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IntroductionThe international Surviving Sepsis Campaign guidelines highlight the need for recognising sepsis in a timely and accurate manner. Early diagnosis and treatment of sepsis are crucial and associated with reduced mortality. In the early stages of sepsis, heterogeneous clinical signs are difficult to interpret, often leading to missed or delayed diagnoses, as well as inappropriate or late use of antibiotics. There is an urgent need to quickly and accurately identify patients with potential infection in the emergency department (ED) who are at risk of progressing along the infection-sepsis spectrum. This study aims to compare the immune responses of ED patients presenting with a (suspected) infection, both with and without sepsis, to gain insights into immune aberrations and identify novel biomarkers linked to an increased risk of developing sepsis and its sequelae.Methods and analysisA prospective observational cohort study across three hospitals in the Netherlands will be conducted. Adults presenting to the ED of these hospitals, with a (suspected) infection and a Modified Early Warning Score of 2 or higher, will be eligible for enrolment. We aim to include up to 3330 patients. The main study parameters will be characterisation of the host immune and metabolic response using multiomics analysis, Raman spectroscopy, mass spectrometry and gut microbiota profiling in relation to clinical outcomes such as 30-day mortality, length of hospital stay, readmission and postsepsis sequelae.Ethics and disseminationVerbal and written informed consent will be obtained from all participants or their legal representatives. The study was approved by the Amsterdam University Medical Centre Ethics Committee (No. 2022.0279) and will adhere to the Declaration of Helsinki and the Medical Research Involving Human Subjects Act (WMO). Research results will be published in peer-reviewed journals.Trail registration numberClinicalTrials.gov, NCT06178822.

Clostridium difficile infection (CDI) has become more refractory to standard therapy. We describe 4 patients with severe refractory CDI who were successfully treated with tigecycline. Symptoms improved within 1 week. No relapses were observed. This favorable outcome suggests that tigecycline might be a useful alternative for treating severe refractory CDI.

ObjectivesThe aim of this multicentre COVID-PREDICT study (a nationwide observational cohort study that aims to better understand clinical course of COVID-19 and to predict which COVID-19 patients should receive which treatment and which type of care) was to determine the association between atrial fibrillation (AF) and mortality, intensive care unit (ICU) admission, complications and discharge destination in hospitalised COVID-19 patients.SettingData from a historical cohort study in eight hospitals (both academic and non-academic) in the Netherlands between January 2020 and July 2021 were used in this study.Participants3064 hospitalised COVID-19 patients >18 years old.Primary and secondary outcome measuresThe primary outcome was the incidence of new-onset AF during hospitalisation. Secondary outcomes were the association between new-onset AF (vs prevalent or non-AF) and mortality, ICU admissions, complications and discharge destination, performed by univariable and multivariable logistic regression analyses.ResultsOf the 3064 included patients (60.6% men, median age: 65 years, IQR 55–75 years), 72 (2.3%) patients had prevalent AF and 164 (5.4%) patients developed new-onset AF during hospitalisation. Compared with patients without AF, patients with new-onset AF had a higher incidence of death (adjusted OR (aOR) 1.71, 95% CI 1.17 to 2.59) an ICU admission (aOR 5.45, 95% CI 3.90 to 7.61). Mortality was non-significantly different between patients with prevalent AF and those with new-onset AF (aOR 0.97, 95% CI 0.53 to 1.76). However, new-onset AF was associated with a higher incidence of ICU admission and complications compared with prevalent AF (OR 6.34, 95% CI 2.95 to 13.63, OR 3.04, 95% CI 1.67 to 5.55, respectively).ConclusionNew-onset AF was associated with an increased incidence of death, ICU admission, complications and a lower chance to be discharged home. These effects were far less pronounced in patients with prevalent AF. Therefore, new-onset AF seems to represent a marker of disease severity, rather than a cause of adverse outcomes.

In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19. Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19. This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand. As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024. This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment. ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359. DERR1-10.2196/48183.

Abstract Introduction: Many COVID-19 survivors suffer from persisting sequelae after acute disease. This is referred to as long COVID. The objectives of this study were to assess factors associated with long COVID and to analyze differences in persistent symptoms, findings on chest imaging, and pulmonary function between intensive care unit (ICU) and non-ICU hospitalized patients. Methods: We conducted a retrospective study including patients hospitalized with COVID-19. Patients were stratified into ICU patients and non-ICU patients. We analyzed the outcomes of patients who were in clinical follow-up 6 months after discharge with persistent symptoms, radiological and/or functional abnormalities. Logistic regression was used to examine the association between long COVID and patient characteristics. Results: A total of 549 patients were included. Eighty-one ICU patients (66%) and 146 (34%) non-ICU patients had persistent symptoms or abnormalities on chest imaging or lung function test minimally 6 months after discharge. Significantly more ICU patients had residual fibrotic abnormalities on chest CT and functional impairment. Female gender, myocardial infarction, OSAS, low PCO2 at admission, and longer hospital stay were associated with a higher risk of developing long COVID. Diabetes and treatment with tocilizumab were associated with a lower risk of developing long COVID. Conclusion: Of the patients hospitalized for COVID-19, 34–66% suffered from persistent symptoms, residual abnormalities on chest imaging, or reduced lung function at around 6 months after discharge. While persistent sequelae were more frequent in ICU patients, admission to the ICU was not found to be an independent risk factor for developing long COVID.

ObjectiveA fixed 6 mg dexamethasone dose for 10 days is the standard treatment for all hospitalised COVID-19 patients who require supplemental oxygen. Yet, the pharmacokinetic properties of dexamethasone can lead to diminishing systemic dexamethasone exposure with increasing body mass index (BMI). The present study examines whether this translates to overweight and obesity being associated with worse clinical outcomes, defined as ICU admission or in hospital death, in COVID-19 patients treated with fixed-dose dexamethasone.MethodsWe conducted a single centre retrospective cohort study in COVID-19 patients who were admitted to a non-ICU ward and were treated with dexamethasone (6 mg once daily for a maximum of ten days) between June 2020 and January 2021. Univariable and multivariable logistic regression analyses were conducted to assess the association between BMI-categories and an unfavourable clinical course (ICU admission and/or in hospital death). Analyses were adjusted for age, comorbidities, inflammatory status, and oxygen requirement at admission. For reference, similar analyses were repeated in a cohort of patients hospitalised before dexamethasone was introduced (March 2020 through May 2020).ResultsIn patients treated with dexamethasone (n = 385) an unfavourable clinical course was most prevalent in patients with normal weight (BMI < 25) compared to patients with overweight (BMI 25–30) and patients with obesity (BMI ≥ 30) with percentages of 33, 26 and 21% respectively. In multivariable analyses, there was no association between BMI-category and an unfavourable clinical course (respectively with aORs of 0.81 (0.43–1.53) and 0.61 (0.30–1.27) with normal weight as reference). In the reference cohort (n = 249) the opposite was observed with an unfavourable clinical course being most prevalent in patients with overweight (39% vs 28%; aOR 2.17 (0.99–4.76)). In both cohorts, CRP level at admission was higher and lymphocyte count was lower in patients with normal weight compared to patients with obesity.ConclusionsOverweight and obesity are not associated with an unfavourable clinical course in COVID-19 patients admitted to a non-ICU ward and treated with 6 mg dexamethasone once daily.

Schultz and colleagues discuss the factors hindering implementation of intensive insulin therapy.

Abstract Introduction: During the first COVID-19 outbreak in 2020 in the Netherlands, the incidence of pulmonary embolism (PE) appeared to be high in COVID-19 patients admitted to the intensive care unit (ICU). This study was performed to evaluate the incidence of PE during hospital stay in COVID-19 patients not admitted to the ICU. Methods: Data were retrospectively collected from 8 hospitals in the Netherlands. Patients admitted between February 27, 2020, and July 31, 2020, were included. Data extracted comprised clinical characteristics, medication use, first onset of COVID-19-related symptoms, admission date due to COVID-19, and date of PE diagnosis. Only polymerase chain reaction (PCR)-positive patients were included. All PEs were diagnosed with computed tomography pulmonary angiography (CTPA). Results: Data from 1,852 patients who were admitted to the hospital ward were collected. Forty patients (2.2%) were diagnosed with PE within 28 days following hospital admission. The median time to PE since admission was 4.5 days (IQR 0.0–9.0). In all 40 patients, PE was diagnosed within the first 2 weeks after hospital admission and for 22 (55%) patients within 2 weeks after onset of symptoms. Patient characteristics, pre-existing comorbidities, anticoagulant use, and laboratory parameters at admission were not related to the development of PE. Conclusion: In this retrospective multicenter cohort study of 1,852 COVID-19 patients only admitted to the non-ICU wards, the incidence of CTPA-confirmed PE was 2.2% during the first 4 weeks after onset of symptoms and occurred exclusively within 2 weeks after hospital admission.

Background Evidence for benefit of high positive end-expiratory pressure (PEEP) is largely lacking for invasively ventilated, critically ill patients with uninjured lungs. We hypothesize that ventilation with low PEEP is noninferior to ventilation with high PEEP with regard to the number of ventilator-free days and being alive at day 28 in this population.  Methods/Design The “REstricted versus Liberal positive end-expiratory pressure in patients without ARDS” trial (RELAx) is a national, multicenter, randomized controlled, noninferiority trial in adult intensive care unit (ICU) patients with uninjured lungs who are expected not to be extubated within 24 h. RELAx will run in 13 ICUs in the Netherlands to enroll 980 patients under invasive ventilation. In all patients, low tidal volumes are used. Patients assigned to ventilation with low PEEP will receive the lowest possible PEEP between 0 and 5 cm H 2 O, while patients assigned to ventilation with high PEEP will receive PEEP of 8 cm H 2 O. The primary endpoint is the number of ventilator-free days and being alive at day 28, a composite endpoint for liberation from the ventilator and mortality until day 28, with a noninferiority margin for a difference between groups of 0.5 days. Secondary endpoints are length of stay (LOS), mortality, and occurrence of pulmonary complications, including severe hypoxemia, major atelectasis, need for rescue therapies, pneumonia, pneumothorax, and development of acute respiratory distress syndrome (ARDS). Hemodynamic support and sedation needs will be collected and compared. Discussion RELAx will be the first sufficiently sized randomized controlled trial in invasively ventilated, critically ill patients with uninjured lungs using a clinically relevant and objective endpoint to determine whether invasive, low-tidal-volume ventilation with low PEEP is noninferior to ventilation with high PEEP. Trial registration ClinicalTrials.gov , ID: NCT03167580 . Registered on 23 May 2017.