Home High-Flow Nasal Cannula Oxygen Therapy for Stable Hypercapnic COPD: A Randomized Clinical Trial.

Rationale: The long-term effects of using a high-flow nasal cannula for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease remain unclear. Objectives: To assess whether long-term high-flow nasal cannula use reduces the number of exacerbations and improves other physiological parameters in patients with chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease. Methods: We enrolled 104 participants (aged ⩾40 yr) with daytime hypercapnia (Global Initiative for Chronic Obstructive Lung Disease stages 2-4) receiving long-term oxygen therapy (⩾16 h/d for ⩾1 mo) and randomly assigned them to high-flow nasal cannula/long-term oxygen therapy and long-term oxygen therapy groups. The primary endpoint was the moderate or severe exacerbation rate. We compared changes from baseline in arterial blood gas values, peripheral oxygen saturation, pulmonary function, health-related quality-of-life scores, and the 6-minute-walk test. Measurements and Main Results: High-flow nasal cannula use significantly reduced the rate of moderate/severe exacerbations (unadjusted mean count 1.0 vs. 2.5, a ratio of the adjusted mean count between groups [95% confidence interval] of 2.85 [1.48-5.47]) and prolonged the duration without moderate or severe exacerbations. The median time to first moderate or severe exacerbation in the long-term oxygen therapy group was 25 (14.1-47.4) weeks; this was not reached in the high-flow nasal cannula/long-term oxygen therapy group. High-flow nasal cannula use significantly improved health-related quality of life scores, peripheral oxygen saturation, and specific pulmonary function parameters. No safety concerns were identified. Conclusions: A high-flow nasal cannula is a reasonable therapeutic option for patients with stable hypercapnic chronic obstructive pulmonary disease and a history of exacerbations. Clinical trial registered with www.umin/ac.jp (UMIN000028581) and www.clinicaltrials.gov (NCT03282019).

Cicatricial organising pneumonia associated with fibrosing interstitial pneumonia - a clinicopathological study.

AIMS: The recent recognition of cicatricial organising pneumonia (ciOP) indicates that the ciOP may resemble or simulate fibrotic interstitial pneumonia; however, there has been great uncertainty regarding the affected populations, pathogenesis, clinical relevance and characteristics. In this study, we compared the characteristics of fibrotic interstitial pneumonia with and without ciOP. METHODS AND RESULTS: We enrolled 121 patients from the consultation archive whose pathological findings were fibrotic interstitial pneumonia and for whom follow-up clinical data were available. We reviewed these cases histopathologically and classified them according to whether or not they showed ciOP. We compared the clinicopathological features between the two groups. CiOP, histopathologically characterised by deposition of dense collagenous fibres within the alveolar space without destruction of the lung structure, was found in 48 patients (39.7%). None of the cases with ciOP experienced acute exacerbation during 12 months' follow-up. The group with ciOP had more severe diffusion impairment but this, together with restrictive ventilatory impairment, improved significantly compared to the group without ciOP. CONCLUSION: CiOP is a histopathological finding commonly found in fibrotic interstitial pneumonia. It does not relate to acute exacerbation or decrease in pulmonary function.

Chest computed tomography findings of adult patients with antimelanoma differentiation-associated protein 5 antibody-positive interstitial lung disease.

OBJECTIVES: Interstitial lung disease (ILD) associated with the antimelanoma differentiation-associated protein 5 (anti-MDA5) antibody is a rapidly progressive disease that requires timely, aggressive treatment. However, prompt diagnosis is difficult due to the longer time required for antibody detection. This study described the computed tomography (CT) findings of anti-MDA5 antibody-positive ILD (anti-MDA5-ILD). METHODS: CT findings of 20 patients (7 men, 13 women; mean age, 53.6 ± 13.5 years) with anti-MDA5-ILD were retrospectively reviewed. All patients had clinical diagnoses of dermatomyositis, and 14 patients presented with amyopathic findings. RESULTS: Bilateral ground-glass attenuation, air-space consolidation, and reticular shadows were observed in 20 (100%), 15 (75%), and 3 (15%) patients, respectively. The spread of air-space consolidation was 6.0 ± 5.6% (mean ± standard deviation). Univariate analysis revealed that high Krebs von den Lungen-6, high spread of consolidation, low partial pressure of oxygen, and low forced vital capacity were significant predictors for poor survival. The final radiological diagnoses were nonspecific interstitial pneumonia and organising pneumonia (OP) in 2 (10%) and 16 (80%) patients, respectively. Further, 30% of OP patients showed fibrosis. CONCLUSION: The characteristic CT findings of patients with anti-MDA5-ILD were ground-glass attenuation, air-space consolidation, and less reticulation. These CT findings were compatible with those of OP.

Effects of Oral Morphine on Dyspnea in Patients with Cancer: Response Rate, Predictive Factors, and Clinically Meaningful Change (CJLSG1101).

BACKGROUND: Although the efficacy of parenteral morphine for alleviating dyspnea has been previously demonstrated in several studies, little is known regarding the efficacy of oral morphine for dyspnea among patients with cancer, including its response rate and predictive factors of effectiveness. Therefore, the aim of this study was to clarify the effectiveness of oral morphine on dyspnea in patients with cancer and elucidate the predictive factors of its effectiveness. SUBJECTS, MATERIALS, AND METHODS: In this multicenter prospective observational study, we investigated the change in dyspnea intensity in patients with cancer before and after the administration of oral morphine by using a visual analog scale (VAS). We also administered a self-assessment questionnaire to determine whether the patients believed oral morphine was effective. RESULTS: Eighty patients were enrolled in the study, and 71 of these patients were eligible. The least square mean of the VAS scores for dyspnea intensity was 53.5 at baseline, which decreased significantly to 44.7, 40.8, and 35.0 at 30, 60, and 120 minutes after morphine administration, respectively. Fifty-four patients (76.1%) reported that oral morphine was effective on the self-assessment questionnaire. Among the background factors, a high score for "sense of discomfort" on the Cancer Dyspnea Scale (CDS) and a smoking history of fewer pack-years were associated with greater effectiveness. CONCLUSION: Oral morphine was effective and feasible for treating cancer-related dyspnea. A higher score for "sense of discomfort" on the CDS and a smaller cumulative amount of smoking may be predictive factors of the effectiveness of oral morphine. IMPLICATIONS FOR PRACTICE: This study demonstrated that oral morphine was effective in alleviating cancer-related dyspnea due to multiple factors including primary lung lesions, airway narrowing, and pleural effusion. Approximately 76% of patients reported that oral morphine was effective. A higher score for "sense of discomfort" on the Cancer Dyspnea Scale and a lower cumulative amount of smoking may be predictive factors for the effectiveness of oral morphine. Interestingly, respiratory rates in patients who reported the morphine to be effective decreased significantly after oral morphine administration, unlike the respiratory rates in "morphine-ineffective" patients.

How Many Passes Are Needed for Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Sarcoidosis? A Prospective Multicenter Study.

BACKGROUND: While endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is widely used as an initial diagnostic procedure for pathological confirmation of sarcoidosis, it is unclear how many passes are required to obtain diagnostic materials. OBJECTIVES: The aim of this study was to determine the number of needle passes needed for the diagnosis of stage I/II sarcoidosis using EBUS-TBNA. METHODS: At three institutions, 109 patients with suspected stage I/II sarcoidosis were recruited and underwent 6 passes of EBUS-TBNA for the main target lesion. Additional EBUS-TBNA for other lesions was permitted. The cumulative yields of needle passes for detecting noncaseating epithelioid cell granulomas were analyzed. RESULTS: A total of 109 patients underwent EBUS-TBNA for 184 lesions. EBUS-TBNA identified specimens containing granulomas in 81 of 92 patients (88%) with a final diagnosis of sarcoidosis. The cumulative yields through the first, second, third, fourth, fifth, and sixth passes for the main target lesion were 63, 75, 82, 85, 86 and 88%, respectively. In the 55 patients that underwent EBUS-TBNA for multiple lesions, the cumulative yields of 2 passes per lesion for 2 lesions (total of 4 passes) and of 4 passes for single lesions were 86 and 84%, respectively (p = 1.00). CONCLUSIONS: If rapid on-site cytological evaluation is not available, we recommend at least 4 passes per patient for either single or multiple lesions with EBUS-TBNA for pathological diagnosis of stage I/II sarcoidosis.

Problems of elderly patients on inhalation therapy: Difference in problem recognition between patients and medical professionals.

BACKGROUND: There is no systematic analysis to identify problems involved with instruction on inhalation therapy for elderly patients. We conducted a nationwide questionnaire survey for patients and medical professionals. METHODS: A questionnaire survey was conducted of adult patients on inhaled drugs (ages 18-92 years, 820 individuals) and medical professionals (pharmacists or nurses) who provided instruction on inhalation therapy to these patients in 23 institutions in Japan to investigate the technique and the level of understanding (knowledge) of the inhalation therapy. Changes in the recognition of performance of inhalation technique and inhalation knowledge with increasing age were analyzed. RESULTS: According to patients' subjective assessment, there was no deterioration in the performance of the inhalation technique or loss of the knowledge with increasing age. On the other hand, medical professionals' objective assessment revealed a significant loss of both inhalation technique and knowledge with increasing age. Not many elderly patients noticed their own problems themselves, revealing a great perception gap between elderly patients and medical professionals. Thus, there was concern that patients would unconsciously practice the inhalation procedure improperly. On the other hand, in comparison with non-elderly patients, elderly patients were less resistant to continuation of therapy, suggesting that they would be more likely to accept instruction on inhalation therapy. CONCLUSIONS: Elderly patients are apt to assume that they "understand well", therefore, in order to recognize and close the perception gap between elderly patients and medical professionals, it is necessary to provide them with more aggressive (frequent) instructions on inhalation therapy.

Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.

RATIONALE: Identification of patients with drug-resistant pathogens at initial diagnosis is essential for treatment of pneumonia. OBJECTIVES: To elucidate clinical features of community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP), and to clarify risk factors for drug-resistant pathogens in patients with CAP and HCAP. METHODS: A prospective observational study was conducted in hospitalized patients with pneumonia at 10 institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillin-sulbactam, macrolides, and respiratory fluoroquinolones were defined as CAP drug-resistant pathogens (CAP-DRPs). MEASUREMENTS AND MAIN RESULTS: In total, 1,413 patients (887 CAP and 526 HCAP) were analyzed. CAP-DRPs were more frequently found in patients with HCAP (26.6%) than in patients with CAP (8.6%). Independent risk factors for CAP-DRPs were almost identical in patients with CAP and HCAP. These included prior hospitalization (adjusted odds ratio [AOR], 2.06; 95% confidence interval [CI], 1.23-3.43), immunosuppression (AOR, 2.31; 95% CI, 1.05-5.11), previous antibiotic use (AOR, 2.45; 95% CI, 1.51-3.98), use of gastric acid-suppressive agents (AOR, 2.22; 95% CI, 1.39-3.57), tube feeding (AOR, 2.43; 95% CI, 1.18-5.00), and nonambulatory status (AOR, 2.45; 95% CI, 1.40-4.30) in the combined patients with CAP and HCAP. The area under the receiver operating characteristic curve for counting the number of risk factors was 0.79 (95% CI, 0.74-0.84). CONCLUSIONS: The clinical profile of HCAP was different from that of CAP. However, physicians can predict drug resistance in patients with either CAP or HCAP by taking account of the cumulative number of the risk factors. Clinical trial registered with https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000004001&language=E ; number UMIN000003306.

Role of sphingosine-1-phosphate inß-adrenoceptor desensitization via Ca(2+) sensitization in airway smooth muscle.

BACKGROUND: The correlation between inflammatory cells and airway smooth muscle plays fundamental roles in the pathophysiology of asthma. This study was designed to determine whether pre-exposure of airway smooth muscle to sphingosine-1-phosphate (S1P), which is released from mast cells by allergic reactions, causes a deterioration of ß-adrenoceptor function. METHODS: Isometric tension and the ratio of fluorescence intensities at 340 and 380 nm (F(340)/F(380)), an indicator of intracellular Ca2+ levels, were simultaneously measured using fura-2 loaded guinea-pig tracheal tissues. Intracellular cAMP levels were also measured. RESULTS: Pre-exposure to S1P caused a reduction in the inhibitory effects of 0.3µM isoprenaline, a ß-adrenoceptor agonist, and 10µM forskolin, a direct activator of adenylyl cyclase, against 1µM methacholine-induced contraction in concentration- and time- dependent manners. In contrast, the values of F(340)/F(380) were not augmented under this experimental condition. After incubation with S1P in the presence of 0.001-1µM Y-27632, a Rho-kinase inhibitor, the reduced responsiveness to forskolin induced by S1P was reversed in a concentration-dependent manner. Moreover, pre-treatment with pertussis toxin (PTX), an inhibitor of G(i), suppressed the loss of forskolin-induced relaxation induced by S1P. Pre-exposure to S1P markedly inhibited the augmentation of cAMP accumulation induced by forskolin. However, addition of Y-27632 and pre-exposure to PTX returned forsokin-induced cAMP accumulation to the control level. CONCLUSIONS: Pre-exposure to S1P causes heterologus desensitization of ß-adrenoceptors by increasing the sensitivity of airway smooth muscle to intracellular Ca2+. Ca2+ sensitization regulated by G(i) and Rho-kinase is involved in this phenomenon.

[A case of irinotecan or panitumumab-induced interstitial pneumonia successfully treated by steroid pulse therapy].

We report a case of a 58-year-old man suffering from advanced colon cancer with liver metastases. After the sigmoidectomy and left lateral segmentectomy, mFOLFOX6+bevacizumab was initiated. The mFOLFOX6+bevacizumab therapy was performed for 15 courses, but it was stopped because of an increase in serum levels of tumor markers(CEA and CA19-9). For the next treatment, FOLFIRI+panitumumab therapy was performed. At the beginning of the second course, he suffered from dyspnea. Computed tomography showed ground-glass opacities and traction bronchiectasis in both lung fields. He was diagnosed with interstitial pneumonitis induced by irinotecan or panitumumab. Corticosteroid therapy consisting of methyl- prednisolone(1 g/day)administered for three days was significantly effective for treating respiratory failure. Two courses of the therapy were performed, and he was discharged without aftereffects. As with other EGFR tyrosine kinase inhibitors, the frequency of interstitial pneumonitis induced by irinotecan in Japan may increase to European and American levels.

Protocol for long-term effect of pulmonary rehabilitation under nintedanib in idiopathic pulmonary fibrosis.

BACKGROUND: Pulmonary rehabilitation causes short-term improvement in exercise capacity, dyspnoea and health-related quality of life in idiopathic pulmonary fibrosis (IPF); however, long-term maintenance of the improvement is difficult. Nintedanib, an antifibrotic drug, has been shown to delay the worsening of pulmonary function in IPF. Therefore, the concomitant use of nintedanib with pulmonary rehabilitation is anticipated to contribute to the long-term maintenance of the pulmonary rehabilitation effects. The long-term effect of pulmonary rehabilitation under nintedanib treatment in IPF (FITNESS) study is a multicenter, randomised, prospective, parallel-group, open-label trial. METHODS: The study will enrol 84 patients with IPF who have been treated with nintedanib. Patients in the pulmonary rehabilitation group will receive a programmed short-term induction pulmonary rehabilitation programme, followed by a maintenance home-based pulmonary rehabilitation programme, while patients in the control group will receive usual outpatient care. Patients in both groups will continue to receive nintedanib treatment throughout the study period. The primary end-point of the study is to compare the change in the 6-min walk distance from the baseline to 12 months between the pulmonary rehabilitation and control groups. The main secondary end-point is endurance exercise time, measured using a bicycle ergometer. DISCUSSION: FITNESS is the first randomised controlled study to evaluate the long-term effects of pulmonary rehabilitation in IPF treated with nintedanib. This study will address the hypothesis that concomitant use of nintedanib contributes to the maintenance of long-term effects of pulmonary rehabilitation, thus leading to a comprehensive therapeutic approach of "nintedanib and pulmonary rehabilitation" in the antifibrotic era.

Pleuropulmonary pathology of vascular Ehlers-Danlos syndrome: spontaneous laceration, haematoma and fibrous nodules.

AIMS: The aim was to clarify the pleuropulmonary pathological findings of vascular Ehlers-Danlos syndrome (vEDS). METHODS AND RESULTS: Nine patients with confirmed vEDS by means of cell culture and/or molecular biological studies who had undergone surgical lung biopsy (SLB), lobectomy or autopsy were studied. Six patients were male and three were female with a mean age of 23.2 years. Histological features were as follows: (i) the main pulmonary lesions related to fragility and spontaneous laceration, these being haematomas in seven, acute haemorrhage in nine, fibrous nodule in eight, with ossification or bone marrow formation in six; vascular disruption in five; intraluminal haemosiderosis in nine; interstitial haemosiderosis in seven, with iron deposition in the alveolar wall and/or vessel wall in five and foreign body reaction in two; emphysematous changes in eight; and bleb formation in two; (ii) secondary iatrogenic pleuropulmonary injuries during SLB or lobectomy comprised pleural laceration in seven of 10 and lung laceration in eight of 10 specimens. CONCLUSIONS: Spontaneous laceration of lung tissue is an essential feature and is followed by haematoma and possible fibrous nodule formation.

[Disseminated nocardiosis presenting as retroperitoneal abscess: a case report].

A 64-year-old man presented to our emergency room with right back pain on July 10, 2009. At the emergency room, abdominal enhanced computed tomography revealed a cystic lesion in the retroperitoneum. Then he was referred to our department. We performed percutaneous drainage of the retroperitoneal lesion and aspirated white pus. The retroperitoneal cystic lesion proved to be an abscess. Microscopic examination of a Gram stained specimen of the abscess revealed gram-positive bacillary fragments ; therefore, we suspected the pathogen to be Nocardia. He had a history of chronic glomerulonephritis and had received treatment consisting of 20 mg prednisolone, and 75 mg cyclosporine per day. He was regularly visiting the department of cardiovascular for follow-up of chronic heart failure. On the day before his visit to our emergency room, his chest X-ray medicine had revealed a nodular shadow. Then he was referred to the department of respiratory medicine and was scheduled to receive a bronchoscopy later. We suspected the nodule of the lung also to be an abscess of Nocardia. Later, head computed tomography (CT) revealed a brain abscess the pathogen of which was Nocardia. Nocardia is a filamentous, gram-positive, branched bacterium and classified as an aerobic actinobacteria. Nocardia species are difficult to diagnose due to non-specific clinical and histological manifestation. We report this case of disseminated nocardiosis presenting as retroperitoneal abscess. The disseminated nocardiosis was diagnosed without delay by percutaneous drainage and appropriate treatment was provided.

Analysis of systemic lupus erythematosus-related interstitial pneumonia: a retrospective multicentre study.

Thoracic diseases in patients with systemic lupus erythematosus (SLE), especially interstitial pneumonia (SLE-IP), are rare and have been poorly studied. The aims of this multicentre study were to evaluate SLE-IP and elucidate its clinical characteristics and prognosis. Fifty-five patients with SLE-IP who had attended the respiratory departments of participating hospitals were retrospectively evaluated in this multicentre study. Clinical information, high-resolution computed tomography (HRCT), and surgical lung biopsy/autopsy specimens were analysed by respiratory physicians, pulmonary radiologists, and pulmonary pathologists. IP patterns on HRCT and lung specimens were classified based on the international classification statement/guideline for idiopathic interstitial pneumonias. The most frequent form of SLE-IP at diagnosis was chronic IP (63.6%), followed by subacute (20.0%), and acute IP (12.7%). Radiologically, the most common HRCT pattern was "Unclassifiable" (54%). Histologically, "Unclassifiable" was the most frequently found (41.7%) among 12 patients with histologically proven IP. Interestingly, accompanying airway diseases were present in nine of these patients (75%). In multivariate analysis, current smoking (hazard ratio [HR] 6.105, p = 0.027), thrombocytopenia (HR 7.676, p = 0.010), anti-double-strand DNA titre (HR 0.956, p = 0.027), and nonspecific interstitial pneumonia (NSIP) + organizing pneumonia (OP) pattern on HRCT (vs. NSIP, HR 0.089, p = 0.023) were significant prognostic factors. In conclusion, chronic IP was the most frequent form of IP in patients with SLE-IP, and "Unclassifiable" was the commonest pattern radiologically and histologically.

Role of Ca(2+) mobilization in desensitization of beta-adrenoceptors by platelet-derived growth factor in airway smooth muscle.

Platelet-derived growth factor (PDGF), which is released from eosinophils and fibroblasts, may be implicated in the pathophysiology of bronchial asthma. To examine the involvement of airway inflammation in beta-adrenergic desensitization, the present study was designed to determine whether pre-exposure to PDGF deteriorates beta-adrenoceptor function in airway smooth muscle. We focused on Ca(2+) signaling as an intracellular mechanism involved in this phenomenon. Isometric tension and F(340)/F(380) (an indicator of intracellular Ca(2+) concentration) induced by isoprenaline and other cAMP-related agents were simultaneously measured before and after exposure to PDGF in fura-2-loaded guinea-pig tracheal smooth muscle. Indomethacin was applied throughout the experiments to abolish prostaglandin synthesis by PDGF. After exposure of the tissues to 10 ng/ml PDGF for 15 min, the effects of isoprenaline, a beta-adrenoceptor agonist, and forskolin, a direct inhibitor of adenylyl cyclase, against methacholine-induced contraction were markedly reduced with increasing F(340)/F(380). However, in the presence of verapamil, an inhibitor of voltage-dependent Ca(2+) channels, the reduced responsiveness to isoprenaline and forskolin induced by pre-exposure to PDGF was reversed with reducing F(340)/F(380). Reduced responsiveness to isoprenaline by PDGF was also not observed in the presence of Ca(2+)-free solution. The inhibitory effects of db-cAMP, an analogue of cAMP, and theophylline, a nonselective inhibitor of phosphodiesterase, were not attenuated by PDGF. In conclusion, pre-exposure to PDGF causes impairment of the beta-adrenoceptors/adenylyl cyclase processes in airway smooth muscle that is independent of cyclooxygenase synthesis by PDGF. Ca(2+) mobilization by Ca(2+) influx through voltage-dependent Ca(2+) channels is involved in this heterologous desensitization of beta-adrenoceptors.

The clinical practice of high-flow nasal cannula oxygen therapy in adults: A Japanese cross-sectional multicenter survey.

BACKGROUND: High-flow nasal cannula oxygen therapy (HFNC) is widely used mainly in the acute care setting, but limited data are available on real-world practice in adults. The objective of this study was to describe HFNC practices in Japanese adults. METHODS: A retrospective cross-sectional multicenter survey of adult patients receiving HFNC from January through March 2015 was conducted in 33 participating hospitals in Japan. RESULTS: We obtained information on 321 patients (median age, 76; 218 men, 103 women; median estimated PaO2/FIO2, 178 mm Hg) from 22 hospitals. Do-not-intubate status was determined in 37.4% of patients. Prior to HFNC, 57.9% of patients received conventional oxygen therapy; 25.9%, noninvasive ventilation; and 15.0%, invasive mechanical ventilation. The common indications for HFNC were acute hypoxemic respiratory failure (ARF) (65.4%), postoperative respiratory support (15.9%), and post-extubation respiratory support (11.2%). The underlying etiology of ARF included interstitial lung disease, pneumonia, and cardiogenic pulmonary edema. HFNC was administered mostly in intensive care units or intermittent care units (60.7%) and general wards (36.1%). Median duration of HFNC was 4 days; median total flow rate, 40 L/min; and median FIO2, 50%. HFNC significantly improved PaO2, PaCO2, SpO2 and respiratory rate from baseline. Two-thirds of patients finally survived to be discharged or transferred. CONCLUSIONS: We documented patient demographics, clinical indications, and settings of HFNC use in the real world. We also demonstrated positive effects of HFNC on respiratory parameters. Further studies are urgently needed regarding the efficacy and safety of HFNC in populations outside of previous clinical trials.

Domiciliary High-Flow Nasal Cannula Oxygen Therapy for Patients with Stable Hypercapnic Chronic Obstructive Pulmonary Disease. A Multicenter Randomized Crossover Trial.

RATIONALE: A growing evidence base suggests a benefit of using high-flow nasal cannula oxygen therapy in the acute setting. However, the clinical benefit of domiciliary use of high-flow nasal cannula oxygen therapy in patients with chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease remains unclear. OBJECTIVES: To evaluate the efficacy and safety of high-flow nasal cannula oxygen therapy use in patients with stable chronic obstructive pulmonary disease. METHODS: We conducted a multicenter, randomized crossover trial comparing high-flow nasal cannula oxygen therapy plus long-term oxygen therapy with long-term oxygen therapy only in 32 adults with stable hypercapnic chronic obstructive pulmonary disease. Participants were randomized to receive either 6 weeks of high-flow nasal cannula oxygen therapy/long-term oxygen therapy using the myAIRVO 2 device followed by another 6 weeks of long-term oxygen therapy only or long-term oxygen therapy only followed by high-flow nasal cannula oxygen therapy/long-term oxygen therapy. The primary outcome was the change in quality of life as assessed by St. George's Respiratory Questionnaire for chronic obstructive pulmonary disease. A linear mixed-effects model was used to account for treatment effect, time effect, allocation effect, and participant effect. RESULTS: Of 32 study participants, 29 completed the study. At the end of 12 weeks, high-flow nasal cannula oxygen therapy/long-term oxygen therapy treatment improved the mean total St. George's Respiratory Questionnaire for chronic obstructive pulmonary disease score compared with long-term oxygen therapy only (7.8 points; 95% confidence interval, 3.7 to 11.9; P < 0.01). Similarly, high-flow nasal cannula oxygen therapy/long-term oxygen therapy treatment improved the arterial partial pressure of carbon dioxide (adjusted treatment effect, -4.1 mm Hg; 95% confidence interval, -6.5 to -1.7 mm Hg), pH (adjusted treatment effect, +0.02; 95% confidence interval, 0.01 to 0.02), and median nocturnal transcutaneous carbon dioxide pressure (adjusted treatment effect, -5.1 mm Hg; 95% confidence interval, -8.4 to -1.8 mm Hg). High-flow nasal cannula oxygen therapy/long-term oxygen therapy treatment did not improve the arterial partial pressure of oxygen, dyspnea, spirometry, lung volume, 6-minute walk test, or physical activity. The most frequent high-flow nasal cannula oxygen therapy-related adverse event encountered was nocturnal sweating (n = 6 [20.7%]). Four severe adverse events occurred (two in each group) and were deemed unrelated to the intervention. CONCLUSIONS: Six weeks of treatment with high-flow nasal cannula oxygen therapy improved health-related quality of life and reduced hypercapnia in patients with stable hypercapnic chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT02545855) and www.umin/ac.jp (UMIN000017639).

Treatment Rationale and Design for J-SONIC: A Randomized Study of Carboplatin Plus Nab-paclitaxel With or Without Nintedanib for Advanced Non-Small-cell Lung Cancer With Idiopathic Pulmonary Fibrosis.

We describe the treatment rationale and procedure for a randomized study (J-SONIC; University Hospital Medical Information Network Clinical Trials Registry identification no., UMIN000026799) of carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without nintedanib for patients with advanced non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF). The study was designed to examine the efficacy and safety of nintedanib administered with carboplatin plus nab-paclitaxel versus carboplatin plus nab-paclitaxel alone in chemotherapy-naive patients with advanced NSCLC associated with IPF. Eligible patients (enrollment target, n = 170) will be randomized at a 1:1 ratio to receive 4 cycles of carboplatin (area under the curve, 6 on day 1) plus nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg twice daily), to be followed in arm B by single-agent administration of nintedanib (150 mg twice daily). The present trial is the first randomized controlled study for the treatment of NSCLC associated with IPF. The goal of the study is to demonstrate that nintedanib combined with carboplatin plus nab-paclitaxel prolongs the interval to acute exacerbation of IPF compared with carboplatin plus nab-paclitaxel alone.

Direct effects of hydrogen peroxide on airway smooth muscle tone: roles of Ca2+ influx and Rho-kinase.

Reactive oxidant species are implicated in the chronic airway inflammation related to asthma and chronic obstructive pulmonary disease. This study was designed to determine mechanisms underlying contraction induced by hydrogen peroxide (H(2)O(2)), a clinical marker of oxidative stress, in airway smooth muscle. Isometric tension and fluorescent intensities of fura-2, an index of intracellular Ca(2+) concentrations ([Ca(2+)](i)), were measured in epithelium-denuded tracheal smooth muscle tissues isolated from guinea pigs. H(2)O(2) (0.01-1 mM) caused contraction with an augmentation of [Ca(2+)](i) in a concentration-dependent manner in the normal physiological solution containing 2.4 mM of extracellular Ca(2+) concentrations. The contractile force and [Ca(2+)](i) by H(2)O(2) (1 mM) were approximately half of those in response to 1 microM methacholine. However, contraction by H(2)O(2) was not generated under the condition that extracellular Ca(2+) concentrations were less than 0.15 mM. Verapamil (10 microM), an inhibitor of voltage-operated Ca(2+) channels, partially but significantly inhibited the H(2)O(2)-induced contraction. In contrast, SKF-96365 (1-{beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride) (100 microM), a non-selective inhibitor of Ca(2+) channels, completely abolished both the contraction and the increase in [Ca(2+)](i) elicited by H(2)O(2). Moreover, Y-27632 ((R)-(+)-trans-N-(4-Pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide) (0.03-10 microM), an inhibitor of Rho-kinase, caused a concentration-dependent inhibition of the H(2)O(2)-induced contraction. In conclusion, both the Ca(2+) influx from the extracellular side and the Ca(2+) sensitization by Rho-kinase are involved in the regulation of airway smooth muscle tone induced by H(2)O(2). An inhibition of the Rho/Rho-kinase pathway may be beneficial for the treatment of airflow limitation mediated by oxidative stress.

[Prevalence of myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) in patients with interstitial pneumonia].

Myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) is an autoantibody that is frequently found in patients with vasculitides. We encountered some MPO-ANCA positive patients with interstitial pneumonia who lacked vasculitides, but its meaning remains unclear. We measured MPO-ANCA titers in 69 patients with interstitial pneumonia (IP) who did not have collagen vascular diseases and observed their outcome. MPO-ANCA was positive in 5 patients and its prevalence was 7.2%. Patients with MPO-ANCA positive showed higher positivity in rheumatoid factor (RF) than patients with MPO-ANCA negative. The sensitivity and specificity of a combination of anti-nuclear antibody-negative and RF-positive were 80.0% and 87.7%, respectively. Two patients were accompanied by microscopic polyangiitis and the 3-year survival rate was 40% in all patients with MPO-ANCA. Measurement of MPO-ANCA titers in patients with IPs is meaningful for determining therapeutic strategy.