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Subcutaneous emphysema is a possible but infrequent consequence of dental procedures. We present the case of a 6-year-old healthy boy transferred from a dental clinic immediately after local anaesthesia for tooth extraction, due to sudden orbital and facial swelling. On physical examination, oedema of the left upper eyelid with fine crepitus on palpation and left hemiface oedema with local pain were observed. Ophthalmologic observation was normal. CT scan of the face and orbits documented extensive infiltration of the subcutaneous tissue planes of the left face by air, with extension to the external part of the body of the mandible, retromaxillary fat, masticatory muscle spaces, parapharyngeal space and adjacent to the orbital roof. After completing initial evaluation, the dentist confirmed the use of an air-driven device during local anaesthesia administration. The patient improved with conservative treatment. Early recognition of this condition is essential to provide an adequate clinical assessment with exclusion of possible life-threatening complications.

Chest drains are placed after surgery to enable lung re-expansion. However, there remains little guidance on optimal placement. This study aims to identify the ideal size and position for chest drain insertion with regards to post-operative outcomes.383 patients undergoing lobectomy in 1-year had their chest drain size and x-ray position noted (1 (apical), 2 (mid-zone) or 3 (basal)). Primary outcome was residual air space on immediate post-operative x-ray. Secondary outcomes were length of drain in situ (72 versus ≥72 h), persisting pleural effusion, surgical emphysema, post-operative pneumonia (POP), and length of hospital stay (5 versus ≥5 days). Fisher's exact analysis for the primary outcome and binary logistic regression analysis for all outcomes were used. Results presented as odds ratios (OR±95%CI).Univariate analysis for residual air space showed increased risk in area 2 (OR = 1.61, p = 0.041) and 3 (OR = 2.59, p = 0.0043) compared with area 1. Multivariate analysis for residual air space showed increased risk in area 2 (OR = 2.39, p 0.001) and 3 (OR = 2.86, p 0.001) compared with area 1. Drain size had no impact on residual air space in univariate or multivariate analysis. Multivariate analysis showed area 2 drains remained in situ for72 h (OR = 1.49, p = 0.017), had persisting effusions (OR = 2.03, p = 0.004) and POP (OR = 2.10, p = 0.023) compared with area 1. This risk is magnified further for drains in area 3. Drains ≥28F had reduced risk of surgical emphysema (OR = 0.23, p = 0.027) in multivariate analysis.A ≥28F, apical chest drain reduces the risk of post-operative complications, allowing early removal and discharge.

To compare an artificial intelligence (AI)-based prototype and subjective grading for predicting disease severity in patients with emphysema.Our IRB approved HIPAA-compliant study included 113 adults (71±8 years; 47 females, 66 males) who had both non-contrast chest CT and pulmonary function tests performed within a span of 2 months. The disease severity was classified based on the forced expiratory volume in 1 second (FEV1 as % of predicted) into mild, moderate, and severe. 2 thoracic radiologists (RA), blinded to the clinical and AI results, graded severity of emphysema on a 5-point scale suggested by the Fleischner Society for each lobe. The whole lung scores were derived from the summation of lobar scores. Thin-section CT images were processed with the AI-Rad Companion Chest prototype (Siemens Healthineers) to quantify low attenuation areas (LAA- 950 HU) in whole lung and each lobe separately. Bronchial abnormality was assessed by both radiologists and a fully automated software (Philips Healthcare).Both AI (AUC of 0.77; 95% CI: 0.68 - 0.85) and RA (AUC: 0.76, 95% CI: 0.65 - 0.84) emphysema quantification could differentiate mild, moderate, and severe disease based on FEV1. There was a strong positive correlation between AI and RA (r = 0.72 - 0.80; p0.001). The combination of emphysema and bronchial abnormality quantification from radiologists' and AI assessment could differentiate between different severities with AUC of 0.80 - 0.82 and 0.87, respectively.The assessed AI-prototypes can predict the disease severity in patients with emphysema with the same predictive value as the radiologists.

A 22-year-old woman with a history of type 1 diabetes mellitus (DM) presented with nausea, vomiting and epigastric discomfort for 3 days. On presentation, she had blood pressure of 80/50 mm Hg and a heart rate of 120 bpm. No significant findings were noted on systemic physical examination. She

A 66-year-old man with rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD) presented to our hospital with exertional dyspnoea. He smoked three packs a day for 34 years until he was diagnosed with RA and COPD at the age of 54. He still smokes a half pack a day. RA was in

Background and objectives In Spain, epidemiological studies of the prevalence of diffuse interstitial lung disease (ILD) in rheumatoid arthritis (RA) are limited. Our objective was to estimate the prevalence of symptomatic ILD in RA and its characteristics in our area. Materials and methods In our hospital's interdisciplinary rheumatology and pulmonology clinic, a prospective longitudinal observational study was designed in which we included RA with respiratory symptoms and ILD confirmed by high resolution computed tomography. Results Of the 2729 people with RA in our area, 47 had symptomatic ILD, estimating a prevalence of symptomatic ILD in RA of 1.72% (95% CI 1.26-2.29) with an age at diagnosis of RA of 57.3 ± 13.3 years. It was more frequent in men, 60.6% had a history of smoking, and 84.3% and 84.7% had rheumatoid factor (RF) and anti-cyclic citrullinated peptide (Anti-CCP) antibodies, respectively. The most frequent pattern was usual interstitial pneumonitis (UIP), appearing in 28 (31.1%). Nonspecific interstitial pneumonia (NSIP) was more frequent in women, while the combined pulmonary fibrosis-emphysema (CPFE) syndrome presented exclusively in men. Conclusions We have analysed the prevalence of symptomatic RA-ILD in our area, which is lower than expected, probably in relation to the definitions used. We have also described that the UIP pattern is the most frequent in RA in our environment, followed by the NSIP. Lastly, we have analysed the prevalence of CPFE in RA, which reaches 13%, for the first time.

Most pulmonary conditions reduce FVC, but studies of patients with combined pulmonary fibrosis and emphysema demonstrate that reductions in FVC are less than expected when these two conditions coexist clinically.Do interstitial lung abnormalities (ILAs), chest CT imaging findings that may suggest an early stage of pulmonary fibrosis in individuals with undiagnosed disease, affect the association between emphysema and FVC?Measures of ILA and emphysema were available for 9,579 and 5,277 participants from phases 1 (2007-2011) and 2 (2012-2016) of the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study (COPDGene), respectively. ILA were defined by Fleischner Society guidelines. Adjusted linear regression models were used to assess the associations and interactions among ILA, emphysema, measures of spirometry, and lung function.ILA were present in 528 (6%) and 580 (11%) of participants in phases 1 and 2 of COPDGene, respectively. ILA modified the association between emphysema and FVC (P .0001 for interaction) in both phases. In phase 1, in those without ILA, a 5% increase in emphysema was associated with a reduction in FVC (-110 mL; 95% CI, -121 to -100 mL; P .0001); however, in those with ILA, it was not (-11 mL; 95% CI, -53 to 31; P = .59). In contrast, no interaction was found between ILA and emphysema on total lung capacity or on diffusing capacity of carbon monoxide.The presence of ILA attenuates the reduction in FVC associated with emphysema.

Incidental respiratory disease-related findings are frequently observed on low-dose CT (LDCT) lung cancer screenings. This study analyzed data from the National Lung Screening Trial (NLST) to assess the relationship between such findings and respiratory disease mortality (RDM), excluding lung cancer.Are incidental respiratory findings on LDCT scanning associated with increased RDM?Subjects in the NLST LDCT arm received three annual screens. Trial radiologists noted findings related to possible lung cancer, as well as respiratory-related incidental findings. Demographic characteristics, smoking history, and medical history were captured in a baseline questionnaire. Kaplan-Meier curves were used to assess cumulative RDM. Multivariate proportional hazards models were used to assess risk factors for RDM; in addition to incidental CT scan findings, variables included respiratory disease history (COPD/emphysema, and asthma), smoking history, and demographic factors (age, race, sex, and BMI).Of 26,722 subjects in the NLST LDCT arm, 25,002 received the baseline screen and a subsequent LDCT screen. Overall, 59% were male, 26.5% were aged ≥ 65 years at baseline, and 10.6% reported a history of COPD/emphysema. Emphysema on LDCT scanning was reported in 30.7% of subjects at baseline and in 44.2% at any screen. Of those with emphysema on baseline LDCT scanning, 18% reported a history of COPD/emphysema. Median mortality follow-up was 10.3 years. There were 3,639 deaths, and 708 were from respiratory diseases. Among subjects with no history of COPD/emphysema, 10-year cumulative RDM ranged from 3.9% for subjects with emphysema and reticular opacities to 1.1% for those with neither condition; the corresponding range among subjects with a COPD/emphysema history was 17.3% (both) to 3.7% (neither). Emphysema on LDCT imaging was associated with a significantly elevated RDM hazard ratio (2.27; 95% CI, 1.92-2.7) in the multivariate model. Reticular opacities (including honeycombing/fibrosis/scar) also had a significantly elevated hazard ratio (1.39; 95% CI, 1.19-1.62).Incidental respiratory disease-related findings observed on NLST LDCT screens were frequent and associated with increased mortality from respiratory diseases.

Purpose This study aims to develop and validate a parametric response mapping (PRM) methodology to accurately identify diseased regions of the lung by using variable thresholds to account for alterations in regional lung function between the gravitationally-independent (anterior) and gravitationally-dependent (posterior) lung in CT images acquired in the supine position. Methods 34 male Sprague-Dawley rats (260-540 g) were imaged, 4 of which received elastase injection (100 units/kg) as a model for emphysema (EMPH). Gated volumetric CT was performed at end-inspiration (EI) and end-expiration (EE) on separate groups of free-breathing (n = 20) and ventilated (n = 10) rats in the supine position. To derive variable thresholds for the new PRM methodology, voxels were first grouped into 100 bins based on the fractional distance along the anterior-to-posterior direction. Lower limits of normal (LLN) for x-ray attenuation in each bin were set by determining the smallest region that enclosed 98% of voxels from healthy, ventilated animals. Results When utilizing fixed thresholds in the conventional PRM methodology, a distinct posterior-anterior gradient was seen, in which nearly the entire posterior region of the lung was identified as HEALTHY, while the anterior lung was labeled as significantly less so (t(29) = -3.27, p = 0.003). In both cohorts, %SAD progressively increased from posterior to anterior, while %HEALTHY lung decreased in the same direction. After applying our PRM methodology with variable thresholds to the same rat images, the posterior-anterior trend in %SAD quantification was removed from all rats and the significant increase of diseased lung in the anterior was removed. Conclusions The PRM methodology using variable thresholds provides regionally specific markers of %SAD and %EMPH by correcting for alterations in regional lung function associated with the naturally occurring vertical gradient of dependent vs. non-dependent lung density and compliance.

Background: HIV is associated with accelerated decline in lung function and increased risk for chronic obstructive pulmonary disease (COPD). Recently, there has been growing attention toward the impairment in the diffusing capacity of the lungs for carbon monoxide (DLCO), a marker of pulmonary gas exchange, observed among persons living with HIV. Although increased emphysema can contribute to the DLCO impairment observed, other factors may drive this association. Methods: Using cross-sectional data from the Study of HIV in the Etiology of Lung Disease, we studied the association between HIV and DLCO independent of emphysema. We also analyzed the joint influence of HIV and COPD on DLCO impairment. An analysis was conducted among 339 participants (229 with HIV) with lung function and chest CT imaging data. Multivariable regression models were generated with percent predicted DLCO and odds of DLCO impairment as outcomes. Results: After adjusting for confounders, including emphysema severity, HIV was associated with lower DLCO (β −4.02%; P = 0.020) and higher odds of DLCO impairment (odds ratio 1.93; P = 0.017). Even among those without COPD, HIV was independently associated with lower DLCO (β −3.89%; P = 0.049). Compared with HIV-uninfected participants without COPD, those with both HIV and COPD experienced the greatest impairment in DLCO (β −14.81; P < 0.001). Conclusions: HIV is associated with impaired pulmonary gas exchange independent of emphysema severity. Our data also suggest a potentially additive influence between HIV and COPD on DLCO impairment. Further studies should investigate the other factors, including pulmonary vascular disease, which may contribute to DLCO impairment among persons living with HIV.

Lung volume reduction surgery continues to have a high morbidity despite National Emphysema Treatment Trial selection criteria. This study evaluated the association between analytic morphomics on chest computed tomography scans and outcomes after lung volume reduction surgery. In a retrospective review of 85 lung volume reduction surgery patients from 1998-2013, dorsal muscle group area, subcutaneous and visceral fat area, and bone mineral density were assessed using analytic morphomics. Lung density was divided into five levels of increasing density (Lung density 1, emphysema; 2, normal lung; 4-5, scarring). Outcomes including survival, hospital length of stay, readmission at 30 days, and pulmonary complications were analyzed using univariate and multivariable techniques. Pulmonary complications developed in 27.1% (23/85). Mortality at 90 days was 9.4% (8/85). On multivariable analysis, lower bone mineral density (Odds ratio 0.61; 95% confidence interval 0.39-0.95) was associated with decreased survival, longer length of stay (0.83; 0.77-0.89), and readmissions (0.39; 0.15-1.00). Higher lung density 5:lung density 2 volume (1.84; 1.05-3.23), possibly due to scarring, was associated with pulmonary complications and longer length of stay (1.32; 1.23-1.41) while lower subcutaneous fat area:height was associated with readmissions which may reflect decreased metabolic reserve (0.35; 0.13-0.93). Patients with signs of frailty including lower bone mineral density may be at increased risk of adverse outcomes including decreased survival after lung volume reduction surgery. The results of this hypothesis-generating study will need to be confirmed in larger, multicenter trials to determine whether analytic morphomics can improve risk stratification and patient selection.

BACKGROUND This study aims to correlate nodule, patient, and technical risk factors less commonly investigated in the literature with pneumothorax development during computed tomography-guided core needle lung nodule biopsy. PATIENTS AND METHODS Retrospective data on 671 computed tomography-guided percutaneous core needle lung biopsies from 671 patients at a tertiary care center between March 2014 and August 2016. Univariate and multivariable logistic regression analyses were used to identify pneumothorax risk factors. RESULTS The overall incidence of pneumothorax was 26.7% (n=179). Risk factors identified on univariate analysis include anterior [odds ratio (OR)=1.98; P

RATIONALE: New advanced bronchoscopic treatment options for patients with severe COPD have led to increased interest for COPD phenotyping, including fissure completeness.OBJECTIVES: We investigated clinical, environmental, and genetic factors contributing to fissure completeness in patients with and without COPD.METHODS: We used data of 9926 participants of the COPDGene study who underwent chest computed tomography (CT). Fissure completeness was calculated from CT scans following quantitative CT analysis at baseline and five-year follow-up. The clinical and environmental factors sex, race, smoking, COPD, emphysema, maternal smoking during pregnancy and maternal COPD were tested for impact on fissure completeness. Genome-wide association analyses were performed separately in non-Hispanic whites and African-Americans.MEASUREMENTS AND MAIN RESULTS: African-Americans had significant higher fissure completeness than non-Hispanic whites for all three fissures (pCONCLUSIONS: Fissure completeness is genetically determined and not dependent on age, sex, smoking status, the presence and severity of COPD including exacerbation frequency, maternal smoking during pregnancy, or maternal COPD.

Barak Pertzov,1,2 Maysaa Soliman,2 Yael Shostak,1,2 Moshe Heching,1,2 Dror Rosengarten,1,2 Gabriel Izbicki,3,4,&ast; Mordechai Reuven Kramer1,2,&ast; 1Pulmonary Division, Rabin Medical Center, Petach Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Pulmonary Institute, Shaare Zedek Medical Center, Jerusalem, Israel; 4Hebrew University-Hadassah Medical School, Jerusalem, Israel&ast;These authors contributed equally to this workCorrespondence: Barak PertzovPulmonary Division, Rabin Medical Center, Petach Tikva, IsraelTel +972-3-9377221/3Fax +972-3-9242091Email pertzovb@gmail.comBackground: Lung volume reduction with endobronchial coils treatment (ECT), for patients with severe emphysema, has shown modest improvement in exercise capacity and lung functions in clinical trials, yet the benefit of this procedure is still unclear.Methods: We conducted a multicenter retrospective cohort study including all patients who underwent ECT in Israel and a propensity score matched control group of patients with chronic obstructive pulmonary disease (COPD) that were treated with usual care. The primary outcome was six-minute walk test distance (6MWTD), secondary outcomes were lung function tests and patient survival.Results: Overall, 46 patients were included in the ECT group. Their mean 6MWTD at baseline and at 6 and at 24 months post procedure was 331.0± 101.4, 372.9± 76.8 and 338.8± 104.8, respectively (overall P=0.04, pairwise comparison: baseline to 6 months (P=0.1), baseline to 24 months (P=1.0)). Mean FEV1 values at baseline and at 6 and at 24 months post procedure were 0.86± 0.38, 0.92± 0.37 and 0.82± 0.36 liters, respectively (overall P=0.003, pairwise comparison: baseline to 6 months (P=0.04), baseline to 24 months (P=0.75)). The median 6MWTD for the ECT and control groups at 24 months were 333.0 (262.5– 390) and 280 (210– 405), respectively (P=0.16). There was no difference in overall survival (P=0.84). Heterogenous emphysema was a significant predictor of treatment success in univariate analysis (p=0.004).Conclusion: Lung volume reduction with endobronchial coils may improve the exercise capacity and FEV1 of COPD patients. However, the majority of the effect was diminished after 24 months. The current state of evidence does not support regulatory approval of ECT and warrant its use only after consideration of the benefit-harm ratio in a highly selected patient population.Keywords: emphysema, endobronchial coils, lung volume reduction, six-minute walk, residual volume, FEV1, survival

Chronic obstructive lung disease (COPD), predominantly emphysema, causes several thoracic anatomical and hemodynamic changes which may cause changes in various electrocardiographic parameters. A 12-lead electrocardiogram (ECG), which is often a part of routine evaluation in most clinical settings, may serve as a useful screening modality for diagnosis of COPD or emphysema. Our current article aims to provide a comprehensive review of the electrocardiographic changes encountered in COPD/emphysema utilizing published PubMed and Medline literature database. Several important ECG changes are present in COPD/emphysema and may serve as a good diagnostic tool. Verticalization of P-vector, changes in QRS duration, pattern recognition of precordial R-wave progression and axial shifts can be considered some of the most valuable markers among other changes. In conclusion, 12-lead surface electrocardiogram can serve as a valuable tool for the diagnosis of COPD and/or emphysema. An appropriate knowledge of these ECG changes can not only help in the diagnosis but can also immensely help in an appropriate clinical management of these patients.

Chronic obstructive pulmonary disease (COPD) is a complex lung disease characterized by a combination of airway disease and emphysema. Emphysema is classified as centrilobular emphysema (CLE), paraseptal emphysema (PSE), or panlobular emphysema (PLE), and airway disease extends from the respiratory, terminal, and preterminal bronchioles to the central segmental airways. Although clinical computed tomography (CT) cannot be used to visualize the small airways, micro-CT has shown that terminal bronchiole disease is more severe in CLE than in PSE and PLE, and micro-CT findings suggest that the loss and luminal narrowing of terminal bronchioles is an early pathological change in CLE. Furthermore, the introduction of ultra-high-resolution CT has enabled direct evaluation of the proximal small (1 to 2-mm diameter) airways, and new CT analytical methods have enabled estimation of small airway disease and prediction of future COPD onset and lung function decline in smokers with and without COPD. This review discusses the literature on micro-CT and the technical advancements in clinical CT analysis for COPD. Hopefully, novel micro-CT findings will improve our understanding of the distinct pathogeneses of the emphysema subtypes to enable exploration of new therapeutic targets, and sophisticated CT imaging methods will be integrated into clinical practice to achieve more personalized management.

Nobuhiro Fujioka,1 Masahiro Kitabatake,2 Noriko Ouji-Sageshima,2 Takahiro Ibaraki,1 Makiko Kumamoto,1 Yukio Fujita,1 Shigeto Hontsu,1 Motoo Yamauchi,1 Masanori Yoshikawa,1 Shigeo Muro,1 Toshihiro Ito2 1Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan; 2Department of Immunology, Nara Medical University, Kashihara, Nara, JapanCorrespondence: Toshihiro ItoDepartment of Immunology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, JapanTel +81-744-22-3051Fax +81-744-29-7503Email toshi-ito@naramed-u.ac.jpPurpose: Chronic obstructive pulmonary disease (COPD) is a worldwide problem because of its high prevalence and mortality. However, there is no fundamental treatment to ameliorate their pathological change in COPD lung. Recently, adipose-derived mesenchymal stem cells (ADSCs) have attracted attention in the field of regenerative medicine to repair damaged organs. Moreover, their utility in treating respiratory diseases has been reported in some animal models. However, the detailed mechanism by which ADSCs improve chronic respiratory diseases, including COPD, remains to be elucidated. We examined whether human ADSCs (hADSCs) ameliorated elastase-induced emphysema and whether hADSCs differentiated into alveolar epithelial cells in a murine model of COPD.Methods: Female SCID-beige mice (6 weeks old) were divided into the following four groups according to whether they received an intratracheal injection of phosphate-buffered saline or porcine pancreatic elastase, and whether they received an intravenous injection of saline or hADSCs 3 days after intratracheal injection; Control group, hADSC group, Elastase group, and Elastase-hADSC group. We evaluated the lung function, assessed histological changes, and compared gene expression between hADSCs isolated from the lung of Elastase-hADSC group and naïve hADSCs 28 days after saline or elastase administration.Results: hADSCs improved the pathogenesis of COPD, including the mean linear intercept and forced expiratory volume, in an elastase-induced emphysema model in mice. Furthermore, hADSCs were observed in the lungs of elastase-treated mice at 25 days after administration. These cells expressed genes related to mesenchymal–epithelial transition and surface markers of alveolar epithelial cells, such as TTF-1, β-catenin, and E-cadherin.Conclusion: hADSCs have the potential to improve the pathogenesis of COPD by differentiating into alveolar epithelial cells by mesenchymal–epithelial transition.Keywords: chronic obstructive pulmonary disease, mesenchymal–epithelial transition, adipose derived mesenchymal stem cell, pulmonary function test

The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.

Introduction: This study aimed to evaluate the correlation between different densitometric parameters on chest computed tomography (CT) and pulmonary function tests (PFT) of patients with emphysema-predominant chronic obstructive pulmonary disease (COPD). Materials and methods: A retrospective evaluation was made of 56 patients with COPD. The lungs were segmented into nine sections. Normal and emphysematous parenchyma were measured using low attenuation area percentage (%LAA), percentile density (PD), and mean lung density (MLD) parameters. The effects of emphysema distribution on PFT were evaluated using %LAA, PD, MLD, kurtosis and skewness methods. Result: Fifty-six patients, all diagnosed with COPD, were evaluated. The %LAA-910 method showed significant correlation with forced expiratory volume in one second (FEV1) compared to other densitometric parameters (p=

Rationale: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. Objectives: We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Methods: Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects in vivo and/or in vitro were studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Measurements and Main Results: Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin’s protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (−0.92%; 95% confidence interval [CI], −1.7% to −0.14%; P = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L; P = 0.01). Conclusions: Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.

Shinsuke Kitazawa, Ashoka Indranatha Wijesinghe, Naoki Maki, Takahiro Yanagihara, Yusuke Saeki, Naohiro Kobayashi, Shinji Kikuchi, Yukinobu Goto, Hideo Ichimura, Yukio Sato Department of General Thoracic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, JapanCorrespondence: Yukio SatoDepartment of General Thoracic Surgery, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8575, JapanTel +81 29 853 3210Fax +81 29 853 7991Email ysato@md.tsukuba.ac.jpPurpose: In performing surgery for lung cancer, emphysema is a risk factor related to postoperative respiratory complications (PRC). However, few studies have addressed the risk of radiological emphysematous volume affecting PRC. The aim of this study was to investigate the relationship between emphysematous volume as measured on 3-dimensional computed tomography and PRC.Patients and Methods: We reviewed 342 lung cancer patients undergoing lobectomy between 2013 and 2018. The percentage of low attenuation area (LAA%) was defined as the percentage of the lung area showing attenuation of − 950 Hounsfield units or lower. Preoperative factors including age, sex, body mass index, smoking index, respiratory function, tumour histology, and LAA% were evaluated. PRC included pneumonia, atelectasis, prolonged air leakage, empyema, hypoxia, ischemic bronchitis, bronchopleural fistula, and exacerbation of interstitial pneumonia. Uni- and multivariable analyses were performed to investigate the relationship between independent clinical variables and postoperative adverse events.Results: Median LAA% was 5.0% (range, 0– 40%) and PRC was observed in 50 patients (14.6%). Patients who presented with PRC showed significantly high LAA% compared to those without complications (median: 8.1% vs 3.8%; p < 0.001). Based on univariable analysis, age, sex, smoking index, percentage of forced expiratory volume in 1 s (FEV1.0%), histology, and LAA% were significant predictors for PRC. Multivariable analysis revealed higher LAA% as a significant risk factor for PRC (odds ratio = 1.040; 95% confidence interval, 1.001– 1.080; p = 0.046).Conclusion: In addition to respiratory function with spirometry, LAA% can be used as a predictor of PRC.Keywords: lung cancer, emphysema, radiology and other imaging, respiratory function tests, thoracic surgery

Background Lung emphysema is an important phenotype of chronic obstructive pulmonary disease (COPD), and CT scanning is strongly recommended to establish the diagnosis. This study aimed to identify criteria by which physicians with limited technical resources can improve the diagnosis of emphysema. Methods We studied 436 COPD patients with prospective CT scans from the COSYCONET cohort. All items of the COPD Assessment Test (CAT) and the St George’s Respiratory Questionnaire (SGRQ), the modified Medical Research Council (mMRC) scale, as well as data from spirometry and CO diffusing capacity, were used to construct binary decision trees. The importance of parameters was checked by the Random Forest and AdaBoost machine learning algorithms. Results When relying on questionnaires only, items CAT 1 & 7 and SGRQ 8 & 12 sub-item 3 were most important for the emphysema- versus airway-dominated phenotype, and among the spirometric measures FEV1/FVC. The combination of CAT item 1 (≤ 2) with mMRC (> 1) and FEV1/FVC, could raise the odds for emphysema by factor 7.7. About 50% of patients showed combinations of values that did not markedly alter the likelihood for the phenotypes, and these could be easily identified in the trees. Inclusion of CO diffusing capacity revealed the transfer coefficient as dominant measure. The results of machine learning were consistent with those of the single trees. Conclusions Selected items (cough, sleep, breathlessness, chest condition, slow walking) from comprehensive COPD questionnaires in combination with FEV1/FVC could raise or lower the likelihood for lung emphysema in patients with COPD. The simple, parsimonious approach proposed by us might help if diagnostic resources regarding respiratory diseases are limited. Trial registration ClinicalTrials.gov, Identifier: NCT01245933, registered 18 November 2010, https://clinicaltrials.gov/ct2/show/record/NCT01245933. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-021-01837-2.

Background: Bronchoscopic lung volume reduction using endobronchial coils is a new treatment for patients with severe emphysema. To date, the benefits have been modest and have been suggested to be much larger in patients with severe hyperinflation and nonmulti-comorbidity. Objective: We aimed to evaluate the efficacy and safety of endobronchial coil treatment in a randomized multicenter clinical trial using optimized patient selection. Method: Patients with severe emphysema on HRCT scan with severe hyperinflation (residual volume [RV] ≥200% predicted and RV/total lung capacity [TLC] >55%) were randomized to coil treatment or control. Primary outcome measures were differences in the forced expiratory volume in 1 s (FEV1) and St George’s Respiratory Questionnaire (SGRQ) total score at 6 months. Results: Due to premature study termination, a total of 120 patients (age 63 ± 7 years, FEV1 29 ± 7% predicted, RV 251 ± 41% predicted, RV/TLC 67 ± 6%, and SGRQ 58 ± 13 points), instead of 210 patients, were randomized. At study termination, 91 patients (57 coil and 34 control) had 6-month results available. Analyses showed significantly greater improvements in favor of the coil group. The increase in FEV1 was greater in the coil group than that in the control group by + 10.3 [+4.7 to +16.0] % and in SGRQ by −10.6 [−15.9 to −5.4] points. At study termination, there were 5 (6.8%) deaths in the coil cohort reported. Conclusion: Despite early study termination, coil treatment compared to control results in a significant improvement in the lung function and quality of life benefits for up to 6 months in patients with emphysema and severe hyperinflation. These improvements were of clinical importance but were associated with a higher likelihood of serious adverse events.

Exposures to dust, vapors, or fumes (DVF) are associated with chronic bronchitis (CB) and emphysema. The 2007-2012 National Health and Nutrition Examination Survey data were used to estimate age-standardized prevalence of CB and emphysema among ever-employed adults by exposure status and industry and occupation groups. Age-standardized CB and emphysema prevalence were 2.3% and 1.9%, respectively. Of the estimated 111 million U.S. workers exposed to DVF, 2.7% reported CB and 2.8% reported emphysema. Workers in the "accommodation, food services" industry and "food preparation, serving related" occupations were more likely to report CB and emphysema. Current findings indicate that workplace exposures may be associated with high prevalence of CB and emphysema in certain industry and occupational groups. Early diagnosis and identifying associated workplace exposures are important steps in CB and emphysema prevention efforts.

Jae-Kwang Lim,1 Byunggeon Park,1 Jongmin Park,1 Keum-Ju Choi,2 Chi-Young Jung,2 Young Hwan Kim,3 Jin Young Kim,4 Sungjun Moon,5 Yong Hoon Lee,6 Jaehee Lee6 1Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Republic of Korea; 3Department of Radiology, Daegu Catholic University School of Medicine, Daegu, Republic of Korea; 4Department of Radiology, Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea; 5Department of Radiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea; 6Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of KoreaCorrespondence: Jaehee LeeDepartment of Internal Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, 41944, Daegu, Republic of KoreaTel +82-53-420-5536Fax +82-53-426-2046Email jaelee@knu.ac.krBackground: Chronic obstructive pulmonary disease (COPD) is considered a risk factor for poor outcomes in patients with coronavirus disease 2019 (COVID-19). However, data on the prognostic impact of radiological emphysema extent on patients with COVID-19 are limited. Thus, this study aimed to examine whether computed tomography (CT)-quantified emphysema score is associated with a worse clinical outcome in patients with COVID-19.Methods: Volumetric quantitative analyses of CT images were performed to obtain emphysema scores in COVID-19 patients admitted to four tertiary referral hospitals in Daegu, South Korea, between February 18 and March 25, 2020. Patients were divided into three groups according to emphysema score (emphysema score ≤ 1%, 1%< emphysema score ≤ 5%, and emphysema score > 5%).Results: A total of 146 patients with confirmed SARS-CoV-2 infection were included. The median emphysema score was 1.0% (interquartile range, 0.5– 1.8%). Eight patients (6%) had a previous COPD diagnosis. Eighty (55%), 55 (38%), and 11 (8%) patients had emphysema scores ≤ 1%, between 1% and 5%, and > 5%, respectively. The number of patients who received oxygen therapy two weeks after admission was significantly higher in the group with emphysema scores > 5% than in other groups (p=0.025). The frequency of deaths was three (27%) in the group with emphysema scores > 5% and tended to be higher than that in other groups. Multivariate analysis revealed that age, COPD, and serum lactate dehydrogenase levels were associated with a greater risk of in-hospital mortality in patients with COVID-19.Conclusion: The current study demonstrated that patients with CT-quantified emphysema scores > 5% tended to progress to severe disease over time; however, they did not exhibit an increased risk of mortality in our COVID-19 cohort. Further studies with consideration of both emphysema extent and airflow limitation degree are warranted.Keywords: COVID-19, emphysema, computed tomography, COPD, mortality

Because patients with chronic obstructive pulmonary disease (COPD) are often physically inactive, it is still unclear whether the lower respiratory capacity in the locomotor muscles of these patients is due to cigarette smoking per se or is secondary to physical deconditioning. Accordingly, the purpose of this study was to examine mitochondrial alterations in the quadriceps muscle of 10 mice exposed to 8 mo of cigarette smoke, a sedentary mouse model of emphysema, and 9 control mice, using immunoblotting, spectrophotometry, and high-resolution respirometry in permeabilized muscle fibers. Mice exposed to smoke displayed a twofold increase in the oxidative stress marker, 4-HNE, (P < 0.05) compared with control mice. This was accompanied by significant decrease in protein expression of UCP3 (65%), ANT (58%), and mitochondrial complexes II-V (∼60%–75%). In contrast, maximal ADP-stimulated respiration with complex I and II substrates (CON: 23.6 ± 6.6 and SMO: 19.2 ± 8.2 ρM·mg(−1)·s(−1)) or octanoylcarnitine (CON: 21.8 ± 9.0 and SMO: 16.5 ± 6.6 ρM·mg(−1)·s(−1)) measured in permeabilized muscle fibers, as well as citrate synthase activity, were not significantly different between groups. Collectively, our findings revealed that sedentary mice exposed to cigarette smoke for 8 mo, which is typically associated with pulmonary inflammation and emphysema, exhibited a preserved mitochondrial respiratory capacity for various substrates, including fatty acid, in the skeletal muscle. However, the mitochondrial adaptations induced by cigarette smoke favored the development of chronic oxidative stress, which can indirectly contribute to augment the susceptibility to muscle fatigue and exercise intolerance. NEW & NOTEWORTHY It is unclear whether the exercise intolerance and skeletal muscle mitochondrial dysfunction observed in patients with COPD is due to cigarette smoke exposure, per se, or if they are secondary consequences to inactivity. Herein, while long-term exposure to cigarette smoke induces oxidative stress and an altered skeletal muscle phenotype, cigarette smoke does not directly contribute to mitochondrial dysfunction. With this evidence, we demonstrate the critical role of physical inactivity in cigarette smoke-related skeletal muscle dysfunction.

Background Lobar emphysema in dogs and cats is caused by bronchial collapse during expiration and subsequent air trapping. Congenital causes such as bronchial cartilage defects or acquired causes such as compressive neoplastic lesions have been reported. Morbidity results from hyperinflation of the affected lung lobe and compression of adjacent thoracic structures. Objective To describe patient characteristics and imaging findings in dogs and cats with lobar emphysema. Animals Fourteen dogs and 3 cats with lobar emphysema diagnosed by imaging findings were retrospectively identified from veterinary referral hospital populations over a 10‐year period. Methods Cases that included thoracic radiography, thoracic computed tomography (CT), or both were included. All images were reviewed by a European College of Veterinary Diagnostic Imaging diplomate. Relevant case information included signalment, clinical findings, treatment, and histopathology where available. Results Ten of 17 (59%) patients were presented for evaluation of dyspnea and 6 (35%) for coughing. Eleven (65%) patients were

Chao Li, Zhaohui Deng, Guixian Zheng, Ting Xie, Xinyan Wei, Zengyu Huo, Jing Bai Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of ChinaCorrespondence: Jing BaiThe First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Tel +86-771-5356702Fax +86-771-5608132Email bj1312002@aliyun.comBackground: Exposure to cigarette smoke (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD). CS not only causes chronic airway inflammation and lung damage but also is involved in skeletal muscle dysfunction (SMD). Previous studies have shown that histone deacetylase 2 (HDAC2) plays an important role in the progression of COPD. The aim of this study was to determine the role of HDAC2 in CS-induced skeletal muscle atrophy and senescence.Methods: Gastrocnemius muscle weight and cross-sectional area (CSA) were measured in mice with CS-induced emphysema, and changes in the expression of atrophy-related markers and senescence-related markers were detected. In addition, the relationship between HDAC2 expression and skeletal muscle atrophy and senescence was also investigated.Results: Mice exposed to CS for 24 weeks developed emphysema and gastrocnemius atrophy and exhibited a decrease in gastrocnemius weight and skeletal muscle cross-sectional area. In addition, the HDAC2 protein levels were significantly decreased while the levels of atrophy-associated markers, including MURF1 and MAFbx, and senescence-associated markers, including P53 and P21, were significantly increased in the gastrocnemius muscle. In vitro, the exposure of C2C12 cells to cigarette smoke extract (CSE) significantly increased the MAFbx and MURF1 protein levels and decreased the HDAC2 protein levels. Moreover, overexpression of HDAC2 significantly ameliorated CSE-induced atrophy and senescence and reversed the increased MURF1, MAFbx, P53, and P21 expression in C2C12 cells. In addition, CSE treatment significantly increased the IKK and NF-κB p65 protein levels, and PTDC (an NF-kB inhibitor) ameliorated atrophy and senescence.Conclusion: Our findings suggest that HDAC2 plays an important role in CS-induced skeletal muscle atrophy and senescence, possibly through the NF-κB pathway.Keywords: histone deacetylase 2, skeletal muscle, atrophy, senescence, nuclear factor-Ò¡B

OBJECTIVES Despite significant advances in surgical techniques, including thoracoscopic approaches and perioperative care, the morbidity rate remains high after lung resection. This study focused on a low attenuation cluster analysis, which represented the size distribution of pulmonary emphysema and assessed its utility for predicting postoperative pulmonary complications after thoracoscopic lobectomy. METHODS From April 2013 to September 2018, lung cancer patients who received spirometry and computed tomography (CT) before surgery and underwent thoracoscopic lobectomy were included. The cumulative size distribution of the low attenuation area (LAA, defined as ≤−950 Hounsfield unit on CT) clusters followed a power-law characterized by an exponent D-value, a measure of the complexity of the alveolar structure. D-value and LAA% (LAA/total lung volume) were calculated using preoperative 3-dimensional CT software. The relationship between pulmonary complications and patient characteristics, including D-value and LAA%, was investigated. RESULTS Among 471 patients, there were 61 respiratory complication cases (12.9%). Receiver operation characteristic curve analysis revealed that the best predictive cut-off value of D-value and LAA% for pulmonary complications was 2.27 and 16.5, respectively, with an area under the curve of 0.72 and 0.58, respectively. D-value was significantly correlated with % forced expiratory volume in 1 s. Per univariate analysis, gender, smoking history, forced expiratory volume in 1 s/forced vital capacity, LAA% and D-value were risk factors for predicting postoperative pulmonary complications. In the multivariate analysis, D-value remained a significant predictive factor. CONCLUSION Preoperative assessment of emphysema cluster analysis may represent the vulnerability of the operated lung and could be the novel predictor for pulmonary complications after thoracoscopic lobectomy.

Rationale COPD and smoking are characterised by pulmonary inflammation. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging may improve knowledge of pulmonary inflammation in COPD patients and aid early development of novel therapies as an imaging biomarker. Objectives To evaluate pulmonary inflammation, assessed by FDG uptake, in whole and regional lung in “usual” (smoking-related) COPD patients, alpha-1 antitrypsin deficiency (α1ATD) COPD patients, smokers without COPD and never-smokers using FDG PET/CT. Secondly, to explore cross-sectional associations between FDG PET/CT and systemic inflammatory markers in COPD patients and repeatability of the technique in COPD patients. Methods Data from two imaging studies were evaluated. Pulmonary FDG uptake (normalised Ki; nKi) was measured by Patlak graphical analysis in four subject groups: 84 COPD patients, 11 α1ATD-COPD patients, 12 smokers and 10 never-smokers. Within the COPD group, associations between nKi and systemic markers of inflammation were assessed. Repeatability was evaluated in 32 COPD patients comparing nKi values at baseline and at 4-month follow-up. Results COPD patients, α1ATD-COPD patients and smokers had increased whole lung FDG uptake (nKi) compared with never-smokers (0.0037±0.001, 0.0040±0.001, 0.0040±0.001 versus 0.0028±0.001 mL·cm−3·min−1, respectively, p, FDG PET/CT has potential utility to noninvasively evaluate pulmonary inflammation in COPD. Pulmonary FDG uptake is increased in COPD patients, positively associated with systemic inflammatory markers and shows low inter-occasion variability. https://bit.ly/3dELYAW

OBJECTIVES Patients with chronic obstructive pulmonary disease and lung emphysema may benefit from surgical or endoscopic lung volume reduction (ELVR). Previously reported outcomes of nitinol coil-based ELVR techniques have been ambiguous. The analysis was done to analyse outcomes of ELVR with nitinol coils in patients with severe pulmonary emphysema. METHODS From September 2013 to November 2014, our centre performed a total of 41 coil implantations on 29 patients with severe emphysema. Coils were bronchoscopically placed during general anaesthesia. Twelve out of 29 patients received staged contralateral treatments up to 112 days later to avoid bilateral pneumothorax. Lung function and 6-min walking distance were assessed 1 week prior, 1 week after as well as 6–12 months after the procedure. Patients were followed up to 48 months after ELVR and overall mortality was compared to a historic cohort. RESULTS While coil-based ELVR led to significant short-term improvement of vital capacity (VC, +0.14 ± 0.39 l, P = 0.032) and hyperinflation (Δ residual volume/total lung capacity −2.32% ± 6.24%, P = 0.022), no significant changes were observed in 6-min walking distance or forced expiratory volume in 1 s. Benefits were short-lived, with only 15.4% and 14.3% of patients showing sustained improvements in forced expiratory volume in 1 s or residual volume after 6 months. Adverse events included haemoptysis (40%) and pneumothorax (3.4%), major complications occurred in 6.9% of cases. Overall survival without lung transplant was 63.8% after 48 months following ELVR, differing insignificantly from what BODE indices of patients would have predicted as median 4-year survival (57%) at the time of ELVR treatment. CONCLUSIONS ELVR with coils can achieve small and short-lived benefits in lung function at the cost of major complications in a highly morbid cohort. Treatment failed to improve 4-year overall survival. ELVR coils are not worthwhile the risk for most patients with severe emphysema.

Bronchoscopic lung volume reduction with one-way endobronchial valves is a guideline treatment option for patients with advanced emphysema that is supported by extensive scientific data. Patients limited by severe hyperinflation, with a suitable emphysema treatment target lobe and with absence of collateral ventilation, are the responders to this treatment. Detailed patient selection, a professional treatment performance, and dedicated follow up of the valve treatment, including management of complications, are key ingredients to success. This treatment does not stand alone; it especially requires extensive knowledge of COPD for which the most appropriate treatment is discussed in a multidisciplinary approach. We discuss the endobronchial valve treatment for emphysema and provide a guideline for patient selection, treatment guidance, and practice tools, based on our own experience and literature.

PURPOSE To report a minimally invasive drainage technique for large expanding subretinal gas bubble and conduct a review of the literature. METHODS Case report, with schematic diagrams and multimodal imaging including fundus photography and spectral domain optical coherence tomography. Controlled drainage of large subretinal gas bubble using a 30-gauge needle introduced through cryotherapy-treated area in office-based setting. RESULTS Forty-year-old male patient presented with bullous rhegmatogenous retinal detachment and had gas inadvertently injected into the subretinal space during cryo-pneumatic retinopexy. After successful drainage of subretinal gas in clinic, 0.3cc of perfluoropropane (C3F8) gas was injected in different quadrants near the attached retina. The macula remained attached on immediate fundus examination. The gas bubbles of fish eggs coalesced into a single large bubble within 1 week. Spectral domain optical coherence tomography showed unremarkable foveal scans. After 45 days, the gas bubble completely disappeared, the retina remained attached, and vision in the treated eye was 20/20. CONCLUSION To the best of our knowledge, this is the first case report of a large expanding gas bubble injected into the subretinal spaces being drained successfully by the described minimal invasive technique. Although it may offer a possible office-based approach to a rare complication, it is generally recommended that surgeons capable of dealing with its possible complications may attempt such technique when immediate vitrectomy is not accessible.

Background/Aims: Air trapping is associated with unfavorable outcomes in chronic obstructive pulmonary disease (COPD). The present study evaluated the association between longitudinal changes in air trapping with pulmonary func tion, computed tomography (CT) parameters and exacerbation. Methods: Patients enrolled in the Korean Obstructive Lung Disease (KOLD) study cohort from June 2005 to October 2015 were included. The study patients were cat egorized into four groups according to the change in residual volume to total lung capacity ratio (RV/TLC) over 3 years. The RV/TLC was considered abnormal when it was ≥ 40% and normal when it was < 40%. Results: A total of 279 patients were categorized into four groups: 76 in the “normal to normal” (N→N) group, 34 in the “abnormal to normal” (A→N) group, 33 in the “normal to abnormal” (N→A) group, and 136 in the “abnormal to abnormal” (A→A) group. For forced expiratory volume in 1 second and forced vital capacity (FVC), re spectively, group A→N showed a large increase of 266 mL (p < 0.001) and 381 mL (p < 0.001), group N→A showed a marked decrease of 216 mL (p < 0.001) and 332 mL(p = 0.029), and group A→A showed a decrease of 16 mL (p = 0.426) and 6 mL (p = 0.011) compared to group N→N. Group A→N showed a significant decrease of -0.013 in expiratory to inspiratory ratio of the mean lung density (p < 0.001), while group A→N showed an increase of 0.005 (p < 0.001). Conclusions: Patients with COPD whose RV/TLC changed from normal to abnor mal showed deterioration of pulmonary function and worsening of CT parame ters simultaneously.

Cigarette smoking is the major cause of chronic obstructive pulmonary disease. Considerable attention has been paid to the reduced harm potential of nicotine-containing inhalable products such as electronic cigarettes (e-cigarettes). We investigated the effects of mainstream cigarette smoke (CS) and e-vapor aerosols (containing nicotine and flavor) generated by a capillary aerosol generator on emphysematous changes, lung function, and molecular alterations in the respiratory system of female Apoe−/− mice. Mice were exposed daily (3 h/day, 5 days/week) for 6 months to aerosols from three different e-vapor formulations—(1) carrier (propylene glycol and vegetable glycerol), (2) base (carrier and nicotine), or (3) test (base and flavor)—or to CS from 3R4F reference cigarettes. The CS and base/test aerosol concentrations were matched at 35 µg nicotine/L. CS exposure, but not e-vapor exposure, led to impairment of lung function (pressure–volume loop area, A and K parameters, quasi-static elastance and compliance) and caused marked lung inflammation and emphysematous changes, which were confirmed histopathologically and morphometrically. CS exposure caused lung transcriptome (activation of oxidative stress and inflammatory responses), lipidome, and proteome dysregulation and changes in DNA methylation; in contrast, these effects were substantially reduced in response to the e-vapor aerosol exposure. Compared with sham, aerosol exposure (carrier, base, and test) caused a slight impact on lung inflammation and epithelia irritation. Our results demonstrated that, in comparison with CS, e-vapor aerosols induced substantially lower biological and pathological changes in the respiratory tract associated with chronic inflammation and emphysema. Supplementary Information The online version supplementary material available at 10.1007/s00204-021-03020-4.

Hongxia Duan, Long Liang, Xinyang Liu, Shuanshuan Xie, Changhui Wang Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Shuanshuan Xie; Changhui WangDepartment of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, #301, Mid Yanchang Road, Shanghai, People’s Republic of ChinaTel/Fax +86-21-66301685Email xieshuanshuan@aliyun.com; wang-chang-hui@hotmail.comBackground: Pulmonary and activation-regulated chemokine (PARC) also named CC-chemokine ligand 18 (CCL18) is a lung-predominant inflammatory protein that is found in serum. The relationship of PARC/CCL18 with the chronic obstructive pulmonary disease (COPD) is not fully understood. The aim of the present study is to analyze the expression of PARC/CCL18 in COPD.Methods: Ninety-eight hospitalized COPD patients and 60 healthy volunteers from January 2019 to December 2019 were recruited in this retrospective study. Gender, age, height, weight, disease duration, smoking status, blood cell classification and count, length of hospital stay (LOS), symptom score, including COPD Assessment Test (CAT) score, modified British Medical Research Council (mMRC) score, lung function and therapy were recorded and serum PARC/CCL18 was analyzed by ELISA. The correlation between symptom score, blood cell classification and count, CRP, lung function parameters and serum levels of PARC/CCL18 and ROC curves of PARC/CCL18 levels and inhaled corticosteroids (ICS) were accessed.Results: It was found that serum PARC/CCL18 level in hospitalized COPD population was significantly higher than that in healthy people (p=0.003). COPD patients with emphysema had significantly higher serum level of PARC/CCL18 than those without emphysema (p=0.049). Total lung capacity (TLC) and residual volume (RV)/TLC had positive correlation with serum level of PARC/CCL18 (p=0.001, 0.020, respectively). Furthermore, serum PARC/CCL18 level was predictive for the application ICS (p=0.003) and related to C-reactive protein (p < 0.0001) in hospitalized COPD patients.Conclusion: PARC/CCL18 is associated with the severity of inflammation and emphysema in COPD. Furthermore, PARC/CCL18 is a predictor of ICS application in the treatment of hospitalized COPD patients.Keywords: PARC/CCL18, COPD, inflammation, pulmonary function, inhaled corticosteroids

Cigarette smoking is the leading cause of preventable death worldwide. It causes chronic lung disease and predisposes individuals to acute lung injury and pulmonary infection. Alveolar macrophages are sentinel cells strategically positioned in the interface between the airway lumen and the alveolar spaces. These are the most abundant immune cells and are the first line of defence against inhaled particulates and pathogens. Recently, there has been a better understanding about the ontogeny, phenotype and function of alveolar macrophages and their role, not only in phagocytosis, but also in initiating and resolving immune response. Many of the functions of the alveolar macrophage have been shown to be dysregulated following exposure to cigarette smoke. While the mechanisms for these changes remain poorly understood, they are important in the understanding of cigarette smoking-induced lung disease. We review the mechanisms by which smoking influences alveolar macrophage: (1) recruitment, (2) phenotype, (3) immune function (bacterial killing, phagocytosis, proteinase/anti-proteinase release and reactive oxygen species production) and (4) homeostasis (surfactant/lipid processing, iron homeostasis and efferocytosis). Further understanding of the mechanisms of cigarette smoking on alveolar macrophages and other lung monocyte/macrophage populations may allow novel ways of restoring cellular function in those patients who have stopped smoking in order to reduce the risk of subsequent infection or further lung injury.

Significance Orbital emphysema is a well-documented condition where air enters the orbital soft tissue typically because of direct or indirect trauma; however, atraumatic cases can be encountered. The following is a novel case report of acute unilateral atraumatic orbital emphysema 24 hours after bronchoscopy with endobronchial biopsy. Purpose To the best of the authors' knowledge, this is the first known case report of atraumatic orbital emphysema as a postprocedure complication of bronchoscopy with endobronchial biopsy in the literature. Case report A 74-year-old man presented with painless swelling of the left upper and lower eyelids upon awakening. The patient had a history of bronchoscopy and endobronchial biopsy with conscious sedation for a right upper lobe lung mass 24 hours before the visit. Slit-lamp examination revealed air entrapment in the left upper and lower lids with enlarged subconjunctival air pockets of the left eye. Head and maxillofacial computed tomography without contrast revealed extensive emphysema tracking and dissecting along the subcutaneous and deep soft tissue spaces of the neck and face that was more pronounced along the left side. The patient was admitted for overnight observation and prescribed a prophylactic oral course of 250 mg of azithromycin daily for 2 days by the attending hospitalist. The subsequent follow-up visit 3 days later revealed complete resolution of signs and symptoms. Conclusions This case report demonstrates the importance of considering orbital emphysema in patients with a history of recent bronchoscopy with endobronchial biopsy. Clinicians should be aware of this potential complication and refer for appropriate testing and comanagement.

RationalePeripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD.MethodsTen explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling.ResultsMicro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500 and InterpretationThe reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD.

Sharyn A Roodenburg,1,2 Karin Klooster,1,2 Jorine E Hartman,1,2 T David Koster,1,2 Marlies van Dijk,1,2 Dirk-Jan Slebos1,2 1Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 2Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The NetherlandsCorrespondence: Sharyn A RoodenburgDepartment of Pulmonary Diseases, AA11, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713, GZ, The NetherlandsTel +31 50 361 9194Fax +31 050 3619320Email s.a.roodenburg@umcg.nlBackground: Endobronchial valve (EBV) treatment is an effective treatment for patients with severe emphysema. Revision bronchoscopies after endobronchial valve treatment can be essential to prolong the effect of treatment or address long-term complications.Purpose: To evaluate the indications, endoscopic findings and outcomes of revision bronchoscopies and investigate if any predictors for granulation tissue formation, after EBV treatment, can be identified.Patients and Methods: Patients who underwent EBV treatment between 2016 and 2019 in our hospital, as routine care, were included. If a patient underwent a revision bronchoscopy, data regarding revision bronchoscopies, including indication, finding, intervention and pulmonary function testing (PFT) after revision bronchoscopy were analysed.Results: One hundred seventy-nine patients were included of which 41% required at least one revision bronchoscopy. In 43% of the revision bronchoscopy patients, the indication was loss of initial treatment effect. In 53% of the revision bronchoscopy patients, granulation tissue was found to be the underlying cause. Valve replacement(s) were performed in 51% of the revision bronchoscopy cases. Permanent valve removal was required in 13% of all patients. Overall, revision bronchoscopies led to improvements in PFT outcomes for patients experiencing no or a loss of initial treatment effect. No clinically relevant predictors for granulation tissue formation were identified.Conclusion: Performing a revision bronchoscopy after EBV treatment is a useful procedure leading to an improved treatment effect in most patients. Granulation tissue formation, causing valve dysfunction, is the most common cause of longer term problems.Keywords: bronchoscopy, lung volume reduction, one-way valve, COPD

Purpose For this study, we aimed to compare dynamic hyperinflation measured by cardiopulmonary exercise testing (CPET), a six-minute walking test (6-MWT), and a manually paced tachypnea test (MPT) in patients with severe emphysema who were treated with endobronchial coils. Additionally, we investigated whether dynamic hyperinflation changed after treatment with endobronchial coils. Methods Dynamic hyperinflation was measured with CPET, 6-MWT, and an MPT in 29 patients before and after coil treatment. Results There was no significant change in dynamic hyperinflation after treatment with coils. Comparison of CPET and MPT showed a strong association (rho 0.660, p Conclusion MPT can be a suitable alternative to CPET to measure dynamic hyperinflation in severe emphysema but may overestimate dynamic hyperinflation possibly due to a higher breathing frequency.

Background This study aimed to analyze the literature systematically to determine the clinical characteristics and prognosis of patients with connective tissue disease (CTD) with combined pulmonary fibrosis and emphysema (CPFE) compared to those of patients with CTD-interstitial lung disease (CTD-ILD) without emphysema. Methods We searched MEDLINE, EMBASE, Cochrane Library, and KoreaMed for relevant articles published before July 2019. Studies meeting all the following criteria were included: (1) original research studies evaluating the effect of CPFE on CTD, (2) studies that compared patients with CTD-CPFE to those with CTD-ILD without emphysema, and (3) studies providing data on physical capacity, pulmonary function, or death in patients with CTD. Clinical characteristics of patients with CTD-CPFE were compared with those of patients with CTD-ILD without emphysema, and the influence of CPFE on physical capacity, pulmonary function, and death was analyzed. Results Six studies between 2013 and 2019 were included. Two hundred ninety-nine (29.5%) and 715 (70.5%) patients had CTD-CPFE and CTD-ILD without emphysema, respectively. Regarding the type of CTD, 711 (68.3%) patients had systemic sclerosis, 263 (25.3%) rheumatoid arthritis, and 67 (6.4%) other CTDs. Patients with CTD-CPFE had a higher frequency of pulmonary hypertension and pulmonary fibrosis > 20% of the total lung volume, higher ratio of the forced vital capacity to the diffusion capacity of the lung for carbon monoxide (DLCO), lower arterial oxygen pressure at rest, and lower DLCO compared to those in patients with CTD-ILD without emphysema. In addition, more deaths occurred among those with CTD-CPFE (odds ratio, 2.95; 95% confidence interval, 1.75–4.96). Conclusion CTD-CPFE is associated with worse physical and pulmonary function and more deaths compared to those in CTD-ILD without emphysema. These findings indicate the need for increased awareness and close monitoring of patients with CTD-CPFE.

A 9 yr old male neutered Staffordshire bull terrier with a history of poorly controlled hyperadrenocorticism, urinary tract infections, and emphysematous cystitis (EC) was presented to a veterinary referral teaching hospital for vomiting. Abdominal radiographs revealed EC and a pneumoperitoneum. The urinary bladder was found to be intact based on ultrasound and a pre- and postiohexol contrast computed tomography study with retrograde contrast cystogram. Urine culture confirmed the presence of a recurrent Escherichia coli urinary tract infection. The patient was managed medically, primarily as an outpatient, and had complete resolution of all problems. This case represents an extremely rare form of EC with pneumoperitoneum, without evidence of concurrent urinary bladder rupture. Only six similar cases have been reported in humans, with no previous cases reported in veterinary medicine. This case demonstrated that surgery is not necessarily indicated in all cases of pneumoperitoneum. The patient remained alive at 2 mo follow-up, with no evidence of recurrence of EC.

Background Many informal caregivers experience significant caregiving burden and report worsening health-related quality of life (HRQoL). Caregiver HRQoL may vary by disease context, but this has rarely been studied. Purpose Informed by the Model of Carer Stress and Burden, we compared HRQoL outcomes of prevalent groups of caregivers of people with chronic illness (i.e., dementia, cancer, chronic obstructive pulmonary disease [COPD]/emphysema, and diabetes) and noncaregivers and examined whether caregiving intensity (e.g., duration and hours) was associated with caregiver HRQoL. Methods Using 2015–2018 Behavioral Risk Factor Surveillance System data, we identified caregivers of people with dementia (n = 4,513), cancer (n = 3,701), COPD/emphysema (n = 1,718), and diabetes (n = 2,504) and noncaregivers (n = 176,749). Regression analyses were used to compare groups. Results Caregiver groups showed small, nonsignificant differences in HRQoL outcomes. Consistent with theory, all caregiver groups reported more mentally unhealthy days than noncaregivers (RRs = 1.29–1.61, ps < .001). Caregivers of people with cancer and COPD/emphysema reported more physically unhealthy days than noncaregivers (RRs = 1.17–1.24, ps < .01), and caregivers of people with diabetes reported a similar pattern (RR = 1.24, p = .01). However, general health and days of interference of poor health did not differ between caregivers and noncaregivers. Across caregiver groups, most caregiving intensity variables were unrelated to HRQoL outcomes; only greater caregiving hours were associated with more mentally unhealthy days (RR = 1.13, p < .001). Conclusions Results suggest that HRQoL decrements associated with caregiving do not vary substantially across chronic illness contexts and are largely unrelated to the perceived intensity of the caregiving. Findings support the development and implementation of strategies to optimize caregiver health across illness contexts.

Background Emphysematous pyelonephritis (EPN) is a necrotizing infection of the renal parenchyma, collecting system and/or perinephric tissues, characterized by gas accumulation. We describe clinical, laboratory and imaging characteristics and in-hospital outcomes of patients with EPN. Methods This retrospective observational study was carried out at BIRDEM General Hospital, Dhaka, Bangladesh between 2014 and 2020. Results We followed 20 patients (mean age 49.4 years; females 70%). Risk factors for EPN were diabetes mellitus (in 100%) and renal stones (in 10%). Fever, loin pain, vomiting and dysuria were common. Complications included acute kidney injury (AKI, 70%; mostly stage 1, 78.6%), hyponatraemia (55%) and bacteraemia (15%). Escherichia coli was the most common (60%) urinary isolate. Most patients (80%) had class 2 EPN, with 15% class 3B and 5% class 3A. Besides medical management, four (20%) required surgery (nephrectomy in 3). Nephrectomised patients had a higher radiological class (p = 0.032) and incidence of AKI (p = 0.034). No deaths occurred. Conclusion EPN occurred predominantly in female diabetic patients, who presented with fever, loin pain, vomiting and dysuria. Two-thirds of patients had AKI and one-fifth required surgery, and there were no deaths.

Background: Hypermetabolism and muscle wasting frequently occur in patients with severe emphysema. Improving respiratory mechanics by bronchoscopic lung volume reduction (BLVR) might contribute to muscle maintenance by decreasing energy requirements and alleviating eating-related dyspnoea. Objective: The goal was to assess the impact of BLVR on energy balance regulation. Design: Twenty emphysematous subjects participated in a controlled clinical experiment before and 6 months after BLVR. Energy requirements were assessed: basal metabolic rate (BMR) by ventilated hood, total daily energy expenditure (TDEE) by doubly labelled water, whole body fat-free mass (FFM) by deuterium dilution, and physical activity by accelerometry. Oxygen saturation, breathing rate, and heart rate were monitored before, during, and after a standardized meal via pulse oximetry and dyspnoea was rated. Results: Sixteen patients completed follow-up, and among those, 10 patients exceeded the minimal clinically important difference of residual volume (RV) reduction. RV was reduced with median (range) 1,285 mL (−2,430, −540). Before BLVR, 90% of patients was FFM-depleted despite a normal BMI (24.3 ± 4.3 kg/m2). BMR was elevated by 130%. TDEE/BMR was 1.4 ± 0.2 despite a very low median (range) daily step count of 2,188 (739, 7,110). Following BLVR, the components of energy metabolism did not change significantly after intervention compared to before intervention, but BLVR treatment decreased meal-related dyspnoea (4.1 vs. 1.7, p = 0.019). Conclusions: Impaired respiratory mechanics in hyperinflated emphysematous patients did not explain hypermetabolism. Clinical Trial Registry Number: NCT02500004 at www.clinicaltrial.gov.

Although activation of adaptive immunity is a common pathological feature of chronic obstructive pulmonary disease (COPD), particularly during later stages of the disease, the underlying mechanisms are poorly understood. In small airways of COPD patients, we found that localized disruption of the secretory immunoglobulin A (SIgA)-containing mucosal immunobarrier correlated with lymphocyte accumulation in airway walls and development of tertiary lymphoid structures (TLS) around small airways. In SIgA-deficient mice, we observed bacterial invasion into the airway epithelial barrier with lymphocytic infiltration and TLS formation, which correlated with the progression of COPD-like pathology with advanced age. Depletion of either CD4+ or CD8+ T lymphocytes reduced the severity of emphysema in SIgA-deficient mice, indicating that adaptive immune activation contributes to progressive lung destruction. Further studies revealed that lymphocyte infiltration into the lungs of SIgA-deficient mice was dependent on monocyte-derived dendritic cells (moDCs), which were recruited through a CCR2-dependent mechanism in response to airway bacteria. Consistent with these results, we found that moDCs were increased in lungs of COPD patients, along with CD4+ and CD8+ effector memory T cells. Together, these data indicate that endogenous bacteria in SIgA-deficient airways orchestrate a persistent and pathologic T lymphocyte response through monocyte recruitment and moDC differentiation.

Placental transmogrification is a peculiar clinical entity of the lung of uncertain etiology. We report 2 cases of pulmonary placental transmogrification in 2 patients of different nationalities. Both of them had no history of smoking or chronic lung disease. The main presentations were dyspnea and chest pain. Radiologic studies showed a unilateral giant bulla in both patients; additional pneumothorax was present in only 1patient. They underwent surgical bullectomy. Histopathologic studies revealed the presence of intracystic placenta-like villous structures and a diagnosis of placental transmogrification was made. Placental transmogrification should be considered in cases of unilateral bullae.

BACKGROUND: Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV(1) progression in current smokers. RESEARCH QUESTION: Is use of ACEi and ARB associated with less progression of emphysema and FEV(1) decline among individuals with COPD or baseline emphysema? METHODS: Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume