Reversibility of the Enlargement of the Pulmonary Artery in COVID-19 Pneumonia as a Marker of Remission of the Disease.

Coronavirus disease 2019 (COVID-19) pneumonia is associated with extensive pulmonary microangiopathy and the enlargement of the pulmonary artery (PA), while its progression after the remission of the disease has not been investigated yet. The aim was to assess the diametral increase in the PA in COVID-19 pneumonia, as revealed on chest computed tomography (CT), and further investigate its progression. This was a retrospective cohort study of patients with COVID-19 pneumonia, without prior history of pulmonary hypertension, who underwent CT pulmonary angiography before, during, and after the infection. Pulmonary embolism was excluded in all cases. The main PA diameter (MPAD) was assessed in consecutive chest imaging. Statistical analysis was performed with the non-parametric Wilcoxon and Kruskal-Wallis tests, while correlations were performed with the non-parametric Spearman test. A mean ± SD MPAD of 3.1 ± 0.3 cm in COVID-19 pneumonia was significantly decreased to 2.8 ± 0.3 cm in the post-infectious state after 2-18 months in 31 patients (p-value: <0.0001). In a subgroup of six patients with more than one post-COVID-19 CT, a significant further decline in the diameter was observed (p-value: 0.0313). On the other hand, in accordance with the literature, a significant increase in the MPAD during COVID-19 pneumonia was noted in a group of 10 patients with a pre-COVID-19 CT (p-value: 0.0371). The enlargement of the PA is a common finding in COVID-19 pneumonia that regresses after the remission of the disease, indicating that this reversible cardiovascular event is a potential marker of disease activity, while its course in long COVID is yet to be determined.

Corrigendum: Post-COVID-19 interstitial lung disease: Insights from a machine learning radiographic model.

[This corrects the article DOI: 10.3389/fmed.2022.1083264.].

Post-COVID-19 interstitial lung disease: Insights from a machine learning radiographic model.

Introduction: Post-acute sequelae of COVID-19 seem to be an emerging global crisis. Machine learning radiographic models have great potential for meticulous evaluation of post-COVID-19 interstitial lung disease (ILD). Methods: In this multicenter, retrospective study, we included consecutive patients that had been evaluated 3 months following severe acute respiratory syndrome coronavirus 2 infection between 01/02/2021 and 12/5/2022. High-resolution computed tomography was evaluated through Imbio Lung Texture Analysis 2.1. Results: Two hundred thirty-two (n = 232) patients were analyzed. FVC% predicted was ≥80, between 60 and 79 and <60 in 74.2% (n = 172), 21.1% (n = 49), and 4.7% (n = 11) of the cohort, respectively. DLCO% predicted was ≥80, between 60 and 79 and <60 in 69.4% (n = 161), 15.5% (n = 36), and 15.1% (n = 35), respectively. Extent of ground glass opacities was ≥30% in 4.3% of patients (n = 10), between 5 and 29% in 48.7% of patients (n = 113) and <5% in 47.0% of patients (n = 109). The extent of reticulation was ≥30%, 5-29% and <5% in 1.3% (n = 3), 24.1% (n = 56), and 74.6% (n = 173) of the cohort, respectively. Patients (n = 13, 5.6%) with fibrotic lung disease and persistent functional impairment at the 6-month follow-up received antifibrotics and presented with an absolute change of +10.3 (p = 0.01) and +14.6 (p = 0.01) in FVC% predicted at 3 and 6 months after the initiation of antifibrotic. Conclusion: Post-COVID-19-ILD represents an emerging entity. A substantial minority of patients presents with fibrotic lung disease and might experience benefit from antifibrotic initiation at the time point that fibrotic-like changes are "immature." Machine learning radiographic models could be of major significance for accurate radiographic evaluation and subsequently for the guidance of therapeutic approaches.

Real-life Cretan asthma registry focused on severe asthma: On behalf of 'The Cretan registry of the use of Biologics in Severe Asthma'.

Asthma diagnosis and management remains a challenging task for the medical community. The aim of the present study was to present the functional and inflammatory profiles of patients with difficult-to-treat asthma in a real-life clinical setting referred to the specialized asthma clinic at the University Hospital of Heraklion. The registry included a cohort of 267 patients who were referred to the severe asthma clinic. Patients were assessed with emphasis on the history of allergies, nasal polyposis or other comorbidities. Blood testing for eosinophils counts and total and specific IgE, and pulmonary function tests were performed at baseline. The median age of patients with asthma was 55 years old, 68.5% were women and 58.3% were never smokers. The vast majority presented with late onset asthma (75.7%), whereas eight (3%) patients were on oral corticosteroids. The median number of exacerbations during the last 12 months was 1 (0-3). Furthermore, 50.7% of patients had a positive serum allergy test, the median eosinophil count was 300 (188-508.5) cells/µl of blood and median total IgE level was 117.5 (29.4-360.5) IU/ml. Patients were retrospectively grouped in the following categories: Group 1, mild-moderate asthma; group 2, patients prescribed a step 4 or 5 asthma therapy according to Global Initiative for Asthma; and group 3, patients on biologic agents. Group 1 had significantly higher FEV1% than groups 2 and 3 (93.4 vs. 79.9 and 79.4%, respectively; P<0.001). Finally, the median Asthma Control Questionnaire 7 (ACQ7) score was 1.14, with patients from groups 2 and 3 presenting higher ACQ7 scores compared with group 1 patients as expected (1.1 and 2.1 vs. 0.7, respectively; P<0.001). To the best of our knowledge, this was the first real-life asthma study in Crete that demonstrated that severe asthmatics predominantly have late-onset asthma with airflow obstruction and uncontrolled symptoms.

Somatic DNA alterations in lung epithelial barrier cells in COPD patients.

BACKGROUND: Instability of the Microsatellite DNA Instability (MSI) and Loss of Heterozygosity (LOH) have been previously detected in sputum cells of COPD patients. However, the particular cell subpopulation exhibiting genetic instability in COPD was uncertain. The aim of this study was to determine which cell type expresses Microsatellite DNA Instability in sputum and BALF samples from COPD patients. METHODS: Thirty-five COPD patients and 30 non-COPD smokers were studied. Sputum was induced from 20 COPD patients and 20 non-COPD smokers and BALF was obtained from 15 COPD patients and 10 non-COPD smokers. The sputum cell pellet and BALF samples were processed using immunomagnetic technology to separate antibody-specific cell subpopulations, using CD45+ for leukocytes, Epithelial enrich (MACS) for sputum epithelial cells and HEA-human epithelial antigen-(Dynal) for BAL epithelial cells. Microsatellite DNA amplification was performed using specific primers, namely G29802, D6S2223, D6S344, D6S263, D5S207, D13S71, RH70958, and D17S250. The presence of MSI and/or LOH was analyzed with LI-COR Saga GT Microsatellite Analysis Software. MEASUREMENTS AND MAIN RESULTS: None of the non-COPD smokers exhibited any genetic alteration. MSI and LOH were found in 15 cases (8 MSI and 7 LOH) in sputum and BAL samples. MSI and/or LOH were revealed only in the epithelial barrier cells. LOH was detected in D5S207, D6S344, G29802 and D17S250 microsatellite markers, while MSI in D13S71, D5S207 and D6S344. The entire leukocyte subpopulation exhibited no genetic alteration. CONCLUSIONS: Our results support the hypothesis that chronic inflammation and oxidative burden in COPD can lead to DNA damage of the lung epithelial barrier cells, detected at the Microsatellite DNA level. Further studies are required to investigate the significance of these findings in the pathogenesis of COPD.

Biomarkers in COPD.

Chronic Obstructive Pulmonary Disease is characterized by an abnormal inflammatory response of the lungs to noxious particles and gases, caused primarily by cigarette smoking. Although COPD affects the lung, it also produces significant systemic consequences. Inflammation, proteases-antiproteases imbalance, oxidative stress, tissue damage and tissue repair, apoptosis and several genes seem to be involved in the pathogenesis of the disease. The cellular and molecular events underlying COPD pathogenesis are driven by multifunctional molecules including enzymes, cytokines, chemokines, growth factors, lipid mediators and their respective receptors. A large number of biomarkers evaluated in COPD, showed a high degree of redundancy. Nevertheless, current understanding of the pathobiology of COPD suggests a number of biomarkers as potential candidates. The development of relevant markers of lung damage, pulmonary inflammation, and systemic disease will be essential to our further understanding of the natural history of COPD and the discovery of new, effective treatments for its progression. This review summarizes recent findings, on potential pulmonary biomarkers in the induced sputum, the exhaled air condensate, the peripheral blood, the urine, the bronchoalveolar lavage fluid, and in selective cases, in bronchial biopsies.

Effects of antifibrotic agents on TGF-beta1, CTGF and IFN-gamma expression in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a deadly disease, largely unresponsive to treatment with corticosteroids and immunosuppressives. The aim of this randomized, prospective, open-label study was to characterize the molecular effects of IFN-gamma-1b and colchicine, on biomarkers expression associated with fibrosis (TGF-beta, CTGF) and immunomodulatory/antimicrobial activity (IFN-gamma), in the lungs of patients with IPF. Fourteen (14) patients with an established diagnosis of IPF received either 200 microg of IFN-gamma-1b subcutaneously three times per week, or 1mg of oral colchicine per day, for 24 months. Using RT-PCR assay, we evaluated the transcription levels of transforming growth factor beta1 (TGF-beta1), connective-tissue growth factor (CTGF), and interferon-gamma (IFN-gamma) genes in lung tissue before and after treatment with IFN-gamma-1b or colchicine. Marked mRNA expression of TGF-beta1 and CTGF, but complete lack of interferon-gamma was detected in fibrotic lung tissue at entry. After treatment, both groups exhibited increased expression of IFN-gamma gene at 6 months that was sustained at 24 months. The expression of CTGF and TGF-beta1 remained almost stable before and after treatment, in the IFN-gamma-1b group, while TGF-beta1 was statistically decreased after therapy, in the colchicine group (p=0.0002). Significant difference in DLCO (% pred), was found between the two treatment groups in favor of IFN-gamma-1b group (p=0.04). In addition, the IFN-gamma-1b group showed stability in arterial PO2 while the colchicine group significantly deteriorated (p=0.02). In conclusion, we report the effect of antifibrotic agents (IFN-gamma-1b and colchicine) in TGF-beta, CTGF, and endogenous IFN-gamma gene expression, in human fibrosis. However, extended studies are needed to verify the pathophysiological consequences of these findings.

Active remodeling in idiopathic interstitial pneumonias: evaluation of collagen types XII and XIV.

Fibril-associated collagens with interrupted triple helices (FACITs) XII and XIV act as fibril organizers and assist in the maintenance of uniform fibril size. We investigated the spatial expression patterns of collagens XII and XIV in cryptogenic organizing pneumonia (COP)/organizing pneumonia (OP) and in idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) and compared them to normal human lung. Study subjects included 10 patients with COP/OP, 10 patients with IPF/UIP, and 8 control subjects. Immunostaining for collagens XII and XIV was carried out in paraffin-embedded human lung tissue sections. Picrosirius red histochemical staining for collagen I expression and electron microcopy to evaluate fibril diameter were also performed. In normal lung, collagens XII and XIV were expressed in perivascular and subpleural connective tissue. In COP/OP, both collagens showed intense staining in perivascular connective tissue, thickened alveolar septae, and subpleural areas. In IPF/UIP, XII and XIV were expressed in perivascular connective tissue, in areas of established fibrosis, and in areas of subpleural thickening. Only collagen XII was expressed in granulation tissue plugs in COP/OP and in fibroblastic foci in IPF/UIP. Collagen type I was overexpressed in fibrotic areas. Electron micrographs revealed obvious fibril diameter alteration and fusion in the same areas. FACITs XII and XIV are expressed in normal and fibrotic lung. Unlike collagen XIV, collagen XII was expressed in granulation tissue plugs in COP/OP and in fibroblast foci in IPF/UIP. This may suggest a possible distinct role for both collagens in the modulation of the extracellular matrix during the onset of fibrotic process.

Investigation of angiogenetic axis Angiopoietin-1 and -2/Tie-2 in fibrotic lung diseases: a bronchoalveolar lavage study.

Increasing evidence implicates angiogenesis in the pathogenesis of fibrotic lung diseases. Distinct angiogenic profiles may, in part, explain differences in immunopathogenesis, clinical course and prognosis. The aim of the study was to seek evidence of involvement of the angiogenic axis Angiopoietin-1 and -2 and their tyrosine kinase receptor, Tie-2 in pathogenesis of idiopathic pulmonary fibrosis (IPF) and interstitial pneumonias associated to collagen tissue disorders (CTD-IPs). We prospectively studied 36 patients with IPF, 23 patients with CTD-IP and 10 healthy subjects. Ang-1, Ang-2 and Tie-2 mRNA expression and protein levels were measured in bronchoalveolar lavage fluid pellets and supernatants, respectively. A statistically significant decrease of Ang-1 protein level has been found in IPF in comparison to controls (p=0.02). We also detected an increased expression of Ang-2 protein in IPF in comparison to CTD-IPs. A significant co-expression was detected between Ang-2 and Tie-2 in protein level (p=0.007) in IPF group. In conclusion, a suppression of the angiogenetic factor Ang-1 was observed at the protein level in IPF which may be important in the pathogenesis of this devastating disease. A differential angiogenetic profile regarding Ang-2 was detected between IPF and CTD-IPs.

Evaluation of health-related quality-of-life and dyspnea scales in patients with idiopathic pulmonary fibrosis. Correlation with pulmonary function tests.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has a profound impact on the functional status of patients. We sought to determine whether the health-related quality of life is affected in patients with IPF. METHODS: A total of 25 patients with IPF (aged 41-72 years) and 30 healthy subjects were evaluated in a cross-sectional study. All subjects were asked to complete three dyspnea scales-the Borg (BORG), the oxygen-cost diagram (OCD) and the modified MRC questionnaire-as well as a number of health-related quality-of-life (HRQoL) questionnaires, i.e., the Saint-George Respiratory Questionnaire (SGRQ), the Quality of Well-Being (QWB) and the Hospital Anxiety and Depression Questionnaire (HAD). Pulmonary function tests, arterial blood gas measurements at rest and during exercise, chest radiographs and the duration of disease were used for correlation. RESULTS: The mean total values of all of the scales used were near the lower best values of each scale in IPF patients and were significantly different from values in the control group. Lung volumes (FVC and TLC) correlated significantly with the SGRQ. All dyspnea scales (BORG, OCD and MRC) showed a significant correlation with diffusing capacity and blood oxygenation at rest and during exercise. The duration of the disease correlated with all dyspnea scales used and with the SGRQ and HAD Questionnaires. CONCLUSIONS: Our results suggest that dyspnea scales and the SGRQ are sensitive tools for assessing health-related quality of life in patients with IPF.