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To verify whether the new hemodynamic definition of pulmonary hypertension (PH) has any implication in treatment of Chronic Thrombo-Embolic Pulmonary Disease (CTEPD) patients without PH, we retrospectively analysed the clinical and functional changes determined by pulmonary endarterectomy (PEA) in 63 CTEPD patients without PH who underwent surgery at our center, comparing those in whom the hemodynamic diagnosis of PH met recent guideline recommendations versus those in whom the diagnosis only met previous hemodynamic thresholds. The results show that the vast majority of CTEPD patients without PH operated at our center would now be defined as chronic thromboembolic pulmonary hypertension (CTEPH) patients. PEA did not result in any improvement in exercise capacity nor in right ventricular function or lung function test in patients with mean pulmonary artery pressure (mPAP) ≤ 20 mm Hg and pulmonary vascular resistance (PVR) ≤ 2 WU; on the contrary, hemodynamic parameters, exercise capacity, right ventricular function and lung function significantly improved in patients with mPAP between 21 and 24 mm Hg. [ABSTRACT FROM AUTHOR]

Background: The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals with the PI*SS genotype is poorly defined despite its substantial prevalence. Our study aimed to characterize this genotype and its risk for lung disease and compare it with the PI*ZZ and PI*SZ genotypes using data from the European Alpha-1 antitrypsin Deficiency Research Collaboration international registry. Method: Demographic, clinical, functional, and quality of life (QoL) parameters were assessed to compare the PI*SS characteristics with the PI*SZ and PI*ZZ controls. A propensity score with 1:3 nearest-neighbour matching was performed for the most important confounding variables. Results: The study included 1007 individuals, with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). The PI*SS population consisted of 58.9% men, with a mean age of 59.2 years and a mean FEV1(% predicted) of 83.4%. Compared to PI*ZZ individuals they had less frequent lung disease (71.4% vs. 82.2%, p = 0.037), COPD (41.4% vs. 60%, p = 0.002), and emphysema (23.2% vs. 51.9%, p < 0.001) and better preserved lung function, fewer exacerbations, lower level of dyspnoea, and better QoL. In contrast, no significant differences were found in the prevalence of lung diseases between PI*SS and PI*SZ, or lung function parameters, exacerbations, dyspnoea, or QoL. Conclusions: We found that, as expected, the risk of lung disease associated with the PI*SS genotype is significantly lower compared with PI*ZZ, but does not differ from that observed in PI*SZ individuals, despite having higher serum AAT levels. Trial registration: www.clinicaltrials.gov (ID: NCT04180319). [ABSTRACT FROM AUTHOR]

Simple Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic coronavirus disease-2019 (COVID-19), which can lead to severe pneumonia and acute respiratory distress syndrome (ARDS). The immune system plays a key role in the defense against COVID-19. Nonetheless, if dysregulated and hyperactivated, the immune response can trigger the deleterious "cytokine storm". Multiple studies are aimed at finding potential immunomodulators to rebalance the immune response against the virus, thus limiting its dangerous effects. Moreover, the development of vaccines against SARS-CoV-2 has represented a global challenge. The aim of this narrative review is to describe the state-of-the-art knowledge on the immune system response in COVID-19 and to underline the main therapeutic strategies and the key role of vaccines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 19 (COVID-19). COVID-19 can manifest with a heterogenous spectrum of disease severity, from mild upper airways infection to severe interstitial pneumonia and devastating acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection may induce an over activation of the immune system and the release of high concentrations of pro-inflammatory cytokines, leading to a "cytokine storm", a recognized pathogenetic mechanism in the genesis of SARS-CoV-2-induced lung disease. This overproduction of inflammatory cytokines has been recognized as a poor prognostic factor, since it can lead to disease progression, organ failure, ARDS and death. Moreover, the immune system shows dysregulated activity, particularly through activated macrophages and T-helper cells and in the co-occurrent exhaustion of lymphocytes. We carried out a non-systematic literature review aimed at providing an overview of the current knowledge on the pathologic mechanisms played by the immune system and the inflammation in the genesis of SARS-CoV-2-induced lung disease. An overview on potential treatments for this harmful condition and for contrasting the "cytokine storm" has also been presented. Finally, a look at the experimented experimental vaccines against SARS-CoV-2 has been included. [ABSTRACT FROM AUTHOR]

Background: Alpha-1 antitrypsin deficiency (AATD) is a rare disease that is associated with an increased risk of pulmonary emphysema. The European AATD Research Collaboration (EARCO) international registry was founded with the objective of characterising the individuals with AATD and investigating their natural history. Methods: The EARCO registry is an international, observational and prospective study of individuals with AATD, defined as AAT serum levels < 11 μM and/or proteinase inhibitor genotypes PI*ZZ, PI*SZ and compound heterozygotes or homozygotes of other rare deficient variants. We describe the characteristics of the individuals included from February 2020 to May 2022. Results: A total of 1044 individuals from 15 countries were analysed. The most frequent genotype was PI*ZZ (60.2%), followed by PI*SZ (29.2%). Among PI*ZZ patients, emphysema was the most frequent lung disease (57.2%) followed by COPD (57.2%) and bronchiectasis (22%). Up to 76.4% had concordant values of FEV1(%) and KCO(%). Those with impairment in FEV1(%) alone had more frequently bronchiectasis and asthma and those with impairment in KCO(%) alone had more frequent emphysema and liver disease. Multivariate analysis showed that advanced age, male sex, exacerbations, increased blood platelets and neutrophils, augmentation and lower AAT serum levels were associated with worse FEV1(%). Conclusions: EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registrationwww.clinicaltrials.gov (ID: NCT04180319) [ABSTRACT FROM AUTHOR]

Alpha1-antitrypsin (AAT) is a serine protease inhibitor that is encoded by the highly polymorphic SERPINA1 gene. Mutations in this gene can lead to AAT deficiency (AATD), which is associated with an increased risk of lung and/or liver disease. On the basis of electrophoretic migration, AAT variants are named with capital letters; M (medium) signifies the normal protein. Among pathological variants, the M-like ones represent a heterogeneous group of rare allelic variants that exhibit the same electrophoretic pattern as the M wild-type protein, which makes them difficult to detect with routine methods. In order to avoid their misdiagnosis, the present study defines and validates effective methods for the detection of two pathogenic M-like variants, Mwurzburg and Mwhitstable. Comparison of protein phenotypes using isoelectric focusing of samples that presented the Mwurzburg variant, as revealed by exons 5 sequencing, identified a particular electrophoretic pattern amenable to the Mwurzburg protein. The specific phenotyping pattern was retrospectively validated, thus enabling the detection of 16 patients with Mwurzburg variant among the subjects already tested but not sequenced according to our diagnostic algorithm. The Mwhitstable allele was detected by intron 4 sequencing of SERPINA1 gene. Mwurzburg and Mwhitstable are often misdiagnosed and the introduction of diagnostic improvements can help the clinical management, especially in patients with established lung disease without any other reported risk factors. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to describe the radiological features of chronic thromboembolic pulmonary disease (CTEPD), not yet systematically described in the literature. Furthermore, we compared vascular scores between CTEPD and chronic thromboembolic pulmonary hypertension (CTEPH) patients, trying to explain why pulmonary hypertension does not develop at rest in CTEPD patients. Methods: Eighty-five patients (40 CTEPD, 45 CTEPH) referred to our centre for pulmonary endarterectomy underwent dual-energy computed tomography pulmonary angiography (DE-CTPA) with iodine perfusion maps; other 6 CTEPD patients underwent single-source CTPA. CT scans were reviewed independently by an experienced cardiothoracic radiologist and a radiology resident to evaluate scores of vascular obstruction, hypoperfusion and mosaic attenuation, signs of pulmonary hypertension and other CT features typical of CTEPH. Results: Vascular obstruction burden was similar in the two groups (p = 0.073), but CTEPD patients have a smaller extension of perfusion defects in the iodine map (p = 0.009) and a smaller number of these patients had mosaic attenuation (p < 0.001) than CTEPH patients, suggesting the absence of microvascular disease. Furthermore, as expected, the two groups were significantly different considering the indirect signs of pulmonary hypertension (p < 0.001). Conclusions: CTEPD and CTEPH patients have significantly different radiological characteristics, in terms of signs of pulmonary hypertension, mosaic attenuation and iodine map perfusion extension. Importantly, our results suggest that the absence of peripheral microvascular disease, even in presence of an important thrombotic burden, might be the reason for the absence of pulmonary hypertension in CTEPD. Key Points: • CTEPD and CTEPH patients have significantly different radiological characteristics. • The absence of peripheral microvascular disease might be the reason for the absence of pulmonary hypertension in CTEPD. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that Mesenchymal Stem/Stromal Cells (MSCs) exert their therapeutic effects by the release of secretome, made of both soluble proteins and nano/microstructured extracellular vesicles (EVs). In this work, for the first time, we proved by a proteomic investigation that adipose-derived (AD)-MSC-secretome contains alpha-1-antitrypsin (AAT), the main elastase inhibitor in the lung, 72 other proteins involved in protease/antiprotease balance, and 46 proteins involved in the response to bacteria. By secretome fractionation, we proved that AAT is present both in the soluble fraction of secretome and aggregated and/or adsorbed on the surface of EVs, that can act as natural carriers promoting AAT in vivo stability and activity. To modulate secretome composition, AD-MSCs were cultured in different stimulating conditions, such as serum starvation or chemicals (IL-1β and/or dexamethasone) and the expression of the gene encoding for AAT was increased. By testing in vitro the anti-elastase activity of MSC-secretome, a dose-dependent effect was observed; chemical stimulation of AD-MSCs did not increase their secretome anti-elastase activity. Finally, MSC-secretome showed anti-bacterial activity on Gram-negative bacteria, especially for Klebsiella pneumoniae. These preliminary results, in addition to the already demonstrated immunomodulation, pave the way for the use of MSC-secretome in the treatment of AAT-deficiency lung diseases. [ABSTRACT FROM AUTHOR]