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Alessandro Marchioni,1 Roberto Tonelli,1,2 Riccardo Fantini,1 Luca Tabbì,1 Ivana Castaniere,1,2 Francesco Livrieri,1,3 Sabrina Bedogni,4 Valentina Ruggieri,1 Lara Pisani,5 Stefano Nava,5 Enrico Clini1 1University Hospital of Modena, Pneumology Unit and Center for Rare Lung Diseases, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy; 2PhD Course in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Respiratory Disease Unit, Hospital Carlo Poma, Mantova, Italy; 4School of Medicine, University of Modena and Reggio Emilia, Modena, Italy; 5Department of Specialistic, Diagnostic and Experimental Medicine (DIMES), University of Bologna, Bologna, ItalyCorrespondence: Roberto TonelliUniversity Hospital of Modena, Pneumology Unit and Center for Rare Lung Diseases, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via del Pozzo, 71 – 41125, Modena, ItalyTel +39-342-7241672Email roberto.tonelli@me.com Skype roberto.tonelli150288Background: Although non-invasive mechanical ventilation (NIV) is the gold standard treatment for patients with acute exacerbation of COPD (AECOPD) developing respiratory acidosis, failure rates still range from 5% to 40%. Recent studies have shown that the onset of severe diaphragmatic dysfunction (DD) during AECOPD increases risk of NIV failure and mortality in this subset of patients. Although the imbalance between the load and the contractile capacity of inspiratory muscles seems the main cause of AECOPD-induced hypercapnic respiratory failure, data regarding the influence of mechanical derangement on DD in this acute phase are lacking. With this study, we investigate the impact of respiratory mechanics on diaphragm function in AECOPD patients experiencing NIV failure.Methods: Twelve AECOPD patients with respiratory acidosis admitted to the Respiratory ICU of the University Hospital of Modena from 2017 to 2018 undergoing mechanical ventilation (MV) due to NIV failure were enrolled. Static respiratory mechanics and end-expiratory lung volume (EELV) were measured after 30 mins of volume control mode MV. Subsequently, transdiaphragmatic pressure (Pdi) was calculated by means of a sniff maneuver (Pdisniff) after 30 mins of spontaneous breathing trial. Linear regression analysis and Pearson’s correlation coefficient served to assess associations.Results: Average Pdisniff was 23.3 cmH2O (standard deviation 29 cmH2O) with 3 patients presenting bilateral diaphragm palsy. Pdisniff was directly correlated with static lung elastance (r=0.69, p=0.001) while inverse correlation was found with dynamic intrinsic PEEP (r=−0.73, p=0.007). No significant correlation was found with static intrinsic PEEP (r=−0.55, p=0.06), EELV (r=−0.4, p=0.3), airway resistance (r=−0.2, p=0.54), chest wall, and total elastance (r=−0-01, p=0.96 and r=0.3, p=0.36, respectively). Significant linear inverse correlation was found between Pdisniff and the ratio between Pdi assessed at tidal volume and Pdi sniff (r=−0.82, p=0.02).Conclusion: The causes of extreme DD in AECOPD patients who experienced NIV failure might be predominantly mechanical, driven by a severe dynamic hyperinflation that overlaps on an elastic lung substrate favoring volume overload.Keywords: acute exacerbation of COPD, non-invasive mechanical ventilation, respiratory failure, transdiaphragmatic pressure

Non-invasive respiratory support, namely, non-invasive ventilation, continuous positive airway pressure, and high-flow nasal cannula, has been increasingly used worldwide to treat acute hypoxemic respiratory failure, giving the benefits of keeping spontaneous breathing preserved. In this scenario, monitoring and controlling respiratory drive could be helpful to avoid patient self-inflicted lung injury and promptly identify those patients that require an upgrade to invasive mechanical ventilation. In this review, we first describe the physiological components affecting respiratory drive to outline the risks associated with its hyperactivation. Further, we analyze and compare the leading strategies implemented for respiratory drive monitoring and discuss the sedative drugs and the non-pharmacological approaches used to modulate respiratory drive during non-invasive respiratory support. Refining the available techniques and rethinking our therapeutic and monitoring targets can help critical care physicians develop a personalized and minimally invasive approach., Competing Interests: Declarations. Conflict of interest: RT, RF, LT, IC, AMarchioni, and EC declare patent N. 102021000007478 “APPARATO PER IL RILEVAMENTO ED IL MONITORAGGIO DELLA PRESSIONE NASALE” released on March 28th 2023 by the Italian Ministry of Enterprises and Made in Italy. RT, RF, LT, AMarchioni, and EC are co-founders of IREC ltd (VAT 02959080355) (Reggio Emilia, Italy). RT received travel support and fees from GSK, SEDA, Guidotti, United HealthCare Services. AMocellin, FG, SR, MT, AP, GB, JM, and DP have no competing interests with any organization or entity with a financial interest in competition with the subject, matter, or materials discussed in this manuscript., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

High flow nasal oxygen (HFNO) is recommended as a first-line respiratory support during acute hypoxic respiratory failure (AHRF) and represents a proportionate treatment option for patients with do not intubate (DNI) orders. The aim of the study is to assess the effect of HFNO on inspiratory effort as assessed by esophageal manometry in a population of DNI patients suffering from AHRF. Patients with AHRF and DNI orders admitted to Respiratory intermediate Care Unit between January 1st, 2018 and May 31st, 2023 to receive HFNO and subjected to esophageal manometry were enrolled. Esophageal pressure swing (ΔP es ), clinical variables before and after 2 h of HFNO and clinical outcome (including HFNO failure) were collected and compared as appropriate. The change in physiological and clinical parameters according to the intensity of baseline breathing effort was assessed and the correlation between baseline ΔP es values and the relative change in breathing effort and clinical variables after 2 h of HFNO was explored. Eighty-two consecutive patients were enrolled according to sample size calculation. Two hours after HFNO start, patients presented significant improvement in ΔP es (12 VS 16 cmH 2 O, p < 0.0001), respiratory rate (RR) (22 VS 28 bpm, p < 0.0001), PaO 2 /FiO 2 (133 VS 126 mmHg, p < 0.0001), Heart rate, Acidosis, Consciousness, Oxygenation and respiratory rate (HACOR) score, (4 VS 6, p < 0.0001), Respiratory rate Oxygenation (ROX) index (8.5 VS 6.1, p < 0.0001) and BORG (1 VS 4, p < 000.1). Patients with baseline ΔP es below 20 cmH 2 O where those who improved all the explored variables, while patients with baseline ΔP es above 30 cmH 2 O did not report significant changes in physiological or clinical features. A significant correlation was found between baseline ΔP es values and after 2 h of HFNO (R 2  = 0.9, p < 0.0001). ΔP es change 2 h after HFNO significantly correlated with change in BORG (p < 0.0001), ROX index (p < 0.0001), HACOR score (p < 0.001) and RR (p < 0.001). In DNI patients with AHRF, HFNO was effective in reducing breathing effort and improving respiratory and clinical variables only for those patients with not excessive inspiratory effort., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Introduction: Idiopathic pulmonary fibrosis (IPF) severely affects the lung leading to aberrant deposition of extracellular matrix and parenchymal stiffness with progressive functional derangement. The limited availability of fresh tissues represents one of the major limitations to study the molecular profiling of IPF lung tissue. The primary aim of this study was to explore the proteomic profiling yield of archived formalin-fixed paraffin-embedded (FFPE) specimens of IPF lung tissues., Methods: We further determined the protein expression according to respiratory functional decline at the time of biopsy. The total proteins isolated from 11 FFPE samples of IPF patients compared to 3 FFPE samples from a non-fibrotic lung defined as controls, were subjected to label-free quantitative proteomic analysis by liquid chromatography-mass spectrometry (LC-MS/MS) and resulted in the detection of about 400 proteins., Results: After the pairwise comparison between controls and IPF, functional enrichment analysis identified differentially expressed proteins that were involved in extracellular matrix signaling pathways, focal adhesion and transforming growth factor β (TGF-β) signaling pathways strongly associated with IPF onset and progression. Five proteins were significantly over- expressed in the lung of IPF patients with either advanced disease stage (Stage II) or impaired pulmonary function (FVC<75, DLCO<55) compared to controls; these were lymphocyte cytosolic protein 1 (LCP1), peroxiredoxin-2 (PRDX2), transgelin 2 (TAGLN2), lumican (LUM) and mimecan (OGN) that might play a key role in the fibrogenic processes., Discussion: Our work showed that the analysis of FFPE samples was able to identify key proteins that might be crucial for the IPF pathogenesis. These proteins are correlated with lung carcinogenesis or involved in the immune landscape of lung cancer, thus making possible common mechanisms between lung carcinogenesis and fibrosis progression, two pathological conditions at risk for each other in the real life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Samarelli, Tonelli, Raineri, Bruzzi, Andrisani, Gozzi, Marchioni, Costantini, Fabbiani, Genovese, Pinetti, Manicardi, Castaniere, Masciale, Aramini, Tabbì, Rizzato, Bettelli, Manfredini, Dominici, Clini and Cerri.)

Background: Although patients with interstitial pneumonia pattern (ILD-UIP) and acute exacerbation (AE) leading to severe acute respiratory failure may require invasive mechanical ventilation (MV), physiological data on lung mechanics during MV are lacking. We aimed at describing the physiological effect of lung-protective ventilation in patients with AE-ILD-UIP compared with primary ARDS., Methods: Partitioned lung and chest wall mechanics were assessed in a series of AE-ILD-UIP patients matched 1:1 with primary ARDS as controls (based on BMI and PaO 2 /FiO 2 ratio). Three PEEP levels (zero = ZEEP, 4-8 cmH 2 O = PEEP LOW , and titrated to achieve positive end-expiratory transpulmonary pressure P L,EE  = PEEP TITRATED ) were used for measurements., Results: Ten AE-ILD-UIP patients and 10 matched ARDS were included. In AE-ILD-UIP median P L,EE at ZEEP was - 4.3 [- 7.6- - 2.3] cmH 2 O and lung elastance (E L ) 44 [40-51] cmH 2 O/L. At PEEP LOW , P L,EE remained negative and E L did not change (p = 0.995) versus ZEEP. At PEEP TITRATED , P L,EE increased to 0.8 [0.3-1.5] cmH 2 O and E L to 49 [43-59] (p = 0.004 and p < 0.001 compared to ZEEP and PEEP LOW , respectively). ΔP L decreased at PEEP LOW (p = 0.018) and increased at PEEP TITRATED (p = 0.003). In matched ARDS control PEEP titration to obtain a positive P L,EE did not result in significant changes in E L and ΔP L ., Conclusions: In mechanically ventilated AE-ILD-UIP patients, differently than in patients with primary ARDS, PEEP titrated to obtain a positive P L,EE significantly worsened lung mechanics., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Noninvasive ventilation (NIV) still has high failure rate when used for de novo acute respiratory failure (ARF). Delirium may impact the outcome, however data regarding its incidence, timing of occurrence and clinical predictors in this subset of patients are scarce., Methods: Consecutive patients with de novo ARF subjected to NIV were recruited in 10 Italian Respiratory Intensive Care Units (RICUs) and Intensive Care Units (ICUs). Demographics and clinical features, including tolerance to interface and NIV setting were recorded on admission and during stay, whereas delirium onset and type was assessed by the Confusion Assessment Method for ICU (CAM-ICU)-7 scale and Richmond Agitation Sedation Scale (RASS) twice/per day up to a week. The association between clinical variables and the occurrence of delirium and its influence on NIV failure and other clinical outcomes were analyzed., Results: Thirty-two out of 90 enrolled patients (36%) developed delirium over seven days upon admission; median time to onset was 48 hours (24-60). Older age (OR=2.7 [1.9-9], P=0.01), the presence of cancer OR=3.7 [2-5.4], P=0.002), sepsis (OR=1.7 [1.1-3.4], P=0.01), SOFA Score (OR=1.8 [1.1-3.1], P=0.01), low tolerance to interface (OR=3.2 [2.1-5], P=0.002), use of helmet (OR=1.9 [1.2-4.3] P=0.04), and higher PRE-DELIRIC (OR=3.5 [1.3-15], P=0.03) and BORG (OR=1.7 [1.1-4.6], P=0.02] scores were significantly associated with delirium. Delirium had high risk for NIV failure (HR=3.5 95% CI: [1.4-8.6], P=0.0002) and it significantly associated with longer RICU/ICU stay and higher mortality., Conclusions: Delirium onset in acute hypoxic patients undergoing NIV is frequent and negatively affects the outcome. Multiple related clinical factors should be addressed early on admission to prevent the delirium-related risk of NIV failure in these patients.

Background/materials and Methods: This retrospective cohort study was conducted in two teaching hospitals over a 3-month period (March 2010-June 2020) comparing severe and critical COVID-19 patients admitted to Respiratory Intensive Care Unit for non-invasive respiratory support (NRS) and subjected to awake prone position (PP) with those receiving standard care (SC). Primary outcome was endotracheal intubation (ETI) rate. In-hospital mortality, time to ETI, tracheostomy, length of RICU and hospital stay served as secondary outcomes. Risk factors associated to ETI among PP patients were also investigated., Results: A total of 114 patients were included, 76 in the SC and 38 in the PP group. Unadjusted Kaplan-Meier estimates showed greater effect of PP compared to SC on ETI rate (HR = 0.45 95% CI [0.2-0.9], p = 0.02) even after adjustment for baseline confounders (HR = 0.59 95% CI [0.3-0.94], p = 0.03). After stratification according to non-invasive respiratory support, PP showed greater significant benefit for those on High Flow Nasal Cannulae (HR = 0.34 95% CI [0.12-0.84], p = 0.04). Compared to SC, PP patients also showed a favorable difference in terms of days free from respiratory support, length of RICU and hospital stay while mortality and tracheostomy rate were not significantly different., Conclusions: Prone positioning in awake and spontaneously breathing Covid-19 patients is feasible and associated with a reduction of intubation rate, especially in those patients undergoing HFNC. Although our results are intriguing, further randomized controlled trials are needed to answer all the open questions remaining pending about the real efficacy of PP in this setting., (Copyright © 2021 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The role of excessive inspiratory effort in promoting alveolar and pleural rupture resulting in air leak (AL) in patients with SARS-CoV-2 induced acute respiratory failure (ARF) while on spontaneous breathing is undetermined., Methods: Among all patients with COVID-19 related ARF admitted to a respiratory intensive care unit (RICU) and receiving non-invasive respiratory support, those developing an AL were and matched 1:1 [by means of PaO2/FiO2 ratio, age, body mass index-BMI and subsequent organ failure assessment (SOFA)] with a comparable population who did not (NAL group). Esophageal pressure (ΔP es ) and dynamic transpulmonary pressure (ΔP L ) swings were compared between groups. Risk factors affecting AL onset were evaluated. The composite outcome of ventilator-free-days (VFD) at day 28 (including ETI, mortality, tracheostomy) was compared between groups., Results: Air leak and NAL groups ( n = 28) showed similar ΔP es , whereas AL had higher ΔP L (20 [16-21] and 17 [11-20], p = 0.01, respectively). Higher ΔP L (OR = 1.5 95%CI[1-1.8], p = 0.01), positive end-expiratory pressure (OR = 2.4 95%CI[1.2-5.9], p = 0.04) and pressure support (OR = 1.8 95%CI[1.1-3.5], p = 0.03), D-dimer on admission (OR = 2.1 95%CI[1.3-9.8], p = 0.03), and features suggestive of consolidation on computed tomography scan (OR = 3.8 95%CI[1.1-15], p = 0.04) were all significantly associated with AL. A lower VFD score resulted in a higher risk (HR = 3.7 95%CI [1.2-11.3], p = 0.01) in the AL group compared with NAL. RICU stay and 90-day mortality were also higher in the AL group compared with NAL., Conclusion: In spontaneously breathing patients with COVID-19 related ARF, higher levels of ΔP L , blood D-dimer, NIV delivery pressures and a consolidative lung pattern were associated with AL onset., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tonelli, Bruzzi, Manicardi, Tabbì, Fantini, Castaniere, Andrisani, Gozzi, Pellegrino, Trentacosti, Dall’Ara, Busani, Franceschini, Baroncini, Manco, Meschiari, Mussini, Girardis, Beghè, Marchioni and Clini.)

Background: Excessive inspiratory effort could translate into self-inflicted lung injury, thus worsening clinical outcomes of spontaneously breathing patients with acute respiratory failure (ARF). Although esophageal manometry is a reliable method to estimate the magnitude of inspiratory effort, procedural issues significantly limit its use in daily clinical practice. The aim of this study is to describe the correlation between esophageal pressure swings (ΔP es ) and nasal (ΔP nos ) as a potential measure of inspiratory effort in spontaneously breathing patients with de novo ARF., Methods: From January 1, 2021, to September 1, 2021, 61 consecutive patients with ARF (83.6% related to COVID-19) admitted to the Respiratory Intensive Care Unit (RICU) of the University Hospital of Modena (Italy) and candidate to escalation of non-invasive respiratory support (NRS) were enrolled. Clinical features and tidal changes in esophageal and nasal pressure were recorded on admission and 24 h after starting NRS. Correlation between ΔP es and ΔP nos served as primary outcome. The effect of ΔP nos measurements on respiratory rate and ΔP es was also assessed., Results: ΔP es and ΔP nos were strongly correlated at admission (R 2  = 0.88, p < 0.001) and 24 h apart (R 2  = 0.94, p < 0.001). The nasal plug insertion and the mouth closure required for ΔP nos measurement did not result in significant change of respiratory rate and ΔP es . The correlation between measures at 24 h remained significant even after splitting the study population according to the type of NRS (high-flow nasal cannulas [R 2  = 0.79, p < 0.001] or non-invasive ventilation [R 2  = 0.95, p < 0.001])., Conclusions: In a cohort of patients with ARF, nasal pressure swings did not alter respiratory mechanics in the short term and were highly correlated with esophageal pressure swings during spontaneous tidal breathing. ΔP nos might warrant further investigation as a measure of inspiratory effort in patients with ARF., Trial Registration: NCT03826797 . Registered October 2016., (© 2022. The Author(s).)

Background: It is well known that benign tracheal stenosis represents an obstacle to open surgery, and that its treatment could be challenging. Two endoscopic techniques have so far been adopted to restore tracheal patency: balloon dilatation (BA) through laryngoscopy, and tracheal stenting (ST) with rigid bronchoscopy. The main objective of this study was to compare the efficacy of BA and ST to treat benign tracheal stenosis not eligible for surgery. We also compared the rate of adverse events in the two treatment groups., Methods: A retrospective, observational cohort study was carried out at the University Hospital of Modena (Italy) from November 2012 to November 2017 in two separate departments. Patients were considered to be "stabilized" (primary outcome) if they did not report significant respiratory symptoms, or restenosis in the long-term (2 years) following the endoscopic procedure., Results: Sixty-six patients were included in the study (33 in the BA and 33 in the ST group, respectively). Unadjusted Kaplan-Meier estimates showed a greater therapeutic effect of ST compared to BA at 2 years (hazard ratio = 3.9 95%CI [1.5-9.8], p  = .01). After adjusting for confounders, stratified analyses showed that this effect was significant in patients with complex stenosis, idiopathic etiology, and degree of stenosis >70%. Compared with BA, ST showed a higher rate of adverse events ( p  = .01)., Conclusions: Compared to BA, ST seems to be more effective in achieving stabilization of tracheal patency in complex benign tracheal stenosis, although burdened with a significantly higher number of adverse effects. These findings warrant future prospective study for confirmation. Level of evidence: 3., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS.

Patients with acute asthma attack usually access the emergency room with severe functional impairment, despite low perception of symptoms. In this scenario, early functional assessment is essential focusing on vital parameters and respiratory function, alongside perceived dyspnea. Impairment of ventilatory mechanics due to progressive dynamic pulmonary hyperinflation should be promptly treated with medical inhalation and/or intravenous therapy, reserving intensive treatment in case of non-response and/or worsening of the clinical conditions. Therapeutic planning at patient's discharge is no less important than treatment management during emergency room access as educating the patient about therapeutic adherence significantly impact long-term outcomes of asthma. With this review we aimed at exploring current evidence on acute asthma attack management, focusing of pharmacological and ventilatory strategies of care and highlighting the importance of patient education once clinical stability allows discharge from the emergency department.

Interstitial lung diseases (ILDs) that are known as diffuse parenchymal lung diseases (DPLDs) lead to the damage of alveolar epithelium and lung parenchyma, culminating in inflammation and widespread fibrosis. ILDs that account for more than 200 different pathologies can be divided into two groups: ILDs that have a known cause and those where the cause is unknown, classified as idiopathic interstitial pneumonia (IIP). IIPs include idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) known also as bronchiolitis obliterans organizing pneumonia (BOOP), acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and lymphocytic interstitial pneumonia (LIP). In this review, our aim is to describe the pathogenic mechanisms that lead to the onset and progression of the different IIPs, starting from IPF as the most studied, in order to find both the common and standalone molecular and cellular key players among them. Finally, a deeper molecular and cellular characterization of different interstitial lung diseases without a known cause would contribute to giving a more accurate diagnosis to the patients, which would translate to a more effective treatment decision.

Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, which is followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of the extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress-strain curve but follows the mechano-elastic models of "squishy balls", where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity that are surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with associated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review, we aim to summarize the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support.

The mechanisms of acute respiratory failure other than inflammation and complicating the SARS-CoV-2 infection are still far from being fully understood, thus challenging the management of COVID-19 patients in the critical care setting. In this unforeseen scenario, the role of an individual's excessive spontaneous breathing may acquire critical importance, being one potential and important driver of lung injury and disease progression. The consequences of this acute lung damage may impair lung structure, forecasting the model of a fragile respiratory system. This perspective article aims to analyze the progression of injured lung phenotypes across the SARS-CoV-2 induced respiratory failure, pointing out the role of spontaneous breathing and also tackling the specific respiratory/ventilatory strategy required by the fragile lung type.

Data on the presence of subclinical fibrosis across multiple organs in patients with idiopathic lung fibrosis (IPF) are lacking. Our study aimed at investigating through hepatic transient elastography (HTE) the prevalence and clinical impact of subclinical liver fibrosis in a cohort of patients with IPF. Patients referred to the Centre for Rare Lung Disease of the University Hospital of Modena (Italy) from March 2012 to February 2013 with established diagnosis of IPF and without a documented history of liver diseases were consecutively enrolled and underwent HTE. Based on hepatic stiffness status as assessed through METAVIR score patients were categorized as "with liver fibrosis" (corresponding to a METAVIR score of F1-F4) and "without liver fibrosis" (METAVIR F0). Potential predictors of liver fibrosis were investigated through logistic regression model among clinical and serological variables. The overall survival (OS) was assessed according to liver fibrosis and multivariate Cox regression analysis was used to identify independent predictors. In 13 out of 37 patients (35%) with IPF, a certain degree of liver fibrosis was documented. No correlation was found between liver stiffness and clinical-functional parameters. OS was lower in patients 'with liver fibrosis' than in patients 'without liver fibrosis' (median months 33 [23-55] vs. 63 [26-94], p = 0.038). Patients 'with liver fibrosis' presented a higher risk of death at seven years as compared to patients 'without liver fibrosis' (HR = 2.6, 95% CI [1.003-6.7], p = 0.049). Higher level of AST to platelet ratio index (APRI) was an independent predictor of survival (HR = 4.52 95% CI [1.3-15.6], p = 0.02). In our cohort, more than one-third of IPF patients had concomitant subclinical liver fibrosis that negatively affected OS. These preliminary claims further investigation aimed at clarifying the mechanisms beyond multiorgan fibrosis and its clinical implication in patients with IPF.