Emanuela Barisione

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. 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 minutes (6MWD). 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. 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.

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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%) patients still presented one or more symptoms and 332 (44.0%) were symptom free. In those who remained symptomatic, the mean number of symptoms significantly reduced between the two evaluations. Compared to the first evaluation, the overall mean symptom regression rate was 72%, with lower regression rates observed for dyspnea (53%), anxiety (54%) and sleep disturbances (55%). The risk of persistence was increased for female sex, higher BMI, hospitalization and stronger ventilatory support during acute disease, higher number of initial symptoms and particular comorbidities (anxiety, chronic pulmonary disease, asthma), and decreased with the increase of age and time from acute SARS-CoV-2 infection. Neither SARS-CoV-2 vaccination nor reinfection showed significant associations with persistence. In this case series, roughly half of the patients that were symptomatic 7 months after acute SARS-CoV-2 infection remained symptomatic after an additional 7 months. The pattern and predictors of persistence draw attention to certain particular risk factors and manifestations that tend to persist longer than others.

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.

Broncho-alveolar lavage (BAL) represents a safe tool for the differential diagnosis of various pulmonary fibrotic diseases. Idiopathic pulmonary fibrosis (IPF) belongs to a heterogeneous group of di

Background: Few studies have assessed the differences of patterns of Long COVID (L-COVID) with regards to the pathogenetic SARS-CoV-2 strains. Objectives: To investigate the relationship between demographic and clinical characteristics of acute phase of infection and the persistence of L-COVID symptoms and clinical presentation across different SARS-CoV-2 strains. Methods: In this observational-multicenter study we recorded all demographic and clinical characteristics, severity of infection, presence/persistence of symptoms of fatigue, dyspnoea and altered quality of life (QoL) at baseline and after 6 months, in a sample of Italian patients from Liguria between March 2020 and March 2022. Results: 308 patients (mean age 63.2 years; 55.5% men) with previous COVID were enrolled. Obese patients were 21.2% with a significant difference in obesity prevalence across the second and third wave (p = 0.012). Treatment strategies differed between waves (p < 0.001): more patients required invasive mechanical ventilation in the first wave, more patients were treated with high-flow nasal cannula/non-invasive ventilation in the in the second and more patients were treated with oxygen-therapy in the fourth wave. At baseline, a high proportion of patients were symptomatic (dyspnoea and fatigue), with impairment in some QoL indicators. A higher prevalence of patients with pain, were seen in the first wave compared to later infections (p = 0.01). At follow-up, we observed improvement of dyspnoea, fatigue and some dimensions of QoL scale evaluation such as mobility, usual activities, pain evaluations; instead there was no improvement in remaining QoL scale indicators (usual care and anxiety-depression). Conclusions: There were no significant differences in the prevalence of the most frequent L-COVID symptoms, except for QoL pain domain that was especially associated with classical variant. Our results show substantial impact on social and professional life and usual care activities. These findings highlight the importance of multidisciplinary post COVID follow-up care including mental health support and rehabilitation program.

We described nailfold videocapillaroscopy (NVC) findings and estimated the prevalence of serum anti-nuclear (ANA) and extractable nuclear antigen autoantibodies (ENA) in a cohort of sarcoidosis patients, comparing them with adequate healthy controls (HCs) and with primary Raynaud’s phenomenon patients (PRPs). NVC findings were also correlated with the occurrence of autoantibodies, current treatment, laboratory parameters, variables of lung function and whole-body imaging data. Twenty-six patients with sarcoidosis were assessed through NVC, laboratory parameters, pulmonary function tests, chest-X ray and 18- fluorodeoxyglucose positron emission tomography/computed tomography. The NVC parameters and ANA/ENA dosage were recorded also in 30 PRPs and 30 HCs. Sarcoidosis patients showed a higher rate of capillary dilations and nonspecific abnormalities and a lower mean capillary absolute number than PRPs and HCs (p < 0.01 for all comparisons). The prevalence of ANA positivity was higher in patients with sarcoidosis compared with PRPs and HCs (p < 0.02 for both), whereas ENA positivity was detected in one sarcoidosis patient (Ro52). Among sarcoidosis patients, the mean capillary absolute number negatively correlated with the C-reactive protein concentrations and was positively associated with the forced vital capacity percentage. Instead, a negative correlation was detected between serum ACE levels and the presence of capillary dilations (all p < 0.05). Our findings suggest a microvascular involvement in sarcoidosis whose investigation by NVC might be useful for the follow-up of patients displaying RP. Autoantibody positivity in sarcoidosis might suggest autoimmune implications in the disease or the production of autoantibodies reactive to tissue damage.

Lung fibrosis has specific computed tomography (CT) findings and represents a common finding in advanced COVID-19 pneumonia whose reversibility has been poorly investigated. The aim of this study was to quantify the extension of collagen deposition and aeration in postmortem cryobiopsies of critically ill COVID-19 patients and to describe the correlations with qualitative and quantitative analyses of lung CT. Postmortem transbronchial cryobiopsy samples were obtained, formalin fixed, paraffin embedded and stained with Sirius red to quantify collagen deposition, defining fibrotic samples as those with collagen deposition above 10%. Lung CT images were analyzed qualitatively with a radiographic score and quantitatively with computer-based analysis at the lobe level. Thirty samples from 10 patients with COVID-19 pneumonia deceased during invasive mechanical ventilation were included in this study. The median [interquartile range] percent collagen extension was 6.8% (4.6–16.2%). In fibrotic compared to nonfibrotic samples, the qualitative score was higher (260 (250–290) vs. 190 (120–270), p = 0.036) while the gas fraction was lower (0.46 (0.32–0.47) vs. 0.59 (0.37–0.68), p = 0.047). A radiographic score above 230 had 100% sensitivity (95% confidence interval, CI: 66.4% to 100%) and 66.7% specificity (95% CI: 41.0% to 92.3%) to detect fibrotic samples, while a gas fraction below 0.57 had 100% sensitivity (95% CI: 66.4% to 100%) and 57.1% specificity (95% CI: 26.3% to 88.0%). In COVID-19 pneumonia, qualitative and quantitative analyses of lung CT images have high sensitivity but moderate to low specificity to detect histopathological fibrosis. Pseudofibrotic CT findings do not always correspond to increased collagen deposition.