Exhaled breath analysis for diagnosis of acute respiratory distress syndrome

Acute Respiratory Distress Syndrome (ARDS) is common in patients with respiratory failure in the intensive care unit (ICU). Despite improvements in ventilation strategies, a high mortality remains exceeding 40% in the severe cases. Numerous pathways involved in this syndrome are known, but the exact pathophysiology of ARDS is still not entirely clear. Also, it is not yet possible to capture the processes at the bedside. The greatest challenges remain the early and objective recognition of ARDS. One of the methods that might increase recognition is exhaled breath analysis. Assessment of breath biomarkers has the major advantage that it can be performed entirely non-invasive. In this thesis we focussed on non-invasive methods to diagnose ARDS. In a review minimally and non-invasive diagnostic methods assessing biological processes of ARDS on their diagnostic accuracy were listed, with taking into account the risk of bias. To gain insight in the reliability of the diagnosis, interobserver agreement among a panel of experts was quantified. To bring exhaled breath analysis from bench to bedside a number of steps were taken. A novel point-of-care (POC) breath test for ARDS diagnosis was created and validated. Subsequently the diagnostic accuracy of the POC breath test was assessed in a large multicentre observational cohort study. At last the rest of the breath pattern using gas chromatography and mass spectrometry was assessed on possible biomarkers for ARDS

Exhaled breath analysis for diagnosis of acute respiratory distress syndrome

Acute Respiratory Distress Syndrome (ARDS) is common in patients with respiratory failure in the intensive care unit (ICU). Despite improvements in ventilation strategies, a high mortality remains exceeding 40% in the severe cases. Numerous pathways involved in this syndrome are known, but the exact pathophysiology of ARDS is still not entirely clear. Also, it is not yet possible to capture the processes at the bedside. The greatest challenges remain the early and objective recognition of ARDS. One of the methods that might increase recognition is exhaled breath analysis. Assessment of breath biomarkers has the major advantage that it can be performed entirely non-invasive. In this thesis we focussed on non-invasive methods to diagnose ARDS. In a review minimally and non-invasive diagnostic methods assessing biological processes of ARDS on their diagnostic accuracy were listed, with taking into account the risk of bias. To gain insight in the reliability of the diagnosis, interobserver agreement among a panel of experts was quantified. To bring exhaled breath analysis from bench to bedside a number of steps were taken. A novel point-of-care (POC) breath test for ARDS diagnosis was created and validated. Subsequently the diagnostic accuracy of the POC breath test was assessed in a large multicentre observational cohort study. At last the rest of the breath pattern using gas chromatography and mass spectrometry was assessed on possible biomarkers for ARDS

Biological Subphenotypes of Acute Respiratory Distress Syndrome Show Prognostic Enrichment in Mechanically Ventilated Patients without Acute Respiratory Distress Syndrome

Rationale: Recent studies showed that biological subphenotypes in acute respiratory distress syndrome (ARDS) provide prognostic enrichment and show potential for predictive enrichment.Objectives: To determine whether these subphenotypes and their prognostic and potential for predictive enrichment could be extended to other patients in the ICU, irrespective of fulfilling the definition of ARDS.Methods: This is a secondary analysis of a prospective observational study of adult patients admitted to the ICU. We tested the prognostic enrichment of both cluster-derived and latentclass analysis (LCA)-derived biological ARDS subphenotypes by evaluating the association with clinical outcome (ICU-day, 30-day mortality, and ventilator-free days) using logistic regression and Cox regression analysis. We performed a principal component analysis to compare blood leukocyte gene expression profiles between subphenotypes and the presence of ARDS.Measurements and Main Results: We included 2,499 mechanically ventilated patients (674 with and 1,825 without ARDS). The cluster-derived "reactive" subphenotype was, independently of ARDS, significantly associated with a higher probability of ICU mortality, higher 30-day mortality, and a lower probability of successful extubation while alive compared with the "uninflamed" subphenotype. The blood leukocyte gene expression profiles of individual subphenotypes were similar for patients with and without ARDS. LCA-derived subphenotypes also showed similar profiles.Conclusions: The prognostic and potential for predictive enrichment of biological ARDS subphenotypes may be extended to mechanically ventilated critically ill patients without ARDS. Using the concept of biological subphenotypes for splitting cohorts of critically ill patients could add to improving future precision-based trial strategies and lead to identifying treatable traits for all critically ill patients

ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells

BACKGROUND\nMETHODS\nRESULTS\nCONCLUSION\nPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim of this study was to investigate mechanisms underlying paclitaxel resistance in PDAC and explore strategies to overcome it.\nThree paclitaxel (PR) and gemcitabine resistant (GR) PDAC models were established. Transcriptomics and proteomics were used to identify conserved mechanisms of drug resistance. Genetic and pharmacological approaches were used to overcome paclitaxel resistance.\nUpregulation of ABCB1 through locus amplification was identified as a conserved feature unique to PR cells. ABCB1 was not affected in any of the GR models and no cross resistance was observed. The ABCB1 inhibitor verapamil or siRNA-mediated ABCB1 depletion sensitized PR cells to paclitaxel and prevented efflux of ABCB1 substrates in all models. ABCB1 expression was associated with a trend towards shorter survival in patients who had received gemcitabine/nab-paclitaxel treatment. A pharmacological screen identified known and novel kinase inhibitors that attenuate efflux of ABCB1 substrates and sensitize PR PDAC cells to paclitaxel.\nUpregulation of ABCB1 through locus amplification represents a novel, conserved mechanism of PDAC paclitaxel resistance. Kinase inhibitors identified in this study can be further (pre) clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC.Toxicolog

A lower global lung ultrasound score is associated with higher likelihood of successful extubation in invasively ventilated COVID-19 patients

Lung ultrasound (LUS) can be used to assess loss of aeration, which is associated with outcome in patients with coronavirus disease 2019 (COVID-19) presenting to the emergency department. We hypothesized that LUS scores are associated with outcome in critically ill COVID-19 patients receiving invasive ventilation. This retrospective international multicenter study evaluated patients with COVID-19-related acute respiratory distress syndrome (ARDS) with at least one LUS study within 5 days after invasive mechanical ventilation initiation. The global LUS score was calculated by summing the 12 regional scores (range 0-36). Pleural line abnormalities and subpleural consolidations were also scored. The outcomes were successful liberation from the ventilator and intensive care mortality within 28 days, analyzed with multistate, competing risk proportional hazard models. One hundred thirty-seven patients with COVID-19-related ARDS were included in our study. The global LUS score was associated with successful liberation from mechanical ventilation (hazard ratio [HR]: 0.91 95% confidence interval [CI] 0.87-0.96; P = 0.0007) independently of the ARDS severity, but not with 28 days mortality (HR: 1.03; 95% CI 0.97-1.08; P = 0.36). Subpleural consolidation and pleural line abnormalities did not add to the prognostic value of the global LUS score. Examinations within 24 hours of intubation showed no prognostic value. To conclude, a lower global LUS score 24 hours after invasive ventilation initiation is associated with increased probability of liberation from the mechanical ventilator COVID-19 ARDS patients, independently of the ARDS severity.Pathogenesis and treatment of chronic pulmonary disease

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged >= 18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10).Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0.95 [95% CI 0.76-1.20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0.51 [0.27-0.95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0.52 (95% CI 0.26-1.05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1.07 (0.63-1.80; p=0.81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0.0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. Copyright (C) 2021 Elsevier Ltd. All rights reserved.Pathogenesis and treatment of chronic pulmonary disease

Exhaled breath analysis for diagnosis of acute respiratory distress syndrome

Acute Respiratory Distress Syndrome (ARDS) is common in patients with respiratory failure in the intensive care unit (ICU). Despite improvements in ventilation strategies, a high mortality remains exceeding 40% in the severe cases. Numerous pathways involved in this syndrome are known, but the exact pathophysiology of ARDS is still not entirely clear. Also, it is not yet possible to capture the processes at the bedside. The greatest challenges remain the early and objective recognition of ARDS. One of the methods that might increase recognition is exhaled breath analysis. Assessment of breath biomarkers has the major advantage that it can be performed entirely non-invasive. In this thesis we focussed on non-invasive methods to diagnose ARDS. In a review minimally and non-invasive diagnostic methods assessing biological processes of ARDS on their diagnostic accuracy were listed, with taking into account the risk of bias. To gain insight in the reliability of the diagnosis, interobserver agreement among a panel of experts was quantified. To bring exhaled breath analysis from bench to bedside a number of steps were taken. A novel point-of-care (POC) breath test for ARDS diagnosis was created and validated. Subsequently the diagnostic accuracy of the POC breath test was assessed in a large multicentre observational cohort study. At last the rest of the breath pattern using gas chromatography and mass spectrometry was assessed on possible biomarkers for ARDS

Systematic review of diagnostic methods for acute respiratory distress syndrome

Rationale: Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin definition, which does not include a direct measure of pulmonary oedema, endothelial permeability or pulmonary inflammation. We hypothesised that biomarkers of these processes have good diagnostic accuracy for ARDS.Methods: Medline and Scopus were searched for original diagnostic studies using minimally invasive testing. Primary outcome was the diagnostic accuracy per test and was categorised by control group. The methodological quality was assessed with QUADAS-2 tool. Biomarkers that had an area under the receiver operating characteristic curve (AUROCC) of >0.75 and were studied with minimal bias against an unselected control group were considered to be promising.Results: Forty-four articles were included. The median AUROCC for all evaluated tests was 0.80 (25th to 75th percentile: 0.72-0.88). The type of control group influenced the diagnostic accuracy (p=0.0095). Higher risk of bias was associated with higher diagnostic accuracy (AUROCC 0.75 for low-bias, 0.77 for intermediate-bias and 0.84 for high-bias studies; p=0.0023). Club cell protein 16 and soluble receptor for advanced glycation end-products in plasma and two panels with biomarkers of oxidative stress in breath showed good diagnostic accuracy in low-bias studies that compared ARDS patients to an unselected intensive care unit (ICU) population.Conclusion: This systematic review revealed only four diagnostic tests fulfilling stringent criteria for a promising biomarker in a low-bias setting. For implementation into the clinical setting, prospective studies in a general unselected ICU population with good methodological quality are needed

Assessment of the Effect of Recruitment Maneuver on Lung Aeration Through Imaging Analysis in Invasively Ventilated Patients: A Systematic Review

Background: Recruitment maneuvers (RMs) have heterogeneous effects on lung aeration and have adverse side effects. We aimed to identify morphological, anatomical, and functional imaging characteristics that might be used to predict the RMs on lung aeration in invasively ventilated patients.Methods: We performed a systemic review. Studies included invasively ventilated patients who received an RM and in whom re-aeration was examined with chest computed tomography (CT), electrical impedance tomography (EIT), and lung ultrasound (LUS) were included.Results: Twenty studies were identified. Different types of RMs were applied. The amount of re-aerated lung tissue after an RM was highly variable between patients in all studies, irrespective of the used imaging technique and the type of patients (ARDS or non-ARDS). Imaging findings suggesting a non-focal morphology (i.e., radiologic findings consistent with attenuations with diffuse or patchy loss of aeration) were associated with higher likelihood of recruitment and lower chance of overdistention than a focal morphology (i.e., radiological findings suggestive of lobar or segmental loss of aeration). This was independent of the used imaging technique but only observed in patients with ARDS. In patients without ARDS, the results were inconclusive.Conclusions: ARDS patients with imaging findings suggestive of non-focal morphology show most re-aeration of previously consolidated lung tissue after RMs. The role of imaging techniques in predicting the effect of RMs on re-aeration in patients without ARDS remains uncertain

Diagnosis of acute respiratory distress syndrome (DARTS) by bedside exhaled breath octane measurements in invasively ventilated patients: protocol of a multicentre observational cohort study

Background: Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin Definition. Diagnosis is subjective and often late. Untargeted metabolomics analysis of exhaled breath with gas chromatography and mass spectrometry (GC-MS) showed that the breath concentration of octane has a high diagnostic accuracy for ARDS. To facilitate rapid bedside measurement of this biomarker, a point-of care (POC) breath test was developed. A prototype already showed good reproducibility and repeatability for the detection of octane. In this study we aim to measure octane in exhaled breath of invasively ventilated intensive care unit (ICU) patients and validate the diagnostic accuracy of the breath test for the early diagnosis of ARDS. Methods: This is a multicentre observational cohort study in patients admitted to the ICU receiving invasive ventilation for at least 24 hours. At least 500 patients in two academic hospitals in The Netherlands will be included. ARDS patients will be compared to patients without ARDS. ARDS diagnosis will be based on the Berlin Definition. Two diagnostic assessments will be performed during the first 72 hours of invasive ventilation, including breath sampling, arterial blood gas analysis and lung ultrasound (LUS). In patients fulfilling the criteria for ARDS, three additional breath samples will be taken to assess resolution. The primary endpoint is the diagnostic accuracy for ARDS, defined by the area under the receiver operating characteristics curve (AUROCC) of octane concentration in exhaled breath. Secondary endpoints are the association between exhaled breath octane and ARDS adjusted for confounders, and the added diagnostic accuracy of the breath test on top of the Lung Injury Prediction Score (LIPS). Discussion: This is the first study that validates a metabolic biomarker of ARDS in an adequate sample size. The major novelty is the use of a POC breath test that has been specifically developed for the purpose of diagnosing ARDS. Strengths are; assessment in the early phase, in patients at risk for ARDS, longitudinal sampling and an expert panel to reliably diagnose ARDS. This study will provide a decisive answer on the question if exhaled breath metabolomics can be used to diagnose ARDS. Trial registration: The trial is registered at trialregister.nl (ID: NL8226) with the tag "DARTS"