CT-Guided Core Needle Biopsy of Pulmonary Lesions Associated With Cystic Airspaces: A Case-Control Study.

BACKGROUND. Concern may exist that pulmonary lesions associated with cystic airspaces are at risk of increased biopsy complications or lower biopsy accuracy given challenges in targeting tissue abutting or intermingled with the cystic airspaces. OBJECTIVE. The purpose of this study was to evaluate the safety and diagnostic performance of CT-guided core needle biopsy (CNB) of pulmonary lesions associated with cystic airspaces. METHODS. This retrospective study included 90 patients (median age, 69.5 years; 28 women, 62 men) who underwent CT-guided CNB of pulmonary lesions associated with cystic airspaces (based on review of procedural images) from February 2010 to December 2022 and a matched control group (2:1 ratio) of 180 patients (median age, 68.0 years; 56 women, 124 men) who underwent CNB of noncystic noncavitary lesions during the same period. The groups were compared in terms of complications, nondiagnostic biopsies (i.e., nonspecific benignities, atypical cells, or insufficient specimens), and CNB diagnostic performance for detecting malignancy using as reference the final diagnosis from a joint review of all available records. For lesions associated with cystic airspaces that underwent surgical resection after CNB, histologic slides were reviewed to explore the nature of the cystic airspace. RESULTS. The final diagnosis was malignant in 90% (81/90) of lesions associated with cystic airspaces and 92% (165/180) of noncystic noncavitary lesions. Patients with lesions associated with cystic airspaces and patients with noncystic noncavitary lesions showed no significant difference in frequency of complications (overall: 40% [36/90] vs 38% [68/180], p = .79; major: 4% [4/90] vs 6% [10/180], p = .78; minor: 36% [32/90] vs 32% [58/180], p = .59), frequency of nondiagnostic biopsies (12% [11/90] vs 9% [16/180], p = .40), or diagnostic performance (accuracy: 94% [85/90] vs 97% [175/180], p = .50; sensitivity: 94% [76/81] vs 97% [160/165], p = .50; specificity: 100% [9/9] vs 100% [15/15]; p > .99), respectively. All false-negative results for malignancy in both groups occurred in patients with nondiagnostic CNB results. Among lesions associated with cystic airspaces that were resected after CNB (all malignant), the cystic airspaces most commonly represented tumor degeneration (22/31 [71%]). CONCLUSION. CT-guided CNB is safe and accurate for assessing pulmonary lesions associated with cystic airspaces. CLINICAL IMPACT. CNB may help avoid a missed or delayed cancer diagnosis in pulmonary lesions with cystic airspaces.

Alveolar Nitric Oxide and Peripheral Oxygen Saturation in Frequent Exacerbators with Asthma: A Pilot Study.

INTRODUCTION: Asthmatics can experience recurrent exacerbations (AEs), irrespectively of asthma severity. Airway inflammatory monitoring could be fundamental to optimize the asthma management. The present study evaluated whether exhaled NO concentrations in proximal and distal respiratory compartments are different in AE-prone patients in combination with T2 blood biomarkers and resting oxygen saturation (SpO2). METHODS: In this observational cross-sectional study, 91 mild-to-severe asthmatics were enrolled. Clinical characteristics, blood and lung function parameters including SpO2, and FENO were evaluated. On 50 randomly selected patients, CANO and JawNO were also analyzed. Then, patients were stratified in frequent exacerbators (FEs) or non-frequent exacerbators (nFEs), according to AE frequency in the previous year (phase I). Chart data were re-evaluated through a 12-month follow-up period post exhaled NO measurement to detect occurrence of novel AE (phase II). RESULTS: FE asthmatics had poorer asthma control and required higher therapeutic intensity (p < 0.05). FENO, CANO, and JawNO were similar between FE and nFE. FE exhibited higher total serum IgE levels and residual volume values but reduced SpO2 than nFE (p < 0.05); SpO2<96.5% characterized the FE patient (odds ratio = 2.94). In phase II, CANO was higher in the group with novel AE at 1-month post-NO measurement (p < 0.05), but not afterward. A higher prevalence of CANO >6 ppb was detected in asthmatics who developed AE within 1 month, suggesting its potential clinical use as biomarker in predicting near-future AE (RR = 11.20). CONCLUSION: AE-susceptible asthmatics are characterized by air trapping and distal airway inflammation in conjunction with lower oxygen saturation. CANO and SpO2 could exert specific roles, respectively, in predicting AE and monitoring FE asthmatics.

Asthma in the Real-World: The Relevance of Gender.

BACKGROUND: The possible gender impact on asthma arouses current and outstanding interest, but few studies addressed this issue in the real-world setting. OBJECTIVE: This cross-sectional study tested the hypothesis of a potential difference between asthmatic males and females in a real-life setting, such as a third-level asthma clinic. METHODS: A total of 499 asthmatic outpatients (301 females and 198 males, mean age 58.25 years) were consecutively visited. The visit included history, asthma control, and severity grade, physical examination, lung function, fractional exhaled nitric oxide assessment, and blood sample for biomarkers. RESULTS: There were more females than males (about 3 of 5). Asthmatic females smoked less (p < 0.0001) than males and had higher FEV1 (p = 0.0022) and FVC (p = 0.0004) values than asthmatic males. CONCLUSIONS: Gender difference was associated with smoking and lung function impairment; thus, this issue should be carefully considered in asthmatic patients in daily clinical practice.

A real-world assessment of asthma with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) includes 2 main phenotypes: CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP). CRS has been reported to be a comorbidity of asthma. OBJECTIVE: This study aimed to investigate the role of CRS in outpatients with asthma visited in real-world setting. METHODS: This cross-sectional study enrolled 499 consecutive outpatients with asthma. Age, sex, body mass index, smoking status, lung function, Asthma Control Test, inflammatory type 2 biomarkers (including fractional exhaled nitric oxide, blood eosinophils, serum total immunoglobulin E, and allergy), treatment step according to the Global Initiative for Asthma, and comorbidities (obstructive sleep apnea syndrome, arterial hypertension, bronchiectasis, diabetes mellitus type 2, and osteoporosis) were evaluated. RESULTS: A total of 179 (35.87%) patients had CRS, in particular 93 (18.64%) had CRSsNP and 86 (17.23%) had CRSwNP. Type 2 inflammation (defined by at least 1 positive biomarker) was present in 81.44% of patients (fractional exhaled nitric oxide > 30 parts per billion in 46.9%, blood eosinophil count > 300 cell/µL in 39.67%, serum total immunoglobulin E >100 IU/mL in 51.54%, and allergy in 53.71%). By multivariate analysis, type 2 inflammation and blood eosinophils greater than 300 cell/µL were the main predictors (odds ratio [OR] 2.54 and 2.26, respectively) of CRS-asthma association. In particular, CRSwNP comorbidity was predicted by type 2 inflammation (OR 3.4) and blood eosinophils greater than 300 cell/µL (OR 3.0). Smoking had conflicting outcome. CONCLUSION: This study confirmed that CRS is a frequent asthma comorbidity because it affects more than one-third of outpatients with asthma. CRSwNP is associated with type 2 inflammation and blood eosinophilia. These outcomes underline that CRSwNP asthma phenotype deserves adequate attention for careful management and optimal identification of the best-tailored therapy.

Biologics in T2 Severe Asthma: Unveiling Different Effectiveness by Real-World Indirect Comparison.

Background: Indirect comparison among biologics in severe asthma (SA) is a challenging but desirable goal for clinicians in real life. The aim of the study is to define characteristics of a biologic-treated T2-driven-SA population and to evaluate the effectiveness of biologic treatments in a real-world setting by variation in intra/inter-biologic parameters in an up to 4-year follow-up. Methods: Demographic, clinical, functional, and biological characteristics were evaluated retrospectively in 104 patients recruited until July 2022 at baseline (T0) and over a maximum of 4 years (T4) of biologic therapy (omalizumab/OmaG = 41, from T0 to T4, mepolizumab/MepoG = 26, from T0 to T4, benralizumab/BenraG = 18, from T0 to T2, and dupilumab/DupiG = 19, from T0 to T1). Variations of parameters using means of paired Delta were assessed. Results: At baseline, patients had high prevalence of T2-driven comorbidities, low asthma control test (ACT mean 17.65 ± 4.41), impaired pulmonary function (FEV1 65 ± 18 %pred), frequent exacerbations/year (AEs 3.5 ± 3), and OCS dependence (60%). DupiG had lower T2 biomarkers/comorbidities and AEs, and worse FEV1 (57 ± 19 %pred) compared to other biologics (p < 0.05). All biologics improved ACT, FEV1%, FVC%, AEs rate, and OCS use. FEV1% improved in MepoG and BenraG over the minimal clinically important difference and was sustained over 4 years in OmaG and MepoG. A significant RV reduction in OmaG (T4) and DupiG (T1), and BenraG normalization (T2) of airflow limitation were found. We observed through inter-biologic parameters pair delta variation comparison a significant nocturnal awakenings reduction in BenraG vs. OmaG/MepoG, and neutrophils reduction in BenraG/DupiG vs. OmaG. Conclusions: Indirect comparison among biologics unveils clinical and functional improvements that may mark a different effectiveness. These results may highlight the preference of a single biologic compared to another with regard to specific treatable traits.

Reliability of Total Serum IgE Levels to Define Type 2 High and Low Asthma Phenotypes.

Background: High total IgE levels are weak predictors of T2High and have been reported in nonallergic asthma. Therefore, the role of total serum IgE (IgE) in the T2High phenotype is still debated. Objective: This study investigated the reliability of stratifying asthmatics into IgEHigh and IgELow within the T2High and T2Low phenotypes. Methods: This cross-sectional single-center study investigated the association of clinical, functional, and bio-humoral parameters in a large asthmatic population stratified by IgE ≥ 100 kU/L, allergen sensitization, B-EOS ≥ 300/µL, and FENO ≥ 30 ppb. Results: Combining T2 biomarkers and IgE identifies (1) T2Low-IgELow (15.5%); (2) T2Low-IgEHigh (5.1%); (3) T2High-IgELow (33.6%); and T2High-IgEHigh (45.7%). T2Low-IgELow patients have more frequent cardiovascular and metabolic comorbidities, a higher prevalence of emphysema, and higher LAMA use than the two T2High subgroups. Higher exacerbation rates, rhinitis, and anxiety/depression syndrome characterize the T2Low-IgEHigh phenotype vs. the T2Low-IgELow phenotype. Within the T2High, low IgE was associated with female sex, obesity, and anxiety/depression. Conclusions: High IgE in T2Low patients is associated with a peculiar clinical phenotype, similar to T2High in terms of disease severity and nasal comorbidities, while retaining the T2Low features. IgE may represent an additional biomarker for clustering asthma in both T2High and T2Low phenotypes rather than a predictor of T2High asthma "per se".

Bone Morphogenic Proteins and Their Antagonists in the Lower Airways of Stable COPD Patients.

BACKGROUND: Bone morphogenic proteins (BMPs) and their antagonists are involved in the tissue development and homeostasis of various organs. OBJECTIVE: To determine transcriptomic and protein expression of BMPs and their antagonists in stable COPD. METHODS: We measured the expression and localization of BMPs and some relevant antagonists in bronchial biopsies of stable mild/moderate COPD (MCOPD) (n = 18), severe/very severe COPD (SCOPD) (n = 16), control smokers (CS) (n = 13), and control non-smokers (CNS) (n = 11), and in lung parenchyma of MCOPD (n = 9), CS (n = 11), and CNS (n = 9) using immunohistochemistry and transcriptome analysis, in vitro after the stimulation of the 16HBE cells. RESULTS: In bronchial biopsies, BMP4 antagonists CRIM1 and chordin were increased in the bronchial epithelium and lamina propria of COPD patients. BMP4 expression was decreased in the bronchial epithelium of SCOPD and MCOPD compared to CNS. Lung transcriptomic data showed non-significant changes between groups. CRIM1 and chordin were significantly decreased in the alveolar macrophages and alveolar septa in COPD patients. External 16HBE treatment with BMP4 protein reduced the bronchial epithelial cell proliferation. CONCLUSIONS: These data show an imbalance between BMP proteins and their antagonists in the lungs of stable COPD. This imbalance may play a role in the remodeling of the airways, altering the regenerative-reparative responses of the diseased bronchioles and lung parenchyma.

Impaired autophagy in the lower airways and lung parenchyma in stable COPD.

Background: There is increasing evidence of autophagy activation in COPD, but its role is complex and probably regulated through cell type-specific mechanisms. This study aims to investigate the autophagic process at multiple levels within the respiratory system, using different methods to clarify conflicting results reported so far. Methods: This cross-sectional study was performed on bronchial biopsies and peripheral lung samples obtained from COPD patients (30 and 12 per sample type, respectively) and healthy controls (25 and 22 per sample type, respectively), divided by smoking history. Subjects were matched for age and smoking history. We analysed some of the most important proteins involved in autophagosome formation, such as LC3 and p62, as well as some molecules essential for lysosome function, such as lysosome-associated membrane protein 1 (LAMP1). Immunohistochemistry was used to assess the autophagic process in both sample types. ELISA and transcriptomic analysis were performed on lung samples. Results: We found increased autophagic stimulus in smoking subjects, regardless of respiratory function. This was revealed by immunohistochemistry through a significant increase in LC3 (p<0.01) and LAMP1 (p<0.01) in small airway bronchiolar epithelium, alveolar septa and alveolar macrophages. Similar results were obtained in bronchial biopsy epithelium by evaluating LC3B (p<0.05), also increased in homogenate lung tissue using ELISA (p<0.05). Patients with COPD, unlike the others, showed an increase in p62 by ELISA (p<0.05). No differences were found in transcriptomics analysis. Conclusions: Different techniques, applied at post-transcriptional level, confirm that cigarette smoke stimulates autophagy at multiple levels inside the respiratory system, and that autophagy failure may characterise COPD.

Long-Term Safety of Antifibrotic Drugs in IPF: A Real-World Experience.

Pirfenidone and nintedanib are the only two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF). Both proved to be safe and well-tolerated in clinical trials, but real-world data and direct comparisons are scarce. This real-life study explored the safety profile of pirfenidone and nintedanib with a prolonged follow-up. We retrospectively collected clinical status, adverse events (AEs), and treatment changes from IPF patients who had started an antifibrotic treatment at our centre from December 2011 to December 2020, including 192 patients treated with pirfenidone and 89 with nintedanib. The majority of patients in both groups experienced one or more AEs during the follow-up. A higher proportion of AEs in the nintedanib group were effectively treated with behavioural modifications or additional medications compared with the pirfenidone group (52.5% vs. 40.6%, p = 0.04). Overall, a difference in the impact of AEs due to nintedanib versus pirfenidone resulted in a lower permanent discontinuation of therapy (8.3% vs. 18.3%, p = 0.02), with the latter being associated with a higher risk of drug discontinuation at 48 months after initiation (OR = 2.52, p = 0.03). Our study confirms the safety profile of antifibrotic drugs in IPF but highlights that AEs due to nintedanib are usually easier to manage and lead to fewer cases of permanent discontinuation of therapy.

Clinical Characterization of the Frequent Exacerbator Phenotype in Asthma.

BACKGROUND: Asthma exacerbation is episodic worsening of respiratory symptoms in conjunction with the deterioration of lung function, which may occur independently from the asthma severity hampering asthmatics' quality of life. This study aimed to characterize the patient phenotype more prone to asthma exacerbation (oral corticosteroid burst ≥2 per year) to allow the proper identification of such patients. METHODS: This real-life, observational, cross-sectional study evaluated 464 asthmatic patients stratified according to the asthma exacerbations experienced in the previous year. Clinical, functional, and blood parameters were retrieved from chart data and were representative of patients in stable conditions. RESULTS: The frequent asthma exacerbator was more commonly female, suffered from chronic rhinosinusitis with nasal polyposis, had reduced lung function and peripheral oxygen saturation, and had increased daily activity limitations. These patients often had severe asthma and more frequently needed hospitalization in their lives. Furthermore, the frequent asthma exacerbator had higher concentrations of serum immunoglobulin E (IgE) and exhaled nitric oxide with cut-off risk values of 107.5 kU/L (OR = 4.1) and 43.35 ppb (OR = 3.8), respectively. CONCLUSIONS: This study illustrates the clinical features of the frequent asthma exacerbator phenotype. Nevertheless, serum IgE and exhaled nitric oxide could allow the identification of this phenotype and the establishment of an appropriate therapeutic approach.

Greenness Availability and Respiratory Health in a Population of Urbanised Children in North-Western Italy.

Paediatric Asthma contributes in paediatric global burden of diseases, as the most common chronic disease in children. Children are exposed to many environmental risk-factors, able to determine or worsen respiratory diseases, and contributing to asthma and asthma-like symptoms increases, especially in metropolitan areas. In urban settings, surrounding vegetation (greenness) may provide important benefits to health, including the promotion of physical activity and the mitigation of air and noise pollution. The aim of this study was to investigate the association between greenness and respiratory health. A total of 187 children (10-13 yrs old) were recruited in Turin, the north-western part of Italy. The prevalence of asthma and asthma-like symptoms was calculated from self-reported data collected by SIDRIA questionnaire. Spirometry test was performed to obtain respiratory flow measurements. Greenness was measured at individual level through the Normalised Difference Vegetation Index (NDVI) estimations from remote-sensing images. Higher exposure (3rd tertile vs. 1st tertile) to NDVI was associated to significantly lower ORs for asthma [0.13 CI 95% 0.02-0.7, p = 0.019], bronchitis [0.14 CI 95% 0.05-0.45, p = 0.001], and current wheezing [0.25 CI 95% 0.09-0.70, p = 0.008]. A significative positive association was found between greenness and FEF25-75, since children exposed to the 2nd tertile of NDVI reported a significantly decreased FEF25-75 compared to those in the 3rd tertile [B: -2.40; C.I.95%: -0.48-0.01; p = 0.049]. This cross-sectional study provided additional data on still inconsistent literature referring to respiratory health in children and green spaces, attesting a positive effect of greenness in a specific area of Italy. Further research is still needed.

Tobacco Smoke Exposure, Urban and Environmental Factors as Respiratory Disease Predictors in Italian Adolescents.

Risk monitoring in childhood is useful to estimate harmful health effects at later stages of life. Thus, here we have assessed the effects of tobacco smoke exposure and environmental pollution on the respiratory health of Italian children and adolescents using spirometry and the forced oscillation technique (FOT). For this purpose, we recruited 188 students aged 6-19 years living in Chivasso, Italy, and collected from them the following data: (1) one filled out questionnaire; (2) two respiratory measurements (i.e., spirometry and FOT); and (3) two urine tests for Cotinine (Cot) and 15-F2t-Isoprostane (15-F2t-IsoP) levels. We found a V-shape distribution for both Cotinine and 15-F2t-IsoP values, according to age groups, as well as a direct correlation (p = 0.000) between Cotinine and tobacco smoke exposure. These models demonstrate that tobacco smoke exposure, traffic, and the living environment play a fundamental role in the modulation of asthma-like symptoms (p = 0.020) and respiratory function (p = 0.007). Furthermore, the results from the 11-15-year group indicate that the growth process is a protective factor against the risk of respiratory disease later in life. Lastly, the FOT findings highlight the detrimental effects of tobacco smoke exposure and urbanization and traffic on respiratory health and asthma-like symptoms, respectively. Overall, monitoring environmental and behavioral factors in childhood can provide valuable information for preventing respiratory diseases in adulthood.