Extracellular Vesicles in Pulmonary Fibrosis Models and Biological Fluids of Interstitial Lung Disease Patients : A Scoping Review

Introduction: Interstitial lung diseases (ILDs) are a heterogeneous group of diffuse parenchymal lung disorders characterized by the pathogenetic involvement of interstitium. Therefore, an elucidation of the etiology and pathogenesis as well as the identification of diagnostic and prognostic biomarkers of such diseases is more compelling than ever. It is of note that there is increasing evidence of the involvement of extracellular vesicles (EVs) in the pathogenesis of lung diseases including lung cancer, chronic obstructive pulmonary disease and pulmonary fibrosis. It has been speculated that EVs play a pivotal role as mediators of intercellular communication, as well as the highlighting of the role of EVs as co-operators in the development of lung diseases such as IPF. Methods: The present study aimed to carry out a systematic exploratory search of the literature (through the scoping review approach) to identify and systematize the main results of the pathogenetic role of EVs in pulmonary fibrosis models and biological fluids from ILD patients, including plasma, bronchoalveolar lavage (BAL) and sputum. Conclusion: Fibroblast-to-mesenchymal differentiation, collagen and extracellular matrix deposition are key mechanisms in the development and progression of IPF. EV-coupled miRNA are important modulators of biological processes in terms of intercellular communication as shown in pulmonary fibrosis models as well as biofluids. The helpfulness of EVs as diagnostic and theranostic markers is worth further investigation. The evolving potential of EVs to translate effective EV-based therapies into clinical practice is of growing interest, due to the urgent need for novel therapeutic strategies for IPF patients

Pirfenidone in idiopathic pulmonary fibrosis: real-life experience in the referral centre of Siena

Background: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and has a median survival after diagnosis of 2–5 years. Pirfenidone is the first approved antifibrotic drug for the treatment of IPF. Here we report the functional progress, side effects and survival data of a population of patients with IPF, diagnosed at our centre and treated with pirfenidone. Methods: We enrolled 91 patients with IPF (71 males) treated with pirfenidone. Clinical, survival and functional details were collected retrospectively at start of therapy and after 12, 24, 36 and 48 months of treatment. Lung function tests at least 12 months before starting therapy were available for 40 patients and were entered in the database, as well as side effects. Results: During the observation period (922 ± 529 days), 27 patients died, 5 patients underwent lung transplant and 10 patients interrupted therapy due to adverse events or IPF progression. The median survival was 1606 days. There was a significant reduction in disease progression rate, as measured by trend of forced vital capacity, after 1 year of therapy with respect to before treatment (p = 0.0085). Forced vital capacity reduction rate was progressively higher in the subsequent years of treatment. Treatment-related side effects were reported in 25 patients and were predominantly mild. Overall, four patients discontinued therapy due to severe photosensitivity. Conclusions: Our findings confirm the efficacy of pirfenidone in reducing functional progression of IPF and its excellent safety profile in a real-life setting. This study, designed on a long-term follow up, contributes to the growing evidence on safety, tolerability and efficacy of pirfenidone in IPF. The reviews of this paper are available via the supplemental material section

Collagen Type IV Alpha 5 Chain in Bronchiolitis Obliterans Syndrome After Lung Transplant: The First Evidence

Introduction: Bronchiolitis obliterans syndrome (BOS) is the most common form of CLAD and is characterized by airflow limitation and an obstructive spirometry pattern without parenchymal opacities. The protein signature of BOS lesions concerns extracellular matrix organization and aberrant basement membrane composition. In this pilot study, we investigated the presence of COL4A5 in the serum of patients with BOS. Methods: 41 patients who had undergone LTX were enrolled. Of these, 27 developed BOS and 14 (control group) were considered stable at the time of serum sampling. Of BOS patients, serum samples were analysed at the time of BOS diagnosis and before the clinical diagnosis (pre-BOS). COL4A5 levels were detected through the ELISA kit. Results: Serum concentrations of COL4A5 were higher in pre-BOS than in stable patients (40.5 ± 13.9 and 24.8 ± 11.4, respectively, p = 0.048). This protein is not influenced by comorbidities, such as acute rejection or infections, or by therapies. Survival analysis also reveals that a higher level of COL4A5 was also associated with less probability of survival. Our data showed a correlation between concentrations of COL4A5 and FEV1 at the time of diagnosis of BOS. Conclusion: Serum concentrations of COL4A5 can be considered a good prognostic marker due to their association with survival and correlation with functional parameters

Prognostic relevance of serum beta2 microglobulin in patients with follicular lymphoma treated with anthracycline-containing regimens. A GISL study.

Background and ObjectivesAlthough serum b2 microglobulin (b2M) is an easy parameter to measure, and overexpressedin a large number of lymphoproliferative diseases, its prognostic value hasbeen largely underestimated. The present study examined the influence of b2M levelson overall survival (OS) of patients with follicular lymphoma (FL).Design and MethodsThe prognostic role of b2M was evaluated in 236 patients with FL identified from thedatabases of the Gruppo Italiano per lo Studio dei Linfomi (GISL) and treated withanthracycline-based regimens from 1993 to 2003.ResultsElevated serum b2M levels were found in 82 patients (35%). According to multivariatelogistic regression analysis, elevated b2M levels were associated with elevatedlactate dehydrogenase (LDH) (p=0.021), age (p=0.029), and number of involvednodal areas (p<0.001). The percentage of elevated b2M levels increased progressivelywith increasing FLIPI scores (17%, 38%, and 63% in the low-, intermediate-, andhigh-risk groups, respectively). Five-year OS was 61% (95% CI, 47-73%) and 89% (95%CI, 82-93%) for patients with elevated vs normal b2M levels respectively (p<0.001).Cox regression analysis showed that b2M level had an independent and stable prognosticvalue (HR=3.0; 95%CI, 1.6-5.7). In a multivariate analysis the impact of b2Mlevel on survival was independent of FLIPI score, with a HR of 2.94 (95% CI, 1.54-5.62).Interpretation and ConclusionsOur results demonstrate that in patients treated in the pre-rituximab era, b2M levelwas an independent prognostic marker in addition to FLIPI score. We thus suggestthat b2M be routinely assessed and tested in future prognostic studies of FL patientstreated with combination chemotherapy and anti-CD20 agents

Pleuroparenchymal fibroelastosis in patients affected by systemic sclerosis: What should the rheumatologist do?

Pleuroparenchymal fibroelastosis (PPFE) is a rare new interstitial lung disease (ILD) characterized by the fibrotic thickening of the visceral pleura and subadjacent parenchymal areas of the upper lobes This study reveals that patients with ILD-SSc associated with chest HRCT evidence of PPFE require close and recurrent follow-up with periodic evaluation of lung function parameters, DLCO and chest HRCT. Rheumatologists should be aware of this new radiological finding which is accompanied by a negative prognosis, especially when associated with a progressive course. Patients with this radiological pattern need to be monitored with particular attention

Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (&lt;60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.Results: Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses.Conclusion: Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19