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Background Patients with COVID-19-related acute respiratory distress syndrome (ARDS) require respiratory support with invasive mechanical ventilation and show varying responses to recruitment manoeuvres. In patients with ARDS not related to COVID-19, two pulmonary subphenotypes that differed in recruitability were identified using latent class analysis (LCA) of imaging and clinical respiratory parameters. We aimed to evaluate if similar subphenotypes are present in patients with COVID-19-related ARDS. Methods This is the retrospective analysis of mechanically ventilated patients with COVID-19-related ARDS who underwent CT scans at positive end-expiratory pressure of 10 cmH 2 O and after a recruitment manoeuvre at 20 cmH 2 O. LCA was applied to quantitative CT-derived parameters, clinical respiratory parameters, blood gas analysis and routine laboratory values before recruitment to identify subphenotypes. Results 99 patients were included. Using 12 variables, a two-class LCA model was identified as best fitting. Subphenotype 2 ( recruitable ) was characterized by a lower PaO 2 /FiO 2 , lower normally aerated lung volume and lower compliance as opposed to a higher non-aerated lung mass and higher mechanical power when compared to subphenotype 1 ( non-recruitable ). Patients with subphenotype 2 had more decrease in non-aerated lung mass in response to a standardized recruitment manoeuvre ( p  = 0.024) and were mechanically ventilated longer until successful extubation (adjusted SHR 0.46, 95% CI 0.23–0.91, p  = 0.026), while no difference in survival was found ( p  = 0.814). Conclusions A recruitable and non-recruitable subphenotype were identified in patients with COVID-19-related ARDS. These findings are in line with previous studies in non-COVID-19-related ARDS and suggest that a combination of imaging and clinical respiratory parameters could facilitate the identification of recruitable lungs before the manoeuvre.

Background Acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on “focal” or “non-focal” lung morphology has the potential to better target mechanical ventilation strategies of individual patients. However, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish “focal” from “non-focal” lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation. Methods The Personalized Mechanical Ventilation Guided by UltraSound in Patients with Acute Respiratory Distress Syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. Eligible patients will receive a LUS exam to classify lung morphology as “focal” or “non-focal”. Thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for “non-focal” ARDS and lower PEEP and prone positioning for “focal” ARDS. The primary endpoint is all-cause mortality at day 90. Secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). After a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated. Discussion PEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach. Trial registration The PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344).

Considerable etiological, physiological and biological heterogeneity is apparent in patients with ARDS, which has likely hampered clinical trials to show benefit of treatment strategies [1]. LUS knows many advantages as it is fast to perform, radiation free and thus can be repeated as often as needed. [...]LUS avoids the need for risky transportation to the radiology department and is available in nearly every hospital [9]. Assessment of lung aeration and recruitment by CT scan and ultrasound in acute respiratory distress syndrome patients.

Introduction The usual interstitial pneumonia (UIP) pattern, hallmark of idiopathic pulmonary fibrosis (IPF), may induce harmful local overdistension during mechanical ventilation given the juxtaposition of different tissue elasticities. Mechanotransduction, linking mechanical stress and strain to molecular pro-fibrotic pathways, likely contributes to fibrosis progression. Understanding the mechanical forces and aeration patterns in the lungs of IPF patients is crucial for unraveling potential mechanisms of disease progression. Quantitative lung computed tomography (CT) can accurately assess the air content of lung regions, thus informing on zonal distension. This study aims to investigate radiological evidence of lung over aeration in spontaneously breathing UIP patients compared to healthy controls during maximal inspiration. Methods Patients with IPF diagnosis referred to the Center for Rare Lung Diseases of the University Hospital of Modena (Italy) in the period 2020–2023 who underwent High Resolution Computed Tomography (HRCT) scans at residual volume (RV) and total lung capacity (TLC) using standardized protocols were retrospectively considered eligible. Patients with no signs of lung disease at HRCT performed with the same image acquisition protocol nor at pulmonary function test (PFTs) served as controls. Lung segmentation and quantitative analysis were performed using 3D Slicer software. Lung volumes were measured, and specific density thresholds defined over aerated and fibrotic regions. Comparison between over aerated lung at RV and TLC in the two groups and according to lung lobes was sought. Further, the correlation between aerated lung and the extent of fibrosis was assessed and compared at RV and TLC. Results IPF patients (N = 20) exhibited higher over aerated lung proportions than controls (N = 15) both at RV and TLC (4.5% vs. 0.7%, p < 0.0001 and 13.8% vs. 7%, p < 0.0001 respectively). Over aeration increased significantly from RV to TLC in both groups, with no intergroup difference (p = 0.67). Sensitivity analysis revealed significant variations in over aerated lung areas among lobes when passing from RV to TLC with no difference within lobes (p = 0.28). Correlation between over aeration and fibrosis extent was moderate at RV (r = 0.62, p < 0.0001) and weak at TLC (r = 0.27, p = 0.01), being the two significantly different at interpolation analysis (p < 0.0001). Conclusions This study provides the first evidence of radiological signs of lung over aeration in patients with UIP-pattern patients when passing from RV to TLC. These findings offer new insights into the complex interplay between mechanical forces, lung structure, and fibrosis and warrant larger and longitudinal investigations.

Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress–strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO 2 /FiO 2 ratio) during a PEEP trial performed within 24 h from intubation. Patient’s stress–strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8–33.2] cmH 2 O versus 11.4 [10.3–14.6] cmH 2 O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress–strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.

Background Lung ultrasound (LUS) in an emerging technique used in the intensive care unit (ICU). The derivative LUS aeration score has been shown to have associations with mortality in invasively ventilated patients. This study assessed the predictive value of baseline and early changes in LUS aeration scores in critically ill invasively ventilated patients with and without ARDS (Acute Respiratory Distress Syndrome) on 30- and 90-day mortality. Methods This is a post hoc analysis of a multicenter prospective observational cohort study, which included patients admitted to the ICU with an expected duration of ventilation for at least 24 h. We restricted participation to patients who underwent a 12-region LUS exam at baseline and had the primary endpoint (30-day mortality) available. Logistic regression was used to analyze the primary and secondary endpoints. The analysis was performed for the complete patient cohort and for predefined subgroups (ARDS and no ARDS). Results A total of 442 patients were included, of whom 245 had a second LUS exam. The baseline LUS aeration score was not associated with mortality (1.02 (95% CI: 0.99 – 1.06), p  = 0.143). This finding was not different in patients with and in patients without ARDS. Early deterioration of the LUS score was associated with mortality (2.09 (95% CI: 1.01 – 4.3), p  = 0.046) in patients without ARDS, but not in patients with ARDS or in the complete patient cohort. Conclusion In this cohort of critically ill invasively ventilated patients, the baseline LUS aeration score was not associated with 30- and 90-day mortality. An early change in the LUS aeration score was associated with mortality, but only in patients without ARDS. Trial registration ClinicalTrials.gov, ID NCT04482621.

Lung ultrasound has become an indispensable tool in the management of acute respiratory failure, offering real-time, radiation-free bedside imaging. Its portability, repeatability, and high sensitivity for detecting pulmonary abnormalities have made it particularly valuable in critical care settings, especially during the Coronavirus disease 2019 pandemic. This narrative review explores the evolving role of lung ultrasound, examining both its established clinical applications and recent advances in artificial intelligence and imaging analysis. These developments emphasize the growing importance of lung ultrasound not only as a diagnostic tool but also as a platform for innovation, with artificial intelligence-driven approaches to further enhance its clinical utility.

Biological subphenotypes have been identified in acute respiratory distress syndrome (ARDS) based on two parsimonious models: the “uninflamed” and “reactive” subphenotype (cluster‐model) and “hypo‐inflammatory” and “hyper‐inflammatory” (latent class analysis (LCA) model). The distinction between the subphenotypes is mainly driven by inflammatory and coagulation markers in plasma. However, systemic inflammation is not specific for ARDS and it is unknown whether these subphenotypes also reflect differences in the alveolar compartment. Alveolar inflammation and dysbiosis of the lung microbiome have shown to be important mediators in the development of lung injury. This study aimed to determine whether the “reactive” or “hyper‐inflammatory” biological subphenotype also had higher concentrations of inflammatory mediators and enrichment of gut‐associated bacteria in the lung. Levels of alveolar inflammatory mediators myeloperoxidase (MPO), surfactant protein D (SPD), interleukin (IL)‐1b, IL‐6, IL‐10, IL‐8, interferon gamma (IFN‐ƴ), and tumor necrosis factor‐alpha (TNFα) were determined in the mini‐BAL fluid. Key features of the lung microbiome were measured: bacterial burden (16S rRNA gene copies/ml), community diversity (Shannon Diversity Index), and community composition. No statistically significant differences between the “uninflamed” and “reactive” ARDS subphenotypes were found in a selected set of alveolar inflammatory mediators and key features of the lung microbiome. LCA‐derived subphenotypes and stratification based on cause of ARDS (direct vs. indirect) showed similar profiles, suggesting that current subphenotypes may not reflect the alveolar host response. It is important for future research to elucidate the pulmonary biology within each subphenotype properly, which is arguably a target for intervention. Preliminary results suggest that biological subphenotypes of ARDS may not reflect differences in alveolar inflammation and key features of the lung microbiome.

We would like to extend our gratitude to Dr. da Hora Passos et al. for their interest in our recently published review and meta-analysis in Critical Care. In this response, we will elaborate on the points raised by the authors. We agree with the authors that LUS, like any other diagnostic technique, is valuable and safe only when utilized by trained operators. The authors expressed uncertainty regarding the sensitivity of LUS in detecting mild ARDS or ARDS at an early stage. This variance in sensitivity is more likely due to diversity in diagnostic thresholds. We advocate for global collaboration among LUS experts to align LUS methodologies and strengthen the evidence supporting LUS in the diagnosis of ARDS and its morphological subphenotypes.