Impact of Energy Malnutrition on Exacerbation Hospitalization in Patients with Chronic Obstructive Pulmonary Disease: Retrospective Observational Study.

Nutritional disorders in patients with chronic obstructive pulmonary disease (COPD) are associated with cachexia, sarcopenia, and weight loss. In particular, weight loss is a prognostic factor in COPD independent of pulmonary function, and energy malnutrition is a contributing factor. Frequent exacerbation hospitalization is also a prognostic factor for COPD patients. The impact of energy malnutrition on adverse events such as exacerbation hospitalization is unknown, and this study aimed to investigate that. We included 163 male subjects with COPD. Respiratory quotient (RQ), an index of energy malnutrition, was calculated by expiratory gas analysis using an indirect calorimeter. RQ <0.85 was categorized as the energy malnutrition group. Kaplan-Meier analysis was used to compare the hospitalization avoidance rate between the with and without energy malnutrition groups. Independent factors associated with exacerbation hospitalization were evaluated by Cox regression analysis. We finally analyzed data from 56 selected subjects (median age: 74 y). The exacerbation hospitalization rate was significantly higher in the energy malnutrition group. Fifty percent of the energy malnutrition group was hospitalized for an exacerbation, and the median hospitalization avoidance time was 701 d. In Cox regression analysis (adjusted for age, BMI, mMRC dyspnea scale score, %FEV1, and 6-min walk test), energy malnutrition was an independent factor associated with exacerbation hospitalization (HR 4.14, 95% CI 1.13-15.1, p=0.03). Energy malnutrition may be the risk factor for exacerbation hospitalization. Energy malnutrition may be an early nutritional disorder and early detection and intervention may reduce exacerbation hospitalizations.

Effect of Azithromycin on Exacerbations in Asthma Patients with Obesity: Protocol for a Multi-Center, Prospective, Single-Arm Intervention Study.

INTRODUCTION: Obesity is associated with severe asthma, but no specific treatment has been established. The gut microbiome is increasingly recognized as a crucial factor, but specific treatments focused on the gut microbiome have not been established. Recently, azithromycin has been found to have the capacity to attenuate exacerbations, a characteristic of severe asthma. The effect of azithromycin on obesity-induced severe asthma is not understood. METHODS: The purpose of the present study is to clarify the effect of azithromycin on exacerbations in asthmatic patients with obesity. To explore the mechanism, the gut microbiome, metabolites of microbes such as short-chain fatty acids, and blood inflammatory cytokines will be analyzed to evaluate the correlation with the effect of azithromycin on exacerbations in obesity-induced severe asthma. A multi-center, prospective, single-arm intervention study is planned. DISCUSSION: The present study will allow us to evaluate the effect of azithromycin on exacerbations, particularly in asthma patients with obesity, and explore biomarkers, targeting molecules including the gut microbiome, which are correlated with decreased exacerbations. The present results could contribute to identifying new therapeutic prospects and targeted microbes or molecules associated with severe clinical characteristics in asthmatic patients with obesity. TRIAL REGISTRATION: This study has been registered as a prospective study with the University Hospital Medical Information Network (UMIN0000484389) and the Japan Registry of Clinical Trials (jRCTs071220023).

The Relationship of Energy Malnutrition, Skeletal Muscle and Physical Functional Performance in Patients with Stable Chronic Obstructive Pulmonary Disease.

Weight loss is a factor that affects prognosis in patients with chronic obstructive pulmonary disease (COPD) independent of lung function. One of the major factors for weight loss is energy malnutrition. There have been no reports on the factors related to energy malnutrition in COPD patients. This retrospective observational study aimed to investigate these factors. We included 163 male subjects with COPD. Respiratory quotient (RQ), an index of energy malnutrition, was calculated by expiratory gas analysis using an indirect calorimeter. RQ < 0.85 was defined as the energy-malnutrition group and RQ ≥ 0.85 as the no energy-malnutrition group. Factors related to energy malnutrition were examined by multivariate and decision-tree analysis. We finally analyzed data from 56 selected subjects (median age: 74 years, BMI: 22.5 kg/m2). Energy malnutrition was observed in 43%. The independent factors associated with energy malnutrition were tidal volume (VT) (OR 0.99; 95% CI 0.985−0.998; p = 0.015) and Th12 erector spinae muscle cross-sectional area SMI (Th12ESMSMI) (OR 0.71; 95% CI 0.535−0.946; p = 0.019). In decision-tree profiling of energy malnutrition, VT was extracted as the first distinguishable factor, and Th12ESMSMI as the second. In ROC analysis, VT < 647 mL (AUC, 0.72) or Th12ESMSMI < 10.1 (AUC, 0.70) was the cutoff value for energy malnutrition. Energy malnutrition may be an early warning sign of nutritional disorders.

Factors Associated with Reduction of Sedentary Time Following Tiotropium/Olodaterol Therapy in Treatment-Naïve Chronic Obstructive Pulmonary Disease.

BACKGROUND: Prolonged sedentary behavior is associated with worse prognosis in patients with chronic obstructive pulmonary disease (COPD). Our previous study found that first-line dual therapy with tiotropium/olodaterol significantly reduces sedentary time compared to tiotropium monotherapy in Japanese patients with treatment-naïve COPD, although the characteristics of responders to dual-therapy versus monotherapy for COPD are still unclear. METHODS: Patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Physical activity was assessed using a triaxle accelerometer for 2 weeks before and after treatment. This analysis focused on the change in sedentary time, indicated by physical activity of 1.0-1.5 metabolic equivalents (METs), with stratification for the following factors: age, body mass index (BMI), pulmonary function, COPD assessment test (CAT), the 6-minute walk distance (6MWD), and physical activity level at study entry. RESULTS: Thirty-five patients received tiotropium/olodaterol and 34 patients received tiotropium. In patients with lower inspiratory capacity at study entry, a significant reduction in sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: -12.8 ± 13.5 min, Tio/Olo: -65.1 ± 21.0 min, mean difference, -52.2 min, 95% CI -103.6 to 0.88, p = 0.046). In patients with a shorter duration of physical activity of ≥2 METs at study entry, a significant reduction of sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: -3.3 ± 17.5 min, Tio/Olo: -72.9 ± 23.1 min, mean difference, -69.7 min, 95% CI -128.7 to -10.6, p = 0.02). There were no differences in terms of age, BMI, CAT score, 6MWD, FEV1, FVC, VC, and physical activity of 1.0-1.5 METs and ≥3.0 METs. CONCLUSION: This study showed that COPD patients with lower inspiratory capacity or shorter active time of ≥2.0 METs at study entry are likely to exhibit significantly greater reduction in sedentary time with tiotropium/olodaterol treatment.

First-Line Treatment with Tiotropium/Olodaterol Improves Physical Activity in Patients with Treatment-Naïve Chronic Obstructive Pulmonary Disease.

Background: Comparative effects on physical activity of mono and dual bronchodilators remain unclear in patients with treatment-naïve chronic obstructive pulmonary disease (COPD). We sought to compare the changes in physical activity before and after tiotropium and tiotropium/olodaterol treatment in treatment-naïve COPD patients. Methods: A prospective, multicenter, randomized, open-labeled, and parallel interventional study was conducted. Eighty Japanese patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Spirometry and dyspnea index were assessed, and COPD assessment test (CAT) and the 6-minute walk distance (6MWD) were conducted before and after treatment. Evaluation of physical activity was assessed by a triaxle accelerometer over a 2-week period before and after treatment. Results: There were no differences in the mean age (69.8 vs 70.4 years), body mass index (BMI) (22.5 vs 22.6 kg/m2) and mean % forced expiratory volume in 1 second (%FEV1) at baseline (61.5 vs 62.6%) between the two groups. Changes in FEV1 (mean±standard error, 242.8±28.8 mL) and transient dyspnea index (TDI) (2.4±0.3 points) before and after tiotropium/olodaterol treatment were greater than with tiotropium treatment (104.1±31.9 mL, p<0.01 and 1.5±0.3, p=0.02, respectively). Changes in the duration of physical activity with 1.0-1.5 metabolic equivalents (METs) estimated in the sedentary position following tiotropium/olodaterol treatment (-38.7±14.7 min) tended to be reduced more than with tiotropium treatment (-4.6±10.6 min) (p=0.06), although those with ≥2.0 METs numerically increased with both treatments (+10.8±7.6 min for tiotropium/olodaterol vs +8.3±7.6 min for tiotropium, p=0.82). Tiotropium/olodaterol treatment reduced the duration of physical activity with 1.0-1.5 METs (regression coefficient, -43.6 [95% CI -84.1, -3.1], p=0.04) in a multiple regression model adjusted for cofounding factors such as age, FEV1, total CAT scores, 6MWD, and TDI. Conclusion: This is the first study to report the impact of dual bronchodilator on physical activity in treatment-naïve COPD patients of Japanese with low BMI.

The Nonantibiotic Macrolide EM900 Attenuates House Dust Mite-Induced Airway Inflammation in a Mouse Model of Obesity-Associated Asthma.

INTRODUCTION: Obesity-associated asthma is characterized by type 2-low airway inflammation. We previously showed that EM900, which is a 12-membered nonantibiotic macrolide, suppressed airway inflammation in a mouse model of asthma exacerbation. The aim of this study was to clarify the effects of EM900 in obesity-associated asthma. METHODS: BALB/c mice were fed a low-fat diet (LFD) or high-fat diet (HFD). Mice were intranasally sensitized and challenged with house dust mites (HDMs) and were orally administered EM900. Airway inflammation was assessed using inflammatory cells in bronchoalveolar lavage (BALF). Cytokines were examined by ELISA in lung tissues. Lung interstitial macrophages (CD45+, CD11clow, CD11b+, and Ly6c-) were counted by flow cytometry in single cells from lung tissues. RESULTS: Body weight increased significantly in the HFD compared with the LFD group. The total cell count and numbers of neutrophils and eosinophils in BALF were significantly suppressed by EM900 administration in the HFD-HDM group. The levels of interleukin (IL)-17A were increased in the HFD-HDM group compared with the LFD-HDM group, although the difference did not reach statistical significance. The levels of IL-17A, macrophage inflammatory protein 2, IL-1ß, IL-5, and regulated on activation, normal T cell expressed and secreted in lung tissue were significantly suppressed by EM900 administration in the HFD-HDM group. The percentage of interstitial macrophages in lungs was significantly decreased by EM900 administration in the HFD-HDM group. CONCLUSION: Both type 2 and type 2-low airway inflammation were attenuated by EM900 in this obesity-associated asthma model. These results show that EM900 might be a candidate agent for the treatment of obesity-associated asthma.

Eosinophilic granulomatous polyangiitis with IgG4 hypergammaglobulinaemia and salivary gland swelling.

A 51-year-old woman was admitted to our hospital for cough, fever, purpura in the legs, and salivary gland swelling. Six years ago, she had been diagnosed with bronchial asthma and was treated with a combination of inhaled corticosteroid and long-acting beta2-agonist. Blood examination showed increased eosinophils at 3027 cells/µL and elevated levels of immunoglobulin (Ig) G4 at 261 mg/dL and C-reactive protein at 2.76 mg/dL. Chest radiograph and computed tomography (CT) showed infiltrates in the bilateral lower lobes. Neck CT showed bilateral salivary gland swelling. Pathological examinations of the lungs and skin purpura showed granuloma with eosinophilic infiltration and perivascular dermatitis, respectively. She was diagnosed with eosinophilic granulomatous polyangiitis (EGPA) and treated with corticosteroids, which resolved the eosinophilia, salivary gland swelling, elevated IgG4 titre, and lung infiltration. As our patient did not meet the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2019 criteria of IgG4-related disease, the diagnostic was EGPA with IgG4 hypergammaglobulinaemia and salivary gland swelling.

Early Life Represents a Vulnerable Time Window for IL-33-Induced Peripheral Lung Pathology.

IL-33, an IL-1 family cytokine, is constitutively expressed in mucosal tissues and other organs in healthy humans and animals, and expression levels increase in inflammatory conditions. Although IL-33-mediated promotion of type 2 immune responses has been well established, a gap in our knowledge regarding the functional diversity of this pleiotropic cytokine remains. To address this gap, we developed a new IL-33 transgenic mouse model in which overexpression of full-length IL-33 is induced in lung epithelial cells under conditional control. In adult mice, an ∼3-fold increase in the steady-state IL-33 levels produced no pathologic effects in the lungs. When exposed to airborne allergens, adult transgenic mice released more IL-33 extracellularly and exhibited robust type 2 immune responses. In neonatal transgenic mice, up to postnatal day 14, a similar increase in steady-state IL-33 levels resulted in increased mortality, enlarged alveolar spaces resembling bronchopulmonary dysplasia, and altered expression of genes associated with tissue morphogenesis. Processed 25-kDa IL-33 protein was detected in bronchoalveolar lavage fluids without any exogenous stimuli, and pathologic changes were abolished in mice deficient in the IL-33 receptor ST2. These findings suggest that adult lungs are relatively resistant to IL-33 overexpression unless they encounter environmental insults, whereas developing lungs are highly susceptible, with IL-33 overexpression resulting in detrimental and pathologic outcomes.

Necrotizing Sarcoid Granulomatosis with Natural Resolution after a Surgical Lung Biopsy.

Necrotizing sarcoid granulomatosis (NSG) is a rare disease that is diagnosed based on pathological findings. We herein report the case of a 27-year-old man who had multiple nodular shadows in bilateral lung fields on chest radiography and elevated levels of C-reactive protein (CRP). The pathological evaluation of a lung biopsy specimen showed the infiltration of lymphocytes, granulomas with necrosis and granulomatous angiitis. He was therefore diagnosed with NSG. He has been followed without treatment, as his fever and CRP levels decreased immediately after the surgical lung biopsy. Thereafter, the pulmonary nodular shadows gradually recovered without any treatment within a few months. Our experience suggests the possibility that surgical invasion might trigger an improvement in disease activity.

Chronic and Asymptomatic Diffuse Alveolar Haemorrhage with Microscopic Polyangiitis: A Case Report and Review of the Literature.

Diffuse alveolar haemorrhage (DAH) is one of the major causes of death in microscopic polyangiitis (MPA) patients, because of acute respiratory failure with various respiratory symptoms. We, herein, present a case of chronic and asymptomatic DAH in a patient with MPA who was diagnosed by fibreoptic bronchoscopy. The patient showed localized reticular shadows, without any respiratory symptoms, and absence of inflammatory reactions, such as fever and CRP elevation, which is atypical for DAH. Three months after appearance of the lung abnormalities, DAH with MPA was diagnosed by fibreoptic bronchoscopy. She was initially treated with only corticosteroids and has thereafter been maintained with corticosteroids and azathioprine without relapse to date. We reviewed the literature for similar cases and opined that physicians should perform fibreoptic bronchoscopy in MPA patients with chronic lung abnormalities and anaemia to identify DAH, even if the patients show no respiratory symptoms and in the absence of inflammatory reactions.

Focus tuning by liquid crystal lens in imaging system.

A quantitative study of the focus tuning by a liquid crystal lens in an imaging system composed of a camera module and the liquid crystal lens that performs the focusing function is reported. The resolving capability of the imaging system is investigated by analyzing the image of an ISO12233 chart formed by the system. Measurements show that with the focus tuning by the liquid crystal lens, the resolving power of the system can be very close to that of the camera module.

Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal form of interstitial lung disease (ILD). The precise molecular mechanisms of IPF remain poorly understood. However, analyses of mice receiving bleomycin (BLM) as a model of IPF established the importance of preceding inflammation for the formation of fibrosis. Periostin is a recently characterized matricellular protein involved in modulating cell functions. We recently found that periostin is highly expressed in the lung tissue of patients with IPF, suggesting that it may play a role in the process of pulmonary fibrosis. To explore this possibility, we administered BLM to periostin-deficient mice, and they subsequently showed a reduction of pulmonary fibrosis. We next determined whether this result was caused by a decrease in the preceding recruitment of neutrophils and macrophages in the lungs because of the lower production of chemokines and proinflammatory cytokines. We performed an in vitro analysis of chemokine production in lung fibroblasts, which indicated that periostin-deficient fibroblasts produced few or no chemokines in response to TNF-α compared with control samples, at least partly explaining the lack of inflammatory response and, therefore, fibrosis after BLM administration to periostin-deficient mice. In addition, we confirmed that periostin is highly expressed in the lung tissue of chemotherapeutic-agent-induced ILD as well as of patients with IPF. Taking these results together, we conclude that periostin plays a unique role as an inducer of chemokines to recruit neutrophils and macrophages important in the process of pulmonary fibrosis in BLM-administered model mice. Our results suggest a therapeutic potential for periostin in IPF and drug-induced ILD.

Ultraviolet Rayleigh-Mie lidar with Mie-scattering correction by Fabry-Perot etalons for temperature profiling of the troposphere.

A Rayleigh-Mie-scattering lidar system at an eye-safe 355-nm ultraviolet wavelength that is based on a high-spectral-resolution lidar technique is demonstrated for measuring the vertical temperature profile of the troposphere. Two Rayleigh signals, which determine the atmospheric temperature, are filtered with two Fabry-Perot etalon filters. The filters are located on the same side of the wings of the Rayleigh-scattering spectrum and are optically constructed with a dual-pass optical layout. This configuration achieves a high rejection rate for Mie scattering and reasonable transmission for Rayleigh scattering. The Mie signal is detected with a third Fabry-Perot etalon filter, which is centered at the laser frequency. The filter parameters were optimized by numerical calculation; the results showed a Mie rejection of approximately -45 dB, and Rayleigh transmittance greater than 1% could be achieved for the two Rayleigh channels. A Mie correction method is demonstrated that uses an independent measure of the aerosol scattering to correct the temperature measurements that have been influenced by the aerosols and clouds. Simulations and preliminary experiments have demonstrated that the performance of the dual-pass etalon and Mie correction method is highly effective in practical applications. Simulation results have shown that the temperature errors that are due to noise are less than 1 K up to a height of 4 km for daytime measurement for 300 W m(-2) sr(-1) microm(-1) sky brightness with a lidar system that uses 200 mJ of laser energy, a 3.5-min integration time, and a 25-cm telescope.

Ultraviolet Rayleigh-Mie lidar for daytime-temperature profiling of the troposphere.

A UV Rayleigh-Mie scattering lidar has been developed for daytime measurement of temperature and aerosol optical properties in the troposphere. The transmitter is a narrowband, injection-seeded, pulsed, third-harmonic Nd:YAG laser at an eye-safe wavelength of 355 nm. Two Fabry-Perot etalons (FPEs) with a dual-pass optical layout filter the molecular Rayleigh scattering components spectrally for retrieval of the temperature and provide a high rejection rate for aerosol Mie scattering in excess of 43 dB. The Mie signal is filtered with a third FPE filter for direct profiling of aerosol optical properties. The Mie scattering component in the Rayleigh signals, which will have influence on temperature measurements, is corrected by using a measure of aerosol scattering because of the relative insufficiency of Mie rejection of Rayleigh filters in the presence of dense aerosols or clouds, and the Mie rejection capability of system is thus improved. A narrowband interference filter is incorporated with the FPEs to block solar radiation. Also, the small field of view (0.1 mrad) of the receiver and the UV wavelength used enhance the ability of the lidar to suppress the solar background signal in daytime measurement. The system is relatively compact, with a power-aperture product of 0.18 W m(-2), and has a high sensitivity to temperature change (0.62%/K). Lidar measurements taken under different weather conditions (winter and summer) are demonstrated. Good agreement between the lidar and the radiosonde measurements was obtained in terms of lapse rates and inversions. Statistical temperature errors of less than 1 K up to a height of 2 km are obtainable, with an averaging time of approximately 12 min for daytime measurements.

Ultraviolet high-spectral-resolution Rayleigh-Mie lidar with a dual-pass Fabry-Perot etalon for measuring atmospheric temperature profiles of the troposphere.

We report what is believed to be the first demonstration of measurement of tropospheric temperature profiles in daytime by use of a high-spectral-resolution Rayleigh-Mie lidar at an eye-safe wavelength of 355 nm. Atmospheric temperature is determined from the linewidth of the Rayleigh spectrum. Two Rayleigh signals are detected with Fabry-Perot etalon filters with a dual-pass optical layout. The Mie signal is detected with a third etalon filter for correcting the Mie component in the Rayleigh signals. The temperature statistical uncertainties are below 1 K up to a height of 3 km in nighttime and 2 km in daytime with a relatively compact system that uses laser energy of 180 mJ and a 25-cm telescope. Good agreement between lidar and radiosonde measurements is obtained.