Extracellular vesicles (EVs) are a family of particles/vesicles present in blood and body fluids, composed of phospholipid bilayers that carry a variety of molecules that can mediate cell communication, modulating crucial cell processes such as homeostasis, induction/dampening of inflammation, and promotion of repair. Their existence, initially suspected in 1946 and confirmed in 1967, spurred a sharp increase in the number of scientific publications. Paradoxically, the increasing interest for EV content and function progressively reduced the relevance for a precise nomenclature in classifying EVs, therefore leading to a confusing scientific production. The aim of this review was to analyze the evolution of the progress in the knowledge and definition of EVs over the years, with an overview of the methodologies used for the identification of the vesicles, their cell of origin, and the detection of their cargo. The MISEV 2018 guidelines for the proper recognition nomenclature and ways to study EVs are summarized. The review finishes with a “more questions than answers” chapter, in which some of the problems we still face to fully understand the EV function and potential as a diagnostic and therapeutic tool are analyzed.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease that commonly affects older adults and is associated with the histopathological and/or radiological patterns of usual interstitial pneumonia (UIP). Despite significant advances in our understanding of disease pathobiology and natural history, what causes IPF remains unknown. A potential role for infection in the disease’s pathogenesis and progression or as a trigger of acute exacerbation has long been postulated, but initial studies based on traditional culture methods have yielded inconsistent results. The recent application to IPF of culture-independent techniques for microbiological analysis has revealed previously unappreciated alterations of the lung microbiome, as well as an increased bacterial burden in the bronchoalveolar lavage (BAL) of IPF patients, although correlation does not necessarily entail causation. In addition, the lung microbiome remains only partially characterized and further research should investigate organisms other than bacteria and viruses, including fungi. The clarification of the role of the microbiome in the pathogenesis and progression of IPF may potentially allow its manipulation, providing an opportunity for targeted therapeutic intervention.

Sarcoidosis is a multisystem disorder of unknown origin and poorly understood pathogenesis that predominantly affects lungs and intrathoracic lymph nodes and is characterized by the presence of noncaseating granulomatous inflammation in involved organs. The disease is highly heterogeneous and can mimic a plethora of other disorders, making diagnosis a challenge even for experienced physicians. The evolution and severity of sarcoidosis are highly variable: many patients are asymptomatic and their disease course is generally benign with spontaneous resolution. However, up to one-third of patients develop chronic or progressive disease mainly due to pulmonary or cardiovascular complications that require long-term therapy. The diagnosis of sarcoidosis requires histopathological evidence of noncaseating granulomatous inflammation in one or more organs coupled with compatible clinical and radiological features and the exclusion of other causes of granulomatous inflammation; however, in the presence of typical disease manifestations such as Löfgren’s syndrome, Heerfordt’s syndrome, lupus pernio and asymptomatic bilateral and symmetrical hilar lymphadenopathy, the diagnosis can be established with high level of certainty on clinical grounds alone. This review critically examines the diagnostic approach to sarcoidosis and emphasizes the importance of a careful exclusion of alternative diagnoses.

Despite the availability of antifibrotic therapies, many patients with idiopathic pulmonary fibrosis (IPF) will progress to advanced disease and require lung transplantation. International guidelines for transplant referral and listing of patients with interstitial lung disease are not specific to those with IPF and were published before the widespread use of antifibrotic therapy. In this review, we discussed difficulties in decision-making when dealing with patients with IPF due to the wide variability in clinical course and life expectancy, as well as the acute deterioration associated with exacerbations. Indeed, the ideal timing for referral and listing for lung transplant remains challenging, and the acute deterioration might be influenced after transplant outcomes. Of note, patients with IPF are frequently affected by multimorbidity, thus a screening program for occurring conditions, such as coronary artery disease and pulmonary hypertension, before lung transplant listing is crucial to candidate selection, risk stratification, and optimal outcomes. Among several comorbidities, it is of extreme importance to highlight that the prevalence of lung cancer is increased amongst patients affected by IPF; therefore, candidates’ surveillance is critical to avoid organ allocation to unsuitable patients. For all these reasons, early referral and close longitudinal follow-up for potential lung transplant candidates are widely encouraged.

Diaphragm ultrasound (DUS) has been extensively used in critically ill patients while data on outpatients with interstitial lung disease (ILD) are limited. We hypothesized that diaphragm function, assessed by ultrasound, could be impaired in patients with ILD, considering both Idiopathic Pulmonary Fibrosis (IPF) and Connective Tissue Disease (CTD-ILD), compared to healthy subjects. Moreover, this impairment could impact clinical and functional parameters. All consecutive CTD-ILD and IPF patients followed in our center (March-October 2020) were screened. Diaphragm displacement (DD), inspiratory thickness (Ti), expiratory thickness (Te), thickening fraction (TF), and respiratory functional parameters were collected. The prevalence of diaphragmatic dysfunction (TF <30%) was then recorded. Eighty-two consecutive patients (41 CTD-ILD, 41 IPF) and 15 age- and sex-matched controls were enrolled. In the overall population, 24 out of 82 (29%) presented diaphragmatic dysfunction. In CTD-ILD, DD and Ti were lower as compared to IPF (p = 0.021 and p = 0.036, respectively); while diaphragmatic dysfunction was more prevalent compared to controls (37% vs 7%, p = 0.043). TF positively correlated to patients' functional parameters in the CTD-ILD group (FVC%pred: p = 0.003; r = 0.45), while not in the IPF group. Diaphragmatic dysfunction was associated with moderate/severe dyspnea in both CTD-ILD and IPF (p = 0.021). The prevalence of diaphragmatic dysfunction was 29% in patients with ILD and was associated with moderate/severe dyspnea. CTD-ILD presented lower DD compared with IPF and a higher prevalence of diaphragmatic dysfunction (TF<30%) compared with controls. TF was associated with lung function only in CTD-ILD patients, suggesting its potential role in the comprehensive patient assessment.

Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic with lung disease representing the main cause of morbidity and mortality. Conventional chest-X ray (CXR) and ultrasound (US) are valuable instruments to assess the extent of lung involvement. We investigated the relationship between CXR scores on admission and the level of medical care required in patients with COVID-19. Further, we assessed the CXR-US correlation to explore the role of ultrasound in monitoring the course of COVID-19 pneumonia. Clinical features and CXR scores were obtained at admission and correlated with the level of intensity of care required [high- (HIMC) versus low-intensity medical care (LIMC)]. In a subgroup of patients, US findings were correlated with clinical and radiographic parameters. On hospital admission, CXR global score was higher in HIMCs compared to LIMC. Smoking history, pO₂ on admission, cardiovascular and oncologic diseases were independent predictors of HIMC. The US score was positively correlated with FiO₂ while the correlation with CXR global score only trended towards significance. Our study identifies clinical and radiographic features that strongly correlate with higher levels of medical care. The role of lung ultrasound in this setting remains undetermined and needs to be explored in larger prospective studies.