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INTRODUCTION: Ventilator-associated pneumonia (VAP) is the most frequent healthcare-associated infection in intensive care units and is associated with high morbidity and mortality. Current diagnostic criteria lack specificity, leading to misclassification and unnecessary antibiotic use. Identifying patient subgroups with a common pathophysiological basis (pneumoclusters) may distinguish true VAP of varying aetiology and severity from non-infectious mimics, enabling more targeted therapy and improved antimicrobial stewardship.

METHODS AND ANALYSIS: ClusterVAP is an exploratory, observational, prospective, multicentre cross-sectional study conducted in intensive care units across Sweden, France, Portugal, Denmark and the UK. Mechanically ventilated patients aged 18 years or older with newly developed clinical signs of lower respiratory tract infection will undergo bronchoalveolar lavage (BAL) or mini BAL sampling on clinical indication. Proteomic profiling using liquid chromatography tandem mass spectrometry will be performed on BAL supernatants. Unsupervised consensus clustering will define pneumoclusters, which will be characterised using clinical, microbiological and radiological data. 30-day outcomes, including mortality, ventilator-free days, antibiotic-free days, intensive care unit-free days and hospital-free days, will be compared across clusters to describe clinical trajectories. Candidate protein biomarkers for pragmatic cluster assignment will be derived using differential expression analysis.

ETHICS AND DISSEMINATION: Ethical approval will be obtained at all participating sites. Deferred consent will be used where permitted, with subsequent patient or proxy consent according to local regulations. Results will be disseminated through peer-reviewed publications and scientific conferences.

TRIAL REGISTRATION NUMBER: NCT07245888.

Pharmacological inhibition of soluble epoxide hydrolase has been shown to attenuate lung injury development in rodents exposed to bacterial lipopolysaccharide. To investigate if these effects can be reproduced in larger animals, we tested soluble epoxide hydrolase (sEH) inhibition using an sEH inhibitor 1-adamantanyl-3-{5-[2-(ethylethoxy)ethoxy]pentyl}urea (AEPU) in a porcine model of lipopolysaccharide-induced acute lung injury. AEPU was selected from 23 sEH inhibitors based on IC50 values and metabolic stability profiles established by a fluorescent based activity assay and porcine liver microsomal test, respectively. Hydrolysis of fatty acid epoxides to their corresponding diols is catalyzed by sEH. Inhibition of sEH reduces this conversion, leading to an accumulation of epoxides relative to diols. Hence, AEPU-treated subjects (n = 9) showed metabolic signs of effective in vivo inhibition of the target enzyme reflected in an increased epoxide/diol ratio of 12 (13)-epoxyoctadecenoic acid to 12,13-dihydroxyoctadecenoic acid compared to placebo-treated controls (p = 0.026). However, there was no difference in lung injury development or survival in subjects treated with the rapidly metabolized AEPU compared to placebo-treated controls (n = 10). In conclusion, administration of the soluble epoxide hydrolase inhibitor AEPU did not attenuate endotoxin induced lung injury with lipopolysaccharide in pigs under the severe conditions tested here.

Objectives: COVID-19 impacts physical and respiratory health, and the clinical presentation ranges from asymptomatic cases to severe infections requiring hospitalisation. While the long-term effects on lung function and physical capacity are well-documented in moderate to severe cases, the long-term outcome for individuals with mild COVID-19 remains poorly understood. This study investigates the long-term recovery of physical capacity and breathlessness among both hospitalised and non-hospitalised individuals.

Methods: This prospective cohort study enrolled individuals with confirmed SARS-CoV-2 infection between April 2020 and May 2021 through the CoVUm-study. Participants underwent assessments of lung function at 3–6 months after infection and attended follow-ups up to three years post-infection. Physical capacity was evaluated at follow-ups, using the one-minute sit-to-stand test and the modified Medical Research Council scale to assess breathlessness.

Results: The cohort included 291 participants, 35% of whom were hospitalised during SARS-CoV-2 infection. At the 3-year follow-up, 191 participants completed the physical capacity test and 179 had an assessment of breathlessness. Physical capacity improved significantly in the total cohort up to two years post-infection, where improvement plateaued. Hospitalisation and impaired diffusing capacity were significantly associated with reduced physical capacity (beta –6.4, p < 0.001; beta –8.9, p < 0.001, respectively) and breathlessness (beta 3.9, p < 0.001; beta 1.6, p = 0.012, respectively). While non-hospitalised participants demonstrated improvements in physical capacity for up to two years, improvement for hospitalised individuals plateaued by six months.

Conclusion: Hospitalisation and impaired diffusing capacity are strong independent predictors of reduced physical capacity and persistent breathlessness up to three years post-infection. Non-hospitalised individuals also experience long-term reductions in physical capacity, underscoring the need for targeted rehabilitation strategies.

Background: Olfactory impairment has been associated with adverse health outcomes, particularly in older populations, including cognitive decline, malnutrition, and frailty. The COVID-19 pandemic highlighted olfactory impairment as a key symptom affecting individuals across all age groups, raising concerns about its long-term impacts. This study investigates the association between post-acute olfactory impairment and long-term physical capacity in COVID-19 patients, hypothesizing that impaired olfaction is linked to reduced physical performance.

Methods: This prospective cohort study included 63 hospitalized and non-hospitalized COVID-19 patients (38.1 % women; median age 51 years, IQR 47.0–60.0) who underwent olfactory testing 1–3 months post-infection. Olfactory assessments included threshold screening, supra-threshold intensity ratings, and an odour identification test. Physical capacity was assessed using the 1-min sit-to-stand test at follow-ups (3, 6, 12, and 24 months). Partial correlation analysis and linear mixed models were used to analyse the data, adjusting for covariates such as age, sex, BMI, comorbidities, smoking status, and severity of infection.

Results: In the early post-acute phase, 36.5 % of participants exhibited olfactory impairment. We identified a significant, negative correlation between objectively tested olfactory impairment and physical capacity at all follow-ups. In a linear mixed model adjusted for relevant covariates, olfactory impairment was associated with reduced physical capacity up to 24 months after infection. The association strengthened over time, reflected by the increasing beta values for the interaction term: 0.09 (p = 0.200) at 6 months, 0.13 (p = 0.053) at 12 months, and 0.23 (p = 0.001) at 24 months.

Conclusion: Individuals with olfactory impairment in the early post-acute phase of COVID-19 infection were more likely to exhibit diminished physical capacity 24 months later. This study highlights the broader implications of olfactory impairment, previously noted mainly in older populations, demonstrating its relevance across age groups. The COVID-19 pandemic presented a unique opportunity to investigate this relationship, enhancing our understanding of how olfactory impairments relate to long-term physical performance. These findings emphasize the need for further research with larger, more diverse cohorts and objective longitudinal assessments to confirm and extend these observations.

Background: Current evidence indicates that Post COVID-19 Condition (PCC) is multifaceted with distinct phenotypes. While previous studies have identified symptom clusters—commonly featuring fatigue, respiratory symptoms, and cognitive impairment—findings have been inconsistent, and no clear consensus exists. Moreover, how these symptom clusters evolve over time, particularly beyond the first year post-infection, remains poorly understood.

Methods: This multicentre prospective cohort study included 470 hospitalised and non-hospitalised adult individuals from the CoVUm study across four sites in Sweden between 2020 and 2021. Follow-ups were conducted up to 3 years after infection to assess persistent symptoms, health-related quality of life (HRQoL), and work capacity. Symptom clusters at 6 months were identified via hierarchical cluster analysis, and participants were tracked using a k-nearest neighbour algorithm.

Results: The most common symptoms at 6 months were fatigue (33 %), dyspnoea (32 %), mental fatigue (30 %), and concentration difficulties (28 %), with a median EQ-5D-5L index of 0.98 (IQR 0.93–1). Four distinct symptom clusters were identified: (i) “Few Symptoms” (n = 265, 57 %), (ii) “Respiratory Symptoms” (n = 66, 14 %), (iii) “Neurocognitive Symptoms” (n = 75, 16 %), and (iv) “Multisystem Symptoms” (n = 52, 11 %). Participants in the latter three clusters were older, had more comorbidities, and were more often hospitalised during primary COVID-19 infection. These clusters also had significantly lower HRQoL compared to the “Few Symptoms” cluster. Over time, more than half of participants transitioned to a cluster with fewer or no symptoms, with significant perceived HRQoL improvement in the “Multisystem Symptoms” cluster.

Conclusion: While many patients with PCC improved over time, a subset had persistent symptoms at 3 years, especially if primary infection required hospitalisation. The identification of symptom clusters and their trajectories over time contributes to a better understanding of PCC heterogeneity, ultimately bringing the field closer to consensus on the classification and long-term impact of PCC.

In septic shock, administration of large fluid volumes is associated with poor outcomes. Recent evidence shows that non-resuscitation fluids are the major modifiable source of fluids for patients with septic shock in intensive care units (ICUs). This clinical trial is designed to test the hypothesis that restrictive administration of non-resuscitation fluids improves outcomes compared to usual care. Adult patients admitted to ICUs with septic shock will be randomly assigned within 12 h of admission to receive protocolized restrictive administration of non-resuscitation fluids or usual care. The primary outcome is all-cause mortality at 90 days. Secondary outcomes are complications during ICU stay up to 90 days (defined as any acute kidney injury or cerebral, coronary, intestinal, or limb ischemia), mechanical ventilation free days within 90 days, and for survivors cognitive function (by the Montreal Cognitive Assessment [MOCA-BLIND]) and Health-Related Quality of Life (by the EQ Visual Analogue Scale [EQ-VAS]), both at 6 months. In addition, the climate impact of the interventions will be assessed. To detect an absolute reduction in mortality of 7.5%, with an alpha of 5% and a power of 90%, we aim to include 1850 patients. The trial is approved by the Swedish Ethical Review Authority. Results of primary and secondary clinical outcomes and the environmental outcome will be submitted for publication in a peer-reviewed journal. Trial Registration: NCT06140147.

Background: The digitalization of information systems allows automatic measurement of antimicrobial consumption (AMC), helping address antibiotic resistance from inappropriate drug use without compromising patient safety.

Objectives: Describe and characterize a new automated AMC surveillance service for intensive care units (ICUs), with data stratified by referral clinic and linked with individual patient risk factors, disease severity, and mortality.

Methods: An automated service collecting data from the electronic medical record was developed, implemented, and validated in a healthcare region in northern Sweden. We performed an observational study from January 1, 2018, to December 31, 2021, encompassing general ICU care for all ≥18-years-olds in a catchment population of 270000 in secondary care and 900000 in tertiary care. We used descriptive analyses to associate ICU population characteristics with AMC outcomes over time, including days of therapy (DOT), length of therapy, defined daily doses, and mortality.

Results: There were 5608 admissions among 5190 patients with a median age of 65 (IQR 48-75) years, 41.2% females. The 30-day mortality was 18.3%. Total AMC was 1177 DOTs in secondary and 1261 DOTs per 1000 patient days and tertiary care. AMC varied significantly among referral clinics, with the highest total among 810 general surgery admissions in tertiary care at 1486 DOTs per 1000 patient days. Case-mix effects on the AMC were apparent during COVID-19 waves highlighting the need to account for case-mix. Patients exposed to more than three antimicrobial drug classes (N = 242) had a 30-day mortality rate of 40.6%, with significant variability in their expected rates based on admission scores.

Conclusion: We introduce a new service and instructions for automating local ICU-AMC data collection. The versatile long-term ICU-AMC metrics presented, covering patient factors, referral clinics and mortality outcomes, are expected to be beneficial in refining antimicrobial drug use.

Background: Olfactory dysfunction together with neurological and cognitive symptoms are common after COVID-19. We aimed to study whether performance on olfactory and neuropsychological tests following infection predict post-COVID condition (PCC), persisting symptoms, and reduced health-related quality of life.

Methods: Both hospitalized (N = 10) and non-hospitalized individuals (N = 56) were enrolled in this prospective cohort study. Participants were evaluated 1–3 months after infection with an olfactory threshold test and neuropsychological tests, which was used as predictors of PCC. A questionnaire outlining persisting symptoms and the validated instrument EuroQol five-dimension five-level for health-related quality of life assessment were used as outcome data 1 year after infection (N = 59). Principal component analysis was used to identify relevant predictors for PCC at 1 year.

Results: Objectively assessed olfactory dysfunction at 1–3 months post infection, but not subjective olfactory symptoms, predicted post-COVID condition with reduced health-related quality of life (PCC+) at 1 year. The PCC+ group scored more often below the cut off for mild cognitive impairment on the Montreal Cognitive Assessment (61.5% vs. 21.7%) and higher on the Multidimensional Fatigue Inventory-20, compared to the group without PCC+.

Conclusion: Our results indicate that objectively assessed, olfactory dysfunction is a predictor for PCC+. These findings underscore the importance of objective olfactory testing. We propose that olfactory screening in the early post-acute phase of COVID-19 infection might identify individuals that are at higher risk of developing long-term health sequalae.

We previously demonstrated that the lungs of deceased COVID-19 patients were filled with a clear hydrogel consisting of hyaluronan (HA). In this translational study, we investigated the role of HA at all stages of COVID-19 disease to map the consequences of elevated HA on morbidity and identify the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced HA production. A reduced alveolar surface area was observed in the lungs of deceased COVID-19 patients compared to healthy controls, as visualized by a 3D rendering of lung morphology using light-sheet fluorescence microscopy. We confirmed the presence of HA in lung biopsies and found large quantities of proinflammatory fragmented HA. The association of systemic HA in blood plasma and disease severity was assessed in patients with mild (WHO Clinical Progression Scale, WHO-CPS, 1–5) and severe COVID-19 (WHO-CPS, 6–9) during the acute and convalescent phases and related to lung function. We found that systemic levels of HA were high during acute COVID-19 disease, remained elevated during convalescence, and were associated with a reduced diffusion capacity. In vitro 3D-lung models, differentiated from primary human bronchial epithelial cells, were used to study the effects of SARS-CoV-2 infection on HA metabolism, and transcriptomic analyses revealed a dysregulation of HA synthases and hyaluronidases, both contributing to increased HA in apical secretions. Furthermore, corticosteroid treatment reduced the inflammation and downregulated HA synthases. Our findings demonstrate that HA plays a role in COVID-19 morbidity and that sustained elevated HA concentrations may contribute to long-term respiratory impairment.