bGWAS studies, we identified the gene papGII (p-value < 0.001), which encodes the adhesin subunit of the E. coli P-pilus, to be associated with 'bacteraemia' in our bGWAS. In our GLM, correcting for patient characteristics, papGII remained highly significant (odds ratio = 5.27, 95% confidence interval = [3.48, 7.97], p-value < 0.001). An independent cohort of cases which we screened for papGII-carrying E. coli at two healthcare centres further confirmed the increased relative frequency of papGII-positive strains causing invasive infection, compared to papGII-negative strains (p-value = 0.033, chi-squared test). CONCLUSIONS: This study builds on previous work linking papGII with invasive infection by showing that it is a major risk factor for progression from UTI to bacteraemia that has diagnostic potential.

Occurrence of sensitive topics during ward round: an ancillary analysis of the BEDSIDE-OUTSIDE trial.

OBJECTIVE: Discussing sensitive topics (eg, medical uncertainty, social issues, non-adherence) during ward rounds is challenging and may negatively impact patient satisfaction with the healthcare they are receiving. In the previous multicentre randomised BEDSIDE-OUTSIDE trial focusing on communication during ward rounds, we investigated the interplay between sensitive topics and low reported satisfaction with care. DESIGN: Pre-planned secondary analysis of a randomised controlled trial. For this analysis data of the original trial was pooled across intervention groups. SETTING: Three Swiss teaching hospitals. PARTICIPANTS: Adult patients hospitalised for medical care. INTERVENTIONS: We analysed predefined sensitive health topics and specific elements of communication from audiotapes recorded during ward rounds, for both patients dealing with and without sensitive topics. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was overall patient satisfaction with care; measured on a Visual Analogue Scale from 0 to 100. Secondary endpoints included duration of ward rounds and further satisfaction outcomes. RESULTS: Of the 919 included patients, 474 had at least one sensitive topic including medical uncertainty (n=251), psychiatric comorbidities (n=161), tumour diagnosis (n=137) and social issues (n=125). Compared with patients without sensitive topics, patients with sensitive topics reported lower satisfaction with care (mean (SD), 87.7 (±14.6) vs 90.2 (±12.1), adjusted difference -2.5 (95% CI -4.28 to -0.72), p=0.006. Among patients with sensitive topics, risk factors for low satisfaction included several parameters concerning patient-physician interaction such as disagreements during ward rounds (mean (SD), 14/212 (6.6%) vs 41/254 (16.1%), adjusted OR 2.78 (95% CI 1.47 to 5.27), p=0.002). CONCLUSIONS: A large proportion of medical inpatients must deal with sensitive health topics. This is associated with lower satisfaction with care, particularly if the patient perceives the interaction with doctors during ward rounds as unsatisfactory. Educating physicians on specific communication techniques may help improve care for these patients. TRIAL REGISTRATION NUMBER: NCT03210987.

A long-term retrospective observational study at a medium-sized medical oncology service in Switzerland: comparison of overall survival with a national cohort and adherence to treatment guidelines.

AIMS: There is a lack of national and international publicly available long-term survival outcome data from individual healthcare providers in medical oncology. In this study, the overall survival at a medium-sized medical oncology service at Olten Cantonal Hospital was evaluated and compared as a local benchmark report with national data from the Swiss Cancer Registries. Furthermore, adherence to treatment guidelines was investigated as an additional quality indicator. METHODS: The 1- and 5-year overall survival of all patients with breast cancer, testicular cancer, colon cancer, non-small-cell lung cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma in Switzerland from 2008 to 2017 with at least one outpatient visit at the in-house medical oncology service at Olten Cantonal Hospital was analysed and compared with the specific overall population-based outcome data provided by the National Agency for Cancer Registration (NACR), which were set as a national benchmark. Until 2020, no data from the Canton of Solothurn, to which Olten belongs, were reported to the NACR. Further, adherence to internationally recognized clinical guidelines for stage-specific treatment was assessed. RESULTS: Until September 8, 2020, data on 842 patients with a median follow-up period of 70 months were collected and analysed. The 1- and 5-year overall survival for colon and non-small cell cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma and the 5-year overall survival for testicular cancer in the Olten cohort did not significantly differ from the NACR data. The 1-year overall survival for testicular cancer was not comparable statistically. The 5-year overall survival for breast cancer (unadjusted for stage) was significantly higher in the NACR collective (84.5%) than in the Olten collective (79.7%) but not for the individual breast cancer stages. The Olten collective included approximately 2.5 times as many patients with stage 4 breast cancer (17.5%) as the NACR collective (6.9%). Approximately 92.4% of the patients in the curative setting and 85.8% of the patients in the palliative setting received first-line treatment according to guidelines. CONCLUSIONS: The statistically comparable local 1- and 5-year overall survival of the analysed malignancies, with adjustment for stage for the 5-year overall survival for breast cancer, is in line with the national benchmark. Adherence to treatment guidelines is high.

A systematic outbreak investigation of SARS-CoV-2 transmission clusters in a tertiary academic care center.

BACKGROUND: We sought to decipher transmission pathways in healthcare-associated infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within our hospital by epidemiological work-up and complementary whole genome sequencing (WGS). We report the findings of the four largest epidemiologic clusters of SARS-CoV-2 transmission occurring during the second wave of the pandemic from 11/2020 to 12/2020. METHODS: At the University Hospital Basel, Switzerland, systematic outbreak investigation is initiated at detection of any nosocomial case of SARS-CoV-2 infection, as confirmed by polymerase chain reaction, occurring more than five days after admission. Clusters of nosocomial infections, defined as the detection of at least two positive patients and/or healthcare workers (HCWs) within one week with an epidemiological link, were further investigated by WGS on respective strains. RESULTS: The four epidemiologic clusters included 40 patients and 60 HCWs. Sequencing data was available for 70% of all involved cases (28 patients and 42 HCWs), confirmed epidemiologically suspected in house transmission in 33 cases (47.1% of sequenced cases) and excluded transmission in the remaining 37 cases (52.9%). Among cases with identical strains, epidemiologic work-up suggested transmission mainly through a ward-based exposure (24/33, 72.7%), more commonly affecting HCWs (16/24, 66.7%) than patients (8/24, 33.3%), followed by transmission between patients (6/33, 18.2%), and among HCWs and patients (3/33, 9.1%, respectively two HCWs and one patient). CONCLUSIONS: Phylogenetic analyses revealed important insights into transmission pathways supporting less than 50% of epidemiologically suspected SARS-CoV-2 transmissions. The remainder of cases most likely reflect community-acquired infection randomly detected by outbreak investigation. Notably, most transmissions occurred between HCWs, possibly indicating lower perception of the risk of infection during contacts among HCWs.

Free-living core body temperature monitoring using a wrist-worn sensor after COVID-19 booster vaccination: a pilot study.

Core body temperature (CBT) is a key vital sign and fever is an important indicator of disease. In the past decade, there has been growing interest for vital sign monitoring technology that may be embedded in wearable devices, and the COVID-19 pandemic has highlighted the need for remote patient monitoring systems. While wrist-worn sensors allow continuous assessment of heart rate and oxygen saturation, reliable measurement of CBT at the wrist remains challenging. In this study, CBT was measured continuously in a free-living setting using a novel technology worn at the wrist and compared to reference core body temperature measurements, i.e., CBT values acquired with an ingestible temperature-sensing pill. Fifty individuals who received the COVID-19 booster vaccination were included. The datasets of 33 individuals were used to develop the CBT prediction algorithm, and the algorithm was then validated on the datasets of 17 participants. Mean observation time was 26.4 h and CBT > 38.0 °C occurred in 66% of the participants. CBT predicted by the wrist-worn sensor showed good correlation to the reference CBT (r = 0.72). Bland-Altman statistics showed an average bias of 0.11 °C of CBT predicted by the wrist-worn device compared to reference CBT, and limits of agreement were - 0.67 to + 0.93 °C, which is comparable to the bias and limits of agreement of commonly used tympanic membrane thermometers. The small size of the components needed for this technology would allow its integration into a variety of wearable monitoring systems assessing other vital signs and at the same time allowing maximal freedom of movement to the user.

Factors impacting the pre-analytical quality of blood cultures-Analysis at a tertiary medical center.

BACKGROUND: Blood cultures (BC) are critical for the diagnosis of bloodstream infections, pathogen identification, and resistance testing. Guidelines recommend a blood volume of 8-10 mL per bottle as lower volumes result in decreased sensitivity. We aimed to evaluate factors for non-adherence to recommended volumes and assess the effects on diagnostic performance. METHODS: From February to April 2020, we measured collected blood volumes by weighing all BC containers from inpatient samples at the University Hospital Basel. Information on BC volumes was merged with clinical and microbiological data, as well as nursing staff schedules. We analyzed factors associated with (i) BC sampling volume, (ii) reaching recommended volumes (≥8 mL), (iii) BC positivity, and (iv) time to positivity using linear and generalized linear mixed effect models. RESULTS: We evaluated a total of 4'118 BC bottles collected from 686 patients. A total of 1'495 (36.3%) of all bottles contained the recommended filling volume of ≥8 mL. Using a central venous and arterial catheter for drawing blood resulted in an increase of filling volume by 0.26 mL (95% CI 0.10, 0.41) and 0.50 mL (95% CI 0.31, 0.69) compared to peripheral venipuncture, respectively. Each additional nursing staff working at the time of blood drawing was associated with 6% higher odds of achieving the recommended filling volume. We found no significant correlation between the filling volume and the positivity rate. CONCLUSION: Our results indicate critical pre-analytical quality markers linked to BC collection procedures to reach recommended collection volumes. No significant impact on the positivity rate was found.

PorinPredict: In Silico Identification of OprD Loss from WGS Data for Improved Genotype-Phenotype Predictions of P. aeruginosa Carbapenem Resistance.

The increasing integration of genomics into routine clinical diagnostics requires reliable computational tools to identify determinants of antimicrobial resistance (AMR) from whole-genome sequencing data. Here, we developed PorinPredict, a bioinformatic tool that predicts defects of the Pseudomonas aeruginosa outer membrane porin OprD, which are strongly associated with reduced carbapenem susceptibility. PorinPredict relies on a database of intact OprD variants and reports inactivating mutations in the coding or promoter region. PorinPredict was validated against 987 carbapenemase-negative P. aeruginosa genomes, of which OprD loss was predicted for 454 out of 522 (87.0%) meropenem-nonsusceptible and 46 out of 465 (9.9%) meropenem-susceptible isolates. OprD loss was also found to be common among carbapenemase-producing isolates, resulting in even further increased MICs. Chromosomal mutations in quinolone resistance-determining regions and OprD loss commonly co-occurred, likely reflecting the restricted use of carbapenems for multidrug-resistant infections as recommended in antimicrobial stewardship programs. In combination with available AMR gene detection tools, PorinPredict provides a robust and standardized approach to link P. aeruginosa phenotypes to genotypes. IMPORTANCE Pseudomonas aeruginosa is a major cause of multidrug-resistant nosocomial infections. The emergence and spread of clones exhibiting resistance to carbapenems, a class of critical last-line antibiotics, is therefore closely monitored. Carbapenem resistance is frequently mediated by chromosomal mutations that lead to a defective outer membrane porin OprD. Here, we determined the genetic diversity of OprD variants across the P. aeruginosa population and developed PorinPredict, a bioinformatic tool that enables the prediction of OprD loss from whole-genome sequencing data. We show a high correlation between predicted OprD loss and meropenem nonsusceptibility irrespective of the presence of carbapenemases, which are a second widespread determinant of carbapenem resistance. Isolates with resistance determinants to other antibiotics were disproportionally affected by OprD loss, possibly due to an increased exposure to carbapenems. Integration of PorinPredict into genomic surveillance platforms will facilitate a better understanding of the clinical impact of OprD modifications and transmission dynamics of resistant clones.

Patients' Preference for Participation in Medical Decision-Making: Secondary Analysis of the BEDSIDE-OUTSIDE Trial.

BACKGROUND: Patients may prefer different levels of involvement in decision-making regarding their medical care which may influence their medical knowledge. OBJECTIVE: We investigated associations of patients' decisional control preference (DCP) with their medical knowledge, ward round performance measures (e.g., duration, occurrence of sensitive topics), and perceived quality of care measures (e.g., trust in the healthcare team, satisfaction with hospital stay). DESIGN: This is a secondary analysis of a randomized controlled multicenter trial conducted between 2017 and 2019 at 3 Swiss teaching hospitals. PARTICIPANTS: Adult patients that were hospitalized for inpatient care. MAIN MEASURES: The primary outcome was patients' subjective average knowledge of their medical care (rated on a visual analog scale from 0 to 100). We classified patients as active, collaborative, and passive according to the Control Preference Scale. Data collection was performed before, during, and after the ward round. KEY RESULTS: Among the 761 included patients, those with a passive DCP had a similar subjective average (mean ± SD) knowledge (81.3 ± 19.4 points) compared to patients with a collaborative DCP (78.7 ± 20.3 points) and active DCP (81.3 ± 21.5 points), p = 0.25. Regarding patients' trust in physicians and nurses, we found that patients with an active vs. passive DCP reported significantly less trust in physicians (adjusted difference, - 5.08 [95% CI, - 8.69 to - 1.48 points], p = 0.006) and in nurses (adjusted difference, - 3.41 [95% CI, - 6.51 to - 0.31 points], p = 0.031). Also, patients with an active vs. passive DCP were significantly less satisfied with their hospital stay (adjusted difference, - 7.17 [95% CI, - 11.01 to - 3.34 points], p < 0.001). CONCLUSION: Patients with active DCP have lower trust in the healthcare team and lower overall satisfaction despite similar perceived medical knowledge. The knowledge of a patient's DCP may help to individualize patient-centered care. A personalized approach may improve the patient-physician relationship and increase patients' satisfaction with medical care. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03210987).

[Better Late than Never - Fever of Unknown Origin in a Patient with a Prosthetic Valve]. / Besser spät als nie ­ Fieber unklarer Ursache bei einem Patienten mit Kunstklappe.

Better Late than Never - Fever of Unknown Origin in a Patient with a Prosthetic Valve Abstract. A patient presents with worsening of his general condition, chills and dyspnoea on exertion. With a history of aortic valve replacement, infective endocarditis is suspected, but due to negative imaging by transesophageal echocardiography and negative blood cultures cannot be confirmed. Finally, Cutibacterium acnes prosthetic valve endocarditis is diagnosed after culture of C. acnes during an extended incubation period of blood cultures, the presence of embolic complications and a characteristic finding on PET-CT scan.

Complement and endothelial cell activation in COVID-19 patients compared to controls with suspected SARS-CoV-2 infection: A prospective cohort study.

Background: Thromboinflammation may influence disease outcome in COVID-19. We aimed to evaluate complement and endothelial cell activation in patients with confirmed COVID-19 compared to controls with clinically suspected but excluded SARS-CoV-2 infection. Methods: In a prospective, observational, single-center study, patients presenting with clinically suspected COVID-19 were recruited in the emergency department. Blood samples on presentation were obtained for analysis of C5a, sC5b-9, E-selectin, Galectin-3, ICAM-1 and VCAM-1. Results: 153 cases and 166 controls (suffering mainly from non-SARS-CoV-2 respiratory viral infections, non-infectious inflammatory conditions and bacterial pneumonia) were included. Hospital admission occurred in 62% and 45% of cases and controls, respectively. C5a and VCAM-1 concentrations were significantly elevated and E-selectin concentrations decreased in COVID-19 out- and inpatients compared to the respective controls. However, relative differences in outpatients vs. inpatients in most biomarkers were comparable between cases and controls. Elevated concentrations of C5a, Galectin-3, ICAM-1 and VCAM-1 on presentation were associated with the composite outcome of ICU- admission or 30-day mortality in COVID-19 and controls, yet more pronounced in COVID-19. C5a and sC5b-9 concentrations were significantly higher in COVID-19 males vs. females, which was not observed in the control group. Conclusions: Our data indicate an activation of the complement cascade and endothelium in COVID-19 beyond a nonspecific inflammatory trigger as observed in controls (i.e., "over"-activation).

Community-acquired pneumonia - An EFIM guideline critical appraisal adaptation for internists.

BACKGROUND: In real-life settings, guidelines frequently cannot be followed since many patients are multimorbid and/or elderly or have other complicating conditions which carry an increased risk of drug-drug interactions. This document aimed to adapt recommendations from existing clinical practice guidelines (CPGs) to assist physicians' decision-making processes concerning specific and complex scenarios related to acute CAP. METHODS: The process for the adaptation procedure started with the identification of unsolved clinical questions (PICOs) in patients with CAP and continued with critically appraising the updated existing CPGs and choosing the recommendations, which are most applicable to these specific scenarios. RESULTS: Seventeen CPGs were appraised to address five PICOs. Twenty-seven recommendations were endorsed based on 7 high, 9 moderate, 10 low, and 1 very low-quality evidence. The most valid recommendations applicable to the clinical practice were the following ones: Respiratory virus testing is strongly recommended during periods of increased respiratory virus activity. Assessing the severity with a validated prediction rule to discriminate where to treat the patient is strongly recommended along with reassessing the patient periodically for improvement as expected. In adults with multiple comorbidities, polypharmacy, or advanced age, it is strongly recommended to check for possible drug interactions before starting treatment. Strong graded recommendations exist on antibiotic treatment and its duration. Recommendations on the use of biomarkers such as C-reactive protein or procalcitonin to improve severity assessment are reported. CONCLUSION: This document provides a simple and reliable updated guide for clinical decision-making in the management of complex patients with multimorbidity and CAP in the real-life setting.

Physicians' responsibility toward environmental degradation and climate change: A position paper of the European Federation of Internal Medicine.

The current data on climate change and environmental degradation are dramatic. The consequences of these changes are already having a significant impact on people's health. Physicians - as advocates of the patients, but also as citizens - have an ethical obligation to be involved in efforts to stop these changes. The European Federation of Internal Medicine (EFIM) strongly encourages the Internal Medicine societies and internists across Europe to play an active role in matters related to climate change and environmental degradation. At a national level, this includes advocating the adoption of measures that reduce greenhouse gas (GHG) emissions and environmental degradation and contributing to policy decisions related to these issues. At a hospital level and in clinical practice, supporting actions by the health sector to reduce its ecological footprint is vital. At the level of EFIM and its associated internal societies, promoting educational activities and developing a toolkit to prepare internists to better care for citizens who suffer from the consequences of climate change. In addition to advocating and implementing effective actions to reduce the ecological footprint of the health industry, recommending the introduction of these themes in scientific programs of Internal Medicine meetings and congresses and the pre- and postgraduate medical training. At a personal level, internists must be active agents in advocating sustainable practices for the environment, increasing the awareness of the community about the health risks of climate change and environmental degradation, and being role models in the adoption of environmentally friendly behaviour.

Characterization of pathogen-inactivated COVID-19 convalescent plasma and responses in transfused patients.

BACKGROUND: Efficacy of donated COVID-19 convalescent plasma (dCCP) is uncertain and may depend on antibody titers, neutralizing capacity, timing of administration, and patient characteristics. STUDY DESIGN AND METHODS: In a single-center hypothesis-generating prospective case-control study with 1:2 matched dCCP recipients to controls according to disease severity at day 1, hospitalized adults with COVID-19 pneumonia received 2 × 200 ml pathogen-reduced treated dCCP from 2 different donors. We evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 convalescent plasma donors and recipients using multiple antibody assays including a Coronavirus antigen microarray (COVAM), and binding and neutralizing antibody assays. Outcomes were dCCP characteristics, antibody responses, 28-day mortality, and dCCP -related adverse events in recipients. RESULTS: Eleven of 13 dCCPs (85%) contained neutralizing antibodies (nAb). PRT did not affect dCCP antibody activity. Fifteen CCP recipients and 30 controls (median age 64 and 65 years, respectively) were enrolled. dCCP recipients received 2 dCCPs from 2 different donors after a median of one hospital day and 11 days after symptom onset. One dCCP recipient (6.7%) and 6 controls (20%) died (p = 0.233). We observed no dCCP-related adverse events. Transfusion of unselected dCCP led to heterogeneous SARS CoV-2 antibody responses. COVAM clustered dCCPs in 4 distinct groups and showed endogenous immune responses to SARS-CoV-2 antigens over 14-21 days post dCCP in all except 4 immunosuppressed recipients. DISCUSSION: PRT did not impact dCCP anti-virus neutralizing activity. Transfusion of unselected dCCP did not impact survival and had no adverse effects. Variable dCCP antibodies and post-transfusion antibody responses indicate the need for controlled trials using well-characterized dCCP with informative assays.

Association of Interprofessional Discharge Planning Using an Electronic Health Record Tool With Hospital Length of Stay Among Patients with Multimorbidity: A Nonrandomized Controlled Trial.

Importance: Whether interprofessional collaboration is effective and safe in decreasing hospital length of stay remains controversial. Objective: To evaluate the outcomes and safety associated with an electronic interprofessional-led discharge planning tool vs standard discharge planning to safely reduce length of stay among medical inpatients with multimorbidity. Design, Setting, and Participants: This multicenter prospective nonrandomized controlled trial used interrupted time series analysis to examine medical acute hospitalizations at 82 hospitals in Switzerland. It was conducted from February 2017 through January 2019. Data analysis was conducted from March 2021 to July 2022. Intervention: After a 12-month preintervention phase (February 2017 through January 2018), an electronic interprofessional-led discharge planning tool was implemented in February 2018 in 7 intervention hospitals in addition to standard discharge planning. Main Outcomes and Measures: Mixed-effects segmented regression analyses were used to compare monthly changes in trends of length of stay, hospital readmission, in-hospital mortality, and facility discharge after the implementation of the tool with changes in trends among control hospitals. Results: There were 54 695 hospitalizations at intervention hospitals, with 27 219 in the preintervention period (median [IQR] age, 72 [59-82] years; 14 400 [52.9%] men) and 27 476 in the intervention phase (median [IQR] age, 72 [59-82] years; 14 448 [52.6%] men) and 438 791 at control hospitals, with 216 261 in the preintervention period (median [IQR] age, 74 [60-83] years; 109 770 [50.8%] men) and 222 530 in the intervention phase (median [IQR] age, 74 [60-83] years; 113 053 [50.8%] men). The mean (SD) length of stay in the preintervention phase was 7.6 (7.1) days for intervention hospitals and 7.5 (7.4) days for control hospitals. During the preintervention phase, population-averaged length of stay decreased by -0.344 hr/mo (95% CI, -0.599 to -0.090 hr/mo) in control hospitals; however, no change in trend was observed among intervention hospitals (-0.034 hr/mo; 95% CI, -0.646 to 0.714 hr/mo; difference in slopes, P = .09). Over the intervention phase (February 2018 through January 2019), length of stay remained unchanged in control hospitals (slope, -0.011 hr/mo; 95% CI, -0.281 to 0.260 hr/mo; change in slope, P = .03), but decreased steadily among intervention hospitals by -0.879 hr/mo (95% CI, -1.607 to -0.150 hr/mo; change in slope, P = .04, difference in slopes, P = .03). Safety analyses showed no change in trends of hospital readmission, in-hospital mortality, or facility discharge over the whole study time. Conclusions and Relevance: In this nonrandomized controlled trial, the implementation of an electronic interprofessional-led discharge planning tool was associated with a decline in length of stay without an increase in hospital readmission, in-hospital mortality, or facility discharge. Trial Registration: isrctn.org Identifier: ISRCTN83274049.

Clinical utility of inflammatory biomarkers in COVID-19 in direct comparison to other respiratory infections-A prospective cohort study.

BACKGROUND: Inflammatory biomarkers are associated with severity of coronavirus disease 2019 (COVID-19). However, direct comparisons of their utility in COVID-19 versus other respiratory infections are largely missing. OBJECTIVE: We aimed to investigate the prognostic utility of various inflammatory biomarkers in COVID-19 compared to patients with other respiratory infections. MATERIALS AND METHODS: Patients presenting to the emergency department with symptoms suggestive of COVID-19 were prospectively enrolled. Levels of Interleukin-6 (IL-6), c-reactive protein (CRP), procalcitonin, ferritin, and leukocytes were compared between COVID-19, other viral respiratory infections, and bacterial pneumonia. Primary outcome was the need for hospitalisation, secondary outcome was the composite of intensive care unit (ICU) admission or death at 30 days. RESULTS: Among 514 patients with confirmed respiratory infections, 191 (37%) were diagnosed with COVID-19, 227 (44%) with another viral respiratory infection (viral controls), and 96 (19%) with bacterial pneumonia (bacterial controls). All inflammatory biomarkers differed significantly between diagnoses and were numerically higher in hospitalized patients, regardless of diagnoses. Discriminative accuracy for hospitalisation was highest for IL-6 and CRP in all three diagnoses (in COVID-19, area under the curve (AUC) for IL-6 0.899 [95%CI 0.850-0.948]; AUC for CRP 0.922 [95%CI 0.879-0.964]). Similarly, IL-6 and CRP ranged among the strongest predictors for ICU admission or death at 30 days in COVID-19 (AUC for IL-6 0.794 [95%CI 0.694-0.894]; AUC for CRP 0.807 [95%CI 0.721-0.893]) and both controls. Predictive values of inflammatory biomarkers were generally higher in COVID-19 than in controls. CONCLUSION: In patients with COVID-19 and other respiratory infections, inflammatory biomarkers harbour strong prognostic information, particularly IL-6 and CRP. Their routine use may support early management decisions.

Fast multiplex bacterial PCR of bronchoalveolar lavage for antibiotic stewardship in hospitalised patients with pneumonia at risk of Gram-negative bacterial infection (Flagship II): a multicentre, randomised controlled trial.

BACKGROUND: PCR-based testing has transformed the management of suspected respiratory viral infections. We aimed to determine whether multiplex bacterial PCR of bronchoalveolar lavage fluid aids antibiotic stewardship in patients with pneumonia. METHODS: This investigator-initiated, multicentre, randomised controlled trial was conducted at two tertiary care centres in Switzerland (University Hospital of Basel and Kantonsspital St Gallen). Patients aged 18 years or older who were admitted to hospital with suspected pneumonia, had a clinical indication for bronchoscopy with bronchoalveolar lavage, and were at risk of Gram-negative bacterial infection were included. Patients were randomly assigned (1:1) to either the multiplex bacterial PCR group or the conventional microbiology control group using a random allocation sequence. Treating physicians were not masked, but the committee panel was masked to patient randomisation. All patients underwent bronchoscopy with bronchoalveolar lavage and samples were assessed by conventional microbiological culture (and additionally, in the PCR group, by multiplex bacterial PCR for Gram-negative rods using the Unyvero Hospitalized Pneumonia [HPN] Cartridge; Curetis, Holzgerlingen, Germany). Patients received empirical antibiotic therapy as clinically indicated by the treating physician. In the PCR group, a recommendation regarding antibiotic therapy was made approximately 5 h after taking the sample. The primary outcome was the time in hours on inappropriate antibiotic therapy from bronchoscopy to discharge or to 30 days after bronchoscopy. This trial was registered with the International Clinical Trials Registry Platform, ISRCTN95828556. FINDINGS: Between May 31, 2017, and Sept 25, 2019, 740 patients with pneumonia were screened for eligibility and 208 were included and randomly assigned to the PCR group (n=100) or conventional microbiology control group (n=108). The mean age of patients was 65·9 years (SD 14·0) and 135 (65%) were male. After daily follow-up until hospital discharge or for a maximum of 30 days, the duration of inappropriate antibiotic treatment was significantly shorter by 38·6 h (95% CI 19·5-57·7) in the PCR group than in the control group (adjusted mean 47·1 h [34·7-59·5] vs 85·7 h [78·8-95·6]; p<0·0001), which translates as a decrease in the duration of inappropriate antibiotic therapy of 45·0% (37·9-52·1). Adverse events due to antimicrobial therapy occurred in nine patients (five [5%] in the PCR group vs four [4%] in the control group) and due to bronchoscopy occurred in four patients (two [1%] vs two [1%]). There were eight (8%) deaths in the PCR group and 11 (10%) in the control group. All in-hospital deaths were attributed to a respiratory cause. INTERPRETATION: Multiplex bacterial PCR examination of bronchoalveolar lavage decreases the duration of inappropriate antibiotic therapy of patients admitted to hospital with pneumonia and at risk of Gram-negative rod infection. This approach warrants further consideration in future antibiotic stewardship strategies. FUNDING: Curetis and the Clinic of Respiratory Medicine and Pulmonary Cell Research, University Hospital Basel, Switzerland.