Perspectives on End-of-Life Treatment among Patients with COPD: A Multicenter, Cross-sectional Study in Japan.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality. Since patients with severe COPD may experience exacerbations and eventually face mortality, advanced care planning (ACP) has been increasingly emphasized in the recent COPD guidelines. We conducted a multicenter, cross-sectional study to survey the current perspectives of Japanese COPD patients toward ACP. "High-risk" COPD patients and their attending physicians were consecutively recruited. The patients' family configurations, understanding of COPD pathophysiology, current end-of-life care communication with physicians and family members, and preferences for invasive life-sustaining treatments including mechanical ventilation (MV) and cardiopulmonary resuscitation (CPR) were evaluated using a custom-made, structured, self-administered questionnaire. Attending physicians were also interviewed, and we evaluated the patient-physician agreement. Among the 224 eligible "high-risk" patients, 162 participated. Half of the physicians (54.4%) thought they had communicated detailed information; however, only 19.4% of the COPD patients thought the physicians did so (κ score = 0.16). Less than 10% of patients wanted to receive invasive treatment (MV, 6.3% and CPR, 9.4%); interestingly, more than half marked their decision as "refer to the physician" (MV 42.5% and CPR 44.4%) or "refer to family" (MV, 13.8% and CPR, 14.4%). Patients with less knowledge of COPD were less likely to indicate that they had already made a decision. Although ACP is necessary to cope with severe COPD, Japanese "high-risk" COPD patients were unable to make a decision on their preferences for invasive treatments. Lack of disease knowledge and communication gaps between patients and physicians should be addressed as part of these patients' care.

Annual decline in arterial blood oxygen predicts development of chronic respiratory failure in COPD with mild hypoxaemia: A 6-year follow-up study.

BACKGROUND AND OBJECTIVE: Chronic respiratory failure (CRF) with hypoxaemia is an important pathophysiology in patients with chronic obstructive pulmonary disease (COPD), and existing mild hypoxaemia may be a sign of future CRF development. However, little is known about the trajectory of partial arterial pressure of oxygen (PaO2 ) decline in patients with COPD. We assessed decline in PaO2 and the impact of short-term reductions in PaO2 to predict future decline in PaO2 . METHODS: A total of 172 outpatients with COPD from a prospective cohort study were enrolled. Pulmonary function tests and arterial blood gas (ABG) analyses were conducted at baseline and 1 year after enrolment and changes in PaO2 (ΔPaO2 ) and other parameters were calculated. Survival and incidence of CRF (as assessed by prescription of long-term home oxygen therapy) were monitored for 6 years. RESULTS: A total of 164 patients completed the observation period and 101 patients had mild hypoxaemia (PaO2 < 80 Torr) at baseline. No patients with normal PaO2 (≥80 Torr) developed CRF, and 10 patients with mild hypoxaemia developed CRF in 6 years. Baseline airflow limitation and diffusion capacity were significantly associated with development of CRF. Receiver-operating characteristic curve analysis showed that ΔPaO2 of -3.05 Torr/year is a useful cut-off value to predict development of CRF in 6 years (hazard ratio (HR): 12.6, 95% CI: 3.48-58.73, P < 0.0001). CONCLUSION: Patients with COPD and mild hypoxaemia may benefit from repeat ABG after 1 year. Although PaO2 trajectories widely varied, significant annual changes in PaO2 of at least -3.0 Torr/year were predictive of CRF development.

Complementary regional heterogeneity information from COPD patients obtained using oxygen-enhanced MRI and chest CT.

BACKGROUND: The heterogeneous distribution of emphysema is a key feature of chronic obstructive pulmonary disease (COPD) patients that typically is evaluated using high-resolution chest computed tomography (HRCT). Oxygen-enhanced pulmonary magnetic resonance imaging (OEMRI) is a new method to obtain information regarding regional ventilation, diffusion, and perfusion in the lung without radiation exposure. We aimed to compare OEMRI with HRCT for the assessment of heterogeneity in COPD patients. METHODS: Forty patients with stable COPD underwent quantitative HRCT, OEMRI, and pulmonary function tests, including arterial blood gas analysis. OEMRI was also performed on nine healthy control subjects. We measured the severity of emphysema (percent low attenuation volume; LAV%) in whole lungs and the standard deviations (SDs) of the LAV% values of 10 isovolumetric partitions (SD-LAV) as an index of cranial-caudal heterogeneity. Similarly, relative enhancement ratios of oxygen (RERs) in whole lungs from OEMRI and SD-RER were analyzed. RESULTS: COPD patients showed a lower mean RER than control subjects (12.6% vs 22.0%, p<0.01). The regional heterogeneity of the RERs was not always consistent with the LAV distribution. Both the HRCT (LAV% and SD-LAV) and the OEMRI (RER and SD-RER) indices were significantly associated with the diffusion capacity (DLCO) and partial pressure of oxygen in arterial blood (PaO2). The PaO2 was associated only with the heterogeneity index of HRCT (SD-LAV) (R2 = 0.39); however, the PaO2 was associated with both the mean RER and heterogeneity (SD-RER) in the multivariate analysis (R2 = 0.38). CONCLUSIONS: OEMRI-derived parameters were directly associated with oxygen uptake in COPD patients. Although the OEMRI-derived parameters were not identical to the HRCT-derived parameters, the cranial-caudal heterogeneity in HRCT or OEMRI was complementary to that in evaluations of oxygen uptake in the lungs. Functional imaging seems to provide new insights into COPD pathophysiology without radiation exposure.

Gastroesophageal reflux symptoms and nasal symptoms affect the severity of bronchitis symptoms in patients with chronic obstructive pulmonary disease.

BACKGROUND: Cough and sputum production (symptoms of bronchitis) are common in chronic obstructive pulmonary disease (COPD). Extrapulmonary comorbidities, such as gastroesophageal reflux disease (GERD) and post-nasal drip, also cause bronchitis symptoms. The impact of extrapulmonary comorbidities on the severity of bronchitis symptoms in COPD is unknown. The aim of this study was to quantify bronchitis symptoms and assess the impact of GERD and nasal symptoms on the severity of bronchitis symptoms in COPD. METHODS: In this cross-sectional study, stable COPD patients were recruited and completed the COPD assessment test (CAT) and Cough and Sputum Assessment Questionnaire (CASA-Q) to quantify bronchitis symptoms. To evaluate extrapulmonary comorbidities, the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and nasal symptom questionnaire were completed. The impact of these comorbidities on the severity of bronchitis symptoms was analyzed. RESULTS: Ninety-nine COPD patients were recruited. The presence of GERD symptoms (24.2% in the study population) was associated with more sputum symptoms. The presence of nasal discharge (43.4%) was associated with more cough and sputum symptoms, whereas post-nasal drip (13.1%) was associated with more sputum symptoms. On multivariate analyses, nasal discharge was associated with more cough symptoms. GERD and post-nasal drip were associated with more sputum symptoms. CONCLUSION: This study showed that the presence of GERD and/or nasal symptoms is associated with an increase in bronchitis symptoms. Careful assessment of extrapulmonary comorbidities is necessary in the evaluation of bronchitis symptoms in COPD patients.

Fraction of MHCII and EpCAM expression characterizes distal lung epithelial cells for alveolar type 2 cell isolation.

BACKGOUND: Alveolar type 2 (AT2) cells play important roles in maintaining adult lung homeostasis. AT2 cells isolated from the lung have revealed the cell-specific functions of AT2 cells. Comprehensive molecular and transcriptional profiling of purified AT2 cells would be helpful for elucidating the underlying mechanisms of their cell-specific functions. To enable the further purification of AT2 cells, we aimed to discriminate AT2 cells from non-AT2 lung epithelial cells based on surface antigen expression via fluorescence activated cell sorting (FACS). METHODS: Single-cell suspensions obtained from enzymatically digested murine lungs were labeled for surface antigens (CD45/CD31/epithelial cell adhesion molecule (EpCAM)/ major histocompatibility complex class II (MHCII)) and for pro-surfactant protein C (proSP-C), followed by FACS analysis for surface antigen expression on AT2 cells. AT2 cells were sorted, and purity was evaluated by immunofluorescence and FACS. This newly developed strategy for AT2 cell isolation was validated in different strains and ages of mice, as well as in a lung injury model. RESULTS: FACS analysis revealed that EpCAM+ epithelial cells existed in 3 subpopulations based on EpCAM and MHCII expression: EpCAMmedMHCII+ cells (Population1:P1), EpCAMhiMHCII- cells (P2), and EpCAMlowMHCII- cells (P3). proSP-C+ cells were enriched in P1 cells, and the purity values of the sorted AT2 cells in P1 were 99.0% by immunofluorescence analysis and 98.0% by FACS analysis. P2 cells were mainly composed of ciliated cells and P3 cells were composed of AT1 cells, respectively, based on the gene expression analysis and immunofluorescence. EpCAM and MHCII expression levels were not significantly altered in different strains or ages of mice or following lipopolysaccharide (LPS)-induced lung injury. CONCLUSIONS: We successfully classified murine distal lung epithelial cells based on EpCAM and MHCII expression. The discrimination of AT2 cells from non-AT2 epithelial cells resulted in the isolation of pure AT2 cells. Highly pure AT2 cells will provide accurate and deeper insights into the cell-specific mechanisms of alveolar homeostasis.

Quantitative Assessment of Erector Spinae Muscles in Patients with Chronic Obstructive Pulmonary Disease. Novel Chest Computed Tomography-derived Index for Prognosis.

RATIONALE: Loss of skeletal muscle mass and physical inactivity are important manifestations of chronic obstructive pulmonary disease (COPD), and both are closely related to poor prognoses in patients with COPD. Antigravity muscles are involved in maintaining normal posture and are prone to atrophy with inactivity. The erector spinae muscles (ESM) are one of the antigravity muscle groups, and they can be assessed by chest computed tomography (CT). OBJECTIVES: We hypothesized that the cross-sectional area of ESM (ESMCSA) visualized on chest CT images may serve as a predictor of mortality in patients with COPD. METHODS: This study was part of the prospective observational study undertaken at Kyoto University Hospital. ESMCSA was measured on a single-slice axial CT image at the level of the 12th thoracic vertebra in patients with COPD. The cross-sectional area of the pectoralis muscles (PMCSA) was also measured. We evaluated the relationship between ESMCSA and clinical parameters, including mortality, in patients with COPD. Age- and height-matched smoking control subjects were also evaluated. MEASUREMENTS AND MAIN RESULTS: In total, 130 male patients and 20 smoking control males were enrolled in this study. ESMCSA was significantly lower in patients with COPD than in the smoking control subjects and was significantly correlated with disease severity. There was a significant but only moderate correlation between ESMCSA and PMCSA. ESMCSA was significantly correlated with previously reported prognostic factors, such as body mass index, dyspnea (modified Medical Research Council dyspnea scale score), FEV1 percent predicted value, inspiratory capacity to total lung capacity ratio, and emphysema severity (percentage of the lung field occupied by low attenuation area). Compared with PMCSA, ESMCSA was more strongly associated with mortality in patients with COPD. Stepwise multivariate Cox proportional hazards analysis revealed that, among these known prognostic factors, ESMCSA was the strongest risk factor for mortality (hazard ratio, 0.85; 95% confidence interval, 0.79-0.92; P < 0.001) and mMRC dyspnea scale score was an additional factor (hazard ratio, 2.35; 95% confidence interval, 1.51-3.65; P < 0.001). CONCLUSIONS: ESMCSA assessed by chest CT may be a valuable clinical parameter, as ESACSA correlates significantly with physiological parameters, symptoms, and disease prognosis.

Emphysema and airway disease affect within-breath changes in respiratory resistance in COPD patients.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by a mixture of emphysema and airway disease. The forced oscillation technique (FOT) has been applied to COPD patients to clarify changes in respiratory mechanics; dynamic changes in respiratory resistance (Rrs) during breathing (within-breath changes in Rrs, ΔRrs) are characteristic of COPD. However, the pathophysiological significance of these changes is unknown. The aim of this study was to assess how emphysema and airway disease influence ΔRrs in COPD patients. METHODS: In this cross-sectional study, stable COPD patients were recruited and underwent respiratory impedance measurements with a commercially available FOT device. Rrs was recorded during tidal breathing and then analyzed as whole-breath Rrs (Rrs at 5 Hz, R5; Rrs at 20 Hz, R20; and their difference, R5-R20) or as ΔRrs, the difference between the expiratory and inspiratory Rrs (ΔR5, ΔR20 and ΔR5-R20). The percentage of the low attenuation area (LAA%) and airway wall area (WA%) was quantified by computed tomography analysis, and their contributions to ΔRrs were examined. RESULTS: Seventy-five COPD patients were recruited. LAA% was negatively correlated with ΔR5 and ΔR5-R20 (P = 0.0002 and P = 0.0033, respectively); meanwhile, WA% in B(10) was positively correlated with ΔR5 and ΔR5-R20 (P = 0.0057 and P < 0.0001, respectively). Multivariate analysis revealed that the contribution of both LAA% and WA% in B(10) to ΔRrs was independent of the severity of airflow limitations. CONCLUSION: This study shows that emphysema suppresses ΔRrs in COPD patients, while airway disease increases ΔRrs in these patients.

Peri-diaphragmatic lung volume assessed by computed tomography correlates with quality of life in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Health-related quality of life (HRQoL) is important in the management of chronic obstructive pulmonary disease (COPD). In patients with emphysema, lung hyperinflation identified radiologically as shortening and flattening of the diaphragm is associated with impaired HRQoL. It remains unclear whether shortening of the diaphragm and/or alteration in chest wall shape are associated with reduced pulmonary function and HRQoL. METHODS: Pulmonary function testing and chest computed tomography (CT) were performed, and the St. George's Respiratory Questionnaire (SGRQ) was administered to 123 patients with COPD. Using CT images, the ratio of volume of lung region adjacent to the diaphragm dome to total lung volume (DLV%) was evaluated as a novel CT index, and conventional indices, including percent low attenuation volume (LAV%), wall area percent (WA%), total lung volume and diaphragm length (Ldi) were calculated. RESULTS: DLV% was significantly correlated with Ldi. DLV% and Ldi were inversely correlated with lung hyperinflation, assessed as the ratio of residual volume to total lung capacity, independent of LAV% and WA%. Unlike Ldi, DLV% was inversely associated with all components and total scores for the SGRQ, independent of the severity of emphysema and airflow limitation. CONCLUSIONS: Reduced lung volume around the diaphragm correlated with lung hyperinflation and HRQoL, independent of emphysema severity. This needs to be verified in additional studies.

[A case of Paragonimus westermani with elevated FDG uptake into a pulmonary nodular lesion and right hilar and mediastinal lymph nodes on FDG-positron-emission tomography].

A 47-year-old Chinese woman living in Japan was referred with a 2-month history of cough with hemoptysis. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed increased FDG uptake into a pulmonary nodular lesion 25 mm in greatest dimension in the right upper lobe, and right hilar and mediastinal lymph nodes. Laboratory investigation did not reveal either eosinophilia or a marked elevation of serum IgE titer. A culture of bronchial lavage fluid was sterile and culture for mycobacteria was negative. Cytological examination results of transbronchial brushing samples were Class III. A partial resection of the right upper lobe was performed because of the possibility of primary lung cancer. Pathological examination of the nodular lesion showed helminthic eggs surrounded by dense inflammatory infiltrates, which mainly consisted of lymphocytes and eosinophils. Based on the findings of a serological study for helminth, the morphological characteristics of the eggs and the patient's history of eating raw crab, the patient was given a diagnosis of Paragonimus westermani, which can mimic primary lung cancer.

[Interstitial pneumonitis caused by seasonal influenza vaccine].

A 74-year-old man who received seasonal influenza vaccination at a clinic developed fever and cough the following morning. He was referred to our hospital on the 5th day after vaccination because of bilateral pulmonary infiltration shadows on a chest X-ray film. Despite the administration of sulbactam/ampicillin and roxithromycin after admission, his symptoms did not improve. His bronchoalveolar lavage fluid (BALF) obtained by bronchoscopy on the 8th hospital day revealed a CD4/CD8 ratio of 6.8, 109 x 10(4)/ml, and 39% and 16% increases in lymphocyte fractions and eosinophil levels, respectively. Transbronchial lung biopsy showed organizing pneumonia. A drug-induced lymphocyte stimulation test (DLST) for seasonal influenza vaccine with BALF showed 210% of seasonal influenza (S.I). These results indicate that this vaccine caused pneumonitis with a hypersensitive reaction, according to drug-induced lung injury criteria.

[Therapeutic effect of omalizumab on 10 patients with severe persistent asthma].

BACKGROUND: Therapeutic effect of omalizumab was studied in Japanese patients with severe asthma. METHODS: Omalizumab was administered to 10 patients with bronchial asthma diagnosed as severe or very severe persistent asthma according to Asthma Prevention Management Guideline 2009, Japan (JGL 2009). Therapeutic efficacy was assessed 16 weeks after starting the treatment using Asthma Control Test (ACT), pulmonary function tests, and the peripheral eosinophil counts. In addition, number of acute exacerbation in 16-week period after starting the treatment was compared with that in 16-week period before the treatment and the previous year respectively. The questionnaire whether or not to continue omalizumab was conducted 16 weeks after starting the treatment. RESULTS: The total ACT score rose from 14.8 to 19.1 and peripheral eosinophil count decreased from 355.2 /microl to 209.8 /microl after starting the treatment. Peak expiratory flow and forced expiratory volume in one second also increased, though differences were insignificant. Number of acute exacerbation decreased from 3.0 times before the treatment and 2.4 times the same time last year to 1.3 times after starting the treatment. The result of the questionnaire revealed that patients wanted to discontinue because of financial burden, ambulant burden, and side effect, but no one responded to be ineffective. In fact, only the one discontinued omalizumab. CONCLUSION: Omalizumab produced improvement in subject symptoms and reduced acute exacerbation in patients with severe or very severe persistent asthma. The future challenge is to reduce financial and ambulant burden on patients.