Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD:the value of inhaled corticosteroids

BACKGROUND: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm(3). METHODS: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 μg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 μg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. RESULTS: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV(1)] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV(1) were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. CONCLUSIONS: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting β(2)-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component’s contribution in patients with moderate-to-severe COPD. Trial registration: ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-021-01772-2

Bronchial wall parameters on CT in healthy never-smoking, smoking, COPD, and asthma populations:a systematic review and meta-analysis

OBJECTIVE: Research on computed tomography (CT) bronchial parameter measurements shows that there are conflicting results on the values for bronchial parameters in the never-smoking, smoking, asthma, and chronic obstructive pulmonary disease (COPD) populations. This review assesses the current CT methods for obtaining bronchial wall parameters and their comparison between populations. METHODS: A systematic review of MEDLINE and Embase was conducted following PRISMA guidelines (last search date 25th October 2021). Methodology data was collected and summarised. Values of percentage wall area (WA%), wall thickness (WT), summary airway measure (Pi10), and luminal area (Ai) were pooled and compared between populations. RESULTS: A total of 169 articles were included for methodologic review; 66 of these were included for meta-analysis. Most measurements were obtained from multiplanar reconstructions of segmented airways (93 of 169 articles), using various tools and algorithms; third generation airways in the upper and lower lobes were most frequently studied. COPD (12,746) and smoking (15,092) populations were largest across studies and mostly consisted of men (median 64.4%, IQR 61.5 - 66.1%). There were significant differences between populations; the largest WA% was found in COPD (mean SD 62.93 ± 7.41%, n = 6,045), and the asthma population had the largest Pi10 (4.03 ± 0.27 mm, n = 442). Ai normalised to body surface area (Ai/BSA) (12.46 ± 4 mm2, n = 134) was largest in the never-smoking population. CONCLUSIONS: Studies on CT-derived bronchial parameter measurements are heterogenous in methodology and population, resulting in challenges to compare outcomes between studies. Significant differences between populations exist for several parameters, most notably in the wall area percentage; however, there is a large overlap in their ranges. KEY POINTS: • Diverse methodology in measuring airways contributes to overlap in ranges of bronchial parameters among the never-smoking, smoking, COPD, and asthma populations. • The combined number of never-smoking participants in studies is low, limiting insight into this population and the impact of participant characteristics on bronchial parameters. • Wall area percent of the right upper lobe apical segment is the most studied (87 articles) and differentiates all except smoking vs asthma populations

Improved precision of noise estimation in CT with a volume-based approach

Assessment of image noise is a relevant issue in computed tomography (CT). Noise is routinely measured by the standard deviation of density values (Hounsfield units, HU) within a circular region of interest (ROI). We explored the effect of a spherical volume of interest (VOI) on noise measurements. Forty-nine chronic obstructive pulmonary disease patients underwent CT with clinical protocol (regular dose [RD], volumetric CT dose index [CTDIvol] 3.04 mGy, 64-slice unit), and ultra-low dose (ULD) protocol (median CTDIvol 0.38 mGy, dual-source unit). Noise was measured in 27 1-cm(2) ROIs and 27 0.75-cm(3) VOIs inside the trachea. Median true noise was 21 HU (range 17-29) for RD-CT and 33 HU (26-39) for ULD-CT. The VOI approach resulted in a lower mean distance between limits of agreement compared to ROI: 5.9 versus 10.0 HU for RD-CT (−40%); 4.7 versus 9.9 HU for ULD-CT (−53%). Mean systematic bias barely changed: −1.6 versus −0.9HU for RD-CT; 0.0 to 0.4HU for ULD-CT. The average measurement time was 6.8 s (ROI) versus 9.7 (VOI), independent of dose level. For chest CT, measuring noise with a VOI-based instead of a ROI-based approach reduces variability by 40-53%, without a relevant effect on systematic bias and measurement time

COPD-derived fibroblasts secrete higher levels of senescence-associated secretory phenotype proteins

COPD-derived fibroblasts have increased cellular senescence. Senescent cell accumulation can induce tissue dysfunction by their senescence-associated secretory phenotype (SASP). We aimed to determine the SASP of senescent fibroblasts and COPD-derived lung fibroblasts, including severe, early-onset (SEO)-COPD. SASP protein secretion was measured after paraquat-induced senescence in lung fibroblasts using Olink Proteomics and compared between (SEO-)COPD-derived and control-derived fibroblasts. We identified 124 SASP proteins of senescent lung fibroblasts, of which 42 were secreted at higher levels by COPD-derived fibroblasts and 35 by SEO-COPD-derived fibroblasts compared with controls. Interestingly, the (SEO-)COPD-associated SASP included proteins involved in chronic inflammation, which may contribute to (SEO-)COPD pathogenesis

Viral mimic poly-(I:C) attenuates airway epithelial T cell suppressive capacity; implications for asthma

In allergen-sensitised asthmatic individuals, allergen-specific type-2 T-helper cells proliferate and secrete type-2 cytokines (e.g. interleukin (IL)-4, -5 and -13), driving the airway inflammatory response that gives rise to the clinical symptoms of asthma. Both early-life sensitisation to aeroallergens and lower respiratory viral infections are important environmental risk factors for developing asthma. Additionally, respiratory viral infections are the most common trigger for asthma exacerbations. Of interest, many asthma susceptibility genes are expressed in the airway epithelium [1], which forms the first continuous line of defence against inhaled environmental insults, including viruses and aeroallergens. Impaired immune regulation and failure to maintain tolerance to allergens is thought to contribute to allergic sensitisation. Asthma epithelium may be deficient in its innate immune defence against viral infections, resulting in increased viral replication upon rhinovirus infection compared to nonasthma-derived epithelial cultures [2]. Furthermore, there is evidence for loss of the mucosal immune barrier in asthma, with disruption of epithelial integrity [1, 3]. This may lead not only to increased permeability, but also to the release of pro-inflammatory mediators, specifically of cytokines that drive type-2 responses [3, 4]. We recently observed that the ability of allergens to disrupt epithelial barrier function is related to the development of type-2-mediated inflammation in asthma [5, 6]. Furthermore, we demonstrated that healthy murine lung epithelium is a potent inhibitor of T-cell proliferation and that this inhibition is lost upon viral infection [7]. It is unknown if this immune regulatory effect is displayed by human epithelium and is dysregulated in asthma. We hypothesise that changes in this regulatory effect translate into aberrant regulation of T-cell responses in asthma. We studied the epithelial regulation of T-cell proliferation and cytokine responses upon epithelial stimulation with a viral mimic, using co-culture of human T-cells and primary bronchial epithelial cells (PBECs) from healthy controls and asthma patients

Predicted versus CT-derived total lung volume in a general population:The ImaLife study

Predicted lung volumes based on the Global Lung Function Initiative (GLI) model are used in pulmonary disease detection and monitoring. It is unknown how well the predicted lung volume corresponds with computed tomography (CT) derived total lung volume (TLV). The aim of this study was to compare the GLI-2021 model predictions of total lung capacity (TLC) with CT-derived TLV. 151 female and 139 male healthy participants (age 45-65 years) were consecutively selected from a Dutch general population cohort, the Imaging in Lifelines (ImaLife) cohort. In ImaLife, all participants underwent low-dose, inspiratory chest CT. TLV was measured by an automated analysis, and compared to predicted TLC based on the GLI-2021 model. Bland-Altman analysis was performed for analysis of systematic bias and range between limits of agreement. To further mimic the GLI-cohort all analyses were repeated in a subset of never-smokers (51% of the cohort). Mean±SD of TLV was 4.7 ±0.9 L in women and 6.2±1.2 L in men. TLC overestimated TLV, with systematic bias of 1.0 L in women and 1.6 L in men. Range between limits of agreement was 3.2 L for women and 4.2 L for men, indicating high variability. Performing the analysis with never-smokers yielded similar results. In conclusion, in a healthy cohort, predicted TLC substantially overestimates CT-derived TLV, with low precision and accuracy. In a clinical context where an accurate or precise lung volume is required, measurement of lung volume should be considered.</p

From Differential DNA Methylation in COPD to Mitochondria:Regulation of AHRR Expression Affects Airway Epithelial Response to Cigarette Smoke

Cigarette smoking causes hypomethylation of the gene Aryl Hydrocarbon Receptor Repressor (AHRR), which regulates detoxification and oxidative stress-responses. We investigated whether AHRR DNA methylation is related to chronic obstructive pulmonary disease (COPD) and studied its function in airway epithelial cells (AECs). The association with COPD was assessed in blood from never and current smokers with/without COPD, and in AECs from ex-smoking non-COPD controls and GOLD stage II-IV COPD patients cultured with/without cigarette smoke extract (CSE). The effect of CRISPR/Cas9-induced AHRR knockout on proliferation, CSE-induced mitochondrial membrane potential and apoptosis/necrosis in human bronchial epithelial 16HBE cells was studied. In blood, DNA methylation of AHRR at cg05575921 and cg21161138 was lower in smoking COPD subjects than smoking controls. In vitro, AHRR DNA methylation at these CpG-sites was lower in COPD-derived than control-derived AECs only upon CSE exposure. Upon AHRR knockout, we found a lower proliferation rate at baseline, stronger CSE-induced decrease in mitochondrial membrane potential, and higher CSE-induced late apoptosis/necroptosis. Together, our results show lower DNA methylation of AHRR upon smoking in COPD patients compared to non-COPD controls. Our data suggest that higher airway epithelial AHRR expression may lead to impaired cigarette smoke-induced mitochondrial dysfunction and apoptosis/necroptosis, potentially promoting unprogrammed/immunogenic cell death

Biochemical predictors of outcome of pituitary surgery for cushing's disease

Objective: Transsphenoidal surgery (TS) is the primary therapy for Cushing's disease (CD). The aims of this retrospective study were twofold: (i) investigate early and late results of TS forCD, and (ii) evaluate various postoperative tests in order to predict the outcome of TS. Methods: We reviewed the long-term outcome in 79 patients with CD who underwent TS (median follow-up 84 months, range 6-197). Within 2 weeks after surgery, morning serum cortisol concentrations were obtained (n = 78) and corticotropin-releasing hormone (CRH) (n = 53) and metyrapone tests (n = 72) were performed. Three groups of outcome were identified: sustained remission, early failure (persistent CD), and late relapse. Results: Immediate postoperative remission was achieved in 51 patients (65%), whereas 28 patients (35%) had persistent CD after TS. Ten patients developed recurrent CD after initial remission (20%). Morning cortisol: all relapses but one recorded serum cortisol >50 nmol/l. A cortisol threshold value of 200 nmol/l has a positive predictive value of 79% for immediate surgical failure (negative predictive failure [NPV] 97%). CRH test: CRH-stimulated peak cortisol ≥600 nmol/l predicted early failure in 78% (NPV 100%). All relapses recorded CRH-stimulated peak cortisol ≥485 nmol/l. Metyrapone test: 11-deoxycortisol ≥345 nmol/l predicted an early failure in 86% of cases (NPV 94%). Conclusion: Predictive factors of surgical failure are morning cortisol ≥200 nmol/l, 11-deoxycortisol ≥345 nmol/l after metyrapone and CRH-stimulated cortisol ≥600 nmol/l. CRH and/or metyrapone testing are not superior to morning cortisol concentration in the prediction of outcome of TS. Careful long-term follow-up remains necessary independent of the outcome of biochemical testing. Copyrigh

Imaging the pulmonary extracellular matrix

The pulmonary extracellular matrix (ECM) plays an important role in the structure and function of the lung. In many respiratory diseases the profile of the ECM reflects pathological changes. The capacity to visualize the ECM and its alterations is of considerable importance to facilitate a better understanding of pulmonary diseases and eventually augment therapeutic solutions. This short review summarizes the current and novel possibilities for imaging the pulmonary ECM by the use of computed tomography (CT), optical coherence tomography (OCT), confocal laser endomicroscopy (CLE) and molecular imaging. While not all these techniques are as yet implemented in standard clinical practice, we address their main features along with the key possibilities for the future

Seasonal prevalence and characteristics of low-dose CT detected lung nodules in a general Dutch population

We investigated whether presence and characteristics of lung nodules in the general population using low-dose computed tomography (LDCT) varied by season. Imaging in Lifelines (ImaLife) study participants who underwent chest LDCT-scanning between October 2018 and October 2019 were included in this sub-study. Hay fever season (summer) was defined as 1st April to 30th September and Influenza season (winter) as 1st October to 31st March. All lung nodules with volume of ≥ 30 mm3 (approximately 3 mm in diameter) were registered. In total, 2496 lung nodules were found in 1312 (38%) of the 3456 included participants (nodules per participant ranging from 1 to 21, median 1). In summer, 711 (54%) participants had 1 or more lung nodule(s) compared to 601 (46%) participants in winter (p = 0.002). Of the spherical, perifissural and left-upper-lobe nodules, relatively more were detected in winter, whereas of the polygonal-, irregular-shaped and centrally-calcified nodules, relatively more were detected in summer. Various seasonal diseases with inflammation as underlying pathophysiology may influence presence and characteristics of lung nodules. Further investigation into underlying pathophysiology using short-term LDCT follow-up could help optimize the management strategy for CT-detected lung nodules in clinical practice