Prognostic value of forced expiratory volume in 1 second/forced vital capacity in idiopathic pulmonary fibrosis.

Emphysema on high-resolution computed tomography of the chest is the recent focus in the general practice in idiopathic pulmonary fibrosis (IPF). However, adequate attention has not been paid to obstructive disorder. Therefore, we retrospectively evaluated the association between the degree of airway obstruction and longevity in IPF subjects, with a hypothesis that lower forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) has an impact on prognosis. One hundred and fourteen consecutive IPF subjects who had been diagnosed with IPF and had undergone evaluation including pulmonary function test from January 2008 to May 2013 were included in the study. The relationship between baseline data and survival was examined. FEV1/FVC was widely distributed, ranging from 48.6% to 100%. On both univariate and multivariate Cox's regression analyses, lower FEV1/FVC was significantly associated with better survival (hazard ratio of 1.07 and 1.04 and 95% confidential interval of 1.03-1.10 and 1.01-1.08, respectively). Even on analysis with backward selection, FEV1/FVC remained a significant prognostic factor. FEV1/FVC is widely distributed and negatively predicts survival in IPF. A FEV1/FVC should be assessed in "real-world" general practice. Also, the effect of smoking on the clinical course of IPF should be investigated further.

Exertional dyspnoea and cortical oxygenation in patients with COPD.

This study was designed to investigate the association of perceived dyspnoea intensity with cortical oxygenation and cortical activation during exercise in patients with chronic obstructive pulmonary disease (COPD) and exertional hypoxaemia.Low-intensity exercise was performed at a constant work rate by patients with COPD and exertional hypoxaemia (n=11) or no hypoxaemia (n=16), and in control participants (n=11). Cortical oxyhaemoglobin (oxy-Hb) and deoxyhaemoglobin (deoxy-Hb) concentrations were measured by multichannel near-infrared spectroscopy. Increased deoxy-Hb is assumed to reflect impaired oxygenation, whereas decreased deoxy-Hb signifies cortical activation.Exercise decreased cortical deoxy-Hb in control and nonhypoxaemic patients. Deoxy-Hb was increased in hypoxaemic patients and oxygen supplementation improved cortical oxygenation. Decreased deoxy-Hb in the pre-motor cortex (PMA) was significantly correlated with exertional dyspnoea in control participants and patients with COPD without hypoxaemia. In contrast, increased cortical deoxy-Hb concentration was correlated with dyspnoea in patients with COPD and hypoxaemia. With the administration of oxygen supplementation, exertional dyspnoea was correlated with decreased deoxy-Hb in the PMA of COPD patients with hypoxaemia.During exercise, cortical oxygenation was impaired in patients with COPD and hypoxaemia compared with control and nonhypoxaemic patients; this difference was ameliorated with oxygen supplementation. Exertional dyspnoea was related to activation of the pre-motor cortex in COPD patients.

Significance of Self-Injectable Biologics in Japanese Patients with Severe Allergic Diseases: Focusing on Pen-Type Devices and Copayment.

Patients and Methods: A questionnaire survey was administered to 18, 14, and 3 patients introduced to home self-injection of dupilumab or mepolizumab using a pen-type device for atopic dermatitis, asthma alone, and asthma plus chronic rhinosinusitis with nasal polyps, respectively. Results: All but one participant wished to continue self-injection. Most participants affirmed the reduction in copayment (88.6%) and saving time and labor for hospital visits (88.6%). Six patients who received dupilumab complained of side effects, but all, except for one, continued the treatment. Of the 13 patients who had previously used a syringe-type device, 10 preferred the pen type because of its ease of use, while 3 (23%) preferred the syringe type because of the self-adjustable injection speed for pain control. Conclusion: Administration of biologics using pen-type devices is easier, and the introduction of home self-injection leads to a reduction in outpatient visits and copayment.

Activation of the prefrontal cortex is associated with exertional dyspnea in chronic obstructive pulmonary disease.

BACKGROUND: Exertional dyspnea is the primary symptom that limits exercise in patients with chronic obstructive pulmonary disease (COPD). It is unknown which activated brain area is associated with this symptom in COPD patients. OBJECTIVES: To investigate the activation of cortical areas associated with dyspnea during exercise in COPD patients. METHODS: COPD patients (n = 10) and age-matched controls (n = 10) performed mild-intensity constant work rate cycle exercise (40% of their symptom-limited peak work rates) for 10 min, while cerebral hemodynamics and oxygenation were measured by near-infrared spectroscopy (NIRS). Ventilatory responses (breathing pattern and pulmonary gas exchange) and Borg scale ratings of dyspnea and leg fatigue were measured during exercise. Three NIRS probes were placed over the prefrontal and temporoparietal cortical regions of the subjects' heads. Changes in cortical oxyhemoglobin (oxy-Hb), deoxyhemoglobin (deoxy-Hb), and total hemoglobin (total Hb) concentrations from baseline recordings were measured. Increased oxy-Hb (oxygenation) was assumed to reflect cortical activation. RESULTS: Oxy-Hb concentration was significantly increased in the prefrontal region during exercise in both groups but not in the temporoparietal regions. The change in prefrontal oxy-Hb concentration of COPD patients was not different from that of controls. Dyspnea scores were positively correlated with changes in oxy-Hb concentrations of the prefrontal regions in both groups. Multivariate analysis showed that oxy-Hb concentration in the prefrontal region was the best predictor of dyspnea in both groups. CONCLUSIONS: Exertional dyspnea was related to activation (oxygenation) of the prefrontal cortex in COPD patients and control subjects.

The regulation of amiloride-sensitive epithelial sodium channels by tumor necrosis factor-alpha in injured lungs and alveolar type II cells.

Alveolar liquid clearance, which mainly depends on sodium transport in alveolar epithelial cells, is an important mechanism by which excess water in the alveoli is reabsorbed during the resolution of pulmonary edema. In this study, we examined the regulation of epithelial sodium channel (ENaC), the main contributor to sodium transport, during acute lung injury and the direct impact of tumor necrosis factor-alpha (TNF-alpha), one of the important cytokines in acute lung injury, on the ENaC regulation. During the development of pulmonary edema, the increases in the number of neutrophils and the levels of TNF-alpha in blood and bronchoalveolar lavage were seen. In parallel, the mRNA expression of the alpha-, beta- and gamma-ENaC subunits in the whole lung tissue was inhibited to 72.0, 47.8 and 53.9%, respectively. The direct exposure of rat alveolar type II cells to TNF-alpha inhibited the mRNA expression of alpha- and gamma-ENaC to 64.0 and 78.0%, but not that of the beta-ENaC. TNF-alpha also inhibited the ENaC function as indicated by the reduction of amiloride-sensitive current (control 4.4, TNF-alpha 1.9 microA/cm(2)). These data suggest that TNF-alpha may affect the pathophysiology of acute lung injury and pulmonary edema through the inhibition of alveolar liquid clearance and sodium transport.

The strategy for predicting future exacerbation of asthma using a combination of the Asthma Control Test and lung function test.

BACKGROUND: Various factors have been reported to be useful for predicting future exacerbations. OBJECTIVE: This study was intended to determine a usefulness of a combination of a patient-based questionnaire, such as the Asthma Control Test (ACT) score with objective assessments, such as forced expiratory volume in 1 second (FEV(1)) and/or exhaled nitric oxide (FE(NO)), for predicting future exacerbations in adult asthmatics. METHODS: We therefore enrolled 78 subjects with mild to moderate asthma, who were clinically stable for 3 months who all had been regularly receiving inhaled steroid treatment. All subjects underwent a routine assessment of asthma control including the ACT score, spirometry, and FE(NO), and then were followed up until a severe exacerbation occurred. The predictors of an increased risk of severe exacerbation were identified and validated using decision trees based on a classification and regression tree (CART) analysis. The properties of the developed models were the evaluated with the area under the ROC curve (AUC) (95% confidence interval [CI]). RESULTS: The CART analysis automatically selected the variables and cut-off points, the ACT score

Validation of symptom-based COPD questionnaires in Japanese subjects.

BACKGROUND AND OBJECTIVE: Symptom-based questionnaires may be helpful in diagnosing patients with COPD. The aim of this study was to determine whether two COPD questionnaires designed in Western countries were applicable to Japanese and other Asian patients. METHODS: The participants were Japanese people aged 40 years and over. Each subject answered questions on demographics and symptoms and underwent spirometry before and after administration of a bronchodilator. Questionnaire A was designed to identify previously undiagnosed COPD and questionnaire B was designed to differentiate between COPD and asthma. RESULTS: The numbers of COPD patients who answered questionnaires A and B were 33 of 169 (19.5%) and 112 of 168 (66.7%), respectively. Comparison of the COPD group with the non-COPD group revealed a significant difference in total score in both questionnaire A and questionnaire B (both P < 0.001). The area under the receiver operating characteristic curve (AUC-ROC) for questionnaire A was 0.791. With a cut-off value of 16.5 points, the sensitivity and specificity were 0.939 and 0.404, and with a 19.5-point cut-off, sensitivity and specificity were 0.848 and 0.647, respectively. The AUC-ROC for questionnaire B was 0.765. With cut-off values of 18.5 and 24.5 points, the respective sensitivities and specificities were 0.946 and 0.393, and 0.741 and 0.607. CONCLUSIONS: A simple self-administered questionnaire can help to diagnose COPD in Japanese subjects. When these questionnaires are used in Japan, cut-off values should be set somewhat higher than in Western countries.

Poor sensitivity of symptoms in early detection of COPD.

The prevalence of chronic obstructive pulmonary disease (COPD) has been increasing. However, COPD is often underdiagnosed. The objective of this study was to determine how many outpatients had persistent airflow limitation and could be diagnosed as COPD by post-bronchodilator spirometry. We also evaluated whether the newly diagnosed patients had any symptoms. All outpatients with liver or general diseases over 40 years old who regularly visited to our hospital were tested for pulmonary function by spirometry. Patients with airflow limitation by the first screening spirometry had further examinations including post-bronchodilator spirometry and chest radiograph by pulmonary specialists. A total of 288 patients accepted a first spirometry. The most common chronic diseases of these patients were chronic hepatitis (33.7%), fatty liver (26.4%), liver cirrhosis (8.3%), diabetes (3.5%) and hypertension (3.1%). Approximately half of the patients had a smoking history. 44 of 288 patients (15.3%) showed airflow limitation by pre-bronchodilator spirometry. Of these, 8 patients did not show airflow limitation by a repeat pre-bronchodilator spirometry nor did 5 patients by post-bronchodilator spirometry. The rest were diagnosed as COPD (80.6%), asthma (16.1%) and bronchiectasis (3.2%). The prevalence of COPD was 8.7%. Approximately half of the patients (13/25, 52.0%) diagnosed as COPD had never complained of any respiratory symptoms. Because symptoms such as dyspnea on exertion, cough and sputum are less sensitive for the diagnosis of COPD, the propagation of spirometry in a general practice/setting should be recommended for establishing the diagnosis rate of COPD rather than relying on the presence of respiratory symptoms.

Overexpression of CD-11b and CXCR1 on circulating neutrophils: its possible role in COPD.

BACKGROUND: It has been shown that the beta2-integrin molecule is up-regulated in circulating neutrophils in COPD subjects. However, little has been reported about the expression of the cell surface molecules in such patients and their relationship with pulmonary function. The aim of the present study was to investigate the surface expression of molecules in circulating neutrophils and to clarify their possible role in the airflow limitation of COPD. METHODS: The surface expression of Mac-1 cells (ie, CD-11b and CD-18 cells) and CXC chemokine receptor (CXCR) 1 and CXCR2 of circulating neutrophils obtained from COPD patients and healthy subjects (HSs) was measured by flow cytometry analysis. The serum levels of interleukin (IL)-8 were measured by enzyme-linked immunosorbent assay. RESULTS: Both CD-11b and CXCR1 expression were significantly higher in COPD patients than in HSs (mean [+/- SE] CD-11b concentration: HSs, 9.7 +/- 1.0; COPD patients, 14.2 +/- 1.8 [p < 0.05]; mean CXCR1 concentration: HSs, 9.6 +/- 0.5; COPD patients, 11.9 +/- 0.4 [p < 0.01]). Although aging was positively correlated with the expression of CXCR1 (r = 0.440; p < 0.01), none of the other background factors, including smoking and body mass index, showed a correlation with the expression of the molecules. Although serum IL-8 levels were higher in patients with COPD than in HSs, no significant correlation between serum IL-8 levels and the expression of any molecule was seen. The expression of CD-11b (r = -0.317) and CXCR1 (r = -0.383) showed a significant negative correlation with the severity of airflow limitation (both p < 0.05). CONCLUSIONS: The overexpression of CD-11b and CXCR1 in circulating neutrophils may be associated with the development of airflow limitation in COPD patients.

Factors associated with the effect of pulmonary rehabilitation on physical activity in patients with chronic obstructive pulmonary disease.

AIM: Although the effects of pulmonary rehabilitation (PR) have been well defined for chronic obstructive pulmonary disease (COPD), it remains controversial whether PR improves physical activity (PA). The purpose of the present study was to identify factors associated with the effect of PR on PA. METHODS: This was a prospective study of 29 patients with COPD. They underwent pulmonary rehabilitation twice weekly for 12 weeks, and were assessed using the hospital anxiety and depression score, 6-min walk distance (6MWD), and the St. George Respiratory Questionnaire (SGRQ) before and after they underwent PR. The PA of patients was measured by a three-axis accelerometer. Physical activity level (PAL) was calculated by dividing each patient's total energy expenditure by basal metabolic rate. Correlations between changes in PAL after PR and 6MWD, St. George Respiratory Questionnaire, and hospital anxiety and depression score scores, and clinical parameters, including forced expiratory volume in 1 s were determined. RESULTS: 6MWD was significantly increased, but PAL was unchanged after PR. PAL was positively correlated with 6MWD, but not with percent predicted forced expiratory volume in 1 s nor St. George Respiratory Questionnaire scores before PR. The increase in PAL was negatively correlated with changes in hospital anxiety and depression score anxiety and depression scores, but was not correlated with the change in 6MWD. CONCLUSIONS: A PR program for COPD patients improved results of the 6MWD, but not PAL. Increased PAL was associated with improvements in anxiety and depression, but not with increased exercise capacity. Treating the depression and anxiety of patients with COPD might not only reduce emotional distress, but also improve their PAL. Geriatr Gerontol Int 2017; 17: 17-23.

Agents against cytokine synthesis or receptors.

Various cytokines play a critical role in pathophysiology of chronic inflammatory lung diseases including asthma and chronic obstructive pulmonary disease (COPD). The increasing evidence of the involvement of these cytokines in the development of airway inflammation raises the possibility that these cytokines may become the novel promising therapeutic targets. Studies concerning the inhibition of interleukin (IL)-4 have been discontinued despite promising early results in asthma. Although blocking antibody against IL-5 markedly reduces the infiltration of eosinophils in peripheral blood and airway, it does not seem to be effective in symptomatic asthma, while blocking IL-13 might be more effective. On the contrary, anti-inflammatory cytokines themselves such as IL-10, IL-12, IL-18, IL-23 and interferon-gamma may have a therapeutic potential. Inhibition of TNF-alpha may also be useful in severe asthma or COPD. Many chemokines are also involved in the inflammatory response of asthma and COPD through the recruitment of inflammatory cells. Several small molecule inhibitors of chemokine receptors are now in development for the treatment of asthma and COPD. Antibodies that block IL-8 reduce neutrophilic inflammation. Chemokine CC3 receptor antagonists, which block eosinophil chemotaxis, are now in clinical development for asthma therapy. As many cytokines are involved in the pathophysiology of inflammatory lung diseases, inhibitory agents of the synthesis of multiple cytokines may be more useful tools. Several such agents are now in clinical development.

Influence of comorbidities on the efficacy of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease.

AIM: To evaluate the influence of comorbidities and aging on pulmonary rehabilitation (PR) efficacy in patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a retrospective cohort study of patients with COPD attending an outpatient PR program. Comorbidity information was collected with the Charlson Index, BODE index and COPD-specific comorbidity test, and also included other common conditions not included in these indexes. The efficacy of PR was defined as a 54-m increase in 6-min walk distance or a four-point decrease in St. George's Respiratory Questionnaire score. Patients were divided into two age groups according to the median age of 72 years. RESULTS: A total of 21 of 52 patients (40%) showed a clinically significant benefit by the 6-min walk distance, and 29 patients (55.8%) by the St. George's Respiratory Questionnaire score. PR efficacy was not different between the elderly group and the younger group by either parameter. A total of 98% of the patients had at least one chronic comorbidity. Hypertension was the most frequently reported comorbidity (28.5%). Higher body mass index, Hospital Anxiety and Depression Scale anxiety score and St. George's Respiratory Questionnaire total score were associated with a good response to PR by the 6-min walk distance. None of the individual comorbidities or indexes were correlated with the efficacy of PR. Multiple logistic regression analysis showed that body mass index was independently associated with the response to PR. CONCLUSIONS: PR is equally effective in elderly and younger patients with COPD, with efficacy influenced by body mass index and anxiety. Geriatr Gerontol Int 2016; 16: 934-941.

Effect of a postoperative outpatient pulmonary rehabilitation program on physical activity in patients who underwent pulmonary resection for lung cancer.

AIM: Physical activity (PA) has been associated with an improvement in survival for individuals with cancer. However, little is known about the effect of postoperative pulmonary rehabilitation on PA after lobectomy in patients with lung cancer. The present study investigated the effect of outpatient rehabilitation on PA in patients with cancer after lung resection. METHODS: A total of 19 patients with lung cancer were recruited for this study and completed a preoperative rehabilitation program. One group of nine patients completed a postoperative outpatient pulmonary rehabilitation program (rehabilitation) and another group of 10 patients did not (control), but were similarly followed up. Preoperative lung function, assessed by forced expiratory volume in 1 s (FEV1 ), body mass index (BMI) and St. George's Respiratory Questionnaire (SGRQ) score were not different between groups. PA was measured before and 2 months after surgery using a three-axis accelerometer for 5-6 days. PA level (PAL) was defined as total energy expenditure divided by basal metabolic rate. RESULTS: Preoperative PAL was not different between groups. However, postoperative versus preoperative PAL was significantly lower in the control versus the rehabilitation group (P < 0.01), and PAL decline was less for the rehabilitation versus the control group (P < 0.001). A subgroup analysis showed improvement in postoperative PAL in rehabilitation patients aged <75 years and older. CONCLUSIONS: Two months after lung resection surgery, patients had not recovered to the preoperative PAL. However, compared with the control group, there was an improvement in the postoperative PAL in patients, including older patients, who underwent outpatient pulmonary rehabilitation. Geriatr Gerontol Int 2016; 16: 550-555.

A case of primary lung cancer producing alpha-fetoprotein.

A case of lung carcinoid showing elevated plasma alpha-fetoprotein (AFP) level is reported. A 44-year-old man who complained of the development of bloody sputum had a left hilar lung mass on chest radiograph. The serum level of AFP was markedly increased to 8438 ng/mL. After resection, it was diagnosed as an atypical carcinoid, and the tumour cells were positive for cytoplasmic AFP. AFP is one of the most useful tumour markers for the diagnosis of hepatic cell carcinoma or germ cell tumours. It has also been reported that some primary lung tumours produce AFP. However, these tumours are mainly poorly differentiated adenocarcinomas or large cell carcinomas. A lung carcinoid that produces AFP is extremely rare.

[A case of pulmonary actinomycosis with recurrent hemoptysis].

A 68-year-old man was admitted to our hospital because of hemoptysis in September 1999. Chest CT scans showed a nodular shadow with infiltration in the right S 7. Bronchial arteriography showed vascularization in the right S 7, and bronchial artery embolization was performed. However, in April and October 2000 hemoptysis recurred, and bronchial arteriography showed recurrence of vascularization in the same area, so embolization was performed again. Then, the patient was admitted in March 2001 because of recurrent hemoptysis. CT scans showed growth of the nodular shadow. Right lower lobectomy was performed, and the microscopic findings in the tissue from the resected lobe showed branching filamentous bacteria, and pulmonary actinomycosis was diagnosed. We concluded that pulmonary actinomycosis should be considered in the differential diagnosis of nodular shadows with recurrent hemoptysis.

Effect of ambulatory oxygen on exertional dyspnea in IPF patients without resting hypoxemia.

BACKGROUND AND OBJECTIVE: The effects of ambulatory oxygen for idiopathic pulmonary fibrosis (IPF) patients without resting hypoxemia have not been elucidated. The purpose of this study was to assess the effect of ambulatory oxygen on dyspnea in IPF patients without resting hypoxemia but with desaturation on exertion. METHODS: This was a double-blind, placebo-controlled, randomized crossover trial of ambulatory oxygen versus ambulatory air. Patients with IPF who had a partial pressure of arterial oxygen (PaO2) between 60 mm Hg and 80 mm Hg at rest, and desaturation of 88% or less in a room-air 6-min walk test were eligible. Patients underwent a standardized 6-min walk test and a 6-min free walk test under each ambulatory gas. Oxygen and air were provided at 4 L/min intranasally. Dyspnea was evaluated immediately, 1, and 2 min after the tests. RESULTS: Twenty patients (16 men), with a mean age of 73.5 (SD 4.1) years, % predicted forced vital capacity (FVC) of 71.0 (13.3) %, % predicted diffusion capacity for carbon monoxide (DLco) of 57.0 (13.3) %, and PaO2 of 72.5 (5.4) mm Hg were recruited. No significant differences in dyspnea were observed between ambulatory oxygen and air at each time point. However, some patients showed improvement in dyspnea with oxygen on an individual basis. CONCLUSIONS: Since oxygen provides no additional benefit over air in terms of exertional dyspnea for IPF patients without resting hypoxemia, routine prescription of ambulatory oxygen is not recommended. However, assessment on an individual basis is necessary. Trial registration. UMIN Clinical Trial Registry; No.:UMIN000005098; URL:http://www.umin.ac.jp/ctr/.

Clinical and inflammatory factors associated with body mass index in elderly patients with chronic obstructive pulmonary disease.

AIM: Body mass index (BMI) is closely associated with mortality in chronic obstructive pulmonary disease (COPD). Systemic inflammation has been suggested as one of the mechanisms of malnutrition in COPD. This study investigated the relationships of clinical variables and inflammatory biomarkers with BMI in COPD in an aging population. METHODS: Baseline levels of serum biomarkers were determined for 69 patients with stable male COPD. Multivariate logistic regression was used to evaluate associations between clinical variables, including emphysema scores, and biomarkers with BMI. RESULTS: Twenty eight patients were categorized as low BMI (<20 kg/m2). BMI was inversely correlated with serum α1-antitrypsin (α1-AT) concentration and emphysema scores, and was positively correlated with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). Multivariate logistic regression analysis showed that α1-AT was independently associated with BMI. CONCLUSION: Low BMI was associated with the severity of emphysema and systemic inflammation reflected by elevated α1-AT level.

The possible role of hematopoietic cell kinase in the pathophysiology of COPD.

BACKGROUND: Hematopoietic cell kinase (Hck) is a myeloid cell-specific tyrosine kinase, which is known to induce neutrophil infiltration to the lungs. Although the overexpression of Hck causes emphysema-like histologic changes in mice, its expression and activity in patients with COPD are unclear. METHOD: The aim of this study was to clarify the expression and activity of Hck in neutrophils from COPD patients, and to investigate the association between the degree of Hck expression and the lung function parameters in COPD patients. Peripheral blood neutrophils were isolated from 22 patients with COPD and 9 healthy subjects (HSs). The protein levels of Hck and phosphorylated Hck were assessed, and the correlation with various background characteristics was evaluated. RESULTS: The Hck protein level was significantly higher in neutrophils from COPD patients compared with HSs (COPD patients, 1.094; HSs, 0.801; p < 0.05). A significant positive correlation was observed between the protein level of Hck and the surface expression of the integrin molecule CD-11b (r = 0.540; p < 0.01) or CXC chemokine receptor-1 (r = 0.432; p < 0.05). In contrast, there was no difference in the phosphorylation of the Hck protein between COPD patients and HSs. CONCLUSION: The Hck protein level in peripheral blood neutrophils was increased in COPD patients, suggesting that Hck might have an important role in the neutrophil function and play a key role in the pathophysiology of COPD.