Acute exacerbation of idiopathic interstitial pneumonias related to chemotherapy for lung cancer: nationwide surveillance in Japan.

BACKGROUND: Chemotherapy-induced acute exacerbation (AEx) of idiopathic interstitial pneumonias (IIPs) seriously compromises the success of treatment of Japanese lung cancer patients. Here, we conducted a nationwide surveillance to clarify the risk of AEx and compare it with the survival benefit of chemotherapy for this population. METHODS: Advanced nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC) patients with IIPs were retrospectively analysed. For the surveillance of first-line chemotherapy in 2009, we gathered clinical data from 396 patients who received chemotherapy at 19 institutions between January 1990 and July 2009. In a consecutive retrospective study in 2012, we analysed data from 278 patients from 17 institutions who received second-line chemotherapy between April 2002 and March 2012. RESULTS: Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively. CONCLUSION: Combination chemotherapies consisting of CP or CE are candidates for standard first-line treatments for patients with advanced lung cancer accompanied by IIP. Second-line chemotherapy should be considered for patients remaining fit enough to receive it.

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.

Early decrease in erector spinae muscle area and future risk of mortality in idiopathic pulmonary fibrosis.

Computed tomography (CT) assessment of the cross-sectional area of the erector spinae muscles (ESMCSA) can be used to evaluate sarcopenia and cachexia in patients with lung diseases. This study aimed to confirm whether serial changes in ESMCSA are associated with survival in patients with idiopathic pulmonary fibrosis (IPF). Data from consecutive patients with IPF who were referred to a single centre were retrospectively reviewed. We measured the ESMCSA at the level of the 12th thoracic vertebra on CT images at referral and 6 months later (n = 119). The follow-up time was from 817-1633 days (median, 1335 days) and 59 patients (49.6%) died. A univariate Cox regression analysis showed that the decline in % predicted forced vital capacity (FVC) (Hazard ratios [HR] 1.041, 95% confidence interval [CI] 1.013-1.069, P = 0.004), the decline in body mass index (BMI) (HR 1.084, 95% CI 1.037-1.128; P < 0.001) and that in ESMCSA (HR 1.057, 95% CI 1.027-1.086; P < 0.001) were prognostic factors. For multivariate analyses, the decline in ESMCSA (HR 1.039, 95% CI 1.007-1.071, P = 0.015) was a significant prognostic factor, while those in % FVC and BMI were discarded. Early decrease in ESMCSA may be a useful predictor of prognosis in patients with IPF.

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).

Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor T-251 in rodents.

Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP. PDE10A is selectively expressed in medium spiny neurons in the striatum, suggesting the potential of PDE10A inhibitors in the treatment of schizophrenia. This study presents the pharmacological profile of a novel PDE10A inhibitor, 2-[(E)-2-(7-fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine hydrochloride (T-251) in rodent models of schizophrenia. T-251 showed a potent inhibitory activity against human PDE10A (IC50 = 0.050 nmol/L) and showed high selectivity over other PDE families which have over 10,000-fold IC50 values. Oral administration of T-251 (0.1-1.0 mg/kg) increased cAMP and cGMP in the striatum in a dose-dependent manner. Oral administration of T-251 attenuated MK-801 induced hyperactivity (ED50 = 0.68 mg/kg) and suppressed conditioned avoidance response (ID50 = 0.87 mg/kg) in rats in a dose dependent manner. Furthermore, T-251 significantly attenuated MK-801 induced prepulse inhibition deficits and cognitive deficits in rats. Unlike haloperidol and olanzapine, T-251 (1.0-30 mg/kg) did not cause catalepsy in rats. Moreover, T-251 (0.6 and 6.0 mg/kg) did not increase plasma levels of prolactin at 1 h after administration, whereas haloperidol and olanzapine significantly increased them. The antipsychotic-like effects and cognitive enhancement of T-251 without catalepsy or plasma prolactin elevation observed in rats suggests that T-251 would be a novel antipsychotic with an improved side-effect profile.

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.

Pulmonary interstitial emphysema is a risk factor for poor prognosis and a cause of air leaks.

BACKGROUND: Pulmonary interstitial emphysema is a rare, abnormal condition in which air pressure from the alveolar airspace tears the adjacent interstitial tissues of the lung and causes the formation of cystic spaces. Pulmonary interstitial emphysema is a known indication for mechanical ventilation in premature infants with neonatal respiratory distress syndrome, and it can be observed in various types of interstitial lung disease. Nevertheless, its pathogenesis and clinical impact remain unknown. METHODS: We reviewed data from 433 cases of interstitial lung disease from an external consultation archive. Multidisciplinary diagnosis along with clinical and follow-up data, including events of air leaks such as pneumothorax and mediastinal emphysema, were obtained and compared to those of 150 control cases of interstitial lung disease without pulmonary interstitial emphysema. RESULTS: We found 22 (5.1%) cases of interstitial lung disease with pulmonary interstitial emphysema. The diagnoses included idiopathic pulmonary fibrosis (5/22 [22.7%]), pleuroparenchymal fibroelastosis (4/22 [18.2%]), chronic hypersensitivity pneumonia (4/22 [18.2%]), and others (9/22 [40.9%]). Cases involving pulmonary interstitial emphysema demonstrated a significantly higher frequency of air leaks than did those without pulmonary interstitial emphysema (12/22 [54.5%] versus 23/150 [15.3%]; P < 0.001; odds ratio, 6.63) and were associated with worse prognosis (P = 0.009 [log-rank]) and a lower median percent forced vital capacity (73.2% versus 84.0%; P < 0.001). CONCLUSIONS: We found that pulmonary interstitial emphysema is an independent factor for poor prognosis, which also shows a trend to cause air leaks, including pneumothorax and mediastinal emphysema.

Proposed method of histological separation between connective tissue disease-associated interstitial pneumonia and idiopathic interstitial pneumonias.

OBJECTIVES: Idiopathic interstitial pneumonia (IIP) and connective tissue disease -associated interstitial pneumonia (CTD-IP) are the two most common types of interstitial pneumonia. IIP and CTD-IP share common histological features, yet their clinical management is different. Separation of the two conditions based solely on histology can be challenging, and there are no established criteria. MATERIALS AND METHODS: We selected 105 consecutive cases of IIP (79 usual interstitial pneumonia and 26 non-specific interstitial pneumonia) and 49 cases of CTD-IP for derivation and 32 cases of IIP and 10 cases of CTD-IP for validation. Fourteen histological parameters were evaluated independently by two pathologists for derivation group and graded into 0 to 3. The association between the score for each marker and a diagnosis of CTD was investigated using Fisher's exact test and stepwise logistic regression analysis. A formula for calculating the probability of IIP and CTD-IP was constructed by the markers identified in the regression test with coefficients for each finding. The formula was confirmed using validation case group. RESULTS: Stepwise logistic regression analysis showed that plasmacytosis, lymphoid follicle with germinal center, and airspace fibrin were suggestive of CTD-IP and that fibroblastic foci, smooth muscle hyperplasia, cellular IP, dense perivascular collagen, and fat metaplasia were suggestive of IIP. The formula used to calculate the probabilities based on estimated values for each finding was created, and user-friendly web based app was composed at www.ctdip.com. On the validation study, 30 out of 32 IIP and eight out of 10 CTD-IPs were distinguished correctly by the app (Specificity: 93%, Sensitivity: 80%). CONCLUSIONS: We identified histological markers and derived a practical formula and user-friendly app to distinguish CTD-IPs from IIP.

Outcomes with newly proposed classification of acute respiratory deterioration in idiopathic pulmonary fibrosis.

BACKGROUND: Respiratory-related hospitalization, in particular acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), is common and associated with increasing mortality in patients with IPF. We aimed to evaluate the implications of a newly proposed framework of acute respiratory deterioration (ARD) and AE-IPF in hospitalized patients. METHODS: Using the data of an IPF cohort consisting of 225 consecutive patients, we retrospectively studied first hospitalizations from January 2008 to December 2017. We analysed the demographics and 90-day mortality of patients with AE-IPF and those with parenchymal cause of ARD other than AE. RESULTS: Among 122 patients with first hospitalization for ARD, 35 patients were diagnosed with AE-IPF, including 11 patients with triggered AE. Parenchymal cause of ARD other than AE was diagnosed in 71 patients, and extra-parenchymal cause in 16 patients. Almost all hospitalized patients (93%) underwent chest CT, and 83% of patients with AE-IPF underwent bronchoalveolar lavage. There was a significant difference in the anti-inflammatory therapy between the AE-IPF group and parenchymal cause of ARD other than AE group (p < 0.001). AE-IPF was independently associated with poor survival in multivariate Cox proportional regression analysis. CONCLUSIONS: AE-IPF accounted for about 30% of first hospitalizations for ARD, and differentiation between AE-IPF and the other categories in ARD is important from a therapeutic and a prognostic point of view.

Japanese guideline for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public.

Clinical spectrum and prognostic factors of possible UIP pattern on high-resolution CT in patients who underwent surgical lung biopsy.

BACKGROUND: Few studies have reported the diagnostic variability in patients with a possible usual interstitial pneumonia (UIP) pattern on high-resolution CT (HRCT) who underwent surgical lung biopsy (SLB), and the prognostic factors for these patients have not been fully evaluated. We retrospectively investigated the frequency of idiopathic pulmonary fibrosis (IPF) and prognostic factors in patients with possible UIP pattern on HRCT. METHODS: Consecutive patients who had a possible UIP pattern on HRCT, underwent SLB, and had a diagnosis of IIPs before SLB were retrospectively recruited from 10 hospitals. Diagnoses were made based on multidisciplinary discussion using the criteria for current IPF guidelines and multidisciplinary classification for IIPs in each hospital. RESULTS: 179 patients who underwent SLB were enrolled. The diagnoses were IPF in 91 patients (51%), unclassifiable IIPs in 47 (26%), idiopathic NSIP in 18 (10%), and chronic hypersensitivity pneumonia in 17 (9%). One-year FVC changes showed significant differences between IPF and non-IPF (-138.6 mL versus 18.2 mL, p = 0.014). Patients with IPF had a worse mortality than those with non-IPF (Logrank test, p = 0.025). Multivariable Cox regression analysis demonstrated that diagnoses of IPF (HR, 2.961; 95% CI, 1.183-7.410; p = 0.02), high modified MRC score (HR, 1.587; 95% CI, 1.003-2.510; p = 0.049), and low %FVC (HR, 0.972; 95% CI, 0.953-0.992; p = 0.005). CONCLUSIONS: About a half of patients with a possible UIP pattern on HRCT had diagnoses other than IPF, and patients with IPF had a worse mortality than those with an alternative diagnosis. We reaffirmed that multidisciplinary discussion is crucial in patients with possible UIP pattern on HRCT.

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.

A Volumetric Computed Tomography Analysis of the Normal Lung in Idiopathic Pulmonary Fibrosis: The Relationship with the Survival.

Objective An image analysis of high-resolution computed tomography (HRCT) can provide objective quantitation of the disease status in idiopathic pulmonary fibrosis (IPF). However, to our knowledge, no reports have investigated the utility of the normal lung volume for evaluating mortality from IPF. This study aimed to evaluate the relationship between the normally attenuated lung volume on HRCT as a percentage of whole-lung volume (NL%) and IPF mortality. Methods The NL% was determined by HRCT (between -950 and -701 Hounsfield units) using a density mask technique and volumetric software. The NL%, visual assessments of the normal lung by two radiologists, pulmonary function variables, and the gender, age, and physiology (GAP) index were retrospectively evaluated for 175 patients with IPF. Uni- and multivariate Cox proportional hazards analyses and C statistics for mortality were performed. Results The univariate Cox proportional hazards analysis identified the NL% as a prognostic factor [hazard ratio, 0.949; 95% confidence interval (CI), 0.936-0.964; p<0.0001]. In the multivariate analysis, the NL% was a prognostic factor, but the radiologists' visual assessment scores of normal lung were not. The C index increased when the NL% was included in the models of the pulmonary function variables. Furthermore, the C index for a combined model of GAP stage and categorized NL% (0.758; 95% CI, 0.751-0.762) was higher than for the model with the GAP stage alone (0.689; 95% CI, 0.672-0.709). Conclusion The NL% was a prognostic factor in our study population. Quantification of the normal lung using our method may help improve the IPF staging systems.

Prognostic evaluation by oxygenation with positive end-expiratory pressure in acute exacerbation of idiopathic pulmonary fibrosis: A retrospective cohort study.

INTRODUCTION: Acute exacerbation (AE) is a severe complication of idiopathic pulmonary fibrosis (IPF), which shares some common pathological features with acute respiratory distress syndrome (ARDS). The new definition of ARDS requires positive end-expiratory pressure (PEEP) to assess gas exchange and has better predictive validity for short-term mortality compared with the previous definition. OBJECTIVES: The aim of this study was to evaluate the prognostic utility of oxygenation with PEEP in AE-IPF. METHODS: We performed a retrospective cohort study using the data of AE-IPF patients between 2007 and 2015. At the time of diagnosis, PaO2 /FiO2 was evaluated before and 30 minutes after PEEP. We evaluated the prognostic utility of PaO2 /FiO2 with PEEP after including other candidate prognostic factors. Considering the definition of ARDS, patients with AE-IPF were classified into a severe group (PaO2 /FiO2 ≤ 300 with PEEP) and a non-severe group (PaO2 /FiO2 > 300 with PEEP). RESULTS: We identified 62 consecutive patients with AE-IPF. All patients were treated with mechanical ventilation on the first day. The median PaO2 /FiO2 before and 30 minutes after PEEP was significantly increased (237.5-425.5, P < .001). In multivariate Cox proportional analysis, Krebs von den Lungen-6 (KL-6) (HR 1.239; 95%CI 1.050-1.461; P = .011), D-dimer (HR 1.039; 95%CI 1.015-1.064; P = .001), % neutrophils in bronchoalveolar lavage fluid (HR 1.015; 95%CI 1.003-1.027; P = .017), and being in the severe group (HR 3.233; 95%CI 1.503-6.957; P = .003) had significant impacts on survival up to 90 days. CONCLUSION: Evaluation of oxygenation with PEEP may provide useful information for predicting short-term mortality in patients with AE-IPF.

Idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by progressive lung scarring and the histological picture of usual interstitial pneumonia (UIP). It is associated with increasing cough and dyspnoea and impaired quality of life. IPF affects ∼3 million people worldwide, with incidence increasing dramatically with age. The diagnostic approach includes the exclusion of other interstitial lung diseases or overlapping conditions and depends on the identification of the UIP pattern, usually with high-resolution CT; lung biopsy might be required in some patients. The UIP pattern is predominantly bilateral, peripheral and with a basal distribution of reticular changes associated with traction bronchiectasis and clusters of subpleural cystic airspaces. The biological processes underlying IPF are thought to reflect an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible ageing individual, although many questions remain on how to define susceptibility. Substantial progress has been made in the understanding of the clinical management of IPF, with the availability of two pharmacotherapeutic agents, pirfenidone and nintedanib, that decrease physiological progression and likely improve progression-free survival. Current efforts are directed at identifying IPF early, potentially relying on combinations of biomarkers that include circulating factors, demographics and imaging data.

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.

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.

Depression Is Significantly Associated with the Health Status in Patients with Idiopathic Pulmonary Fibrosis.

Objective Depression is reported to be relatively common in idiopathic pulmonary fibrosis (IPF) patients. Thus far, however, whether or not depression independently determines the health-related quality of life (HRQOL) has not been evaluated exclusively in IPF patients. We designed this study to identify independent determinants of the St. George' s Respiratory Questionnaire (SGRQ) score among various factors, including a depression scale, in IPF patients. Methods We retrospectively analyzed consecutive subjects with IPF who completed a systematic evaluation including pulmonary function tests, PaO2 at rest, 6-minute walk test (6MWT), SGRQ, Baseline Dyspnea Index (BDI), and Hospital Anxiety and Depression Scale (HADS). All eligible patients in the present study had newly diagnosed IPF and had not received any prior treatments, such as antidepressants, pirfenidone, corticosteroids, immunosuppressants, or long-term oxygen therapy. Results The 121 patients with IPF included 99 men. On the SGRQ, mild to moderate disturbance was observed in the total and each component score. According to the HADS, 27 patients (22.3%) had borderline or definite depression. In a univariate regression analysis, the forced vital capacity (FVC), diffusion capacity of carbon monoxide (DLco), PaO2 at rest, BDI, HADS for Anxiety (HADS-A) and Depression (HADS-D), 6-minute walk distance (6MWD), and lowest SpO2 during the 6MWT were significantly correlated with the SGRQ total score. In a stepwise multiple regression model, BDI, 6MWD, and HADS-D were selected as independent determinants of the total SGRQ score. The total variance in this model was 59% (p<0.001). Conclusion We concluded that depression was a significant determinant of the HRQOL or health status in patients with IPF.

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.

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.