Practices to prevent non-ventilator hospital acquired pneumonia: a narrative review.

Nosocomial infection has significant consequences in healthcare, at the individual level driving increased morbidity and mortality, but also at the organisational level due to increased costs. Hospital acquired pneumonia(HAP) is the most common nosocomial infection and is associated with high excess mortality, frequent use of broad spectrum anti-microbials and increased length of stay. In this review we explore the preventative strategies that have been examined in non-ventilator acquired hospital associated pneumonia (NVHAP). We discuss management of aspiration risk, interventions for oral hygiene, the role of mobilisation and physiotherapy, modification of environmental factors, and vaccination. Many of these interventions are low risk, acceptable to patients and have good cost-benefit ratios. However, the evidence base for prevention of NVHAP is weak. We identify lack of a unified research definition, under-recruitment to studies, and variation in intervention and outcome measures as limitations in the existing literature. Given the core risk factors for acquisition of NVHAP are increasing there is an urgent need for research to address the prevention of NVHAP. In this review we call for a unified definition, identification of a core outcome set for studies in NVHAP and suggest future directions for research in NVHAP. Improving care for people with NVHAP will reduce morbidity, mortality, and healthcare costs significantly.

The clinical challenge of diagnosing Non-Ventilator Hospital Acquired Pneumonia and identifying causative pathogens - a narrative review.

Non-ventilated hospital acquired pneumonia (NV-HAP) is associated with significant healthcare burden, arising from high incidence and associated morbidity and mortality. However, accurately identifying cases remains challenging. At present there is no gold-standard test for the diagnosis of NV-HAP, requiring instead the blending of non-specific signs and investigations. Causative organisms are only identified in a minority of cases. This has significant implications for surveillance, patient outcomes and antimicrobial stewardship. Much of the existing research in HAP has been conducted among ventilated patients. The paucity of dedicated NV-HAP research means conclusions regarding diagnostic methods, pathology and interventions must largely be extrapolated from work in other settings. Progress is also limited by the lack of a widely agreed definition for NV-HAP. The diagnosis of NV-HAP has large scope for improvement. Consensus regarding a case definition will allow meaningful research to improve understanding of both aetiology and the heterogeneity of outcomes experienced by patients. There is potential to optimise the role of imaging and to incorporate novel techniques to identify likely causative pathogens. This would facilitate both antimicrobial stewardship and surveillance of an important healthcare-associated infection. This narrative review considers the utility of existing methods to diagnose NV-HAP, with a focus on the significance and challenge of identifying pathogens. It discusses the limitations in current techniques and explores the potential of emergent molecular techniques to improve microbiological diagnosis and outcomes for patients.

Towards personalised anti-microbial and immune approaches to infections in acute care. Can real-time genomic-informed diagnosis of pathogens, and immune-focused therapies improve outcomes for patients? An observational, experimental study protocol.

INTRODUCTION: Infection causes a vast burden of disease, with significant mortality, morbidity and costs to health-care systems. However, identifying the pathogen causative infection can be challenging, resulting in high use of broad-spectrum antibiotics, much of which may be inappropriate. Novel metagenomic methods have potential to rapidly identify pathogens, however their clinical utility for many infections is currently unclear. Outcome from infection is also impacted by the effectiveness of immune responses, which can be impaired by age, co-morbidity and the infection itself. The aims of this study are twofold: To compare diversity of organisms identified and time-to-result using metagenomic methods versus traditional culture -based techniques, to explore the potential clinical role of metagenomic approaches to pathogen identification in a range of infections.To characterise the ex vivo function of immune cells from patients with acute infection, exploring host and pathogen-specific factors which may affect immune function and overall outcomes. METHODS: This is a prospective observational study of patients with acute infection. Patients with symptoms suggestive of an acute infection will be recruited, and blood and bodily fluid relevant to the site of infection collected (for example, sputum and naso-oropharyngeal swabs for respiratory tract infections, or urine for a suspected urinary tract infection). Metagenomic analysis of samples will be compared to traditional microbiology, alongside the antimicrobials received. Blood and respiratory samples such as bronchoalveolar lavage will be used to isolate immune cells and interrogate immune cell function. Where possible, similar samples will be collected from matched participants without a suspected infection to determine the impact of infection on both microbiome and immune cell function.

E-cigarette vapor renders neutrophils dysfunctional due to filamentous actin accumulation.

BACKGROUND: Electronic cigarette (e-cigarette) use continues to rise despite concerns of long-term effects, especially the risk of developing lung diseases such as chronic obstructive pulmonary disease. Neutrophils are central to the pathogenesis of chronic obstructive pulmonary disease, with changes in phenotype and function implicated in tissue damage. OBJECTIVE: We sought to measure the impact of direct exposure to nicotine-containing and nicotine-free e-cigarette vapor on human neutrophil function and phenotype. METHODS: Neutrophils were isolated from the whole blood of self-reported nonsmoking, nonvaping healthy volunteers. Neutrophils were exposed to 40 puffs of e-cigarette vapor generated from e-cigarette devices using flavorless e-cigarette liquids with and without nicotine before functions, deformability, and phenotype were assessed. RESULTS: Neutrophil surface marker expression was altered, with CD62L and CXCR2 expression significantly reduced in neutrophils treated with e-cigarette vapor containing nicotine. Neutrophil migration to IL-8, phagocytosis of Escherichia coli and Staphylococcus aureus pHrodo bioparticles, oxidative burst response, and phorbol 12-myristate 13-acetate-stimulated neutrophil extracellular trap formation were all significantly reduced by e-cigarette vapor treatments, independent of nicotine content. E-cigarette vapor induced increased levels of baseline polymerized filamentous actin levels in the cytoplasm, compared with untreated controls. CONCLUSIONS: The significant reduction in effector neutrophil functions after exposure to high-power e-cigarette devices, even in the absence of nicotine, is associated with excessive filamentous actin polymerization. This highlights the potentially damaging impact of vaping on respiratory health and reinforces the urgency of research to uncover the long-term health implications of e-cigarettes.

Cardiovascular Subphenotypes in ARDS: Diagnostic and Therapeutic Implications and Overlap with Other ARDS Subphenotypes.

Acute respiratory distress syndrome (ARDS) is a highly heterogeneous clinical condition. Shock is a poor prognostic sign in ARDS, and heterogeneity in its pathophysiology may be a barrier to its effective treatment. Although right ventricular dysfunction is commonly implicated, there is no consensus definition for its diagnosis, and left ventricular function is neglected. There is a need to identify the homogenous subgroups within ARDS, that have a similar pathobiology, which can then be treated with targeted therapies. Haemodynamic clustering analyses in patients with ARDS have identified two subphenotypes of increasingly severe right ventricular injury, and a further subphenotype of hyperdynamic left ventricular function. In this review, we discuss how phenotyping the cardiovascular system in ARDS may align with haemodynamic pathophysiology, can aid in optimally defining right ventricular dysfunction and can identify tailored therapeutic targets for shock in ARDS. Additionally, clustering analyses of inflammatory, clinical and radiographic data describe other subphenotypes in ARDS. We detail the potential overlap between these and the cardiovascular phenotypes.

Impaired alveolar macrophage 11ß-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS.

Background: Acute Respiratory Distress Syndrome (ARDS) is a devastating pulmonary inflammatory disorder, commonly precipitated by sepsis. Glucocorticoids are immunomodulatory steroids that can suppress inflammation. Their anti-inflammatory properties within tissues are influenced by their pre-receptor metabolism and amplification from inactive precursors by 11ß-hydroxysteroid dehydrogenase type-1 (HSD-1). We hypothesised that in sepsis-related ARDS, alveolar macrophage (AM) HSD-1 activity and glucocorticoid activation are impaired, and associated with greater inflammatory injury and worse outcomes. Methods: We analysed broncho-alveolar lavage (BAL) and circulating glucocorticoid levels, AM HSD-1 reductase activity and Receptor for Advanced Glycation End-products (RAGE) levels in two cohorts of critically ill sepsis patients, with and without ARDS. AM HSD-1 reductase activity was also measured in lobectomy patients. We assessed inflammatory injury parameters in models of lung injury and sepsis in HSD-1 knockout (KO) and wild type (WT) mice. Results: No difference in serum and BAL cortisol: cortisone ratios are shown between sepsis patients with and without ARDS. Across all sepsis patients, there is no association between BAL cortisol: cortisone ratio and 30-day mortality. However, AM HSD-1 reductase activity is impaired in patients with sepsis-related ARDS, compared to sepsis patients without ARDS and lobectomy patients (0.075 v 0.882 v 0.967 pM/hr/106 AMs, p=0.004). Across all sepsis patients (with and without ARDS), impaired AM HSD-1 reductase activity is associated with defective efferocytosis (r=0.804, p=0.008) and increased 30-day mortality. AM HSD-1 reductase activity negatively correlates with BAL RAGE in sepsis patients with ARDS (r=-0.427, p=0.017). Following intra-tracheal lipopolysaccharide (IT-LPS) injury, HSD-1 KO mice demonstrate increased alveolar neutrophil infiltration, apoptotic neutrophil accumulation, alveolar protein permeability and BAL RAGE concentrations compared to WT mice. Caecal Ligation and Puncture (CLP) injury in HSD-1 KO mice results in greater peritoneal apoptotic neutrophil accumulation compared to WT mice. Conclusions: AM HSD-1 reductase activity does not shape total BAL and serum cortisol: cortisone ratios, however impaired HSD-1 autocrine signalling renders AMs insensitive to the anti-inflammatory effects of local glucocorticoids. This contributes to the decreased efferocytosis, increased BAL RAGE concentrations and mortality seen in sepsis-related ARDS. Upregulation of alveolar HSD-1 activity could restore AM function and improve clinical outcomes in these patients.

Prevalence of physical frailty, including risk factors, up to 1 year after hospitalisation for COVID-19 in the UK: a multicentre, longitudinal cohort study.

Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group-robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)-at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research.

Cardiovascular Subphenotypes in Acute Respiratory Distress Syndrome.

OBJECTIVES: To use clustering methods on transthoracic echocardiography (TTE) findings and hemodynamic parameters to characterize circulatory failure subphenotypes and potentially elucidate underlying mechanisms in patients with acute respiratory distress syndrome (ARDS) and to describe their association with mortality compared with current definitions of right ventricular dysfunction (RVD). DESIGN: Retrospective, single-center cohort study. SETTING: University Hospital ICU, Birmingham, United Kingdom. PATIENTS: ICU patients that received TTE within 7 days of ARDS onset between April 2016 and December 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Latent class analysis (LCA) of TTE/hemodynamic parameters was performed in 801 patients, 62 years old (interquartile range, 50-72 yr old), 63% male, and 40% 90-day mortality rate. Four cardiovascular subphenotypes were identified: class 1 (43%; mostly normal left and right ventricular [LV/RV] function), class 2 (24%; mostly dilated RV with preserved systolic function), class 3 (13%, mostly dilated RV with impaired systolic function), and class 4 (21%; mostly high cardiac output, with hyperdynamic LV function). The four subphenotypes differed in their characteristics and outcomes, with 90-day mortality rates of 19%, 40%, 78%, and 59% in classes 1-4, respectively ( p < 0.0001). Following multivariable logistic regression analysis, class 3 had the highest odds ratio (OR) for mortality (OR, 6.9; 95% CI, 4.0-11.8) compared with other RVD definitions. Different three-variable models had high diagnostic accuracy in identifying each of these latent subphenotypes. CONCLUSIONS: LCA of TTE parameters identified four cardiovascular subphenotypes in ARDS that more closely aligned with circulatory failure mechanisms and mortality than current RVD definitions.

Raised FGF23 Correlates to Increased Mortality in Critical Illness, Independent of Vitamin D.

BACKGROUND: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) patients. We aimed to determine if there was a similar relationship between FGF23 levels and mortality in critically ill patients. METHODS: Plasma FGF23 levels were measured by ELISA in two separate cohorts of patients receiving vitamin D supplementation: critical illness patients (VITdAL-ICU trial, n = 475) and elective oesophagectomy patients (VINDALOO trial, n = 76). Mortality data were recorded at 30 and 180 days or at two years, respectively. FGF23 levels in a healthy control cohort were also measured (n = 27). RESULTS: Elevated FGF23 (quartile 4 vs. quartiles 1-3) was associated with increased short-term (30 and 180 day) mortality in critical illness patients (p < 0.001) and long-term (two-year) mortality in oesophagectomy patients (p = 0.0149). Patients who died had significantly higher FGF23 levels than those who survived: In the critical illness cohort, those who died had 1194.6 pg/mL (range 0-14,000), while those who survived had 120.4 pg/mL (range = 15-14,000) (p = 0.0462). In the oesophagectomy cohort, those who died had 1304 pg/mL (range = 154-77,800), while those who survived had 644 pg/mL (range = 179-54,894) (p < 0.001). This was found to be independent of vitamin D or CKD status (critical illness p = 0.3507; oesophagectomy p = 0.3800). FGF23 levels in healthy controls were similar to those seen in oesophagectomy patients (p = 0.4802). CONCLUSIONS: Elevated baseline serum FGF23 is correlated with increased mortality in both the post-oesophagectomy cohort and the cohort of patients with critical illness requiring intensive care admission. This was independent of vitamin D status, supplementation, or CKD status, which suggests the presence of vitamin D-independent mechanisms of FGF23 action during the acute and convalescent stages of critical illness, warranting further investigation.

Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

Incidence of Gastrointestinal Bleeding After Transesophageal Echocardiography Use in Orthotopic Liver Transplantation.

The risk of upper gastrointestinal bleeding (UGIB) after transesophageal echocardiography (TEE) in patients with high grade esophageal varices (EV) that are undergoing Orthotopic Liver transplantation (OLT) is poorly understood. This was a retrospective single-centre cohort study in all patients that underwent OLT at Queen Elizabeth Hospital Birmingham between September 2016 and September 2018. The primary outcome was to determine the incidence of UGIB in patients that have undergone OLT with EV that received TEE. 401 patients were included in the study, of which 320 (80%) received TEE. The incidence of post-operative UGIB in patients that received TEE was 1.6% (5/320) in the entire cohort: 2.7% (4/149) in patients with no evidence of EV and 0.6% (1/171) in patients with EV. UGIB occurred in 1 patient with grade 2 EV and did not occur in patients with grade 1 or 3 EV. The incidence of UGIB in patients that received TEE was not statistically different to patients that did not: 1.6% (5/320) vs. 3.7% (3/81) p = 0.218. In conclusion, in patients that underwent OLT, intra-operative TEE use was associated with low rates of UGIB, even in cohorts with high grade EV. This suggests that TEE is a relatively safe method of haemodynamic monitoring in patients undergoing OLT.

Dysregulated Neutrophil Phenotype and Function in Hospitalised Non-ICU COVID-19 Pneumonia.

Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets. Objectives: Examine neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia patients (CAP). Methods: Isolated neutrophils underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NETosis and receptor expression. Circulating DNAse 1 activity, levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI were measured and correlated to clinical outcome. Serial sampling on day three to five post hospitalization were also measured. The effect of ex vivo PI3K inhibition was measured in a further cohort of 18 COVID-19 patients. Results: Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p = 0.0397) and NETosis (p = 0.0332), and impaired phagocytosis (p = 0.0036) associated with impaired ROS generation (p < 0.0001). The percentage of CD54+ neutrophils (p < 0.001) was significantly increased, while surface expression of CD11b (p = 0.0014) and PD-L1 (p = 0.006) were significantly decreased in COVID-19. COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p = 0.0396) and impaired DNAse activity (p < 0.0001). The ex vivo inhibition of PI3K γ and δ reduced NET release by COVID-19 neutrophils (p = 0.0129). Conclusions: COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration and NETosis, and impaired antimicrobial responses. These changes highlight that targeting neutrophil function may help modulate COVID-19 severity.

Vitamin D status: a U-shaped relationship for SARS-CoV-2 seropositivity in UK healthcare workers.

BACKGROUND: There is increasing evidence that vitamin D (VD) deficiency may increase individuals' risk of COVID-19 infection and susceptibility. We aimed to determine the relationship between VD deficiency and sufficiency and COVID-19 seropositivity within healthcare workers. METHODS: The study included an observational cohort of healthcare workers who isolated due to COVID-19 symptoms from 12 May to 22 May 2020, from the University Hospitals Birmingham National Health Service Foundation Trust. Data collected included SARS-CoV-2 seroconversion status, serum 25(OH)D3 levels, age, body mass index (BMI), sex, ethnicity, job role and comorbidities. Participants were grouped into four VD categories: (1) Severe VD deficiency (VD<30 nmol/L); (2) VD deficiency (30 nmol/L ≤VD<50 nmol/L); (3) VD insufficiency (50 nmol/L ≤VD<75 nmol/L); (4) VD sufficiency (VD≥75 nmol/L). RESULTS: When VD levels were compared against COVID-19 seropositivity rate, a U-shaped curve was identified. This trend repeated when participants were split into subgroups of age, sex, ethnicity, BMI and comorbidity status. Significant difference was identified in the COVID-19 seropositivity rate between VD groups in the total population and between groups of men and women; black, Asian and minority ethnic (BAME) group; BMI<30 (kg/m2); 0 and +1 comorbidities; the majority of which were differences when the severely VD deficient category were compared with the other groups. A larger proportion of those within the BAME group (vs white ethnicity) were severely VD deficient (p<0.00001). A larger proportion of the 0 comorbidity subgroup were VD deficient in comparison to the 1+ comorbidity subgroup (p=0.046). CONCLUSIONS: Our study has shown a U-shaped relationship for COVID-19 seropositivity in UK healthcare workers. Further investigation is required to determine whether high VD levels can have a detrimental effect on susceptibility to COVID-19 infection. Future randomised clinical trials of VD supplementation could potentially identify 'optimal' VD levels, allowing for targeted therapeutic treatment for those at risk.

Mechanisms of Post-critical Illness Cardiovascular Disease.

Prolonged critical care stays commonly follow trauma, severe burn injury, sepsis, ARDS, and complications of major surgery. Although patients leave critical care following homeostatic recovery, significant additional diseases affect these patients during and beyond the convalescent phase. New cardiovascular and renal disease is commonly seen and roughly one third of all deaths in the year following discharge from critical care may come from this cluster of diseases. During prolonged critical care stays, the immunometabolic, inflammatory and neurohumoral response to severe illness in conjunction with resuscitative treatments primes the immune system and parenchymal tissues to develop a long-lived pro-inflammatory and immunosenescent state. This state is perpetuated by persistent Toll-like receptor signaling, free radical mediated isolevuglandin protein adduct formation and presentation by antigen presenting cells, abnormal circulating HDL and LDL isoforms, redox and metabolite mediated epigenetic reprogramming of the innate immune arm (trained immunity), and the development of immunosenescence through T-cell exhaustion/anergy through epigenetic modification of the T-cell genome. Under this state, tissue remodeling in the vascular, cardiac, and renal parenchymal beds occurs through the activation of pro-fibrotic cellular signaling pathways, causing vascular dysfunction and atherosclerosis, adverse cardiac remodeling and dysfunction, and proteinuria and accelerated chronic kidney disease.

Impact of ethnicity on the accuracy of measurements of oxygen saturations: A retrospective observational cohort study.

Background: Pulse oximeters are routinely used in community and hospital settings worldwide as a rapid, non-invasive, and readily available bedside tool to approximate blood oxygenation. Potential racial biases in peripheral oxygen saturation (SpO2) measurements may influence the accuracy of pulse oximetry readings and impact clinical decision making. We aimed to assess whether the accuracy of oxygen saturation measured by SpO2, relative to arterial blood gas (SaO2), varies by ethnicity. Methods: In this large retrospective observational cohort study covering four NHS Hospitals serving a large urban population in Birmingham, United Kingdom, consecutive pairs of SpO2 and SaO2 measurements taken on the same patient within an interval of less than 20 min were identified from electronic patient records. Where multiple pairs of measurements were recorded in a spell, only the first was included in the analysis. The differences between SpO2 and SaO2 measurements were compared across groups of self-identified ethnicity. These differences were subsequently adjusted for age, sex, bilirubin, systolic blood pressure, carboxyhaemaglobin saturations and the time interval between SpO2 and SaO2 measurements. Findings: Paired O2 saturation measurements from 16,818 inpatient spells between 1st January 2017 and 18th February 2021 were analysed. The cohort self-identified as being of White (81.2%), Asian (11.7%), Black (4.0%), or Other (3.2%) ethnicities. Across the cohort, SpO2 was statistically significantly higher than SaO2 (p < 0.0001), with medians of 98% (interquartile range [IQR]: 95-100%) vs. 97% (IQR: 96-99%), and a median difference of 0.5% points (pps; 95% confidence interval [CI]: 0.5-0.6). However, the size of this difference varied considerably with the magnitude of SaO2, with SpO2 overestimating by a median by 3.8pp (IQR: 0.4, 8.8) for SaO2 values <90% but underestimating by a median of 0.4pp (IQR: -2.0, 1.4) for an SaO2 of 95%. The differences between SpO2 and SaO2 were also found to vary by ethnicity, with this difference being 0.8pp (95% CI: 0.6-1.0, p < 0.0001) greater in those of Black vs. White ethnicity. These differences resulted in 8.7% vs. 6.1% of Black vs. White patients who were classified as normoxic on SpO2 actually being hypoxic on the gold standard SaO2 (odds ratio: 1.47, 95% CI: 1.09-1.98, p = 0.012). Interpretation: Pulse oximetry may overestimate O2 saturation, and this is possibly more pronounced in patients of Black ethnicity. Prospective studies are urgently warranted to assess the impact of ethnicity on the accuracy of pulse oximetry, to ensure care is optimised for all. Funding: PIONEER, the Health Data Research UK (HDR-UK) Health Data Research Hub in acute care.

CD14-positive extracellular vesicles in bronchoalveolar lavage fluid as a new biomarker of acute respiratory distress syndrome.

Recent studies have indicated that extracellular vesicles (EVs) may play a role in the pathogenesis of acute respiratory distress syndrome (ARDS). EVs have been identified as potential biomarkers of disease severity and prognosis in other pulmonary diseases. We sought to characterize the EV phenotype within bronchoalveolar lavage (BAL) fluid of patients with ARDS, and to determine whether BAL EV could be used as a potential biomarker in ARDS. BAL was collected from patients with sepsis with and without ARDS, and from esophagectomy patients postoperatively (of whom a subset later developed ARDS during hospital admission). BAL EVs were characterized with regard to size, number, and cell of origin. Patients with sepsis-related ARDS had significantly higher numbers of CD14+/CD81+ monocyte-derived BAL EV than patients with sepsis without ARDS (P = 0.015). However, the converse was observed in esophagectomy patients who later developed ARDS (P = 0.003). Esophagectomy patients who developed ARDS also had elevated CD31+/CD63+ and CD31+/CD81+ endothelial-derived BAL EV (P ≤ 0.02) compared with esophagectomy patients who did not develop ARDS. Further studies are required to determine whether CD31+ BAL EV may be a predictive biomarker for ARDS in esophagectomy patients. CD14+/CD81+ BAL EV numbers were significantly higher in those patients with sepsis-related ARDS who died during the 30 days following intensive care unit admission (P = 0.027). Thus, CD14+/CD81+ BAL EVs are a potential biomarker for disease severity and mortality in sepsis-related ARDS. These findings provide the impetus to further elucidate the contribution of these EVs to ARDS pathogenesis.