The cofactors potentially affecting exercise performance after COVID-19 are still incompletely investigated. The contribution of several clinical and demographic variables to the exercise capacity measured with the 6-min walk test was assessed in multivariable analyses that used the absolute distance walked in 6 min (6MWD) and an impaired performance (6MWD < 60

BACKGROUND:Dyspnea and fatigue represent common Long-COVID symptoms, but their presence is not always accompanied by lung function abnormalities. Aim of the study was to evaluate dyspnea and fatigue in relation to pulmonary function and exercise capacity. METHODS:Multicenter cohort study. Multivariable analyses were used to characterize, for both symptoms, functional phenotypes with and without pulmonary impairment according to the diffusing lung capacity for carbon monoxide (DLCO). Exercise capacity was assessed through the distance walked in 6 min (6MWD). RESULTS:Among 765 patients evaluated at a mean interval of six months from COVID-19, rates of dyspnea and fatigue were 41.3% and 41.6%, respectively. Roughly half of the patients with these two symptoms (51.6% and 54.7%, respectively) had normal pulmonary function at DLCO testing (≥80% of predicted). Low-DLCO (<80%) dyspnea was significantly associated with female sex, anxiety, duration of hospitalisation, use of corticosteroids and of monoclonal neutralizing antibodies, and its risk decreased at the increasing in time from acute infection. Normal-DLCO dyspnea was associated with younger age and obesity. Low-DLCO fatigue was associated with female sex, heart failure, anxiety and use of corticosteroids. Normal-DLCO fatigue was not associated with demographics, comorbidities, or COVID-19 severity. For both symptoms, the low-DLCO phenotypes had a significantly lower 6MWD. CONCLUSIONS:The clinical phenotypes of dyspnea and fatigue with normal pulmonary function should be further explored, possibly with additional tests that assess cardiorespiratory and cardiovascular function. DLCO testing should be included in the evaluation of patients who report dyspnea and/or fatigue as possible Long-COVID symptoms.

Mucoepidermoid carcinoma of the lung is a rare salivary gland-type tumor with heterogeneous clinical behavior and the potential to mimic neoplasms arising in other organs. The purpose of this report is to describe an exceptionally uncommon presentation of pulmonary mucoepidermoid carcinoma manifesting as a breast metastasis in a male patient, a scenario that poses significant diagnostic challenges due to its rarity and its morphological resemblance to primary breast carcinoma. We evaluated the patient through clinical examination, cross-sectional imaging, endobronchial procedures, ultrasound-guided biopsy, immunohistochemistry, and molecular analysis, integrating these data to establish the diagnosis. Imaging revealed a primary lung mass and a second lesion in the left breast infiltrating the pectoralis muscle. Biopsy of the breast mass showed high-grade salivary gland-type mucoepidermoid carcinoma, clinically and radiologically suggestive of pulmonary origin. Because the lesion showed signs of impending ulceration, palliative surgical debulking was performed with good postoperative recovery. The patient subsequently began systemic therapy with gemcitabine. This case underscores the need for careful clinicopathologic correlation when evaluating atypical breast lesions and highlights the diagnostic value of molecular testing in distinguishing primary from metastatic salivary gland-type tumors. Recognizing such rare metastatic patterns is essential for appropriate therapeutic planning.

Background: Bronchoalveolar lavage (BAL) constitutes a valuable diagnostic approach for the differential diagnosis of various pulmonary fibrotic diseases. BAL fluids from patients with interstitial lung diseases (ILDs) can also be utilized for research purposes, offering cell populations suitable for functional and phenotypical studies. In this study, we demonstrate the feasibility of isolating a discrete number of fibroblasts/myofibroblasts in vitro from the BAL fluid from ILD patients, a procedure typically performed during the early stages of disease when high-resolution computed tomography does not yield a definitive diagnosis. Methods: We obtained BAL samples from a total of 43 patients. Fibroblasts were successfully derived in vitro from 20 patients, with larger quantities of cells from 11 patients. Whenever possible, the cells were cultured and expanded until passage 12–15. Fibroblasts could be expanded to passage 36 in only one case. The expression of typical fibrotic markers, such as type I collagen, α-smooth muscle actin, and fibronectin-extra domain A or B (FN-EDA/-EDB), was therefore compared in fibroblasts obtained from ILD-patients with fibroblasts derived from non-diseased controls by quantitative RT-PCR, immunofluorescence, and cytofluorographic analysis. The rate of proliferation, migration, and response to the anti-fibrotic drug pirfenidone was further determined in 2D and in 3D models of in vitro cultures. Results: A specific morphological heterogeneity among fibroblasts/myofibroblasts derived from patients with fibrotic or non-fibrotic ILD was observed, such as enlarged and flattened shaped cells vs spindle-shaped cells. Moreover, a higher expression of α-smooth muscle actin (α-SMA), type I collagen (collagen I), and fibronectin was demonstrated in ILD fibroblasts than in control fibroblasts. The anti-fibrotic drug pirfenidone was effective in inhibiting the growth and migration of ILD-fibroblasts both in 2D and 3D in vitro models. Conclusions: Collectively, the present study suggests that BAL-derived fibroblasts from ILD patients may serve as a useful in vitro model for studying and assaying pulmonary fibrosis. This approach has the potential to improve our understanding of ILD pathogenesis and overcome ethical and availability concerns associated with biopsy-derived tissues.

BACKGROUND:Interstitial lung diseases (ILDs) are characterized by progressive fibrosis, in which extracellular matrix remodelling is regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). The MMP-9/TIMP-1 balance has been implicated in fibrogenesis, but its role in human ILD remains incompletely defined. This study aimed to assess the MMP-9/TIMP-1 ratio in BAL fluids of ILD patients, its relationship with fibrotic severity, and the cellular contribution of fibroblasts/myofibroblasts. METHODS:BAL samples from 48 consecutive ILD patients (non-fibrotic ILD, fibrotic ILD, idiopathic pulmonary fibrosis [IPF]) were analysed. MMP-9 and TIMP-1 concentrations were quantified by enzyme-linked immunosorbent assay (ELISA), and MMP-9 activity assessed by gelatin zymography. Fibroblasts/myofibroblasts were isolated from BAL of ILD patients and tested for TIMP-1 and MMP-9 release by ELISA, or protein expression by immunofluorescence. Published single-cell RNA sequencing datasets were reanalyzed (DESeq2 model) to define the cellular source of MMP-9 and TIMP-1. RESULTS:The MMP-9/TIMP-1 ratio was significantly reduced in BAL of patients with more advanced fibrosis, correlating with a higher presence of fibroblastic foci (p = .002) and collagen deposition (p < .001). This reduction was driven by both decreased MMP-9 and increased TIMP-1 levels. Zymography confirmed declining MMP-9 enzymatic activity across ILD subgroups. Fibroblasts, derived from BAL of ILD patients, displayed high TIMP-1 secretion but minimal MMP-9 release, consistent with their expression in immunofluorescence. Reanalysis of two independent scRNA-seq datasets confirmed predominant TIMP-1 expression in fibroblast/myofibroblast clusters, with low but detectable MMP-9 expression. CONCLUSIONS:Fibroblast-driven MMP-9/TIMP-1 imbalance in BAL reflects fibrotic severity in ILD. The MMP-9/TIMP-1 ratio may represent a supportive biomarker for differential diagnosis and phenotyping of ILD, warranting validation in larger multicenter studies.

Aim of the study was to define the patterns and determinants of symptom persistence in Long-COVID. The study population was represented by a multicenter cohort of patients with persisting symptoms after SARS-CoV-2 infection. Data collection included demographics, comorbidities, characteristics of acute infection, vaccination, reinfection, plus 30 different symptoms. The associations between covariates and persistence were assessed in multivariable logistic regression models. The study evaluated, at a mean interval of 453 days from acute SARS-CoV-2 infection, symptom persistence in 755 patients who had Long-COVID symptoms at a mean interval of 223 days from COVID-19. At second evaluation, 423 (56.0

BACKGROUND:Sustainability in medicine is gaining increasing importance. In interventional pulmonology only few studies demonstrated the impact of mechanisms involved in CO2 equivalent production; moreover, operators' sensitivity to sustainability and each center's recycling processes are highly variable. We conducted a national survey among interventional pulmonologists on perception of sustainability resulting from their work, and how endoscopic activity impacts the production of recyclable material. METHODS:A 26-item questionnaire was sent to each AIPO member registered in the interventional pulmonology study group. Items were divided in four topics: demographic data, perception of the problem, measures in place to improve sustainability and potentially feasible measure to improve the problem. RESULTS:We obtained a 16.2% response rate and majority of participants work in high volume centers. Climate change was perceived as an important problem but responders though that physicians are few involved mainly due to lack of awareness of the problem. Recycling programs are widely available with differentiation between recyclable and potentially contaminated material. The disposable bronchoscopes use was perceived to increase carbon footprint. Most critical interventions to improve sustainability suggested were: optimization of separate waste collection, instrument reprocessing procedures, adherence to guidelines to reduce unnecessary procedures and improving staff awareness. Most participants believed that scientific societies should establish a working group on climate change. CONCLUSIONS:The sustainability of daily activity in interventional pulmonology is a cause for concern among interventional pulmonologists while the lack of awareness remains the main reason for the poor perception of the problem; sustainability represents a need and an opportunity for interventional pulmonologists to align with other disciplines, but this concept can also be extended to all areas of pneumology.

BACKGROUND AND PURPOSE:Neurological involvement in long COVID (coronavirus disease 2019) is well known. In a previous study we identified two subtypes of neurological long COVID, one characterized by memory disturbances, psychological impairment, headache, anosmia and ageusia, and the other characterized by peripheral nervous system involvement, each of which present a different risk factor profile. In this study, we aimed to clarify the persistence of neurological long COVID symptoms with a significantly longer term follow-up. METHODS:We prospectively collected data from patients with prior COVID-19 infection who showed symptoms of neurological long COVID. We conducted a descriptive analysis to investigate the progression of neurological symptoms over time at 3-, 6-, 12-, and 18-month follow-ups. We performed a k-means clustering analysis on the temporal evolution of the symptoms at 6, 12, and 18 months. Finally, we assessed the difference between the recovery course of vaccinated and non-vaccinated patients by computing the cumulative recovery rate of symptoms in the two groups. RESULTS:The study confirmed the presence of two subtypes of neurological long COVID. Further, 50% of patients presented a complete resolution of symptoms at 18 months of follow-up, regardless of which subtype of neurological long COVID they had. Vaccination against SARS-Cov-2 appeared to imply a higher overall recovery rate for all neurological symptoms, although the statistical reliability of this finding is hampered by the limited sample size of the unvaccinated patients included in this study. CONCLUSIONS:Neurological long COVID can undergo complete resolution after 18 months of follow-up in 50% of patients and vaccination can accelerate the recovery.

Purpose:Some studies have suggested that therapeutic interventions able to mitigate the acute phase of COVID-19 can also reduce the risk of Long-COVID and its severity, but the issue is still controversial. Methods:We examined in a national cohort of patients followed in Long-COVID centers the risk of persistent symptoms according to administration in acute COVID-19 of four drug classes: antivirals, IL-6 inhibitors, monoclonal neutralizing antibodies and systemic corticosteroids. Final risk estimates for 26 symptoms were expressed as adjusted odds ratios calculated in multivariable logistic regression models that included as covariates demographics, comorbidities, BMI, smoking, severity of acute disease, hospitalization, level of respiratory support, SARS-CoV-2 vaccination and treatments administered during acute infection. Results:The final population included 1534 adult patients (mean age 60.3 years, 67.0% hospitalised during acute COVID-19). Treatments administered during acute phase included systemic steroids (52.8%), antivirals (20.7%, mostly remdesivir), IL-6 inhibitors (9.4%) and neutralizing antibodies (3.9%). After a mean interval of 338 days from acute COVID-19, 1181 patients (77.0%) presented persisting symptoms. For the drug classes considered, some protective associations were found in univariate analyses, that were however not maintained adjusting for confounders in multivariate analyses. Systemic corticosteroids and IL-6 inhibitors showed some negative associations with isolated symptoms. Conclusions:Some drug classes showed a protective effect that was however not confirmed in multivariable analyses, underlining the importance of adjusting for a comprehensive number of covariates. Clinicians should consider the possibility that systemic corticosteroids and IL-6 inhibitors administered during acute COVID-19 may prolong the persistence of particular symptoms.

Background:The diagnostic accuracy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the diagnosis of lymphoma has a low overall sensitivity. The lack of tissue architecture obtained by cytological needles decreases the diagnostic accuracy for diagnosis and subtyping of de novo and relapsed mediastinal lymphomas. This study compares the sensitivity of EBUS-TBNA and endobronchial ultrasound-guided transbronchial mediastinal cryobiopsy (EBUS-TMC) for both initial lymphoma diagnosis and recurrent cases, analyses safety, and evaluates the number of mediastinoscopies that could potentially be avoided due to this novel technique. Methods:A multicentre retrospective observational study conducted on 40 patients who underwent both EBUS-TBNA and EBUS-TMC in the same procedure in which a definitive diagnosis of lymphoma was obtained from January 2023 to January 2024. EBUS-TBNA and EBUS-TMC were performed in the same lymph node station. Results:The overall sensitivity of EBUS-TMC was significantly higher compared to EBUS-TBNA alone and EBUS-TBNA+flow cytometry (95% versus 15% versus 25%). In new lymphoma cases, the sensitivity of EBUS-TMC surpassed that of EBUS-TBNA and EBUS-TBNA+flow cytometry (92% versus 15% versus 14%). In recurrent cases, EBUS-TMC showed a sensitivity of 100%, while EBUS-TBNA and EBUS-TBNA+flow cytometry had lower yields of 14% and 41%, respectively. No complications were reported. Conclusions:EBUS-TMC demonstrates superior sensitivity compared to EBUS-TBNA in diagnosing and subtyping lymphoma, both in suspected new cases and recurrences. This technique reduces the need for procedural repetitions and avoids more invasive and costly interventions such as mediastinoscopy.

Background: Rapid On-Site Evaluation (ROSE) during bronchoscopy allows us to assess sample adequacy for diagnosis and molecular analyses in the context of precision oncology. While extemporaneous smears are typically evaluated by pathologists, their presence during bronchoscopy is not always possible. Our aim is to assess the concordance between ROSE performed by interventional pulmonologists and cytopathologists. Methods: We performed ROSE on 133 samples collected from 108 patients who underwent bronchoscopy for the diagnosis of suspect thoracic findings or for mediastinal lymph node staging (May 2023–October 2023). Randomly selected smears (one for each collection site) were independently evaluated for adequacy by a pulmonologist and a pathologist to assess the concordance of their evaluation. Results: Among 133 selected smears evaluated by a pulmonologist and pathologist, 100 were adequate for both, 10 were inadequate for both and 23 were discordant; hence, global concordance was 82.7%; Cohen’s Kappa was 0.385, defining fair agreement. Concordance was similar irrespective of sample collection site (lymph nodes vs. pulmonary lesions; p = 0.999) and among samples which were considered adequate or inadequate by the pulmonologist (p = 0.608). Conclusions: Trained pulmonologists can evaluate the appropriateness of sampling with good concordance with cytopathologists. Our work supports autonomous ROSE by pulmonologists where pathologists are not immediately available.

Background Molecular characterization is pivotal for managing non-small cell lung cancer (NSCLC), although this process is often time-consuming and patients’ conditions might worsen while molecular analyses are processed.Our primary aim was to evaluate the performance of “up-front” next-generation sequencing (NGS) through liquid biopsy (LB) of hospitalized patients with newly detected lung neoplasm in parallel with conventional diagnosis. The secondary aim included longitudinal monitoring through LB of patients with oncogenic alterations at baseline. Methods We enrolled 47 consecutive patients immediately after hospitalization and radiological detection of symptomatic lung neoplasm. LB from peripheral blood was performed at baseline, in parallel with conventional biopsy (CB), when feasible. Additionally, LBs were repeated during treatment in patients with actionable gene alterations at baseline. Oncomine™ Lung cfTNA Research Assay panel was employed for processing plasma samples in NGS. Results 47 hospitalized patients were enrolled. LB identified 28 patients with gene alterations, including mutations of EGFR (n=7), KRAS (n=12), ERBB2 (n=1), TP53 (n=2), BRAF (n=1), one ALK rearrangement, and 4 patients with combined mutations involving EGFR, KRAS and PIK3CA.LB and CB were consistent, except for two patients. Three patients with positive LB for oncogenic drivers did not undergo CB due to contraindications.Median time to molecular results after LB was significantly lower compared to time to molecular report after CB (11 versus 22 days, p< 0.001). Conclusions Despite limited numbers, our study supports the role of front-line LB for improving management of symptomatic patients with lung cancer, potentially leading to early targeted therapy initiation.

Editorial: Pulmonary fibrosis and lung carcinogenesis: do myofibroblasts and cancer-associated fibroblasts share a common identity?

Background While cutaneous melanomas are well-documented, primary melanoma of the lung (PMML), particularly with endobronchial origin, remains rare and poorly characterized. This case report addresses gaps in understanding by presenting a comprehensive case of a 71-year-old male with primary endobronchial melanoma and conducting a systematic review of PMML cases. Case Presentation The patient, a former smoker, presented with dyspnea, cough, and hemoptysis. Imaging revealed left lung atelectasis and a suspicious nodule. Bronchoscopy identified an endobronchial mass, subsequently treated with argon plasma coagulation and resection. Biopsy confirmed melanoma. Extensive examinations ruled out a primary skin lesion. Despite initial treatment, recurrence led to pneumonectomy. Histopathology confirmed melanoma. The patient received treatment with pembrolizumab and ipilimumab, but with poor clinical benefit. Conclusions Primary endobronchial melanoma is a rare entity, comprising 0.01% of lung tumors. This case underscores diagnostic challenges and emphasizes histological criteria to distinguish primary from metastatic lesions. The pathogenesis remains unclear, with theories proposing foetal melanocyte migration or squamous metaplasia. Prognosis varies, necessitating radical surgical extirpation. A systematic review revealed diverse outcomes, supporting the need for further research. In conclusion, endobronchial melanoma involves an endoscopic and surgical management, but evolving therapies, such as immunotherapy, may reshape treatment paradigms. This case contributes to our understanding of PMML, guiding future research and clinical management. As therapeutic options evolve, continued research is crucial to refine our understanding and improve outcomes for this rare malignancy.

Long-COVID symptoms remain incompletely defined due to a large heterogeneity in the populations studied, case definitions, and settings of care. The aim of this study was to assess, in patients accessing care for Long-COVID, the profile of symptoms reported, the possible clustering of symptoms and cases, the functional status compared to pre-infection, and the impact on working activity. Multicentre cohort study with a collection of both retrospective and prospective data. Demographics, comorbidities, severity and timing of acute COVID, subjective functional status, working activity and presence of 30 different symptoms were collected using a shortened version of the WHO Post COVID-19 Case Report Form. The impact on working activity was assessed in multivariable logistic regression models. Clustering of symptoms was analysed by hierarchical clustering and the clustering of cases by two-step automatic clustering. The study evaluated 1297 individuals (51.5

Background: Lung cancer patients diagnosed following emergency admission often present with advanced disease and poor performance status, leading to suboptimal treatment options and outcomes. This study aimed to investigate the clinical and molecular characteristics, treatment initiation, and survival outcomes of these patients. Methods: We retrospectively analyzed data from 124 patients diagnosed with lung cancer following emergency admission at a single institution. Clinical characteristics, results of molecular analyses for therapeutic purpose, systemic treatment initiation, and survival outcomes were assessed. Correlations between patients’ characteristics and treatment initiation were analyzed. Results: Median age at admission was 73 years, and 79.0 % had at least one comorbidity. Most patients (87.1 %) were admitted due to cancer-related symptoms. Molecular analyses were performed in 89.5 % of advanced non-small cell lung cancer (NSCLC) cases. In this subgroup, two-thirds (66.2 %) received first-line therapy. Median overall survival (OS) was 3.9 months for the entire cohort, and 2.9 months for patients with metastatic lung cancer. Among patients with advanced NSCLC, OS was significantly longer for those with actionable oncogenic drivers and those who received first-line therapy. Improvement of performance status during hospitalization resulted in increased probability of receiving first-line systemic therapy. Discussion: Patients diagnosed with lung cancer following emergency admission demonstrated poor survival outcomes. Treatment initiation, particularly for patients with actionable oncogenic drivers, was associated with longer OS. These findings highlight the need for proactive medical approaches, including improving access to molecular diagnostics and targeted treatments, to optimize outcomes in this patient population.

Aim: The aim of our study is to compare respiratory function, physical performance and nutritional parameters at the time of disease diagnosis and after 6 months of follow-up in a cohort of patients with IPF followed-up prospectively in 9 IPF referral centers in northern Italy. Methods: The study consisted of two respiratory assessment and two nutritional evaluations at baseline and 6-month follow-up. Results: 90 patients were included in the study, however only 82 patients with both pneumological assessments were included in this analysis. In regards to PFTs and DLCO did not significantly change between baseline and 6 months follow-up. Similarly, no differences were observed in the 4-meter gait speed test, distance walked at 6MWT and hand-grip strength. Mean BMI significantly decreased (p<0.001) as significantly increased the proportion of patients who lost more than 5% of weight in the prior 6 months (p=0.004). Anthropometric measurements, arm and abdominal circumference significantly decreased between baseline and follow-up. These changes in the nutritional status also led to a modification in the nutritional phenotypes with a reduction in the proportion of obese and normonourished patients and an increase in patients with sarcopenia (Figure 1). Conclusions: We did not observe a significant change in pulmonary function and physical performance parameters iduring the 6-month follow-up. However, worsening of multiple nutritional parameters was detected, including loss of weight, reduction of both body fat and lean mass at BIA. These nutritional changes were reflected in a reduction of patients who showed an obese or normonourished phenotype and increasing in the proportion of sarcopenic patients.

BACKGROUND:Persistent dyspnea is frequent in post-COVID patients, even in the absence of pulmonary embolism (PE). In this scenario, the role of lung perfusion scintigraphy is unclear. The present study correlated scintigraphy-based semiquantitative perfusion parameters with chest high-resolution computed tomography (hrCT) volumetric indexes and clinical data in post-COVID patients with persistent dyspnea.RESEARCH DESIGN AND METHODS:Sixty patients (30 post-COVID and 30 not previously affected by COVID-19) with persistent dyspnea submitted to lung perfusion scintigraphy and hrCT were retrospectively recruited. Perfusion rates of the pulmonary fields and hrCT-based normalized inflated, emphysematous, infiltrated, collapsed, and vascular lung volumes were calculated. Inflammatory and coagulation biomarkers were collected. PE at imaging was an exclusion criterion.RESULTS:Compared to controls, reduced perfusion rates of the lower pulmonary fields and higher perfusion rates of the middle ones were observed in post-COVID patients, while hrCT findings were superimposable between the two groups. Perfusion rates of lower pulmonary fields were significantly associated only with abnormal lung volumes at hrCT.CONCLUSIONS:In post-COVID dyspnea without PE, lung perfusion scintigraphy may reveal a pulmonary involvement not detectable by hrCT. Post-COVID patients may show decreased perfusion rates of lower pulmonary fields in the presence of normal vascular density and markers of inflammation/coagulation.

BACKGROUND:Pleural disease (PD), particularly malignant pleural effusion (MPE), is a common cause of hospital admission and its prevalence is rising worldwide. Recent advances in diagnostic and therapeutic options, such as Indwelling Pleural Catheters (IPCs), have simplified PD treatment, allowing an effective outpatients management. Therefore, dedicated pleural services can improve PD care, guaranteeing specialized management and optimizing time and cost. We aimed to provide an overview on MPE management in Italy, mainly focused on distribution and characteristics of pleural services and IPCs use.METHODS:A nationwide survey, endorsed by the Italian Thoracic Society, was distributed by email to members of selected subgroups in 2021.RESULTS:Ninety (23%) members replied, most of whom being pulmonologists (91%). MPE resulted the most common cause of pleural effusion and was managed with heterogenous approaches, including talc pleurodesis via slurry (43%), talc poudrage (31%), repeated thoracentesis (22%) and IPCs insertion (2%). The setting of IPC insertion was inpatient care in 48% of cases, with a predominance of draining frequency every other day. IPC management mainly relied on caregivers (42%). The presence of a pleural service was reported by 37% of respondents.CONCLUSIONS:The present study provides an extensive overview of MPE management in Italy, showing a highly heterogeneous approach, a scarce prevalence of out-patient pleural services, and a still limited adoption of IPCs, mainly due to lack of dedicated community care systems. This survey emphasizes the need of promoting a higher spreading of pleural services and an innovative healthcare delivery with more favourable cost-benefit ratio.