Bronchiectasis as long-term complication of acute fire smoke inhalation?

In this letter to editor, we discuss the occurrence of radiological and clinical evidence of bronchiectasis syndrome three years after acute exposure to fire smoke in a Caucasian non-smoker asthmatic patient

Molecular mechanisms and cellular contribution from lung fibrosis to lung cancer development.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung 28 disease (ILD) of unknown etiology, with a median survival of 2-4 years from the time of diagnosis. 29 Although IPF has unknown etiology by definition, there have been identified several risks factors 30 increasing the probability of the onset and progression of the disease in IPF patients such as cigarette 31 smoking and environmental risks factors associated to domestic and occupational exposure. Among 32 them, cigarette smoking together with concomitant emphysema might predispose IPF patients to 33 lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer 34 development. To this purpose, IPF and LC share several cellular and molecular processes driving 35 the progression of both pathologies such as fibroblast transition proliferation and activation, endo- 36 plasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose 37 the IPF patients to LC development. Nintedanib, a tyrosine-kinase inhibitor, was firstly developed 38 as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target 39 molecular pathway. In this review our aim is to describe the updated studies on common cellular 40 and molecular mechanisms between IPF and lung cancer, whose knowledge might help to find 41 novel therapeutic targets for this disease combination

Dissecting the Role of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis:Cause or Solution

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung’s architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associated with disease onset and progression, it has been hypothesized that IPF lungs might be affected either by a regenerative deficit of the alveolar epithelium or by a dysregulation of repair mechanisms in response to alveolar and vascular damage. This latter might be related to the progressive dysfunction and exhaustion of the resident stem cells together with a process of cellular and tissue senescence. The role of endogenous mesenchymal stromal/stem cells (MSCs) resident in the lung in the homeostasis of these mechanisms is still a matter of debate. Although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue ageing processes with loss of lung regenerative potential. In addition, MSCs have immunomodulatory properties and can secrete anti-fibrotic factors. Thus, MSCs obtained from other sources administered systemically or directly into the lung have been investigated for lung epithelial repair and have been explored as a potential therapy for the treatment of lung diseases including IPF. Given these multiple potential roles of MSCs, this review aims both at elucidating the role of resident lung MSCs in IPF pathogenesis and the role of administered MSCs from other sources for potential IPF therapies

Risk factors for pulmonary air leak and clinical prognosis in patients with COVID-19 related acute respiratory failure: a retrospective matched control study.

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 (ΔPes) and dynamic transpulmonary pressure (ΔPL) 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- AL and NAL groups (n=28) showed similar ΔPes, whereas AL had higher ΔPL (20 [16‐21] and 17 [11‐20], p=0.01 respectively). Higher ΔPL (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. Conclusions- In spontaneously breathing patients with COVID‐19 related ARF, higher levels of ΔPL, blood D‐dimer, NIV delivery pressures and a consolidative lung pattern were associated with AL onset

Physiological effects of lung protective ventilation in patients with lung fibrosis and usual interstitial pneumonia pattern versus primary ARDS: a matched-control study.

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 PaO2/FiO2 ratio). Three PEEP levels (zero=ZEEP, 4-8 cmH2O=PEEPLOW, and titrated to achieve positive end-expiratory transpulmonary pressure-PL,EE=PEEPTITRATED) were used for measurements. Results- Ten AE-ILD-UIP patients and 10 matched ARDS were included. In AE-ILD-UIP median PL,EE at ZEEP was - 4.3 [-7.6 – -2.3] cmH2O and lung elastance (EL) 44 [40 – 51] cmH2O/L. At PEEPLOW, PL,EE remained negative and EL did not change (p=0.995) versus ZEEP. At PEEPTITRATED, PL,EE increased to 0.8 [0.3 – 1.5] cmH2O and EL to 49 [43 – 59] (p=0.004 and p<0.001 compared to ZEEP and PEEPLOW, respectively). PL decreased at PEEPLOW (p=0.018) and increased at PEEPTITRATED (p=0.003). In matched ARDS control PEEP titration to obtain a positive PL,EE did not result in significant changes in EL and PL. Conclusions- In mechanically ventilated AE-ILD-UIP patients, differently than in patients with primary ARDS, PEEP titrated to obtain a positive PL,EE significantly worsened lung mechanics

Molecular mechanisms and physiological changes behind benign tracheal and subglottic stenosis in adults.

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 etiology. Although iatrogenic etiology 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 etiology 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

L'interazione tra endoscopisti e clinici: significato clinico e risultati della valutazione multimodale e trattamento di malattie benigne e maligne delle vie aeree.

Poiché la gestione delle malattie delle vie aeree risulta difficile per i clinici, l'approccio ottimale dovrebbe essere multimodale. Ciò è dovuto all’eterogeneità delle patologie delle vie aeree: lesioni benigne, dinamiche e maligne possono causare ostruzione delle vie aeree, con una vasta gamma di sintomi respiratori e gravità clinica. L'approccio endoscopico alle lesioni ostruttive delle vie aeree si conferma essere importante per il trattamento adeguato di questi pazienti, in primis per la gestione delle complicazioni letali. In secondo luogo consente di ripristinare la pervietà delle vie aeree. Infine l'ottimizzazione di un approccio integrato può rappresentare una strategia efficace per migliorare la diagnosi, la sopravvivenza e la qualità della vita di questi pazienti. Lo scopo di questo progetto di ricerca è quello di esplorare il significato clinico e i risultati di un approccio multimodale che include trattamenti chirurgici, endoscopici e medici in diverse malattie delle vie aeree, attraverso tre studi clinici. Il primo studio ha arruolato pazienti con la diagnosi di NSCLC in fase IIIB e CAO all'inizio della malattia. L'esito primario era la sopravvivenza a 1 anno. Abbiamo dimostrato che l'integrazione della broncoscopia interventistica, soprattutto quando proposto precocemente, non solo ha uno scopo palliativo, ma ha anche un impatto significativo sulla prognosi del paziente, con un chiaro vantaggio di sopravvivenza a 1 anno per lo stesso stadio della malattia. Inoltre, abbiamo dimostrato che un maggiore aumento dell'aspettativa di vita è correlato alle caratteristiche anatomiche e molecolari del cancro. Il secondo studio è stato condotto in due dipartimenti di broncoscopia e di otorinolaringoiatria. Abbiamo confrontato due tecniche endoscopiche per ripristinare la pervietà tracheale nelle stenosi tracheali benigne non candidabili alla chirurgia: dilatazione con balloon (BA) attraverso laringoscopia e stenting tracheale (ST) con broncoscopia rigida. I pazienti sono stati considerati "stabilizzati" (outcome primario) se non riportavano sintomi respiratori significativi o re-stenosi nei 2 anni successivi alle procedure. ST sembra essere più efficace nel raggiungere la stabilizzazione della pervietà tracheale nelle stenosi tracheali benigne complesse rispetto a BA, anche se è gravato da un maggior numero di effetti avversi. Per il terzo studio pazienti con una diagnosi di cancro sovraglottico con almeno 5 anni di follow-up sono stati considerati arruolabili, escludendo pazienti con metastasi a distanza al momento della diagnosi o con presenza di cancro sincrono. Tutte le variabili demografiche e cliniche sono state raccolte per valutare l'associazione tra esse e l'esordio di metastasi. Lo studio ha confermato che un numero significativo di pazienti con tumore sovraglottico locale può sviluppare metastasi nonostante il trattamento durante il follow-up. Il fumo, lo stadio avanzato al momento della diagnosi e la scarsa risposta al trattamento erano fattori indipendenti associati a questo evento tardivo. La diffusione metastatica ha ridotto significativamente la sopravvivenza, ma solo in quei pazienti che non avevano infezione da HPV. La fenotipizzazione precoce dei pazienti a maggiore rischio di insorgenza di metastasi tardiva potrebbe migliorare la gestione clinica e il follow-up di questi pazienti. In conclusione, con il primo e il secondo studio abbiamo dimostrato che un approccio multimodale può rappresentare la scelta ottimale di trattamento per le lesioni ostruttive maligne delle vie aeree centrali e per la stenosi tracheale benigna. I risultati del terzo studio hanno suggerito che una valutazione multidisciplinare dei pazienti con malattia delle vie aeree maligne superiori può consentire di identificare quelli a rischio maggiore di progressione della malattia, nonostante il trattamento chirurgico e medico.As management of airway diseases results challenging for clinicians, the optimal approach is supposed to be multimodal. This is due to the heterogeneous nature of the airways pathological processes: benign, dynamic and malignant lesions can cause airway obstruction, with a wide range of respiratory symptoms and clinical severity. The endoscopic approach to airways obstructive lesions has been confirmed to be important for the proper treatment of these patients, primarly for the management of life-threatening complications. Secondly, it allows restoring airway patency. Finally, the optimization of an integrated approach based on endoscopic and medical techniques can represent an effective strategy to improve diagnosis, survival and quality of life of patients with clinically relevant airway diseases. The aim of this research project was to explore the clinical significance and the related outcomes of a multi-modal approach including surgical, endoscopic and medical treatment across a spectrum of different airways diseases. The research question has been addressed by means of three clinical studies. The first study enrolled patients with diagnosis of stage IIIB NSCLC and CAO at onset of disease. Primary outcome was 1-year survival. We showed that the integration of interventional bronchoscopy in the management of locally advanced NSCLC with CAO, especially when proposed early, not only has a palliative purpose but also has a significant impact on the patient's prognosis, showing a clear 1-year survival advantage for the same stage of disease. Moreover, we have shown that greater gain in life expectancy is closely related to anatomical and molecular cancer features. The second study was carried out in two departments of Bronchoscopy and Otolaringology Unit. We compared two different endoscopic techniques to restore tracheal patency in benign tracheal stenosis not eligible for surgery: balloon dilatation (BA) through laryngoscopy and tracheal stenting (ST) with rigid bronchoscopy. Patients were considered “stabilized” (primary outcome) if they did not report significant respiratory symptoms or restenosis in the 2 years following the endoscopic procedures. ST seems to be more effective in achieving stabilization of tracheal patency in complex benign tracheal stenosis when compared with BA, although burdened with a higher number of adverse effects. As regards the third study, patients with a diagnosis of sovra-glottic cancer with at least a 5-years follow-up were considered eligible for enrolment. We excluded patients with presence of distal metastasis at the time of diagnosis and presence of synchronous cancer. All demographic and clinical variables were collected to evaluate the association between them and the onset of distal metastasis. The study confirmed that a significant number of patients with local sovra-glottic cancer may develop distal metastasis despite treatment during follow-up. Smoking status, advanced malignant disease at the time of diagnosis and poor response to treatment were independent factors associated with this late event. The metastatic dissemination significantly reduced survival but only in those patients who did not have HPV infection. The early phenotyping of patients at major risk of late metastasis onset might improve the clinical management and the follow-up of these patients. In conclusion, with the first and the second study we have showed that a multi-modal approach may represent the optimal choice of treatment for malignant obstructive lesions of the central airways and for benign tracheal stenosis. The results of third study have suggested that a multidisciplinary evaluation of patients with upper malignant airway disease may allow identifying those at major risk for disease progression despite surgical and medical treatment

Effectiveness of pulmonary rehabilitation in patients with interstitial lung disease of different etiology: a multicenter prospective study

Abstract Background Recent evidences show that Pulmonary Rehabilitation (PR) is effective in patients with Interstitial Lung Disease (ILD). It is still unclear whether disease severity and/or etiology might impact on the reported benefits. We designed this prospective study 1) to confirm the efficacy of rehabilitation in a population of patients with ILDs and 2) to investigate whether baseline exercise capacity, disease severity or ILD etiology might affect outcomes. Methods Forty-one patients (IPF 63%, age 66.9 ± 11 ys) were enrolled in a standard PR course in two centers. Lung function, incremental and endurance cyclo-ergometry, Six Minutes Walking Distance (6MWD), chronic dyspnea (Medical Research Council scale-MRC) and quality of life (St. George Respiratory Questionnaire-SGRQ) were recorded before and at the end of PR to measure any pre-to-post change. Correlation coefficients between the baseline level of Diffuse Lung Capacity for Carbon monoxide (DLCO), Forced Vital Capacity (FVC), 6MWD, power developed during incremental endurance test, GAP index (in IPF patients only) and etiology (IPF or non-IPF) with the functional improvement at the 6MWDT (meters), at the incremental and endurance cyclo-ergometry (endurance time) and the HRQoL were assessed. Results Out of the 41 patients, 97% (n = 40) completed the PR course. Exercise performance (both at peak load and submaximal effort), symptoms (iso-time dyspnea and leg fatigue), SGRQ and MRC significantly improved after PR (p < .001). Patients with lower baseline 6MWD showed greater improvement in 6MWD (Spearman r score = − .359, p = .034) and symptoms relief at SGRQ (r = −.315, p = .025) regardless of underlying disease. Conclusion Present study confirms that comprehensive rehabilitation is feasible and effective in patients with ILD of different severity and etiology. The baseline submaximal exercise capacity inversely correlates with both functional and symptom gains in this heterogeneous population

Fibrosing Progressive Interstitial Lung Disease in Rheumatoid Arthritis: A Multicentre Italian Study

Background: The INBUILD study demonstrated the efficacy of nintedanib in the treatment of progressive fibrosing interstitial lung disease different to idiopathic pulmonary fibrosis, including rheumatoid arthritis (RA)-related ILD. Nevertheless, the prevalence of RA-ILD patients that may potentially benefit from nintedanib remains unknown. Objectives and methods: The aim of the present multicentre study was to investigate the prevalence and possible associated factors of fibrosing progressive patterns in a cross-sectional cohort of RA-ILD patients. Results: One hundred and thirty-four RA-ILD patients with a diagnosis of RA-ILD, who were confirmed at high-resolution computed tomography and with a follow-up of at least 24 months, were enrolled. The patients were defined as having a progressive fibrosing ILD in case of a relative decline in forced vital capacity > 10% predicted and/or an increased extent of fibrotic changes on chest imaging in a 24-month period. Respiratory symptoms were excluded to reduce possible bias due to the retrospective interpretation of cough and dyspnea. According to radiologic features, ILD was classified as usual interstitial pneumonia (UIP) in 50.7% of patients, nonspecific interstitial pneumonia in 19.4%, and other patterns in 29.8%. Globally, a fibrosing progressive pattern was recorded in 36.6% of patients (48.5% of patients with a fibrosing pattern) with a significant association to the UIP pattern. Conclusion: We observed that more than a third of RA-ILD patients showed a fibrosing progressive pattern and might benefit from antifibrotic treatment. This study shows some limitations, such as the retrospective design. The exclusion of respiratory symptoms’ evaluation might underestimate the prevalence of progressive lung disease but increases the value of results

Expression of HOXB7 in the Lung of Patients with Idiopathic Pulmonary Fibrosis: A Proof-of-Concept Study.

Background: The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox (Hox) gene family, has been found involved in various cancers. Methods: Immunohistochemical (IHC) analysis was run on lung tissue samples from surgical lung biopsy (SLB) of 19 patients with IPF, retrospectively selected from the IPF database of the University Hospital of Modena. HOXB7 expression was analyzed and compared with that of five patients with no evidence of pulmonary fibrosis as controls. Results: The semi-quantitative analysis of IHC showed that HOXB7 protein expression was higher in IPF patients compared to controls (difference between means = 6.2 ± 2.37, p = 0.0157). Further, HOXB7 expression was higher in IPF patients with a higher extent of fibrosis (50–75%)—measured with high-resolution computer tomography—compared to those with a lower extent (0–25%) (difference between means = 25.74 ± 6.72, p = 0.004). Conclusions: The expression of HOXB7 is higher in the lung of IPF patients compared to controls, and was represented in different cellular compartments within the lung niche. Further investigations are needed to clarify its role in the pathogenesis and progression of IPF