Computed tomography mucus plugs and airway tree structure in patients with chronic obstructive pulmonary disease: Associations with airflow limitation, health-related independence and mortality.

BACKGROUND AND OBJECTIVE: Mucus plugs and underlying airway tree structure can affect airflow limitation and prognosis in patients with chronic obstructive pulmonary disease (COPD), but their relative roles are unclear. This study used two COPD cohorts to examine whether mucus plugs on computed tomography (CT) were associated with airflow limitation and clinical outcomes independent of other airway structural changes and emphysema. METHODS: Based on visual CT assessment, patients with mucus plugs in 0, 1-2 and ≥3 lung segments were assigned to no-, low- and high-mucus groups. Loss of health-related independence and mortality were prospectively recorded for 3 and 10 years in the Kyoto-Himeji and Hokkaido cohorts, respectively. The percentages of the wall area of the central airways (WA%), total airway count (TAC) and emphysema were quantified on CT. RESULTS: Of 199 and 96 patients in the Kyoto-Himeji and Hokkaido cohorts, 34% and 30%, respectively, had high mucus scores. In both cohorts, TAC was lower in the high-mucus group than in the no-mucus group, whereas their emphysema severity did not differ. High mucus score and low TAC were independently associated with airflow limitation after adjustment for WA% and emphysema. In multivariable models adjusted for WA% and emphysema, TAC, rather than mucus score, was associated with a greater rate of loss of independence, whereas high mucus score, rather than TAC, was associated with increased mortality. CONCLUSION: Mucus plugs and lower airway branch count on CT had distinct roles in airflow limitation, health-related independence and mortality in patients with COPD.

Longitudinal assessment of interstitial lung abnormalities on CT in patients with COPD using artificial intelligence-based segmentation: a prospective observational study.

BACKGROUND: Interstitial lung abnormalities (ILAs) on CT may affect the clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), but their quantification remains unestablished. This study examined whether artificial intelligence (AI)-based segmentation could be applied to identify ILAs using two COPD cohorts. METHODS: ILAs were diagnosed visually based on the Fleischner Society definition. Using an AI-based method, ground-glass opacities, reticulations, and honeycombing were segmented, and their volumes were summed to obtain the percentage ratio of interstitial lung disease-associated volume to total lung volume (ILDvol%). The optimal ILDvol% threshold for ILA detection was determined in cross-sectional data of the discovery and validation cohorts. The 5-year longitudinal changes in ILDvol% were calculated in discovery cohort patients who underwent baseline and follow-up CT scans. RESULTS: ILAs were found in 32 (14%) and 15 (10%) patients with COPD in the discovery (n = 234) and validation (n = 153) cohorts, respectively. ILDvol% was higher in patients with ILAs than in those without ILA in both cohorts. The optimal ILDvol% threshold in the discovery cohort was 1.203%, and good sensitivity and specificity (93.3% and 76.3%) were confirmed in the validation cohort. 124 patients took follow-up CT scan during 5 ± 1 years. 8 out of 124 patients (7%) developed ILAs. In a multivariable model, an increase in ILDvol% was associated with ILA development after adjusting for age, sex, BMI, and smoking exposure. CONCLUSION: AI-based CT quantification of ILDvol% may be a reproducible method for identifying and monitoring ILAs in patients with COPD.

Increased blood eosinophils and airflow obstruction as new-onset asthma predictors in the elderly: The Nagahama study.

BACKGROUND: Asthma in the elderly needs more attention in an aging society. However, it is likely to remain underdiagnosed and undertreated. This study aimed to clarify clinical characteristics of new-onset asthma in the elderly, describing the prevalence, predictive factors, and comorbidities after asthma diagnosis of new-onset asthma in the elderly in the general population. METHODS: This community-based prospective cohort study enrolled 9804 generally healthy participants (30-74 years old) in Nagahama City, and conducted a follow-up assessment after 5 years. Elderly participants were those aged ≥65 years at baseline. Patients with new-onset asthma were defined as participants without asthma at baseline assessment and with asthma at the follow-up assessment. RESULTS: Among the 7948 participants analyzed in this study, 28 (1.4%) elderly and 130 (2.2%) non-elderly had new-onset asthma. Multiple logistic regression analysis revealed low forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and high blood eosinophil counts at baseline as predicting factors for new-onset asthma in the elderly. Additionally, subsequent incidence of new-onset asthma was higher in elderly participants with both predictors (high blood eosinophil counts and low FEV1/FVC at baseline) than those with none or one of the predictors before asthma diagnosis. Lastly, elderly patients with new-onset asthma had more frequent comorbidity of moderate to severe sleep disordered breathing than those non-elderly. CONCLUSIONS: Eosinophilic inflammation and airflow obstruction may predict subsequent new-onset asthma after the age of 65 years. Revealing the characteristics of new-onset asthma in the elderly can aid in the prevention of underdiagnosed asthma.

Evaluation of elevated plasma fatty acids as relevant factors for adult-onset asthma: The Nagahama Study.

BACKGROUND: Obesity and increased body mass index (BMI) are the known risk factors for adult-onset asthma. Serum free fatty acid (FFA) and other blood lipid levels are generally elevated in patients with obesity and may be involved in the onset of asthma. However, it remains largely unknown. This study aimed to elucidate the relationship between plasma fatty acids and new-onset asthma. METHODS: This community-based Nagahama Study in Japan enrolled 9804 residents. We conducted self-reporting questionnaires, lung function tests, and blood tests at baseline and 5 years later as follow-up. At the follow-up, plasma fatty acids were measured using gas chromatography-mass spectrometry. Body composition analysis was also measured at the follow-up. The associations between fatty acids and new-onset asthma were evaluated using a multifaceted approach, including targeted partial least squares discriminant analysis (PLS-DA). RESULTS: In PLS-DA for new-onset asthma, palmitoleic acid was identified as the fatty acid most associated with asthma onset. In the multivariable analysis, higher levels of FFA, palmitoleic acid, or oleic acid were significantly associated with new-onset asthma, independent of other confounding factors. The high body fat percentage itself was not the relevant factor, but showed a positive interaction with plasma palmitoleic acid for new-onset asthma. When stratified by gender, the impacts of higher levels of FFA or palmitoleic acid on new-onset asthma remained significant in females, but not in males. CONCLUSIONS: Elevated levels of plasma fatty acids, particularly palmitoleic acid, may be a relevant factor for new-onset asthma.

Centrilobular Emphysema Is Associated with Pectoralis Muscle Reduction in Current Smokers without Airflow Limitation.

BACKGROUND: Physiological and prognostic associations of centrilobular emphysema (CLE) and paraseptal emphysema (PSE) in smokers with and without chronic obstructive pulmonary disease (COPD) have been increasingly recognized, but the associations with extrapulmonary abnormalities, such as muscle wasting, osteoporosis, and cardiovascular diseases, remain unestablished. OBJECTIVES: The aim of the study was to investigate whether CLE was associated with extrapulmonary abnormalities independent of concomitant PSE in smokers without airflow limitation. METHODS: This retrospective study consecutively enrolled current smokers without airflow limitation who underwent lung cancer screening with computed tomography and spirometry. CLE and PSE were visually identified based on the Fleischner Society classification system. Cross-sectional areas of pectoralis muscles (PM) and adjacent subcutaneous adipose tissue (SAT), bone mineral density (BMD), and coronary artery calcification (CAC) were evaluated. RESULTS: Of 310 current smokers without airflow limitation, 83 (26.8%) had CLE. The PSE prevalence was higher (67.5% vs. 23.3%), and PM area, SAT area, and BMD were lower in smokers with CLE than in those without (PM area (mean), 34.5 versus 38.6 cm2; SAT area (mean), 29.3 versus 36.8 cm2; BMD (mean), 158.3 versus 178.4 Hounsfield unit), while CAC presence did not differ. In multivariable models, CLE was associated with lower PM area but not with SAT area or BMD, after adjusting for PSE presence, demographics, and forced expiratory volume in 1 s. CONCLUSIONS: The observed association between CLE and lower PM area suggests that susceptibility to skeletal muscle loss could be high in smokers with CLE even without COPD.

Clinical characteristics of rheumatoid arthritis patients complicated with pulmonary nontuberculous mycobacterial disease: A cross-sectional case series study.

OBJECTIVES: Pulmonary nontuberculous mycobacterial disease (pNTM) is a common pulmonary complication of rheumatoid arthritis (RA), but their association has rarely been researched. We aimed to reveal the clinical characteristics of RA with pNTM. METHODS: Among all the RA patients who visited Tenri hospital from April 2017 to March 2018, we enrolled those fulfilling the 2007 ATS/IDSA diagnostic criteria of pNTM, and sex- and age- matched control group at a ratio of 1:5. Demographic characteristics were compared between the two groups. RESULTS: Among 865 RA patients, 35 (4.0%) patients were complicated with pNTM. RA patients with pNTM had significantly lower BMI and higher rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity. Bronchiectasis was the most frequent lesion, followed by clusters of small nodules, patchy consolidation and cavity. Multivariable logistic regression analysis revealed bronchiectasis as a strong independent associated factor of pNTM. Treatment for pNTM was needed in 14 of the 35 (40%) RA patients with pNTM and sputum negative conversion was accomplished in 11 of the 14 cases (78.6%). CONCLUSIONS: RA patients with lower BMI, RF/ACPA positivity, and bronchiectasis were associated with pNTM. Treatment for pNTM may attain sputum negative conversion and radiological improvement in patients with RA.

A case report of pulmonary Botrytis sp. infection in an apparently healthy individual.

BACKGROUND: Botrytis species are well known fungal pathogens of various plants but have not been reported as human pathogens, except as allergenic precipitants of asthma and hypersensitivity pneumonitis. CASE PRESENTATION: The asymptomatic patient was referred because of a nodule revealed by chest X-ray. Computed tomography (CT) showed a cavitary nodule in the right upper lobe of the lung. He underwent wedge resection of the nodule, which revealed necrotizing granulomas and a fungus ball containing Y-shaped filamentous fungi, which was confirmed histopathologically. Culture of the specimen yielded white to grayish cotton-like colonies with black sclerotia. We performed multilocus gene sequence analyses including three single-copy nuclear DNA genes encoding glyceraldehyde-3-phosphate dehydrogenase, heat-shock protein 60, and DNA-dependent RNA polymerase subunit II. The analyses revealed that the isolate was most similar to Botrytis elliptica. To date, the pulmonary Botrytis sp. infection has not recurred after lung resection and the patient did not require any additional medication. CONCLUSIONS: We report the first case of an immunocompetent patient with pulmonary Botrytis sp. infection, which has not recurred after lung resection without any additional medication. Precise evaluation is necessary for the diagnosis of pulmonary Botrytis infection because it is indistinguishable from other filamentous fungi both radiologically and by histopathology. The etiology and pathophysiology of pulmonary Botrytis infection remains unclear. Further accumulation and analysis of Botrytis cases is warranted.

A reference equation for lung volume on computed tomography in Japanese middle-aged and elderly adults.

BACKGROUND: Effective use of lung volume data measured on computed tomography (CT) requires reference values for specific populations. This study examined whether an equation previously generated for multiple ethnic groups in the United States, including Asians predominantly composed of Chinese people, in the Multi-Ethnic Study of Atherosclerosis (MESA) could be used for Japanese people and, if necessary, to optimize this equation. Moreover, the equation was used to characterize patients with chronic obstructive pulmonary disease (COPD) and lung hyperexpansion. METHODS: This study included a lung cancer screening CT cohort of asymptomatic never smokers aged ≥40 years from two institutions (n = 364 and 419) to validate and optimize the MESA equation and a COPD cohort (n = 199) to test its applicability. RESULTS: In all asymptomatic never smokers, the variance explained by the predicted values (R2) based on the original MESA equation was 0.60. The original equation was optimized to minimize the root mean squared error (RMSE) by adjusting the scaling factor but not the age, sex, height, or body mass index terms of the equation. The RMSE changed from 714 ml in the original equation to 637 ml in the optimized equation. In the COPD cohort, lung hyperexpansion, defined based on the 95th percentile of the ratio of measured lung volume to predicted lung volume in never smokers (122 %), was observed in 60 (30 %) patients and was associated with centrilobular emphysema and air trapping on inspiratory/expiratory CT. CONCLUSIONS: The MESA equation was optimized for Japanese middle-aged and elderly adults.

Chronic obstructive pulmonary disease features in patients visiting primary respiratory clinic and tertiary hospital in Japan.

Pulmonologists in primary care clinics are positioned between those in tertiary hospitals and general practitioners in clinics and are anticipated to promote hospital-clinic collaboration for patients with chronic obstructive pulmonary disease (COPD). However, the clinical features of patients in primary respiratory clinics are unclear. This multicenter study cross-sectionally compared the characteristics of patients with COPD in a respiratory clinic (n = 69) with those in a university hospital (n = 124). More patients visited the clinic for symptom relief without a referral, whereas more visited the hospital for consultation of abnormal spirometry/computed tomography (CT). The patients in the clinic showed female predilection, higher prevalence of current smokers, severe dyspnea, and concomitant heart failure, and higher CT-measured cross-sectional area ratio of pectoralis muscle to adjacent subcutaneous adipose tissue compared to those in the hospital (all p < 0.05). The observed differences between the two groups suggest the need to establish the role of primary pulmonologists in hospital-clinic collaboration for better COPD management.

Association of age with computed tomography airway tree morphology in male and female never smokers without lung disease history.

BACKGROUND: Sex and aging may affect the airway tree structure in patients with airway diseases and even healthy subjects. Using chest computed tomography (CT), this study sought to determine whether age is associated with airway morphological features differently in healthy males and females. METHODS: This retrospective cross-sectional study consecutively incorporated lung cancer screening CT data of asymptomatic never smokers (n = 431) without lung disease history. Luminal areas were measured at the trachea, main bronchi, bronchus intermedius, segmental and subsegmental bronchus, and the ratio of their geometric mean to total lung volume (airway-to-lung size ratio, ALR) was determined. Airway fractal dimension (AFD) and total airway count (TAC) were calculated for the segmented airway tree resolved on CT. RESULTS: The lumen areas of the trachea, main bronchi, segmental and subsegmental airways, AFD and TAC visible on CT were smaller in females (n = 220) than in males (n = 211) after adjusting for age, height, and body mass index, while ALR or count of the 1st to 5th generation airways did not differ. Furthermore, in males but not in females, older age was associated with larger lumen sizes of the main bronchi, segmental and subsegmental airways, and ALR. In contrast, neither male nor female had any associations between age and AFD or TAC on CT. CONCLUSION: Older age was associated with larger lumen size of the relatively central airways and ALR exclusively in males. Aging may have a more profound effect on airway lumen tree caliber in males than in females.

Physiological impacts of computed tomography airway dysanapsis, fractal dimension, and branch count in asymptomatic never smokers.

Dysanapsis, a mismatch between airway tree caliber and lung size, contributes to a large variation in lung function on spirometry in healthy subjects. However, it remains unclear whether other morphological features of the airway tree could be associated with the variation in lung function independent of dysanapsis. This study used lung cancer screening chest computed tomography (CT) and spirometry data from asymptomatic never smokers. Dysanapsis and the complexity of airway tree geometry were quantified on CT by measuring airway to lung ratio (ALR) and airway fractal dimension (AFD). Moreover, total airway count (TAC), ratio of airway luminal surface area to volume (SA/V), longitudinal tapering and irregularity of the radius of the internal lumen from the central to peripheral airways (Tapering index and Irregularity index) were quantified. In 431 asymptomatic never smokers without a history of lung diseases, lower ALR was associated with lower forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FEV1/FVC). The associations of ALR with AFD and TAC (r = 0.41 and 0.13) were weaker than the association between TAC and AFD (r = 0.64). In multivariable models adjusted for age, sex, height, and mean lung density, lower AFD and TAC were associated with lower FEV1 and FEV1/FVC independent of ALR, whereas SA/V and Tapering index were not. These results suggest that the smaller airway tree relative to a given lung size and the lower complexity of airway tree shape, including lower branch count, are independently associated with lower lung function in healthy subjects.NEW & NOTEWORTHY This study showed that fractal dimension and total airway count of the airway tree on computed tomography are associated with lung function on spirometry independent of a smaller airway for a given lung size (dysanapsis) in asymptomatic never smokers without a history of lung diseases. In addition to dysanapsis, the morphometric complexity of the airway tree and the airway branch count may cause a substantial variation of lung function in these subjects.

Association of lower plasma citric acid with prolonged cough: the Nagahama study.

Little is known about the association of prolonged cough, a common and troublesome symptom, with metabolic pathways. We aimed to clarify this association using data from the Nagahama cohort, a prospective study of participants from the general population. Self-report questionnaires on prolonged cough were collected at baseline and 5-year follow-up assessments. Blood tests at follow-up were used for gas chromatography-mass spectrometry-based metabolomics. The association between metabolites and prolonged cough was examined using the partial least squares discriminant analysis and multiple regression analysis. Among the 7432 participants, 632 had newly developed prolonged cough at follow-up, which was defined as "new-onset prolonged cough". Low plasma citric acid was significantly associated with new-onset prolonged cough, even after the adjustment of confounding factors including the presence of asthma, upper airway cough syndrome (UACS), and gastroesophageal reflux disease (GERD). A similar association was observed for isocitric acid, 3-hydroxybutyric acid, and 3-hydroxyisobutyric acid. The analysis of these four metabolites revealed that citric acid had the strongest association with new-onset prolonged cough. This significant association remained even when the analysis was confined to participants with UACS or GERD at baseline or follow-up, and these associations were also observed in participants (n = 976) who had prolonged cough at follow-up regardless of baseline status. In conclusion, low blood citric acid may be associated with prolonged cough.

Prediction of forced vital capacity with dynamic chest radiography in interstitial lung disease.

PURPOSE: The pulmonary function test (PFT) has played an essential role in diagnosing and managing interstitial lung disease (ILD) but has its contraindications and difficult conditions to perform. Therefore, the present study aimed to evaluate dynamic chest radiography (DCR) ability to predict forced vital capacity (FVC) and other PFT parameters of ILD patients. METHOD: The prospective observational study included 97 patients who underwent DCR at Tenri Hospital (Tenri, Japan) between June 2019 and April 2020. Twenty-five patients with stable disease status underwent DCR twice to evaluate test-retest reliability using the intraclass correlation coefficient. From the lung field areas measured by DCR, lung volumes at maximum inspiration (V.ins) and expiration (V.exp) were estimated. Correlation coefficients between the measured values of DCR and PFT parameters were calculated. Multilinear models for predicting FVC and other PFT parameters were developed. RESULTS: Intraclass correlation coefficients between first and second measurements of V.ins and V.exp were 0.94 (95% CI: 0.89-0.97, p < 0.001) and 0.88 (95% CI: 0.78-0.94, p < 0.001), respectively. The correlation coefficient between V.ins and FVC was 0.86 (95% CI: 0.79-0.90, p < 0.001). A multilinear model for predicting FVC was developed using V.ins, V.exp, age, sex, and body mass index as predictor variables, wherein the adjusted coefficient of determination was 0.814. CONCLUSIONS: Lung volumes measured by DCR correlated with the lung function of ILD patients. Prediction models with high predictive power and internal validity were developed, suggesting that DCR can predict FVC and other PFT parameters of ILD patients.

Impacts of lipid-related metabolites, adiposity, and genetic background on blood eosinophil counts: the Nagahama study.

Blood eosinophil count is a useful measure in asthma or COPD management. Recent epidemiological studies revealed that body mass index (BMI) is positively associated with eosinophil counts. However, few studies focused on the role of adiposity and fatty acid-related metabolites on eosinophil counts, including the effect of genetic polymorphism. In this community-based study involving 8265 participants (30-74 year old) from Nagahama city, we investigated the relationship between eosinophil counts and serum levels of fatty acid-related metabolites. The role of MDC1, a gene that is related to eosinophil counts in our previous study and encodes a protein that is thought to be involved in the repair of deoxyribonucleic acid damage, was also examined taking into account its interaction with adiposity. Serum levels of linoleic acid (LA) and ß-hydroxybutyric acid (BHB) were negatively associated with eosinophil counts after adjustment with various confounders; however, there were positive interactions between serum LA and BMI and between serum BHB and BMI/body fat percentages in terms of eosinophil counts. In never-smokers, there was positive interaction for eosinophil counts between the CC genotype of MDC1 rs4713354 and BMI/body fat percentages. In conclusion, both serum LA and BHB have negative impacts on eosinophil counts, while adiposity shows robust positive effects on eosinophil counts, partly via genetic background in never-smokers.

Pneumonia Caused by Severe Acute Respiratory Syndrome Coronavirus 2 and Influenza Virus: A Multicenter Comparative Study.

BACKGROUND: Detailed differences in clinical information between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia (CP), which is the main phenotype of SARS-CoV-2 disease, and influenza pneumonia (IP) are still unclear. METHODS: A prospective, multicenter cohort study was conducted by including patients with CP who were hospitalized between January and June 2020 and a retrospective cohort of patients with IP hospitalized from 2009 to 2020. We compared the clinical presentations and studied the prognostic factors of CP and IP. RESULTS: Compared with the IP group (n = 66), in the multivariate analysis, the CP group (n = 362) had a lower percentage of patients with underlying asthma or chronic obstructive pulmonary disease (P < .01), lower neutrophil-to-lymphocyte ratio (P < .01), lower systolic blood pressure (P < .01), higher diastolic blood pressure (P < .01), lower aspartate aminotransferase level (P < .05), higher serum sodium level (P < .05), and more frequent multilobar infiltrates (P < .05). The diagnostic scoring system based on these findings showed excellent differentiation between CP and IP (area under the receiver operating characteristic curve, 0.889). Moreover, the prognostic predictors were different between CP and IP. CONCLUSIONS: Comprehensive differences between CP and IP were revealed, highlighting the need for early differentiation between these 2 pneumonias in clinical settings.

Flavin-sensitized photoreduction of thymidine glycol.

Photochemical reactivity of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) toward thymidine glycol (dTg) has been investigated. Fluorescence intensity of FAD was enhanced as increasing the concentration of dTg, suggesting that adenosine moiety of FAD interacts with dTg. However, photoreduction of dTg using reduced form of FAD gave repaired thymidine in almost the same yield as when reduced FMN was used alternatively, and thus such interaction seems to have no effect on the reduction. Oligodeoxynucleotides containing dTg were also photochemically repaired by reduced form of flavins in different yields depending on the sequence, which could be related to electron affinity of the nucleobases in DNA.

Photoinduced reductive repair of thymine glycol: implications for excess electron transfer through DNA containing modified bases.

Photoinduced reduction of thymine glycol in oligodeoxynucleotides was investigated using either a reduced form of flavin adenine dinucleotide (FADH(-)) as an intermolecular electron donor or covalently linked phenothiazine (PTZ) as an intramolecular electron donor. Intermolecular electron donation from photoexcited flavin (FADH(-)) to free thymidine glycol generated thymidine in high yield, along with a small amount of 6-hydroxy-5,6-dihydrothymidine. In the case of photoreduction of 4-mer long single-stranded oligodeoxynucleotides containing thymine glycol by *FADH(-), the restoration yield of thymine was varied depending on the sequence of oligodeoxynucleotides. Time-resolved spectroscopic study on the photoreduction by laser-excited N,N-dimethylaniline (DMA) suggested elimination of a hydroxyl ion from the radical anion of thymidine glycol with a rate constant of approximately 10(4) s(-1) generates 6-hydroxy-5,6-dihydrothymidine (6-HOT(*)) as a key intermediate, followed by further reduction of 6-HOT(*) to thymidine or 6-hydroxy-5,6-dihydrothymdine (6-HOT). On the other hand, an excess electron injected into double-stranded DNA containing thymine glycol was not trapped at the lesion but was further transported along the duplex. Considering redox properties of the nucleobases and PTZ, competitive excess electron trapping at pyrimidine bases (thymine, T and cytosine, C) which leads to protonation of the radical anion (T(-)(*), C(-)(*)) or rapid back electron transfer to the radical cation of PTZ (PTZ(+)(*)), is presumably faster than elimination of the hydroxyl ion from the radical anion of thymine glycol in DNA.