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Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19-related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42-0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42-0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19-related ARDS.

Background With the continued advancement of CFTR modulator therapies there is likely to be a burgeoning population of adult cystic fibrosis (CF) patients unable to expectorate sputum. Consequently, the detection and surveillance of pulmonary colonisation, previously reliant on sputum culture, needs re-examining. We hypothesised that cough swabs analysed with culture-independent analysis of the 16S gene could serve as a surrogate for colonisation of the lower airways. Methods Cough swabs and sputum samples were prospectively collected from consecutive adults and children with CF across two sites at regular outpatient appointments. Conventional culture analysis and next generation sequencing were used to compare paired same day samples. Results Twenty-two adults and 8 paediatric patients provided 75 paired cough swabs and sputum samples. Alpha diversity measures showed increased bacterial richness in sputum, while evenness and Simpson's diveristy index were higher in cough swabs. Within each sampling technique, microbial composition showed greater similarity when considering intra-patient variation. Poor concordance was observed between culture independent cough swabs and culture dependent/independent sputum analysis for specific pathogens, with cough swabs unable to accurately identify commonly associated CF pathogens (AUROCC range: 0.51 to 0.64). Conclusion Culture independent analysis of cough swabs provides an inaccurate diagnosis of lower respiratory tract colonisation and should not be used as a diagnostic test in patients with CF.

Background: Lung ultrasound (LUS) is a non-invasive method to detect and quantify pulmonary edema. However, it remains uncertain how components of the LUS examination should be aggregated into a score for quantifying pulmonary edema. We examined the diagnostic accuracy of various LUS scores with the extravascular lung water index (EVLWi) assessed with PiCCO in patients with moderate-to-severe COVID-19 ARDS. Methods: In this predefined secondary analysis of a multicenter randomized-controlled trial (InventCOVID), patients were included within 48h after intubation and underwent LUS and EVLWi measurement at two time points (first and fourth study day). EVLWi and ∆EVLWi were used as reference standard. Two 12-region scores (global LUS and LUS-ARDS), an 8-region anterior-lateral score and a 4-region B-line score were used as index tests. Pearson correlation was performed and the area under the receiver operating characteristics curve (AUROCC) for severe pulmonary edema (EVLWi>15mL/kg) was calculated. Results: 26 of 30 patients (87%) had complete LUS and EVLWi measurements at time point 1 and 24 of 29 patients (83%) at time point 2. The global LUS (r=0.54), LUS-ARDS (r=0.58) and anterior-lateral score (r=0.54) were significantly correlated with EVLWi, while the B-line score was not (r=0.32). ∆global LUS (r=0.49) and ∆anterior-lateral LUS (r=0.52) were significantly correlated with ∆EVLWi, while correlation of ∆LUS-ARDS (r=0.43) and ∆B-lines (r=0.32) did not reach statistical significance. AUROCC for EVLWi>15ml/kg was 0.73 for the global LUS, 0.79 for the anterior-lateral and 0.85 for the LUS-ARDS score. Conclusions: The global LUS, LUS-ARDS and antero-lateral score can quantify PiCCO-derived pulmonary edema measurements in COVID-19 ARDS. The LUS-ARDS score showed the highest diagnostic accuracy for severe pulmonary edema. Trial registration: ClinicalTrials.gov identifier NCT04794088, registered on 11 March 2021. European Clinical Trials Database number 2020-005447-23.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome that manifests secondary to numerous etiologic insults, and consequently it is associated with a multitude of pathophysiological abnormalities. Despite more than 50 years of experimental studies, translation of these benchside discoveries into effective biological therapies has been elusive. In this review, some of the key advances made in our knowledge of the pathophysiology of ARDS, based on histopathology, imaging, protein, and transcriptomic biomarkers, are presented. Finally, the role of such human studies in understanding the pathophysiology of coronavirus disease 2019-related ARDS is reviewed.

Background Ventilator-associated pneumonia (VAP) is associated with high morbidity and health care costs, yet diagnosis remains a challenge. Analysis of airway microbiota by amplicon sequencing provides a possible solution, as pneumonia is characterised by a disruption of the microbiome. However, studies evaluating the diagnostic capabilities of microbiome analysis are limited, with a lack of alignment on possible biomarkers. Using bronchoalveolar lavage fluid (BALF) from ventilated adult patients suspected of VAP, we aimed to explore how key characteristics of the microbiome differ between patients with positive and negative BALF cultures and whether any differences could have a clinically relevant role. Methods BALF from patients suspected of VAP was analysed using 16s rRNA sequencing in order to: (1) differentiate between patients with and without a positive culture; (2) determine if there was any association between microbiome diversity and local inflammatory response; and (3) correctly identify pathogens detected by conventional culture. Results Thirty-seven of 90 ICU patients with suspected VAP had positive cultures. Patients with a positive culture had significant microbiome dysbiosis with reduced alpha diversity. However, gross compositional variance was not strongly associated with culture positivity (AUROCC range 0.66–0.71). Patients with a positive culture had a significantly higher relative abundance of pathogenic bacteria compared to those without [0.45 (IQR 0.10–0.84), 0.02 (IQR 0.004–0.09), respectively], and an increased interleukin (IL)-1β was associated with reduced species evenness (rs = − 0.33, p rs = 0.28, p = 0.013). Untargeted 16s rRNA pathogen detection was limited by false positives, while the use of pathogen-specific relative abundance thresholds showed better diagnostic accuracy (AUROCC range 0.89–0.998). Conclusion Patients with positive BALF culture had increased dysbiosis and genus dominance. An increased caspase-1-dependent IL-1b expression was associated with a reduced species evenness and increased pathogenic bacterial presence, providing a possible causal link between microbiome dysbiosis and lung injury development in VAP. However, measures of diversity were an unreliable predictor of culture positivity and 16s sequencing used agnostically could not usefully identify pathogens; this could be overcome if pathogen-specific relative abundance thresholds are used.

Two patients with respiratory failure due to confirmed COVID-19 were examined using bedside lung ultrasound (LUS) shortly after intubation and start of invasive ventilation. In the first patient, LUS revealed extensive atelectatic areas. A recruitment maneuver was applied, resulting in some reaeration of areas that showed atelectasis, and some improvement in oxygenation was observed. Oxygenation improved further with the use of prone positioning. In the second patient, LUS showed diffuse abnormalities without atelectatic areas, and ventilation proceeded without a recruitment maneuver but with prone positioning. These two cases illustrate how LUS could be useful in identifying different lung morphologies early after the start of invasive ventilation and help decide on adjunctive therapies. This has possible implications for ventilator management in resource-limited settings, with limited availability of chest computed tomography and blood gas analyzers. Tailoring invasive ventilation based on LUS findings early after the start of invasive ventilation is feasible, but this should be further evaluated in future studies.

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Funder: Amsterdam UMC, Funder: Health Holland, Funder: Dutch lung foundation, Funder: Innovative Medicines Initiative, The pathophysiology of acute respiratory distress syndrome (ARDS) includes the accumulation of protein-rich pulmonary edema in the air spaces and interstitial areas of the lung, variable degrees of epithelial injury, variable degrees of endothelial barrier disruption, transmigration of leukocytes, alongside impaired fluid and ion clearance. These pathophysiological features are different between patients contributing to substantial biological heterogeneity. In this context, it is perhaps unsurprising that a wide range of pharmacological interventions targeting these pathophysiological processes have failed to improve patient outcomes. In this manuscript, our goal is to provide a narrative summary of the potential methods to capture the underlying biological heterogeneity of ARDS and discuss how this information could inform future ARDS redefinitions. We discuss what biological tests are available to identify patients with any of the following predominant biological patterns: (1) epithelial and/or endothelial injury, (2) protein rich pulmonary edema and (3) systemic or within lung inflammatory responses.

The objective of the study was to determine the association between right ventricular (RV) myocardial performance index (MPI) and successful liberation from the ventilator and death within 28 days.A total of 81 patients underwent transthoracic echocardiography at median 30 (24-42) h after the start of ventilation-in 73 (90%) patients, the RV-MPI could be collected. A total of 56 (77%) patients were successfully liberated from the ventilator28 days; A total of 22 (30%) patients had died before or at day 28. A total of 18 (25%) patients had an abnormal RV-MPI. RV-MPI was neither associated with successful liberation from the ventilator within 28 days [HR, 2.2 (95% CI 0.47-10.6);In invasively ventilated critically ill patients without ARDS, an abnormal RV-MPI indicative of RV dysfunction was not associated with time to liberation from invasive ventilation.

The pathophysiology of acute respiratory distress syndrome (ARDS) includes the accumulation of protein-rich pulmonary edema in the air spaces and interstitial areas of the lung, variable degrees of epithelial injury, variable degrees of endothelial barrier disruption, transmigration of leukocytes, alongside impaired fluid and ion clearance. These pathophysiological features are different between patients contributing to substantial biological heterogeneity. In this context, it is perhaps unsurprising that a wide range of pharmacological interventions targeting these pathophysiological processes have failed to improve patient outcomes. In this manuscript, our goal is to provide a narrative summary of the potential methods to capture the underlying biological heterogeneity of ARDS and discuss how this information could inform future ARDS redefinitions. We discuss what biological tests are available to identify patients with any of the following predominant biological patterns: (1) epithelial and/or endothelial injury, (2) protein rich pulmonary edema and (3) systemic or within lung inflammatory responses.

Rationale: Myocardial injury occurs frequently during sepsis and is independently associated with mortality. However, its etiology remains largely unknown. Objectives: To assess the relative contributions of hyperinflammation, activated coagulation, and endothelial dysfunction to myocardial injury in critically ill patients with sepsis. Methods: We included consecutive patients with sepsis presenting to two tertiary intensive care units in the Netherlands between 2011 and 2013. High-sensitivity cardiac troponin I as well as a wide range of plasma biomarkers related to inflammation, coagulation, and endothelial function were measured. Structural equation modeling was used to construct latent variables representing each of these pathophysiological constructs and to subsequently study their associations with troponin elevation while adjusting for confounders. Results: We analyzed 908 (88%) of 1,037 eligible patients, 553 (61%) of whom had raised high-sensitivity cardiac troponin I levels upon intensive care unit admission. The latent variables included interleukin (IL)-6, IL-8, and IL-1b for inflammation; platelet count, prothrombin time, and protein C for coagulation; and soluble E-selectin, intercellular adhesion molecule-1, and angiopoietin-2 for endothelial function. After adjustment for age and cardiovascular comorbidities, structural equation modeling analysis showed that activated coagulation was independently associated with elevated troponin during sepsis (standardized regression coefficient, 0.551; 95% confidence interval [CI], 0.257-0.845; P,0.001) whereas hyperinflammation and endothelial dysfunction were not (standardized regression coefficient, 20.161; 95% CI, 20.418 to 0.096 and 20.054; 95% CI, 20.168 to 0.060, respectively). Conclusions: Our findings suggest that myocardial injury during sepsis is mediated by systemic activation of coagulation rather than by circulating inflammatory mediators or activation of the endothelium. These findings may guide evaluation of strategies to protect the myocardium during sepsis. Clinical trial registered with clinicaltrials.gov (NCT01905033).

Introduction It is highly uncertain whether volatile organic compounds (VOCs) in exhaled breath of critically ill intensive care unit patients are formed in the lung locally, in the air compartment or lung tissue, or elsewhere in the body and transported to the lung via the bloodstream. We compared VOC mixtures in exhaled breath and in air coming from extracorporeal support devices in critically ill patients to address this issue. Methods First, we investigated whether it was safe to connect an electronic nose (eNose) or a gas sampling pump to extracorporeal support membranes. Then, breath and air from extracorporeal support devices were collected simultaneously for continuous monitoring of VOC mixtures using an eNose. In addition, samples for gas chromatography/mass spectrometry (GC-MS) analysis were taken daily at the two measurement sites. Results 10 critically ill patients were monitored for a median (interquartile range) duration of 73 (72–113) h; in total, we had 887 h of air sampling. The eNose signals of breath correlated moderately with signals of air from the extracorporeal support devices (R2=0.25–0.44). After GC-MS analysis, 96 VOCs were found both in breath and air from the extracorporeal support devices; of these, 29 (30%) showed a significant correlation (p, Systemically produced VOCs in exhaled breath and extracorporeal circulation correlate well. About one in three VOCs do not correlate and are found in higher concentrations in breath, suggesting pulmonary production of these VOCs. http://ow.ly/cbjt30nMXY5

Introduction: Awake proning may result in lower intubation and mortality rates in COVID-19 patients with hypoxemia refractory to simple oxygen therapy. Aims. To summarize available evidence for benefit and develop a set of pragmatic recommendations for awake proning in COVID-19 patients. Methods. An international group of 43 healthcare professionals searched MEDLINE for articles on awake proning, and formulated recommendations for its use. Results. The professionals reached consensus regarding indications and contraindications, feasibility and safety; they recommended applying awake proning if SpO2/FiO2 < 315, or SpO2 < 93% under supplementary oxygen, and if patient is able to follow instructions. Severe hypoxemia (SpO2/FiO2 < 140) and hemodynamic instability are absolute contraindications in the ward, but relative contraindications in the ICU. Morbid obesity was also seen as a relative contraindication, depending on assistance needed to help turn the patient. Pregnancy was not seen as a contraindication, but extra monitoring in the last trimester was seen as mandatory, and extra pillows for stabilization and prevention of aortocaval compression are necessary. Five steps may improve safety: i. adequate patient information; ii. help in positioning; iii. ensuring oxygen supply and placing of tubing free at sight; iv. optimized position to prevent harm; and v. monitor oxygen saturation and respiratory rate. Dissensus remained regarding duration, and number of sessions per day, and use of sedation during prone positioning. Conclusion. Awake proning is an attractive, simple and safe way to improve oxygenation in hypoxemic COVID–19 patients. Studies remain needed to see if it effects intubation and mortality rates.

Background: There is a demand for a non-invasive bedside method to diagnose Acute Respiratory Distress Syndrome (ARDS). Octane was discovered and validated as the most important breath biomarker for diagnosis of ARDS using gas-chromatography and mass-spectrometry (GC-MS). However, GC-MS is unsuitable as a point-of-care (POC) test in the intensive care unit (ICU). Therefore, we determined if a newly developed POC breath test can reliably detect octane in exhaled breath of invasively ventilated ICU patients. Methods: Two developmental steps were taken to design a POC breath test that relies on gas-chromatography using air as carrier gas with a photoionization detector. Calibration measurements were performed with a laboratory prototype in healthy subjects. Subsequently, invasively ventilated patients were included for validation and assessment of repeatability. After evolving to a POC breath test, this device was validated in a second group of invasively ventilated patients. Octane concentration was based on the area under the curve, which was extracted from the chromatogram and compared to known values from calibration measurements. Results: Five healthy subjects and 53 invasively ventilated patients were included. Calibration showed a linear relation (R2 = 1.0) between the octane concentration and the quantified octane peak in the low parts per billion (ppb) range. For the POC breath test the repeatability was excellent (R2 = 0.98, ICC = 0.97 (95% CI 0.94–0.99)). Conclusion: This is the first study to show that a POC breath test can rapidly and reliably detect octane, with excellent repeatability, at clinically relevant levels of low ppb in exhaled breath of ventilated ICU patients. This opens possibilities for targeted exhaled breath analysis to be used as a bedside test and makes it a potential diagnostic tool for the early detection of ARDS.

Background: The identification of phenotypes based on lung morphology can be helpful to better target mechanical ventilation of individual patients with acute respiratory distress syndrome (ARDS). We aimed to assess the accuracy of lung ultrasound (LUS) methods for classification of lung morphology in critically ill ARDS patients under mechanical ventilation. Methods: This was a post hoc analysis on two prospective studies that performed LUS and chest computed tomography (CT) scanning at the same time. Expert panels from the two participating centers separately developed two LUS methods for classifying lung morphology based on LUS aeration scores from a 12-region exam (Amsterdam and Lombardy method). Moreover, a previously developed LUS method based on anterior LUS scores was tested (Piedmont method). Sensitivity and specificity of all three LUS methods was assessed in the cohort of the other center(s) by using CT as the gold standard for classification of lung morphology. Results: The Amsterdam and Lombardy cohorts consisted of 32 and 19 ARDS patients, respectively. From these patients, 23 (45%) had focal lung morphology while others had non-focal lung morphology. The Amsterdam method could classify focal lung morphology with a sensitivity of 77% and a specificity of 100%, while the Lombardy method had a sensitivity and specificity of 100 and 61%. The Piedmont method had a sensitivity and specificity of 91 and 75% when tested on both cohorts. With both the Amsterdam and Lombardy method, most patients could be classified based on the anterior regions alone. Conclusion: LUS-based methods can accurately classify lung morphology in invasively ventilated ARDS patients compared to gold standard chest CT. The anterior LUS regions showed to be the most discriminant between focal and non-focal lung morphology, although accuracy increased moderately when lateral and posterior LUS regions were integrated in the method., SCOPUS: ar.j, info:eu-repo/semantics/published

INTRODUCTION Surrogates for impaired ventilation such as estimated dead-space fractions and the ventilatory ratio are independently associated with an increased risk of mortality in the acute respiratory distress syndrome (ARDS) and small case series of COVID-19 related ARDS. METHODS This study aimed to quantify the dynamics and determine the prognostic value of surrogate markers of impaired ventilation in patients with COVID-19 related ARDS. The present study is a secondary analysis of the PRactice Of VENTilation in COVID-19 patients (PROVENT-COVID) in 22 intensive care unit hospitals in the Netherlands. Surrogates of impaired ventilation such as the estimated dead space fraction (by Harris-Benedict-VD/VT HB and direct method-VD/VT DIR), ventilatory ratio (VR), and end-tidal-to-arterial PCO2 ratio (PETCO2/PaCO2) were used. RESULTS 927 consecutive patients admitted with COVID-19 related ARDS were included in this study. Surrogates of impaired ventilation were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p

Background: Patients with coronavirus disease 2019 (COVID-19) may need hospitalization for supplemental oxygen, and some need intensive care unit (ICU) admission for escalation of care. Practice of adjunctive and supportive treatments remain uncertain and may vary widely between countries, within countries between hospitals, and possibly even within ICUs. We aim to investigate practice of adjunctive and supportive treatments, and their associations with outcome, in critically ill COVID-19 patients.Methods: The 'PRactice of Adjunctive Treatments in Intensive Care Unit Patients with Coronavirus Disease 2019' (PRoAcT-COVID) study is a national, observational study to be undertaken in a large set of ICUs in The Netherlands. The PRoAcT-COVID includes consecutive ICU patients, admitted because of COVID-19 to one of the participating ICUs during a 3-month period. Daily follow-up lasts 28 days. The primary endpoint is a combination of adjunctive treatments, including types of oxygen support, ventilation, rescue therapies for hypoxemia refractory to supplementary oxygen or during invasive ventilation, other adjunctive and supportive treatments, and experimental therapies. We will also collect tracheostomy rate, duration of invasive ventilation and ventilator-free days and alive at day 28 (VFD-28), ICU and hospital length of stay, and the mortality rates in the ICU, hospital and at day 90.Discussion: The PRoAcT-COVID study is an observational study combining high density treatment data with relevant clinical outcomes. Information on treatment practices, and their associations with outcomes in COVID-19 patients in highly and urgently needed. The results of the PRoAcT-COVID study will be rapidly available, and circulated through online presentations, such as webinars and electronic conferences, and publications in peer-reviewed journals-findings will also be presented at a dedicated website. At request, and after agreement of the PRoAcT-COVID steering committee, source data will be made available through local, regional and national anonymized datasets.Trial registration: The PRoAcT-COVID study is registered at clinicaltrials.gov (study identifier NCT04719182).

Background: Surrogates for impaired ventilation such as estimated dead-space fractions and the ventilatory ratio have been shown to be independently associated with an increased risk of mortality in the acute respiratory distress syndrome and small case series of COVID-19 related ARDS. Methods: Secondary analysis from the PRoVENT-COVID study. The PRoVENT-COVID is a national, multicentre, retrospective observational study done at 22 intensive care units in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The aim was to quantify the dynamics and determine the prognostic value of surrogate markers of impaired ventilation patients with COVID-19 related ARDS. Results: 927 consecutive patients admitted with COVID-19 related ARDS were included in this study. Surrogates of impaired ventilation such as the estimated dead space fraction (by Harris-Benedict and direct method) and ventilatory ratio were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p 2 ratio was lower in non-survivors than in survivors (p2 ratio. After adjustment for a base risk model that included chronic comorbidities and ventilation- and oxygenation-parameters, none of the surrogates of impaired ventilation measured at the start of ventilation or the following days were significantly associated with 28-day mortality.Conclusions: There is significant impairment of ventilation in the early course of COVID-19 related ARDS but quantification of this impairment does not add prognostic information when added to a baseline risk-model.

Many patients with acute respiratory failure fulfill the diagnosis of Acute Respiratory Distress Syndrome (ARDS), forming a very heterogeneous population. Clinical trials have not yielded beneficial treatment effects in ARDS, possibly caused by this heterogeneity. Dividing patients with ARDS into subgroups, each with similar characteristics, may result in improved treatment strategies as part of a precision medicine approach. In this systematic review, we summarize the subphenotypes identified so far, the current state, and future directions for precision medicine in ARDS. Multiple data-driven subphenotypes have been identified based on a wide range of variables. These subphenotypes are associated with differences in clinical outcomes, which could be used for prognostic- and predictive enrichment of future interventional studies. True treatable traits have not been identified yet, deeper phenotyping will hopefully reveal these along with mechanistic differences.

Background Alkaline phosphatase (AP), a dephosphorylating enzyme, is involved in various physiological processes and has been shown to have anti-inflammatory effects. Aim To determine the correlation between pulmonary AP activity and markers of inflammation in invasively ventilated critically ill patients with or without acute respiratory distress syndrome (ARDS), and to investigate the effect of administration of recombinant AP on pulmonary inflammation in a well-established lung injury model in rats Methods AP activity was determined and compared with levels of various inflammatory mediators in bronchoalveolar lavage fluid (BALF) samples obtained from critically ill patients within 2 days of start of invasive ventilation. The endpoints of this part of the study were the correlations between AP activity and markers of inflammation, i.e., interleukin (IL)-6 levels in BALF. In RccHan Wistar rats, lung injury was induced by intravenous administration of 10 mg/kg lipopolysaccharide, followed by ventilation with a high tidal volume for 4 h. Rats received either an intravenous bolus of 1500 IU/kg recombinant AP or normal saline 2 h after intravenous LPS administration, right before start of ventilation. Endpoints of this part of the study were pulmonary levels of markers of inflammation, including IL-6, and markers of endothelial and epithelial dysfunction. Results BALF was collected from 83 patients; 10 patients had mild ARDS, and 15 had moderate to severe ARDS. AP activity correlated well with levels of IL-6 (r = 0.70), as well as with levels of other inflammatory mediators. Pulmonary AP activity between patients with and without ARDS was comparable (0.33 [0.14–1.20] vs 0.55 [0.21–1.42] U/L; p = 0.37). Animals with acute lung injury had markedly elevated pulmonary AP activity compared to healthy controls (2.58 [2.18–3.59] vs 1.01 [0.80–1.46] U/L; p < 0.01). Intravenous administration of recombinant AP did neither affect pulmonary inflammation nor endothelial and epithelial dysfunction. Conclusions In ventilated critically ill patients, pulmonary AP activity correlates well with markers of pulmonary inflammation, such as IL-6 and IL-8. In animals with lung injury, pulmonary AP activity is elevated. Administration of recombinant AP does not alter pulmonary inflammation and endothelial or epithelial dysfunction in the acute phase of a murine lung injury model.

Supplemental Digital Content is available in the text., Objectives: Previous studies demonstrated that extensive fluid loading and consequently positive fluid balances during sepsis resuscitation are associated with adverse outcome. Yet, the association between fluid balance and mortality after reversal of shock, that is, during deresuscitation, is largely unappreciated. Our objective was to investigate the effects of fluid balance on mortality in the days after septic shock reversal. Design: Retrospective observational cohort study. Setting: ICUs of two university-affiliated hospitals in The Netherlands. Patients: Adult patients admitted with septic shock followed by shock reversal. Reversal of septic shock was defined based on Sepsis-3 criteria as the first day that serum lactate was less than or equal to 2 mmol/L without vasopressor requirement. Interventions: None. Measurements and Main Results: Reversal of septic shock occurred in 636 patients, of whom 20% died in the ICU. Mixed-effects logistic regression modeling, adjusted for possible confounders, showed that fluid balance in the days after reversal of septic shock (until discharge or death) was an independent predictor of ICU mortality: odds ratio 3.18 (1.90–5.32) per 10 mL/kg increase in daily fluid balance. Similar results were found for 30-day, 90-day, hospital, and 1-year mortality: odds ratios 2.09 (1.64–2.67); 1.79 (1.38–2.32); 1.70 (1.40–2.07); and 1.53 (1.17–2.01), respectively. Positive cumulative fluid balances vs. neutral or negative fluid balances on the final day in the ICU were associated with increased ICU, hospital, 30-day, and 90-day mortality: odds ratios 3.46 (2.29–5.23); 3.39 (2.35–4.9); 5.33 (3.51–8.08); and 3.57 (2.49–5.12), respectively. Using restricted cubic splines, we found a dose-response relationship between cumulative fluid balance after shock reversal and ICU mortality. Conclusions: A higher fluid balance in the days after septic shock reversal was associated with increased mortality. This stresses the importance of implementing restrictive and deresuscitative fluid management strategies after initial hemodynamic resuscitation. Prospective interventional studies are needed to confirm our results.

Background: Outcome prediction in invasively ventilated ICU patients remains challenging. Driving pressure (ΔP) and mechanical power of ventilation (MP) are associated with outcomes like mortality. The objective of this study was to assess the predictive validity for mortality of ΔP and MP at 24h after start of invasive ventilation. Methods: Posthoc analysis of MARS, a large observational study in two Dutch ICUs. Patients having received invasive ventilation >24h were selected. The primary outcome was 90–day mortality. The predictive validity of ΔP and MP was measured as incremental 90–day mortality beyond that predicted by the Acute Physiology, Age and Chronic Health Evaluation (APACHE) IV score or the Simplified Acute Physiology Score (SAPS) II. Results: A total of 839 patients were included; 90–day mortality was 42%. ΔP (OR for 1 cm H2O increase in ΔP, 1.05 [CI 1.03–1.08] p Conclusions: In this cohort of invasively ventilated ICU patients, ΔP and MP at 24h were associated with 90–day mortality. However, they have no predictive validity beyond that of the APACHE IV score and the SAPS II.

Purpose: Mechanical power (MP) may unify variables known to be related to development of ventilator-induced lung injury. The aim of this study is to examine the association between MP and mortality in critically ill patients receiving invasive ventilation for at least 48 h. Methods: This is an analysis of data stored in the databases of the MIMIC–III and eICU. Critically ill patients receiving invasive ventilation for at least 48 h were included. The exposure of interest was MP. The primary outcome was in-hospital mortality. Results: Data from 8207 patients were analyzed. Median MP during the second 24 h was 21.4 (16.2–28.1) J/min in MIMIC-III and 16.0 (11.7–22.1) J/min in eICU. MP was independently associated with in-hospital mortality [odds ratio per 5 J/min increase (OR) 1.06 (95% confidence interval (CI) 1.01–1.11); p = 0.021 in MIMIC-III, and 1.10 (1.02–1.18); p = 0.010 in eICU]. MP was also associated with ICU mortality, 30-day mortality, and with ventilator-free days, ICU and hospital length of stay. Even at low tidal volume, high MP was associated with in-hospital mortality [OR 1.70 (1.32–2.18); p < 0.001] and other secondary outcomes. Finally, there is a consistent increase in the risk of death with MP higher than 17.0 J/min. Conclusion: High MP of ventilation is independently associated with higher in-hospital mortality and several other outcomes in ICU patients receiving invasive ventilation for at least 48 h.

Purpose To compare bacteria recovered by standard cultures and metataxonomics, particularly with regard to ventilator-associated pneumonia (VAP) pathogens, and to determine if the presence of particular bacteria or microbiota in tracheal and oropharyngeal secretions during the course of intubation was associated with the development of VAP. Methods In this case–control study, oropharyngeal secretions and endotracheal aspirate were collected daily in mechanically ventilated patients. Culture and metataxonomics (16S rRNA gene-based taxonomic profiling of bacterial communities) were performed on serial upper respiratory samples from patients with late-onset definite VAP and their respective controls. Results Metataxonomic analyses showed that a low relative abundance of Bacilli at the time of intubation in the oropharyngeal secretions was strongly associated with the subsequent development of VAP. On the day of VAP, the quantity of human and bacterial DNA in both tracheal and oropharyngeal secretions was significantly higher in patients with VAP than in matched controls with similar ventilation times. Molecular techniques identified the pathogen(s) of VAP found by culture, but also many more bacteria, classically difficult to culture, such as Mycoplasma spp. and anaerobes. Conclusions Molecular analyses of respiratory specimens identified markers associated with the development of VAP, as well as important differences in the taxa abundance between VAP and controls. Further prospective trials are needed to test the predictive value of these markers, as well as the relevance of uncultured bacteria in the pathogenesis of VAP. Electronic supplementary material The online version of this article (10.1007/s00134-019-05660-8) contains supplementary material, which is available to authorized users.

Background Postoperative pulmonary complications (PPCs) are common after major abdominal surgery. The kinetics of plasma biomarkers could improve identification of patients developing PPCs, but the kinetics may depend on intraoperative ventilator settings. Objective To test whether the kinetics of plasma biomarkers are capable of identifying patients who will develop PPCs, and whether the kinetics depend on the intraoperative level of positive end-expiratory pressure (PEEP). Design A preplanned substudy of a randomised controlled trial. Setting Operation room of five centres. Patients Two hundred and forty-two adult patients scheduled for abdominal surgery at risk of developing PPCs. Interventions High (12 cmH2O) versus low (≤2 cmH2O) levels of PEEP. Main outcome measures Individual PPCs were combined as a composite endpoint. Plasma samples were collected before surgery, directly after surgery and on the fifth postoperative day. The levels of the following were measured: tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8, the soluble form of the Receptor for Advanced Glycation End-products (sRAGE), Surfactant Protein (SP)-D, Clara Cell protein (CC)-16 and Krebs von den Lungen 6 (KL6). Results Blood sampling was complete in 242 patients: 120 patients in the high PEEP group and 122 patients in the low PEEP group. Increases in plasma levels of TNF- IL-6, IL-8 and CC-16, and a decrease in plasma levels of SP-D were greater in patients who developed PPCs; however, the area under the receiver operating characteristic curve was low for all biomarkers. CC-16 was the only biomarker whose level increased more in patients who had received high levels of PEEP. Conclusion In patients undergoing abdominal surgery and at risk of developing PPCs, plasma levels of biomarkers for inflammation or lung injury showed distinct kinetics with development of PPCs, but none of the biomarkers showed sufficient prognostic value. The use of high levels of PEEP was associated with increased levels of CC-16, suggesting lung overdistension. Trial registration The PROVHILO trial, including this substudy, was registered at clinicaltrials.gov (NCT01441791).

PURPOSE OF REVIEW: Although pneumonia, either community or hospital-acquired, is the most frequent severe respiratory infection, it is an infection difficult to diagnose. At present, the diagnosis of pneumonia relies on a combination of clinical, radiologic, and microbiologic criteria. However, these criteria are far from perfect leading to uncertainty in the diagnosis, risk stratification, and choice of antibiotic therapy. Biomarkers have been used to bring additional information in this setting. RECENT FINDINGS: The aim of this review is to provide a clear overview of the current evidence for biomarkers to distinguish between patients in several clinical scenarios: to exclude pneumonia in order to withhold antibiotics, to identify the causative pathogen to target antimicrobial treatment, to identify phenotypes of inflammatory response to facilitate adjunctive treatments, to stratify the risk of severe pneumonia and provide the adequate level of care, and to monitor treatment response and de-escalate antibiotic therapy. SUMMARY: In recent years the number of new biomarkers increased markedly in different areas like pathogen identification or host response. Although far from the ideal, there are several promising areas that could represent true evolutions in the management of pneumonia, in the near future.

Introduction: Reduced lung aeration is currently semi-quantified at the bedside by visual counting of vertical artifacts called B-lines on lung ultrasound (LUS) images. The accuracy of this method can be debated. We hypothesized that visual estimation of B-line coverage is a more accurate alternative to visual B-line counting in invasively ventilated ICU patients. Method: Invasively ventilated patients who received a clinical chest CT scan were included. A 12-region LUS exam was performed minutes before the CT scan. Lung regions scanned through LUS were compared to corresponding regions on CT. Lung aeration on CT was expressed in Hounsfield Units (HU). LUS images with a B-pattern, were visually scored by (a) estimating B-line coverage, expressed as the percentage of the screen covered by B-lines, and (b) counting the number of separately spaced B-lines. Associations between HU from the CT scan and the two B-line scores were tested with linear mixed effects model analysis. Results: The study included 23 patients, who had 87 LUS images with a B-pattern (median 3 [2-4] per patient). The B-line coverage was associated with the HU value from the CT scan; B-line count was not associated with the HU value. Conclusion: The visual B-line count on LUS images is an inaccurate score for lung aeration. Visual estimation of B-line coverage is a promising alternative for semi-quantification of aeration in LUS images.

Introduction: Differentiating ARDS from other forms of respiratory failure can be difficult. By advancing an optic fiber through a diagnostic bronchoscope, followed by an automatic pullback mechanism, OCT enables real-time 3D imaging of the alveolar compartment and peripheral airways. Aim: To investigate feasibility of bronchoscopic OCT, and to describe different OCT patterns of the alveolar compartment in mechanically ventilated patients. Methods: Observational study of OCT imaging in mechanically ventilated patients for non-resolving acute respiratory failure with an indication for diagnostic bronchoscopy. Results: 9 patients were included with clinical features of acute respiratory failure and bilateral pulmonary infiltrates not fully explained by cardiac failure (ARDS). Dominant CT patterns were ground glass(n=4), consolidation(n=3), reticulation(n=1), other(n=1). Total of 47 pullbacks were obtained without adverse events. Different patterns of the alveolar compartment (normal, alveolar filling, thickening of alveolar septae, loss of normal architecture of alveolar septae) were identified (Figure 1). Conclusions: This is the first study to show feasibility and safety of OCT imaging of alveolar compartment in mechanically ventilated patients. We identified different patterns, which could be helpful in the future to differentiate various causes of respiratory failure.

Introduction: Differentiating ARDS from other causes of respiratory failure can be challenging. CLE is a high resolution optical technique that, combined with conventional bronchoscopy, provides real-time, near-histology information about the alveolar compartment. Aim: To investigate feasibility and safety of CLE, and to describe different CLE characteristics of the alveolar compartment in patients with non-resolving respiratory failure on the ICU. Methods: Observational study of CLE imaging in mechanically ventilated patients with an indication for diagnostic bronchoscopy. Results: 10 patients were included with the clinical features of respiratory failure and bilateral chest opacities not fully explained by cardiac failure (ARDS). Dominant CT patterns were ground glass(n=4), consolidation(n=3), reticulation(n=1), other(n=2). High quality CLE imaging of the alveolar compartment was obtained in all patients without adverse events. 5 different CLE patterns (normal, alveolar filling with either fluid or cells, early and late fibrosis) were identified (Figure 1). Conclusion: This is the first study to show feasibility, safety and CLE characteristics of the alveolar compartment for various causes of respiratory failure in mechanically ventilated patients. CLE imaging has added value to chest CT and has the potential to distinguish between important causes of respiratory failure in critically ill patients at the ICU.

Rationale: Analysis of exhaled volatile organic compounds (VOCs) by sensor-driven electronic nose (eNose) technology is a widely suggested measure for non-invasive monitoring of chronic airway diseases. While this technology allows probabilistic (clinical) advise, it is incapable of providing details regarding involved metabolites. Modelling sensor deflections by matching Gas Chromatography-Mass Spectrometry (GC-MS) samples could help to ascertain which VOCs induce a sensor response. Objective: To determine the association between eNose sensor deflections and exhaled VOCs measured by GC-MS. Methods: Paired samples of breath from asthma patients (n=22) were collected on sorbent tubes. One tube was analysed by four different eNoses and the second one by GC-MS. Pooling of resulting datasets consisted of 1) Partial Least Square Regression (PLSR) analysis and 2) clustered heat-mapping of PLSR loadings. Results: Matching data was available for 158 eNose sensors and 1025 GC-MS features, whereby PLSR resulted in R2‘s from 0.25 to 0.72. Figure 1 shows clustered heat-mapping outcomes. Conclusion: This explorative analysis revealed distinctive and associated patterns of exhaled VOCs between eNose and GC-MS. This data matching could help to identify which VOCs are responsible for clinically relevant results obtained by eNose and will facilitate valorisation of breathomics into clinical tests.

Background: Detecting SARS-CoV-2 antibodies may help to diagnose COVID-19. Head-to-head validation of different types of immunoassays in well-characterized cohorts of hospitalized patients remains needed. Methods: We validated three chemiluminescence immunoassays (CLIAs) (Liaison, Elecsys, and Abbott) and one single molecule array assay (SIMOA) (Quanterix) for automated analyzers, one rapid immunoassay RIA (AllTest), and one ELISA (Wantai) in parallel in first samples from 126 PCR confirmed COVID-19 hospitalized patients and 158 pre-COVID-19 patients. Specificity of the AllTest was also tested in 106 patients with confirmed parasitic and dengue virus infections. Specificity of the Wantai assay was not tested due to limitations in sample volumes. Results: Overall sensitivity in first samples was 70.6 % for the Liaison, 71.4 % for the Elecsys, 75.4 % for the Abbott, 70.6 % for the Quanterix, 77.8 % for the AllTest, and 88.9 % for the Wantai assay, respectively. Sensitivity was between 77.4 % (Liaison) and 94.0 % (Wantai) after 10 dpso. No false positive results were observed for the Elecsys and Abbott assays. Specificity was 91.1 % for the Quanterix, 96.2 % for the Liaison, and 98.1 % for the AllTest assay, respectively. Conclusion: We conclude that low sensitivity of all immunoassays limits their use early after onset of illness in diagnosing COVID-19 in hospitalized patients. After 10 dpso, the Wantai ELISA has a relatively high sensitivity, followed by the point-of-care AllTest RIA that compares favorably with automated analyzer immunoassays.

The @ERSTalk ECM Committee present highlights from #ERSLDN16 for Early Career Members http://ow.ly/tRYH305Owmz

In their letter, Drs. Cherian et al. take issue with our interpretation of the respiratory physiology of COVID-19, arguing that it is based merely on “small cohort studies,” instead arguing that “a high proportion of mechanically ventilated COVID-19 patients exhibit near-normal lung compliance” [1]. Yet the low respiratory compliance of COVID-19 patients has now been extensively demonstrated by studies totalling more than 800 COVID-19 patients [2–8], including a direct comparison with non-COVID ARDS patients that revealed no difference in respiratory compliance [8]., We argue that phenotyping of COVID-19 related ARDS should be done using careful, data-driven approaches.

Pseudomonas aeruginosa (PA) is one of the most pathogenic bacteria infecting the airways of patients with cystic fibrosis (CF). Sputum culture is the gold standard for detecting PA. However, this method is time-consuming. In this study we hypothesized that volatile organic compounds (VOCs) in exhaled breath can discriminate between PA infected and non-infected CF patients. Design: Cross-sectional baseline analysis of longitudinal cohort study. We collected exhaled air of both pediatric and adult CF patients with and without PA airways infection, in which VOCs were identified using Gas Chromatography – Mass Spectrometry (GC-MS). Infection was defined as culturing PA on the day of breath sampling, or chronic colonization with PA (in >50% of cultures (minimum of 4 samples) over the previous 12 months, or chronic maintenance treatment for PA). To identify VOCs relevant for distinction between the groups, univariate analysis (Mann Withney U test) was applied for each GC-MS compound. Features with a p-value below 0.05 retained for linear discriminant analysis. Diagnostic performed was evaluated by calculation of the area under the receiver operating characteristic - curve including 95% confidence Interval (CI). Complete data was available of 18 pediatric and 22 adult CF patients; 20 with and 20 without PA infection. Exploratory analysis of unselected patients showed that 3 out of 138 VOCs were consistently different in PA infected and non-infected patients, resulting in an AUC of 0.75 (CI 0.59 – 0.92). We discriminated PA infected and non-infected CF patients based on 3 VOCs with moderate accuracy. However, these preliminary results need to be validated in an independent patient cohort.