Multi-Institutional Prospective Cohort Study of Patients With Pulmonary Hypertension Associated With Respiratory Diseases.

BACKGROUND: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis.Methods and Results:Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI. CONCLUSIONS: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation.Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis.Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).

Supplemental oxygen improves exercise capacity in IPF patients with exertional desaturation.

BACKGROUND AND OBJECTIVE: The efficacy of supplemental oxygen during exercise remains unclear for patients with IPF, as there have been conflicting results from recent prospective studies with small sample sizes. METHODS: This prospective, single-blind, randomized, crossover trial evaluated the efficacy of supplemental oxygen compared with placebo air during exercise in consecutive patients with IPF without resting hypoxaemia at initial evaluation. Patients with <90% SpO2 in a 6MWT using room air were randomly assigned to a CWRET at 80% of peak work rate with oxygen or placebo air gas via nasal cannula at 4 L/min. The primary endpoint was the effect of supplemental oxygen on endurance time. RESULTS: We recruited 72 consecutive patients (median age: 66.5 years, % FVC: 84.6%, % DLCO : 61.4%). Supplemental oxygen significantly increased the endurance time (340-424 s; P < 0.001) and minimum SpO2 (88.0-94.0%; P < 0.001) compared with placebo air. Furthermore, supplemental oxygen significantly improved dyspnoea and leg fatigue. In a multivariate linear regression analysis, the endurance time on air was an independent explanatory variable of the improvement rate of endurance time (P = 0.02). CONCLUSION: In mild-moderate IPF with exercise-induced hypoxaemia even without resting hypoxaemia, supplemental oxygen during exercise improved the endurance time, desaturation and subjective symptoms. Patients with shorter endurance times with placebo air showed better improvement with supplemental oxygen.

Diagnostic Likelihood Thresholds That Define a Working Diagnosis of Idiopathic Pulmonary Fibrosis.

Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown.Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB.Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues.Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician-patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician-patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90-100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90-1.04).Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood ≥ 70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.

Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety.

We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

A scoring system to predict the elevation of mean pulmonary arterial pressure in idiopathic pulmonary fibrosis.

Elevated mean pulmonary arterial pressure (MPAP; ≥21 mmHg) is sometimes seen in patients with idiopathic pulmonary fibrosis (IPF) and has an adverse impact upon survival. Although early diagnosis is crucial, there is no established screening tool that uses a combination of noninvasive examinations.We retrospectively analysed IPF patients at initial evaluation from April 2007 to July 2015 and, using logistic regression analysis, created a screening tool to identify elevated MPAP. Internal validation was also assessed for external validity using a bootstrap method.Using right-heart catheterisation (RHC), elevation of MPAP was determined to be present in 55 out of 273 patients. Multivariate models demonstrated that % predicted diffusing capacity of the lung for carbon monoxide (DLCO) <50%, ratio of pulmonary artery diameter to aorta diameter (PA/Ao) on computed tomography (CT) ≥0.9 and arterial oxygen tension (PaO2 ) <80 Torr were independent predictors. When we assigned a single point to each variable, the prevalence of elevation of MPAP with a score of zero, one, two or three points was 6.7%, 16.0%, 29.1% and 65.4%, respectively. The area under curve (AUC) for the receiver operating characteristic (ROC) curve was good at 0.757 (95% CI 0.682-0.833).A simple clinical scoring system consisting of % predicted DLCO, PA/Ao ratio on CT and PaO2 can easily predict elevation of MPAP in patients with IPF.

Multidimensional improvement in connective tissue disease-associated interstitial lung disease: Two courses of pulse dose methylprednisolone followed by low-dose prednisone and tacrolimus.

BACKGROUND AND OBJECTIVE: Corticosteroids and immunosuppressive agents are considered mainstays of therapy for connective tissue disease-related interstitial lung disease (CTD-ILD); however, tacrolimus with corticosteroid therapy has not been fully investigated. Our objectives were to examine the multidimensional therapeutic benefit and tolerability of the combined therapy for the initial treatment of patients with CTD-ILD. METHODS: In this retrospective case series, we identified consecutive CTD-ILD patients treated with tacrolimus plus intravenous (i.v.) methylprednisolone (1000 mg i.v. 3 days a week for 2 weeks) followed by low-dose prednisolone (10 mg/day). We assessed the multidimensional therapeutic benefit and tolerability including lung physiology, exercise capacity, exercise oxygen desaturation, modified Medical Research Council (MMRC) and St George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 26 ILD patients with the underlying CTD diagnoses included 11 with rheumatoid arthritis, 9 with dermatomyositis, 4 with Sjögren's syndrome and 2 others. From baseline to 12 months, the combined therapy significantly improved forced vital capacity (FVC; 77.8% to 94.6%, P < 0.001), diffusing capacity of the lung for carbon monoxide (DLCO ; 66.1% to 75.1%, P < 0.001), 6-min walk distance (6MWD; 530 to 568 m, P = 0.02), lowest oxygen saturation on pulse oximetry (SpO2 ; 85% to 89%, P = 0.01), MMRC (1.3 to 0.8, P = 0.01) and SGRQ (38 to 21, P < 0.001). During the study period, only one patient's therapy was discontinued due to an adverse event and none had a life-threatening adverse event attributed to the combined therapy. CONCLUSION: In our cohort of CTD-ILD, two courses of pulse dose methylprednisolone therapy followed by prednisone and oral tacrolimus appeared to be well tolerated, and to have multidimensional efficacy.

Mortality in patients with community-onset pneumonia at low risk of drug-resistant pathogens: Impact of ß-lactam plus macrolide combination therapy.

BACKGROUND AND OBJECTIVE: Drug-resistant pathogen (DRP) risk stratification is important for choosing a treatment strategy for community-onset pneumonia. Evidence for benefits of non-antipseudomonal ß-lactam plus macrolide combination therapy (BLM) on mortality is limited in patients at low DRP risk. Risk factors for mortality remain to be clarified. METHODS: Post hoc analysis using a prospective multicentre study cohort of community-onset pneumonia was performed to assess 30-day differences in mortality between non-antipseudomonal ß-lactam monotherapy (BL) and BLM groups. Logistic regression analysis was performed to assess the therapeutic effect and risk factors for mortality in patients at low DRP risk. RESULTS: In total, 594 patients with community-onset pneumonia at low DRP risk (369 BL and 225 BLM) were analysed. The 30-day mortality in BL and BLM was 13.8% and 1.8%, respectively (P < 0.001). Multivariate analysis showed that BLM reduced the 30-day mortality (adjusted odds ratio: 0.28, 95% CI: 0.09-0.87) compared with BL. Independent prognostic factors for 30-day mortality included arterial partial pressure of carbon dioxide (PaCO2 ) > 50 mm Hg, white blood cell count < 4000/mm3 , non-ambulatory status, albumin < 3.0 g/dL, haematocrit < 30%, age ≥ 80 years, respiratory rate > 25/min and body temperature < 36°C. CONCLUSION: In patients with community-onset pneumonia at low DRP risk, BLM treatment reduced 30-day mortality compared with BL. Independent risk factors for mortality are potential confounding factors when assessing antibiotic effects in randomized clinical trials.

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.

BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).

Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis.

Time to first investigator-reported acute exacerbation was a key secondary end-point in the INPULSIS trials of nintedanib in patients with idiopathic pulmonary fibrosis (IPF).We used the INPULSIS trial data to investigate risk factors for acute exacerbation of IPF and to explore the impact of nintedanib on risk and outcome of investigator-reported and adjudicated confirmed/suspected acute exacerbations. Mortality following these events and events adjudicated as not acute exacerbations was analysed using the log rank test.Risk of acute exacerbations was most strongly associated with the following variables: baseline forced vital capacity (higher risk with lower value), baseline supplemental oxygen (higher risk with use), baseline antacid medication (higher risk with use), treatment (higher risk with placebo), and for confirmed/suspected acute exacerbations, cigarette smoking. Mortality was similar following investigator-reported and adjudicated confirmed/suspected acute exacerbations. Nintedanib had no significant effect on risk of mortality post-exacerbation.Investigator-reported acute exacerbations of IPF are associated with similar risk factors and outcomes as adjudicated confirmed/suspected acute exacerbations.

Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: an international case-cohort study.

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts.A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (κw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the C-index.A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw=0.65, IQR 0.53-0.72, p<0.0001) than academic physicians (κw=0.56, IQR 0.45-0.65, p<0.0001) or physicians with access to multidisciplinary team (MDT) meetings (κw=0.54, IQR 0.45-0.64, p<0.0001). The prognostic accuracy of academic physicians with >20 years of experience (C-index=0.72, IQR 0.0-0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70-0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72-0.75).Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts.

The St. George's Respiratory Questionnaire as a prognostic factor in IPF.

BACKGROUND: It is unclear whether health related quality of life (HRQL) may have a predictive value for mortality in idiopathic pulmonary fibrosis (IPF). We investigated the relationship between HRQL assessed using the St. George's Respiratory Questionnaire (SGRQ) and survival time in patients with IPF, and tried to determine a clinical meaningful cut off value to predict poorer survival rates. METHODS: We retrospectively analyzed consecutive patients with IPF who underwent an initial evaluation from May 2007 to December 2012. The diagnosis of IPF was made according to the 2011 international consensus guidelines. We used Cox proportional hazard models to identify independent predictors for mortality rate in patients with IPF. RESULTS: We examined 182 eligible cases, average age was 66 years old, and 86% were male. Mean levels of percent predicted FVC, DLco, six-minute-walk test distance, and the SGRQ total score were around 80%, 58%, 580 m, and 34 points. On multivariate analysis, the SGRQ total score (hazard ratio [HR], 1.012; 95% confidence interval [CI] 1.001-1.023; P = .029) and percent predicted FVC (HR, 0.957; 95% CI 0.944-0.971, P < .001) were independent predictors for mortality rate. Moreover, a score higher than 30 points in the SGRQ total score showed higher mortality rate (HR, 2.047; 95% CI, 1.329-3.153; P = .001). CONCLUSIONS: The SGRQ total score was one of independent prognostic factors in patients with IPF. Total scores higher than 30 points were associated with higher mortality rates. TRIAL REGISTRATION: This study was retrospective, observational study, so it is not applicable.

CT-determined pulmonary artery to aorta ratio as a predictor of elevated pulmonary artery pressure and survival in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Elevated mean pulmonary artery pressure (mPAP) is a significant prognostic indicator in idiopathic pulmonary fibrosis (IPF). It has been reported that the computed tomography-determined ratio of the diameter of the pulmonary artery to the aorta (PA:A) is correlated with mPAP in various respiratory diseases. However, in patients with IPF, whether the PA:A can be used to predict elevated mPAP and the prognostic value of the PA:A has not been fully evaluated. METHODS: We conducted a single-centre, observational study of 177 consecutive IPF patients who underwent right heart catheterization. We examined the association between the PA:A and mPAP in these patients, and performed a receiver operating characteristic (ROC) analysis to test the diagnostic accuracy of the PA:A in predicting mPAP > 20 mm Hg (pulmonary hypertension (PH) or borderline PH) in relation to survival. RESULTS: In a multivariate linear regression analysis, the PA:A, 6-min walk distance and diffusion capacity for carbon monoxide (DLCO ) % predicted were independent explanatory variables of elevated mPAP (P < 0.0001, P = 0.009 and P = 0.002, respectively). ROC analysis revealed a PA:A > 0.9 to be optimal for predicting mPAP > 20 mmHg (area under the curve (AUC) = 0.75; 95% CI: 0.65-0.84). Patients with a PA:A > 0.9 also had a worse prognosis (P = 0.009). CONCLUSION: Measurement of the PA:A is a useful and convenient method to predict elevated mPAP in IPF at initial evaluation. Moreover, a PA:A >0.9 was found to be an indicator of worse prognosis.

Soluble thrombomodulin in bronchoalveolar lavage fluid is an independent predictor of severe drug-induced lung injury.

BACKGROUND AND OBJECTIVE: Drug-induced lung injury (DLI) can result from a vast number of agents, and sometimes presents findings similar to those of acute respiratory distress syndrome (ARDS). Previous studies have reported that circulating levels of soluble thrombomodulin (TM) reflect endothelial injuries, which play key roles in the development of ARDS. We hypothesized that endothelial injuries are an important aspect of pathogenesis in severe DLI. The primary aim of this study was to examine the associations between soluble TM and disease severity in DLI patients. METHODS: Of the 2580 patients who underwent a bronchoalveolar lavage (BAL) procedure at Tosei General Hospital between May 2007 and February 2015, we retrospectively analysed the data of 68 DLI patients. Soluble TM in plasma and BAL fluid (BALF), and other biomarkers were included in our analysis. RESULTS: At the time of diagnosis, 39 patients (57%) had respiratory failure (partial pressure of oxygen/inspiratory oxygen fraction ratio, PaO2 /FiO2 ratio < 300). There was a significant negative linear correlation between the PaO2 /FiO2 ratio and soluble TM in BALF (r = -0.448, P < 0.001). In a stepwise multiple regression analysis, soluble TM in BALF and surfactant protein D (SP-D) were the only independent determinants of the PaO2 /FiO2 ratio. Additionally, in a multivariate logistic regression model, soluble TM in BALF (adjusted OR (aOR): 7.48, 95% CI: 1.60-34.98) and SP-D (aOR: 5.31, 95% CI: 1.40-20.15) was an independent predictor of respiratory failure (PaO2 /FiO2 ratio < 300). CONCLUSION: Soluble TM in BALF is an independent predictor of severe DLI. These findings underscore the importance of pulmonary endothelial injuries in the pathogenesis of severe DLI.

Progression of mean pulmonary arterial pressure in idiopathic pulmonary fibrosis with mild to moderate restriction.

BACKGROUND AND OBJECTIVE: Elevation of mean pulmonary arterial pressure (MPAP) is associated with poor prognosis in patients with idiopathic pulmonary fibrosis (IPF), yet the progression of MPAP in patients with IPF has not been sufficiently elucidated. We evaluated serial changes in MPAP and its determinants in patients with IPF with mild to moderate restriction. METHODS: We retrospectively reviewed patients with IPF who underwent initial evaluations including right heart catheterization (RHC) in our institute from May 2007 to December 2013 with follow-up RHC at least 1 year later. Patients with forced vital capacity (FVC) < 50% predicted or those with pulmonary artery wedge pressure >15 mm Hg were excluded. RESULTS: A total of 95 patients were included. Median follow-up time of second RHC was 1.8 years. MPAP increased significantly at follow-up (from 16.8 to 20.2 mm Hg; P < 0.001), and annual change in MPAP (ΔMPAP) was 1.8 mm Hg/year. In multiple regression analysis, the lowest oxygen saturation (SpO2 ) at 6-min walk test (6MWT) was an independent predictor of ΔMPAP. When adjusted for age, sex, baseline MPAP and FVC % predicted, ΔMPAP was a significant predictor of mortality (hazard ratio: 1.21; P = 0.001). CONCLUSION: ΔMPAP was significantly associated with desaturation in the 6MWT, and with increased mortality in patients with IPF with mild to moderate restriction.

COPD Assessment Test for measurement of health status in patients with idiopathic pulmonary fibrosis: A cross-sectional study.

BACKGROUND AND OBJECTIVE: The COPD Assessment Test (CAT) has been reported to have potential utility for measuring health status of idiopathic pulmonary fibrosis (IPF). Although the CAT has been developed for the assessment of COPD patients, it has not been fully evaluated exclusively in IPF. This study was designed to evaluate the validity of the CAT in IPF. METHODS: The clinical data for 106 consecutive subjects with newly diagnosed IPF who completed pulmonary function tests, partial pressure of oxygen in arterial blood (PaO2 ) at rest, 6-min walk test (6MWT), CAT, St George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnoea grade and Hospital Anxiety and Depression Scale (HADS), were analysed. We assessed the validity of the CAT in comparison with the SGRQ. RESULTS: The present subjects showed mild to moderate restrictive impairment on spirometry. Mean CAT score and total SGRQ were 12.8 ± 8.0 and 30.8 ± 17.7, respectively. The concurrent validity of the CAT score in comparison with the SGRQ total score was significant (r = 0.72, P < 0.001). Internal consistency (Cronbach's α = 0.869) and repeatability over 3 months (intraclass correlation coefficient = 0.742) of the CAT were also significant. Single regression analysis showed that the CAT had significant construct validity. In multiple regression analysis, mMRC, PaO2 at rest, minimum SpO2 during 6MWT and anxiety of HADS were independent predictors for the CAT. CONCLUSIONS: The CAT is a valid health status measurement in IPF patients. Multiple regression analysis showed that the CAT was significantly correlated with dyspnoea severity, oxygenation impairment and anxiety.

Exercise hypoxaemia as a predictor of pulmonary hypertension in COPD patients without severe resting hypoxaemia.

BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) in COPD is associated with morbidity and mortality. Previous studies showed a relationship between resting hypoxaemia and PH, but little is known about the relationship between exercise hypoxaemia and PH in COPD without resting hypoxaemia. METHODS: A retrospective observational study of COPD patients without resting hypoxaemia was conducted to evaluate the relationships between exercise hypoxaemia and pulmonary haemodynamics. Clinical characteristics, pulmonary function, blood gas analysis, 6-min walk distance (6MWD) and oxygen saturation of peripheral artery (SpO2 ) at the end of the 6-min walk test (6MWT) were reviewed. Correlation analysis and stepwise regression analysis were performed to identify the predictor of mean pulmonary artery pressure (mPAP). RESULTS: Eighty-four consecutive patients with a mean predicted forced expiratory volume in 1 s (FEV1 ) of 47 ± 21% were evaluated. In univariate analysis, mPAP had negative correlations with age (r = -0.27, P < 0.05), arterial partial pressure of oxygen (PaO2 , r = -0.24, P < 0.05), % predicted forced vital capacity (FVC, r = -0.28, P < 0.05), % predicted FEV1 (r = -0.40, P < 0.001), FEV1 /FVC ratio (r = -0.33, P < 0.005), % predicted diffusion capacity for carbon monoxide (DLCO , r = -0.40, P < 0.001), 6MWD (r = -0.40, P < 0.001) and SpO2 at the end of the 6MWT (r = -0.74, P < 0.001). In stepwise regression analysis, SpO2 at the end of the 6MWT and 6MWD remained as independent predictors of mPAP (R2 = 0.60). In receiver operating characteristic (ROC) analysis, SpO2 at the end of the 6MWT presented an area under the curve of 0.896 for the prediction of PH, with a sensitivity of 0.86 and specificity of 0.84 for the cut-off point of 81%. CONCLUSION: In addition to 6MWD, exercise hypoxaemia indicates PH in patients with COPD without resting hypoxaemia.

Nintedanib in Japanese patients with idiopathic pulmonary fibrosis: A subgroup analysis of the INPULSIS® randomized trials.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia. Nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) compared with placebo in patients with IPF in two replicate trials (INPULSIS®). We examined the efficacy and safety of nintedanib in Japanese patients. METHODS: We conducted pre-specified subgroup analyses of the annual rate of decline in FVC, time to first acute exacerbation (AE), change from baseline in St George's Respiratory Questionnaire (SGRQ) total score and safety using pooled data from the INPULSIS® trials for Japanese patients. RESULTS: In the overall population, 76 of 638 and 50 of 423 patients in the nintedanib and placebo groups, respectively, were Japanese. Results in Japanese patients were consistent with those in the overall population. In Japanese patients, the adjusted annual rate of decline in FVC was -135.9 mL/year in the nintedanib group and -267.7 mL/year in the placebo group (difference (95% CI): 131.9 (50.7, 213.1) mL/year); the hazard ratio for the time to first AE was 0.25 (0.06, 1.02); and the adjusted mean change from baseline in SGRQ total score at week 52 was 5.81 in the nintedanib group and 9.68 in the placebo group (difference: -3.87 (-8.51, 0.76)). Diarrhoea and liver-related adverse events were the most common events in the nintedanib group, but were reversible following dose reduction, drug interruption or symptomatic therapy. CONCLUSION: The present results indicate that the efficacy and safety of nintedanib in Japanese patients are comparable with those in the overall population.

Disease severity staging system for idiopathic pulmonary fibrosis in Japan.

BACKGROUND AND OBJECTIVE: In Japan, the classification of disease severity of idiopathic pulmonary fibrosis (IPF) (J-system) has been used in making decisions on medical care subsidies. The present J-system consists of arterial partial pressure of oxygen (PaO2 ) and exercise desaturation in stages of I-IV. It provides a good prognostic classification in stages III and IV, but not in stages I and II. Therefore, we propose a revised system to improve discriminative ability in stages I and II. METHODS: We compared the revised J-system with the present J-system using Cox proportional hazards model to predict mortality rate. We also evaluated the recently proposed GAP (Gender, Age and Physiology) system in comparison to both J-systems. RESULTS: Two-hundred and fifteen IPF patients were studied retrospectively. A univariate model showed that the present and revised J-systems and a modified GAP system were all significant prognostic factors. The C-statistic for discriminating prognosis was higher in the revised J-system than the modified GAP system and the present J-system (0.677, 0.652 and 0.659, respectively). The C-statistics of these models produced from the 10 000 bootstrap samples were similar to those of the original models, suggesting good internal validation (0.665 (95% CI: 0.621-0.705), 0.645 (0.600-0.686) and 0.659 (0.616-0.700), respectively). Multivariate analysis revealed that the revised J-system (P = 0.0038) and the modified GAP system (P = 0.0029) were independent prognostic factors. CONCLUSION: The revised J-system can provide a better mortality prediction than the present one. Both the revised J-system and the modified GAP system are independent and valuable tools for prognostication and clinical management for IPF.