Real-world impact of antifibrotics on prognosis in patients with progressive fibrosing interstitial lung disease.

OBJECTIVE: No studies have demonstrated the real-world efficacy of antifibrotics for progressive fibrosing interstitial lung disease (PF-ILD). Therefore, we evaluated the efficacy of antifibrotics in patients with PF-ILD. METHODS: We retrospectively reviewed the medical records of patients with ILD from January 2012 to July 2021. Patients were diagnosed with PF-ILD if they had ≥10% fibrosis on high-resolution CT (HRCT) and a relative forced vital capacity (FVC) decline of either ≥10% or >5% to <10% with clinical deterioration or progression of fibrosis on HRCT during overlapping windows of 2 years and with a %FVC of ≥45%. We compared FVC changes and overall survival (OS) between patients with and without antifibrotics. FVC changes were analysed using generalised estimating equations. We used inverse probability weighting (IPW) and statistical matching to adjust for covariates. RESULTS: Of the 574 patients, 167 were diagnosed with PF-ILD (idiopathic pulmonary fibrosis (IPF), n=64; non-IPF, n=103). Antifibrotics improved the FVC decline in both IPF (p=0.002) and non-IPF (p=0.05) (IPW: IPF, p=0.015; non-IPF, p=0.031). Among patients with IPF, OS was longer in the antifibrotic group (log-rank p=0.001). However, among patients with non-IPF, OS was not longer in the antifibrotic group (p=0.3263) (IPW and statistical matching: IPF, p=0.0534 and p=0.0018; non-IPF, p=0.5663 and p=0.5618). CONCLUSION: This is the first real-world study to show that antifibrotics improve the FVC decline in PF-ILD. However, among patients with non-IPF, we found no significant difference in mortality between those with and without antifibrotics. Future studies must clarify whether antifibrotics improve the prognosis of non-IPF.

Nationwide retrospective observational study of idiopathic dendriform pulmonary ossification: clinical features with a progressive phenotype.

BACKGROUND: Diffuse pulmonary ossification is a specific lung condition that is accompanied by underlying diseases. However, idiopathic dendriform pulmonary ossification (IDPO) is extremely rare, and the clinical features remain unclear. In this study, we aimed to report the clinical characteristics of IDPO. METHODS: We conducted a nationwide survey of patients with IDPO from 2017 to 2019 in Japan and evaluated the clinical, radiological, and histopathological findings of patients diagnosed with IDPO. RESULTS: Twenty-two cases of IDPO were identified. Most subjects (82%) were male, aged 22-56 years (mean (SD), 37.9 (9.1)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed.)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed. CONCLUSIONS: IDPO develops at a young age with gradually progressive phenotype. Further research and long-term (>20 years) follow-up are required to clarify the pathogenesis and clinical findings in IDPO.

Impact of bronchial wall thickness on airflow obstruction in bronchiectasis.

The association between airflow obstruction and bronchial dilation has been researched in bronchiectasis. However, the impact of bronchial wall thickening on airflow obstruction has not been thoroughly investigated. This study assessed the underlying mechanism of airflow obstruction in bronchiectasis due to abnormal bronchial wall thickening using oscillometry. A total of 98 patients with bronchiectasis were retrospectively reviewed. At the time of diagnosis, spirometric and oscillometric parameters, high-resolution computed tomography scores, and clinical characteristics were collected. The bronchial diameter, bronchial wall thickness, and extent of emphysema were evaluated semi-quantitatively. Correlations between patient data and characteristics were analyzed. Thirty-three patients with airflow obstruction showed higher respiratory resistance, more negative respiratory reactance (Xrs) at 5 Hz (X5), and higher bronchial wall thickness score than those without airflow obstruction. The bronchial wall thickness score negatively affected forced expiration volume in 1 s /forced vital capacity and X5. Abnormal bronchial wall thickening might make Xrs more negative and progress airflow obstruction in bronchiectasis.

Pleural Effusion Caused by Mycolicibacterium mageritense in an Immunocompetent Host: A Case Report.

Mycolicibacterium mageritense (M. mageritense) is a rare species among rapidly growing mycobacteria, and M. mageritense pleurisy is very rare. Here, we report for the first time, an immunocompetent patient with pleurisy caused by M. mageritense. The patient had no history of immunodeficiency and no recurrence of lung cancer after surgery. However, 8 months after surgery, he developed a new lung shadow and pleurisy. Although whole-genome analysis of the colony cultured from the patient's pleural fluid revealed M. mageritense, we could not identify it in time, resulting in a poor outcome. M. mageritense pleurisy in this case might have occurred via a bulla rupture of the lung lesion because computed tomography of the patient's chest showed pneumothorax and a lung lesion in contact with thoracic cavity. This case emphasized that nontuberculous mycobacterial pleurisy should be considered in the differential diagnoses of pleural effusion even in immunocompetent patients. Advancement of comprehensive and rapid analyses of genomic data from clinical specimens will lead to better treatment strategies.

Corrigendum: Oxygen Extraction Based on Inspiratory and Expiratory Gas Analysis Identifies Ventilatory Inefficiency in Chronic Obstructive Pulmonary Disease.

[This corrects the article DOI: 10.3389/fphys.2021.703977.].

Oxygen Extraction Based on Inspiratory and Expiratory Gas Analysis Identifies Ventilatory Inefficiency in Chronic Obstructive Pulmonary Disease.

Aims: In contrast to cardiovascular disease, low rather than high ventilatory inefficiency, evaluated by the minute ventilation-carbon dioxide output (V'E-V'CO2)-slope, has been recognized as being related to greater disease severity in chronic obstructive pulmonary disease (COPD). To better care for patients with cardiopulmonary disease, understanding the physiological correlation between ventilatory inefficiency and exercise limitation is necessary, but remains inadequate. Given that oxygen uptake (V'O2) evaluated by cardiopulmonary exercise testing (CPET) depends on both the ventilatory capability and oxygen extraction, i.e., the difference between inspiratory and expiratory oxygen concentration (ΔFO2), the aim of this study was to investigate the correlations between V'E-V'CO2-slope and the ΔFO2 during exercise and their physiological implications in patients with COPD. Methods: A total of 156 COPD patients (mean age, 70.9 ± 7.2 years) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV and 16 controls underwent CPET with blood gas analysis. Results: With the progression of COPD, mechanical ventilatory constraints together with a slower respiratory frequency led to exertional respiratory acidosis. In GOLD IV cases, (1) decrease in the dependence of reduced peak V'O2 on V'E led to an increase in its dependence on peak ΔFO2 during exercise; and (2) the ΔFO2-V'CO2-slope became steeper, correlating with the severity of exertional respiratory acidosis (r = 0.6359, p < 0.0001). No significant differences in peak exercise ΔFO2 or V'E-V'CO2-slope were observed among the various GOLD stages. In all subjects, including controls, peak exercise ΔFO2 had the strongest correlation with the V'E-V'CO2-slope (r = -0.8835, p < 0.0001) and correlated well with body mass index (r = 0.3871, p < 0.0001), although it did not correlate with the heart rate-V'CO2-relationship and V'E. Conclusions: Ventilatory efficiency related to CO2 clearance might depend on exertional oxygen extraction in the body. Measuring ΔFO2 might be a key component for identifying ventilatory inefficiency and oxygen availability. Increasing ΔFO2 would help to improve ventilatory inefficiency and exercise tolerance separately from cardiac and ventilatory capability in COPD patients.

The impact of adjuvant surgical treatment of nontuberculous mycobacterial pulmonary disease on prognosis and outcome.

BACKGROUND: Lung resection in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) has been reported to be associated with favorable outcomes. However, little is known regarding the risk and prognostic factors for refractory and recurrent cases. We aimed to evaluate the overall impact and benefit of adjuvant lung surgery by comparing NTM-PD patients who underwent adjuvant lung resection with those treated exclusively with antibiotics. We also investigated the efficacy of serum IgA antibody against glycopeptidolipid (GPL) core antigen (GPL core antibody) to monitor disease activity and predict the recurrence of disease after adjuvant lung resection. METHODS: We retrospectively evaluated the clinical characteristics and surgical outcomes of 35 patients surgically treated for NTM-PD. Furthermore, we compared surgically treated patients and control patients treated exclusively with antibiotics who were matched statistically 1:1 using a propensity score calculated from age, sex, body mass index, and radiologic features of disease. RESULTS: In the surgically treated patients, the median age was 58 (interquartile range, 47-65) years and 65.7% were female. Twenty-eight patients had Mycobacterium avium complex. Operations comprised four pneumonectomies, two bilobectomies, one bilobectomy plus segmentectomy, 17 lobectomies, two segmentectomies, and nine lobectomies plus segmentectomies. Postoperative complications occurred in seven patients (20%), there were no operative deaths, and 33 (94.3%) patients achieved negative sputum culture conversion. Refractory and recurrent cases were associated with remnant bronchiectasis, contralateral shadows, and positive acid-fast bacilli staining or culture. Of 28 statistically matched pairs, long-term sustained negative culture conversion was observed in 23 (82.2%) surgical group patients and in 14 (50.0%) non-surgical group patients (0.0438). The mortality rate was lower in the surgical group, but did not reach statistical significance (one in the surgical group and four in the non-surgical group, p = 0.3516). GPL core antibody was correlated with disease activity and recurrence. CONCLUSIONS: NTM-PD patients who underwent adjuvant lung resection experienced overall favorable outcomes and achieved sputum culture conversion more frequently. Long-term mortality may have been reduced by this procedure, and the level of GPL core antibody was shown to be a good clinical indicator of disease activity after surgery.

Acute lung injury after plasma exchange in a patient with anti-MDA5 antibody-positive, rapidly progressive, interstitial lung disease：A case report.

The presence of anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is closely associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis. Despite intensive immunosuppressive therapies, some of these patients still have a poor prognosis with few treatment options. Although removal of pathogenic autoantibodies and cytokines by plasma exchange (PE) could be a treatment option, its safety and efficacy have never been determined. We report a patient with anti-MDA5 Ab-positive RP-ILD who was refractory to intensive therapies including steroids, cyclosporine, and intravenous cyclophosphamide, and then treated by PE to prevent the progression of RP-ILD. Shortly after the initiation of PE therapy, however, his respiratory condition suddenly deteriorated due to acute pulmonary edema and the patient died on the following day. Transfusion-related acute lung injury (TRALI) would be the most likely cause of the acute pulmonary edema because there was no sign of circulatory overload. To the best of our knowledge, this is the first report showing a critical adverse event associated with PE therapy for these patients. This case supports the idea that the presence of ILD could increase a risk for TRALI and therefore we should carefully evaluate the eligibility for PE therapy of anti-MDA5 Ab-positive RP-ILD patients given the risk of acute lung injury. Further studies collecting more clinical data are necessary to assess the efficacy, safety, and risk factors of PE therapy for these patients.

Human airway trypsin-like protease enhances interleukin-8 synthesis in bronchial epithelial cells by activating protease-activated receptor 2.

Human airway trypsin-like protease (HAT) localizes at human bronchial epithelial cells (HBECs). HAT enhanced release of interleukin-8 (IL-8) from HBECs at 10-100 mU/mL and the enhanced release was almost completely abolished by 50 µM leupeptin, a serine protease inhibitor. Previous reports suggested that HAT displays its physiological functions via protease-activated receptor 2 (PAR2). In the present study, we examined the mechanism whereby HAT upregulates IL-8 synthesis in HBECs with a focus on PAR2. Northern blot analysis revealed that HAT enhanced IL-8 mRNA expression at concentrations of 10-100 mU/mL. PAR2 activating peptide (PAR2 AP) also enhanced IL-8 release and IL-8 mRNA expression in HBECs at 50-1,000 µM at similar levels as HAT. Knockdown of PAR2 mRNA by siRNA methods showed that PAR2 mRNA expression was significantly depressed in primary HBECs, and both HAT- and PAR2 AP-induced IL-8 mRNA elevation was significantly depressed in PAR2 siRNA-transfected HBECs. Additionally, HAT cleaved the PAR2 activating site (R36-S37 bond) of synthetic PAR2 N-terminal peptide. These results indicate that HAT stimulates IL-8 synthesis in airway epithelial cells via PAR2 and could help to amplify inflammation in chronic respiratory tract disease.

Three Cases of Idiopathic Diffuse Pulmonary Ossification.

Diffuse pulmonary ossification (DPO) is an uncommon diffuse lung disease characterized by metaplastic bone formation in the lung parenchyma and is rarely diagnosed in life. While DPO usually occurs as a secondary disease, idiopathic cases are extremely rare. We describe three cases of idiopathic DPO, two of which were definitively diagnosed by surgical lung biopsy. One case was observed in a 43-year-old man with a history of recurrent pneumothorax who developed pneumothorax after the surgical biopsy. Few reports have described cases of DPO with recurrent pneumothorax; however, pneumothorax should be considered as a potential complication when such patients are encountered.

Congenital cystic adenomatoid malformation in adults detected after infection.

Congenital cystic adenomatoid malformation (CCAM) is a benign congenital tumour in which a part of the lung becomes polycystic. Case 1 was a 64-year-old male who was diagnosed with pneumonia, with multiple cysts in the right lower lung lobe, using chest computed tomography (CT). After treatment of the pneumonia, including Mycobacterium abscessus, a right lower lobectomy was performed. Case 2 was a 41-year-old male who had suffered from pneumonia many times since his youth. Polycystic and infiltrative shadows were observed on chest CT. After treatment of the pneumonia, a right lower lobectomy was performed. Pathologically, both the cases were diagnosed as CCAM type 1. Although CCAM in adults is very rare, it should be considered in the differential diagnosis of cases with repeated pneumonia due to suspected congenital cystic disease. CCAM is better detectable with chest CT and requires active surgical treatment.

Dietary calcium intake is associated with serum high-sensitivity C-reactive protein level in the general Japanese population.

The beneficial effects of dietary calcium intake on high-sensitivity C-reactive protein levels, a risk factor of cardiovascular disease, have not been fully elucidated. This study investigated the associations between dietary calcium intake and serum high-sensitivity C-reactive protein levels in the general Japanese population. We analyzed the data of 2,019 subjects (1,194 men and 825 women) aged 35 to 69 years in a cross-sectional study of the Japan Multi-Institutional Collaborative Cohort Study. Nutrients intake including calcium were estimated using a validated food-frequency questionnaire. Analysis using a general linear model revealed that dietary calcium intake was inversely associated with serum high-sensitivity C-reactive protein levels (p for trend <0.001) after adjustment for age, sex, research group, leisure-time physical activity, smoking habit, drinking habit, dietary intakes (energy, dietary fiber, saturated fatty acids and vitamin D) and menopausal status. The association was slightly attenuated after additional adjustment for body mass index; however, remained significant (p for trend = 0.008). There were no significant interactions between dietary calcium intakes and sex, body mass index, or vitamin D intake for high-sensitivity C-reactive protein levels. This study have demonstrated that dietary calcium intake was inversely associated with serum high-sensitivity C-reactive protein levels in the general population.

Randomized, dose-finding trial of ghrelin treatment for chronic respiratory failure.

OBJECTIVES: Ghrelin, a growth hormone-releasing peptide, has shown efficacy in chronic obstructive pulmonary disease (COPD) patients in previous trials. This study was designed to evaluate the effective dose of ghrelin in chronic respiratory failure patients. METHODS: In this randomized, double-blind, dose-finding, single-center study, 18 patients, including 16 with COPD, were randomly assigned to receive pulmonary rehabilitation (PR) with intravenous ghrelin at 1 µg/kg or 2 µg/kg, twice daily for 3 weeks. The primary outcome was the change in peak oxygen uptake ( V˙o2). Secondary outcomes included changes in plasma vascular endothelial growth factor (VEGF)-A levels, and exertional cardio-respiratory functions with blood gas analysis. RESULTS: With incremental exercise, there was no significant differences in the mean difference (high-dose ghrelin minus low-dose ghrelin) of peak V˙o2 (1.0 mL/kg/min, 95% CI: -0.6 to 2.6 mL/kg/min, between-group, P = 0.193). However, there were significant differences in the mean difference of (i) O2 -pulse (0.6 mL/beats, 95% CI: 0.0 to 1.1 mL/beats, between-group, P = 0.035) at iso-time; and ii) PaO2 (4.2 mmHg, 95% CI: 0.2 to 8.2 mmHg, between-group, P = 0.041) and PaCO2 (-3.1 mmHg, 95% CI: -6.0 to -0.3 mmHg, between-group, P = 0.034) at peak exercise. The mean difference in the plasma VEGF-A level was significantly inhibited by high dose-ghrelin with PR (-125.4 pg/mL, 95% CI: -235.2 to -15.5 pg/mL, between-group, P = 0.028). CONCLUSION: Although the primary outcome of the study was not met, high-dose ghrelin with PR improved exertional cardiac function and blood gas values, and inhibited circulating VEGF-A levels.

[Nutrition management for COPD].

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory reaction of the lung and of the whole body, and pulmonary cachexia often occurs during the advanced stage. The effects of nutritional support upon the management of under-nutrition in COPD remain controversial. However, a study of the effects of nutritional supplement therapy upon such patients with COPD has recently been published. The present report comprises a review of recent articles about the nutritional support of patients with COPD, especially those with cachexia, and a discussion about the roles of nutritional supplement therapy, focusing on exercise and treatment with ghrelin and vitamin D in the management of COPD.

Changes in foot function, disease activity, and disability after forefoot resection arthroplasty in patients with rheumatoid arthritis.

The purpose of this study was to investigate the changes in foot function, disease activity, and disability in patients with RA after resection arthroplasty of the forefoot (arthroplasty). Arthroplasty was performed on 11 patients with RA. All study patients underwent clinical assessment to measure disease activity (Disease Activity Score in 28 Joints-C-reactive protein, DAS28-CRP), disability (Health Assessment Questionnaire-Disability Index, HAQ-DI) and foot function (Foot Function Index, FFI) at the following stages: preoperatively and 1, 3, and 12 months after surgery. Following arthroplasty, foot function improved significantly, as assessed by FFI total and subscales (pain, disability, and limitation of activity) (P<0.001, P<0.001, P<0.001, and P=0.002, respectively). Disease activity was significantly improved in relation to DAS28-CRP and its subscales of number of swollen joints and patient global assessment (PtGA) (P=0.033, P=0.008, and P=0.038, respectively). There was no significant difference in disability, as assessed by the HAQ-DI and its subscale, HAQ-walking (P=0.150 and P=0.597, respectively). Foot function improved significantly after arthroplasty, and was maintained at 12 months postoperatively. Additionally, our study showed that disease activity and its subscale PtGA improved after arthroplasty.

Personalized pulmonary rehabilitation and occupational therapy based on cardiopulmonary exercise testing for patients with advanced chronic obstructive pulmonary disease.

TAKE-HOME SUMMARY: Personalized pulmonary rehabilitation including occupational therapy improves the prognosis of patients with advanced COPD. PURPOSE: We previously reported that patients with chronic obstructive pulmonary disease (COPD) exhibit three exercise-induced life-threatening conditions: hypoxemia, sympathetic overactivity, and respiratory acidosis. We aimed to verify whether mortality in patients with advanced COPD could be reduced by a personalized pulmonary rehabilitation (PPR) program in hospital, which determines individual safe ranges and includes occupational therapy (PPR-OT), to prevent desaturation and sympathetic nerve activation during daily activities. PATIENTS AND METHODS: The novel PPR-OT program was evaluated in a retrospective study of patients with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Grade D) who underwent cardiopulmonary exercise testing (CPET) between April 1990 and December 1999. They received regular treatment without the proposed therapy (control group: n=61; male-to-female ratio [M:F] =57:4; mean age: 68.5±6.7 years) or with the proposed therapy (PPR-OT group: n=46; M:F =44:2; mean age: 68.7±7.1 years). A prospective observational study included patients with COPD receiving home oxygen therapy (HOT) between April 1995 and March 2007 to compare the survival rates of the control group (n=47; M:F ratio =34:13; mean age: 71.3±10.0 years) and the PPR-OT group (n=85; M:F =78:7; mean age: 70.7±6.1 years) who completed the proposed therapy. Survival after CPET or HOT was analyzed using Cox proportional-hazards regression and Kaplan-Meier analyses. RESULTS: In both studies, the program significantly improved all-cause mortality (retrospective study: risk ratio =0.389 [range: 0.172-0.800]; P=0.0094; log-rank test, P=0.0094; observational study: risk ratio =0.515 [range: 0.296-0.933]; P=0.0291; log-rank test, P=0.0232]. At 5 years and 7 years, all-cause mortality was extremely low in patients in the PPR-OT group receiving HOT (18.8% and 28.2%, respectively), compared to that in the control group (34.0% and 44.7%, respectively). Survival of patients with life-threatening pathophysiological conditions also greatly improved. CONCLUSION: The PPR-OT program improved the survival of patients with advanced COPD probably because it modified life-threatening conditions.

Ghrelin administration for chronic respiratory failure: a randomized dose-comparison trial.

BACKGROUND: Repeated ghrelin administration leads to improvements in symptoms, muscle wasting and exercise tolerance in cachectic patients with pulmonary disease. We investigated the optimal ghrelin dose for underweight patients with chronic respiratory failure. METHODS: In this multicenter, randomized, dose-comparison exploratory study, 44 cachectic patients with chronic respiratory failure were randomly assigned pulmonary rehabilitation with intravenous twice-daily administration of 1 or 2 µg/kg ghrelin for 3 weeks. The primary endpoint was improvement in 6-min walking distance (6 MWD). The secondary endpoint was change in peak VO2. RESULTS: Twenty-one patients were assigned to the 1 µg/kg ghrelin group and 23 to the 2 µg/kg ghrelin group. Change from baseline 6 MWD after treatment was similar between groups(1 µg/kg: 53.9 m, 2 µg/kg: 53.9 m, p = 0.99). Mean change in peak VO2 was significantly greater in the 2 µg/kg group (63.1 ml/min) than in the 1 µg/kg group (-63.8 ml/min, p = 0.048). Food intake and lean body mass significantly increased in both groups, and the St. George Respiratory Questionnaire score, body weight, and body mass index were remarkably improved in only the 2 µg/kg group, although there was no significant difference between groups. No treatment-related serious events were reported for either group. CONCLUSION: Improvements in the oxygen uptake capacity were greater in patients receiving 2 µg/kg ghrelin twice daily for 3 weeks than in those receiving 1 µg/kg, although exercise tolerance was similar between groups at the end of the 3-week treatment period. Thus, a twice daily dose of 2 µg/kg ghrelin is recommended over 1 µg/kg ghrelin for patients with chronic respiratory failure and weight loss.

Exertional acidotic responses in idiopathic pulmonary fibrosis: the mechanisms of exertional dyspnea.

To understand the mechanism of exertional dyspnea, we postulated that, despite hyperoxia during exercise, patients with idiopathic pulmonary fibrosis (IPF) might not regulate exertional acidosis by ventilatory compensation to stop exercise. The exercise responses during 30% O(2) or compressed air (CA) were examined in 13 patients with IPF. The PaO(2), PaCO(2), and HCO(3)(-) levels were higher during exercise with hyperoxia than with CA. At peak exercise, hyperoxia reduced the plasma lactate level. The dyspnea-ratio (%) of the ΔV(O(2)) (peak minus resting oxygen uptake) curve reached a break point that occurred at a similar exercise point with hyperoxia and CA, preceded by a break point in the breathing frequency-ratio of the ΔV(O(2)). Accordingly, the dyspnea score and pH each reached similar levels with hyperoxia and CA to stop exercise. Regardless of breathing CA or 30% O(2), IPF patients did not regulate exertional acidosis by ventilatory compensation to stop exercise, resulting in reaching a specific pH.

Whole-genome sequence of the hypervirulent clinical strain Mycobacterium intracellulare M.i.198.

We report herein the draft genome sequence of Mycobacterium intracellulare clinical strain M.i.198, which consistently exhibits hypervirulence in human patients, human macrophages in vitro, and immunocompetent mice.

Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease: a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Pulmonary cachexia is common in advanced chronic obstructive pulmonary disease (COPD), culminating in exercise intolerance and a poor prognosis. Ghrelin is a novel growth hormone (GH)-releasing peptide with GH-independent effects. The efficacy and safety of adding ghrelin to pulmonary rehabilitation (PR) in cachectic COPD patients were investigated. METHODOLOGY/PRINCIPAL FINDINGS: In a multicenter, randomized, double-blind, placebo-controlled trial, 33 cachectic COPD patients were randomly assigned PR with intravenous ghrelin (2 µg/kg) or placebo twice daily for 3 weeks in hospital. The primary outcomes were changes in 6-min walk distance (6-MWD) and the St. George Respiratory Questionnaire (SGRQ) score. Secondary outcomes included changes in the Medical Research Council (MRC) scale, and respiratory muscle strength. At pre-treatment, serum GH levels were increased from baseline levels by a single dose of ghrelin (mean change, +46.5 ng/ml; between-group p<0.0001), the effect of which continued during the 3-week treatment. In the ghrelin group, the mean change from pre-treatment in 6-MWD was improved at Week 3 (+40 m, within-group p = 0.033) and was maintained at Week 7 (+47 m, within-group p = 0.017), although the difference between ghrelin and placebo was not significant. At Week 7, the mean changes in SGRQ symptoms (between-group p = 0.026), in MRC (between-group p = 0.030), and in maximal expiratory pressure (MEP; between-group p = 0.015) were better in the ghrelin group than in the placebo group. Additionally, repeated-measures analysis of variance (ANOVA) indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (p = 0.049) and MEP (p = 0.021). Ghrelin treatment was well tolerated. CONCLUSIONS/SIGNIFICANCE: In cachectic COPD patients, with the safety profile, ghrelin administration provided improvements in symptoms and respiratory strength, despite the lack of a significant between-group difference in 6-MWD. TRIAL REGISTRATION: UMIN Clinical Trial Registry C000000061.