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Idiopathic pulmonary fibrosis (IPF) is a diagnosis of exclusion, requiring that potential etiologies of interstitial lung disease be ruled out. Antinuclear antibody (ANA) testing is commonly performed in individuals with IPF, but the clinical significance of ANA positivity remains uncertain. A retrospective search identified 161 patients diagnosed with IPF between May 2010 and January 2021. Data on ANA titers at the time of diagnosis were available in all cases. Mean age of the patients was 66.4 ± 9.6 years; 70.8% were male. ANA titers were high (≥ 1:160) in 25.4% of the cohort. Baseline characteristics were comparable between those with high and low ANA titers. During follow-up (median 28 months), 93 patients (57%) died. On Cox proportional-hazards analysis with lung transplantation entered as a competing risk and adjusting for potential confounders (age, sex, and baseline forced vital capacity and diffusing lung capacity for carbon monoxide), ANA ≥ 1:160, as a dichotomized variable, was significantly associated with case-specific mortality (HR 2.25, 95% CI 1.14-4.42, P = 0.02) and older age (for each 10-year increment, HR 1.55, 95% CI 1.07-2.25, P = 0.02). High ANA titers appear to be associated with increased mortality in IPF. This finding emphasizes the potential prognostic value of ANA testing. Further studies are needed to validate these findings and explore their implications for patient management., (© 2024. The Author(s).)

Introduction: Most patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotics (AF) have progressive disease despite treatment. A switch of AF may improve survival, but evidence from randomised controlled trials is missing. We aimed to evaluate the efficacy of an AF switch on survival and FVC decline in patients from the European MultiPartner IPF registry (EMPIRE)., Methods: The study included 612 patients who discontinued the first antifibrotic therapy. Patients were grouped and analysed from two perspectives: (1) whether they had received a second antifibrotic treatment after the discontinuation of the first therapy, and (2) a reason for discontinuation of the first AF - "lack of efficacy" (LE) and "intolerance" (INT)., Results: While 263 (43%) of 612 patients received no second AF ("non-switched"), 349 (57%) patients switched. Overall survival was higher in patients who received a second AF (median 50 vs. 29 months; adjusted HR 0.64, P=0.023). Similarly, the annual FVC decline was significantly reduced in switched patients: -98ml/y in switched and -172ml/y in non-switched patients (P=0.023), respectively. The switched patients had similar risk for mortality in both LE and INT groups (adjusted HR 0.95, P=0.85). The high impact of switching on survival was demonstrated in LE patients (adjusted HR 0.27, P<0.001)., Conclusion: The patients without a second AF had significantly shorter overall survival. Our analysis suggests the importance of switching patients with an ineffective first AF therapy to a second AF therapy., (Copyright © 2023 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Patients with interstitial lung disease (ILD) are at high risk of severe COVID-19 infection. Additionally, their anti-inflammatory and antifibrotic treatment may cause immunosuppression. Nevertheless, their ability to mount an adequate immune response to messenger RNA SARS-CoV-2 vaccines was not evaluated. Therefore, we aimed to evaluate the humoral response after the BNT162b2 vaccine among idiopathic pulmonary fibrosis (IPF) patients treated with antifibrotic therapy and among non-IPF ILD patients treated with anti-inflammatory therapy., Methods: We conducted an observational prospective cohort study to evaluate the level of anti-spike (S-IgG) antibodies after two doses of the BNT162b2 vaccine in patients with ILD. The cohort included 40 patients with idiopathic pulmonary fibrosis (IPF) treated with anti-fibrotic therapy and 29 patients with non-IPF ILD treated with anti-inflammatory therapy. For S-IgG titer measurement, one serology test was drawn from all patients 4-6 months after the second vaccine dose. In addition a control group matched for age and sex was created from a healthy control cohort of 107 patients. The study was conducted in Rabin Medical Center (Israel) between June and August 2021., Results: All patients in the anti-fibrotic arm were seropositive (40/40), corresponding to the matched control group (P = 1.0). The anti-fibrotic arm had a significantly lower median antibody titer in comparison to the matched control group (361.10 [IQR, 207-811] AU/ml vs. 820.75 [IQR, 459-1313] AU/ml; P < 0.001). Only 48.3% (14/29) of patients in the anti-inflammatory arm were seropositive in comparison to 100% (29/29) in the healthy control group (P < 0.001). The anti-inflammatory arm had a significantly lower median antibody titer in comparison to the healthy control group (39.6 [IQR, 4.25-165] AU/ml vs. 970.1 [IQR, 505-1926] AU/ml; P < 0.001)., Conclusion: IPF patients treated with antifibrotic therapy mount an adequate immune response after 2 doses of the BNT162b2 vaccine, and maintain a 100% seropositivity rate 4-6 months after vaccination. However, their antibody titer was reduced in comparison to a healthy control group. Among patients with non-IPF ILD treated with anti-inflammatory therapy, 48% were seronegative 4-6 months after the second vaccine dose. Moreover, treatment with rituximab caused significant immunosuppression, even in comparison to other anti-inflammatory treatments., (© 2022. The Author(s).)

Background: There is no clear evidence whether pirfenidone has a benefit in patients with probable or possible UIP, i.e. when idiopathic pulmonary fibrosis (IPF) is diagnosed with a lower degree of diagnostic certainty. We report on outcomes of treatment with pirfenidone in IPF patients diagnosed with various degrees of certainty., Methods and Findings: We followed patients in the multi-national European MultiPartner IPF Registry (EMPIRE) first seen between 2015 and 2018. Patients were assessed with HRCT, histopathology and received a multi-disciplinary team (MDT) IPF diagnosis. Endpoints of interest were overall survival (OS), progression-free survival (PFS) and lung function decline., Results: A total of 1626 patients were analysed, treated with either pirfenidone (N = 808) or receiving no antifibrotic treatment (N = 818). When patients treated with pirfenidone were compared to patients not receiving antifibrotic treatment, OS (one-, two- and three-year probability of survival 0.871 vs 0.798; 0.728 vs 0.632; 0.579 vs 0.556, P = 0.002), and PFS (one-, two- and three-year probability of survival 0.597 vs 0.536; 0.309 vs 0.281; 0.158 vs 0.148, P = 0.043) was higher, and FVC decline smaller (-0.073 l/yr vs -0.169 l/yr, P = 0.017). The benefit of pirfenidone on OS and PFS was also seen in patients with probable or possible IPF., Conclusions: This EMPIRE analysis confirms the favourable outcomes observed for pirfenidone treatment in patients with definitive IPF and indicates benefits also for patients with probable or possible IPF., Competing Interests: Dr. Kirchgässler is an employee of F. Hoffmann-La Roche Ltd. Dr. Lewandowska reports grants, personal fees and non-financial support from F. Hofmann-La Roche, grants, personal fees and non-financial support from Boehringer Ingelheim. Dr. Müller received grants and personal fees from Roche and Boehringer Ingelheim. Dr. Stoeva reports and received fees from Boehringer Ingelheim for participation in advisory boards and from Roche for presentations. Dr. Studnicka reports grants and personal fees from Boehringer-Ingelheim, grants and personal fees from Roche, during the conduct of the study. Dr. Tekavec-Trkanjec reports personal fees from Roche, personal fees and other from Boehringer Ingelheim. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Spectrophotometric techniques provide qualitative but not quantitative data on lung particles. We aimed to quantitate silica content in biopsies of lung-transplanted silicosis patients by applying X-ray fluorescence (XRF) spectrometry. Lung biopsies of 17 lung-transplanted artificial patients were quantitated for silica and other minerals particles by Niton XL3 XRF spectrometry. Occupational and clinical history data were assessed. Lung biopsies of artificial stone-induced silicosis (ASIS) patients contained significantly higher levels of silica compared to those of idiopathic pulmonary fibrosis (IPF) patients (7284.29 ± 4693.75 ppm vs. 898.88 ± 365.66 ppm, p < 0.0001). Silica content correlated negatively with age, body mass index, and pulmonary function test results. A 1128 ppm silica cut-off value yielded 100% sensitivity and 94% specificity for predicting ASIS (AUC = 0.94, p < 0.0001). In conclusion, XRF measurements in lung biopsies can differentiate between silica and mineral particles in ASIS and IPF., Competing Interests: The authors declare no conflict of interest.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix-fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH 4 OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of 'HIF1α signaling pathway' (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1 . IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.

Background: The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis (IPF) at risk of poor outcomes from pulmonary hypertension, whether already present or likely to develop, is uncertain. We aimed to assess the efficacy and safety of sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeks in patients with advanced IPF and at risk of group 3 pulmonary hypertension., Methods: We did a multicentre, international, double-blind, randomised, placebo-controlled, phase 2b study at 56 university clinics, research hospitals, and tertiary sites in Canada, Europe (Belgium, Czech Republic, Germany, Greece, Hungary, Italy, the Netherlands, Spain, and Turkey), Israel, and Africa (Egypt and South Africa). Eligible patients (aged 40-80 years) had advanced IPF (carbon monoxide diffusing capacity ≤40% predicted at screening), and were at risk of group 3 pulmonary hypertension (mean pulmonary artery pressure of ≥20 mm Hg with pulmonary artery wedge pressure of ≤15 mm Hg on previous right-heart catheterisation, or intermediate or high probability of group 3 pulmonary hypertension on echocardiography as defined by the 2015 European Society of Cardiology and European Respiratory Society guidelines). Patients were randomly assigned 1:1 to oral sildenafil tablets (20 mg three times daily) or placebo, both in addition to oral pirfenidone capsules (801 mg three times daily), using a validated interactive voice-based or web-based response system with permuted block randomisation, stratified by previous right-heart catheterisation (yes or no) and forced expiratory volume in 1 s to forced vital capacity ratio (<0·8 or ≥0·8). The composite primary endpoint was disease progression, defined as either a relevant decline in 6-min walk distance, respiratory-related admission to hospital, or all-cause mortality, after 52 weeks and was assessed in the intention-to-treat population; safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02951429, and is no longer recruiting. The 11-month safety follow-up is ongoing., Findings: Between Jan 13, 2017, and Aug 30, 2018, 247 patients were screened for eligibility, 177 of whom were randomly assigned to a treatment group (n=88 sildenafil; n=89 placebo) and were assessed for the primary outcome. There was no difference in the proportion of patients with disease progression over 52 weeks between the sildenafil (64 [73%] of 88 patients) and placebo groups (62 [70%] of 89 patients; between-group difference 3·06% [95% CI -11·30 to 17·97]; p=0·65). Serious treatment-emergent adverse events were reported in 54 (61%) patients in the sildenafil group and 55 (62%) patients in the placebo group. Treatment-emergent adverse events leading to mortality occurred in 22 (25%) patients in the sildenafil group and 26 (29%) in the placebo group., Interpretation: Addition of sildenafil to pirfenidone did not provide a treatment benefit versus pirfenidone plus placebo up to 52 weeks in patients with advanced IPF and risk of pulmonary hypertension. No new safety signals were identified with either treatment. Although the absence of a beneficial treatment effect suggests that sildenafil is not an appropriate treatment in the overall population, further research is required to establish if specific subgroups of patients with IPF might benefit from sildenafil., Funding: F Hoffmann-La Roche., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) has poor prognosis. Anti-fibrotic treatment has been shown to slow disease progression. Lung transplantation (LTx) offers a survival benefit. The 5-year survival after LTx in IPF is between 40 and 50., Objectives: To evaluate which IPF patients have better prognosis following LTx., Methods: A retrospective study was conducted with all IPF patients who had undergone LTx in the Rabin Medical Center between 2010 and 2018. We collected data on pre-evaluation of pulmonary function tests, echocardiographic and right heart catherization, and anti-fibrotic treatments. The Kaplan-Meier method was used for survival analysis., Results: Among148 patients who underwent LTx, 58 were double LTx (DLT) and 90 single LTx (SLT). Mean age was 58.07 ± 9.78 years; 104 males and 44 females. DLT patients had significantly lower survival rates than SLT in the short and medium term after LTx. Patients with saturation above 80% after the 6-minute walk test (6MWT) had higher survival rates. Patients over 65 years of age had a lower survival rates. Those with pulmonary hypertension (PHT) above 30 mmHg had a poorer prognosis with lower survival rates., Conclusions: IPF patients with higher mean PHT, older age (> 65 years), and desaturation following 6MWT had lower survival rates following LTx. DLT may decrease survival rate compared to SLT just for the short and medium period of time after LTx. These results may lead to better selection of IPF patient candidates for LTx. Additional studies are warranted for choosing which patients will have better prognosis after LTx.

Background: Several registries of idiopathic pulmonary fibrosis (IPF) have been established to better understand its natural history, though their size and duration of follow-up are limited. Here, we describe the large European MultiPartner IPF Registry (EMPIRE) and validate predictors of long-term survival in IPF., Methods: The multinational prospective EMPIRE registry enrolled IPF patients from 48 sites in 10 Central and Eastern European countries since 2014. Survival from IPF diagnosis until death was estimated, accounting for left-truncation. The Cox proportional hazards regression model was used to estimate adjusted hazard ratios (HR) of death for prognostic factors, using restricted cubic splines to fit continuous factors., Results: The cohort included 1620 patients (mean age at diagnosis 67.6 years, 71% male, 63% smoking history), including 75% enrolled within 6 months of diagnosis. Median survival was 4.5 years, with 45% surviving 5 years post-diagnosis. Compared with GAP stage I, mortality was higher with GAP stages II (HR 2.9; 95% CI: 2.3-3.7) and III (HR 4.0; 95% CI: 2.8-5.7) while, with redefined cut-offs, the corresponding HRs were 2.7 (95% CI: 1.8-4.0) and 5.8 (95% CI: 4.0-8.3) respectively. Mortality was higher with concurrent pulmonary hypertension (HR 2.0; 95% CI: 1.5-2.9) and lung cancer (HR 2.6; 95% CI: 1.3-4.9)., Conclusions: EMPIRE, one of the largest long-term registries of patients with IPF, provides a more accurate confirmation of prognostic factors and co-morbidities on longer term five-year mortality. It also suggests that some fine-tuning of the indices for mortality may provide a more accurate long-term prognostic profile for these patients.

Background: During cardiopulmonary exercise testing (CPET), Idiopathic Pulmonary Fibrosis (IPF) patients do not reach their direct maximum voluntary ventilation (MVV) and have deranged gas exchange. Their exercise limitation is therefore attributed to a pulmonary vascular mechanism., Methods: We studied two cohorts (derivation and validation) of IPF patients with lung function testing and CPET. Maximal ventilation at exercise (VEpeak) was compared to direct MVV by Bland-Altman analysis., Results: In the derivation cohort (n = 101), direct MVV over-estimated VEpeak by a factor of 1.51, driven by respiratory rate during MVV that was 1.99 times higher at rest as compared to VEpeak at exercise. The formula (FEV1 × 20.1) + 15.4 was shown to predict VEpeak (r 2  = 0.56) in the derivation cohort. In the validation cohort of 78 patients, VEpeak was within a factor of 1.27 (6.8 l/min) of predicted according to the novel formula. According to the novel prediction formula the majority of patients (58%) in the entire cohort have VEpeak within 85% of their predicted MVV, which would indicate a mechanical respiratory limitation to exercise., Conclusion: Estimation of direct MVV performed at rest leads to significant over-estimation of the breathing reserve in IPF patients. This may lead to over-diagnosis of pulmonary vascular limitation in these patients. Expected maximal ventilation at exercise may be accurately predicted indirectly by an IPF-specific formula.

Purpose: This pilot study aimed to compare physiological responses between cycle cardiopulmonary exercise tests (CPETs) and 6-min walk tests (6MWTs) and to assess their prognostic value among patients with idiopathic pulmonary fibrosis (IPF)., Methods: Thirty-four patients with IPF (68 ± 8 yr) underwent CPETs and 6MWTs and were followed up for 40 mo. Differences, levels of agreement, and relative risks for mortality were analyzed between measured and estimated peak responses for the 2 tests., Results: Compared with the CPET, oxygen uptake ((Equation is included in full-text article.)O2), heart rate (HR), and the nadir of SpO2 were lower during the 6MWT, whereas work rate (WR) was higher. Mean differences were as follows: (Equation is included in full-text article.)O2 =-1.9 mL/kg/min, 95% CI, -1.1 to -2.7, P < .001; HR =-9 beats/min, 95% CI, -4 to -14, P = .002; SpO2 =-6%, 95% CI, -4 to -7, P < .001; and WR = 9 W/min, 95% CI, 3 to 16, P = .008. Interclass correlations ranged from 0.84 to 0.90 and both tests demonstrated prognostic value for mortality., Conclusions: Significant differences and variation in peak physiological responses were observed between cycle CPETs and 6MWTs in patients with IPF. However, good agreement was evident, suggesting that both tests provide value for clinical and research settings. Future studies should compare the physiological responses between treadmill CPETs and 6MWTs for prognostic utility in IPF.

Purpose: To assess the prognostic value of the 8-foot-up-and-go test (8-FUGT) in pilot cohort of patients with idiopathic pulmonary fibrosis (IPF)., Methods: Thirty-four patients with IPF (68 ± 8 years) underwent 8-FUGT at baseline and were followed for up to 40 months. Receiver operating characteristics and age-adjusted Cox hazard ratios (HR) were analyzed for 8-FUGT, hospitalizations, and mortality. Correlation coefficients were determined between 8-FUGT and other exercise tests., Results: 8-FUGT ≥ 6.9 s was found to be associated with hospitalization (sensitivity = 77%, specificity = 76%, p = 0.03) and mortality (sensitivity = 91%, specificity = 70% p = 0.008) in patients with IPF. Categorical models demonstrated that 8-FUGT ≥ 6.9 s was associated with 14.1- (p < 0.001) and 55.4-fold (p = 0.001) increased risks for hospitalization and mortality, respectively. In continuous models, for every 1-s slower performance in the 8-FUGT there were 54% [HR = 1.54, 95% CI (1.11-2.15) p = 0.01] increased risk for hospitalization and 94% [HR = 1.94, 95% CI (1.26-2.99) p = 0.003] increased risk for mortality. 8-FUGT was inversely related to 6-min walk distance (r = - 0.61), peak oxygen consumption (r = - 0.58), and peak work rate (r = - 0.72), all p < 0.001., Conclusions: The 8-FUGT was strongly associated with hospitalizations and mortality in patients with IPF, as well as correlated with established prognostic markers. These novel findings suggest a prognostic value of the 8-FUGT for risk stratification, referral to pulmonary rehabilitation, and considering listing for lung transplantation. 8-FUGT is an inexpensive and practical tool that has prospective for implementation in clinical and research settings in IPF. Future prospective studies should evaluate the effect of changes in 8-FUGT on clinical outcomes., Trial Registration: NCT01499745, Clinicaltrials.gov.

Background: A diagnostic lung biopsy may be required in some cases of fibrotic interstitial lung diseases (ILD). Transbronchial cryobiopsy has been suggested as a possible alternative to surgical lung biopsy. However, previous estimates of its diagnostic yield were not validated compared to the definitive diagnosis in explanted lungs., Objectives: We aimed to assess the diagnostic accuracy of cryobiopsy in fibrotic ILD patients who subsequently had lung transplantation., Methods: All 197 patients who underwent lung transplantation at our Center due to fibrotic ILD from January 2010 to May 2018, were screened for the presence of a pre-transplant cryobiopsy. Fourteen patients who underwent cryobiopsy before transplantation were identified. Two expert lung pathologists blindedto the explant diagnoses, independently examined these cryobiopsy specimens to decide if they match guideline criteria for usual interstitial pneumonia (UIP) pattern or an alternative diagnosis. The primary measure was the diagnostic accuracy of cryobiopsy to detect or refute a UIP pattern, as compared to the final explant diagnosis., Results: Median time between cryobiopsy and transplantation was 1.4 years. All 14 cryobiopsy samples contained adequate alveolar tissue. The explant diagnosis of 13/14 patients was UIP. The two pathologists correctly diagnosed or refuted UIP in the cryobiopsy specimen in 12/14 cases (85.7%) and 11/14 cases (78.6%), respectively. The level of diagnostic agreement between pathologists was good (kappa 0.59, p = 0.016)., Conclusions: Compared to the final explant diagnosis, transbronchial cryobiopsy had high diagnostic accuracy and good inter-observer agreement for UIP pattern. These findings support a potential diagnostic role for cryobiopsy in experienced centers., (© 2019 S. Karger AG, Basel.)

Background: Lifestyle behaviors are not well-characterized in idiopathic pulmonary fibrosis (IPF)., Objectives: To assess the association between lifestyle behaviors and clinical outcomes in patients with IPF., Methods: A total of 34 IPF patients (median age 68 years) were assessed for daily sitting and weekly walking times using the International Physical Activity Questionnaire by in-person interview at baseline, and they were followed up for up to 40 months. Cox proportional hazard analysis was conducted for cardiorespiratory-related hospitalizations and mortality as outcomes., Results: Fifty percent of all patients were hospitalized, and 32% died during the follow-up period. Sitting and walking times were associated with hospitalizations and mortality in IPF. Compared to patients who reported a sitting time of <5 h/day, patients who sat 5 to <10 and ≥10 h/day experienced an increased risk of 2.4 and 5.8 (p trend = 0.036) for hospitalization and of 4.6 and 21.2 (p trend = 0.018) for mortality, respectively. Compared to patients walking <100 min/week, patients with a walking time of 100 to <150 and ≥150 min/week were associated with a 49 and 74% reduced risk for hospitalizations (p trend = 0.022) and a 62 and 86% reduced risk for mortality (p trend = 0.018), respectively. The risk for mortality was further reduced with a combination of shorter sitting and extended walking times., Conclusions: Shorter daily sitting and longer weekly walking times were associated with reduced hospitalization and mortality risks in patients with IPF. These findings suggest a clinical importance of assessing lifestyle behaviors in a comprehensive evaluation and prognostication of IPF patients. The results underscore potential clinical benefits of reducing sedentary behaviors among IPF patients; however, this warrants further investigation., (© 2017 S. Karger AG, Basel.)

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease associated with cardiovascular impairments which compromise exercise tolerance and worsen prognosis., Aim: To examine the effect of participating in supervised exercise training (ET) program on cardiovascular function in patients with IPF., Design: A randomized controlled study., Setting: Outpatient hospital., Population: Thirty-two IPF patients (68±8 years)., Methods: An ET group (N.=15) participated in a 12-week twice a week 60-minute supervised exercise program while a control group (N.=17) received usual care. At baseline and after the 12-week intervention all patients underwent resting echocardiography, cardiopulmonary exercise testing and N-terminal pro-brain natriuretic peptide (NT-proBNP) assessments., Results: The ET group significantly improved peak values of exercise cardiovascular indexes while the control group showed a trend of deterioration in the outcomes. The mean difference between the groups (95% CI) for circulatory power was 638 mLO2/kg/min/mmHg (95% CI: 197-1080) (P=0.006), cardiac power output 0.3 W (95% CI: 0.1 to 0.6) (P=0.041), and stroke work 312 mL/beat/mmHg (95% CI: 52-573) (P=0.02). No significant differences between groups were detected in most echocardiography measures and NT-proBNP. Changes in exercise cardiovascular indexes showed significant correlation with improvements in functional capacity, dyspnea and quality of life among ET group., Conclusions: Participation in supervised ET program can improve exercise cardiovascular function in patients with IPF, however resting cardiac evaluations seem to be less sensitive to detect such changes., Clinical Rehabilitation Impact: These findings underscore the utility of supervised ET for cardiovascular enhancement which may also be clinically beneficial in reducing the cardiovascular morbidity and mortality in IPF patients.

Background: Silicosis is a progressive lung disease resulting from the inhalation of respirable crystalline silica. Lung transplantation is the only treatment for end-stage silicosis. The aim of this study was to analyze the survival experience following lung transplantation among patients with silicosis., Methods: We reviewed data for all patients who underwent lung transplantation for silicosis and a matched group undergoing lung transplantation for idiopathic pulmonary fibrosis (IPF) at a single medical center between March 2006 and the end of December 2013. Survival was followed through 2015., Results: A total of 17 lung transplantations were performed for silicosis among 342 lung transplantations (4.9%) during the study period. We observed non-statistically significant survival advantage (hazard ratio 0.6; 95%CI 0.24-1.55) for those undergoing lung transplantation for silicosis relative to IPF patients undergoing lung transplantation during the same period., Conclusions: Within the limits of a small sample, survival in silicosis patients following lung transplantation was not reduced compared to IPF. Am. J. Ind. Med. 60:248-254, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease associated with poor prognosis and limited effective treatment options. Reliable predictors of outcome in daily clinical practice are needed to determine high-risk patients for urgent lung transplantation referral. This study aimed to identify practical prognostic predictors of mortality using cardiopulmonary exercise testing (CPET) in IPF subjects., Methods: Thirty-four subjects with IPF (22 men and 12 women), median age 68 (range 50-81) y were prospectively studied. At baseline, all subjects were assessed with CPET and were followed up for 40 months from baseline. Receiver operating characteristic curve analysis was conducted to determine cut-off points of CPET variables for mortality, Cox regression analysis for survival using a log-rank test, and hazard ratio for death using a Wald test., Results: Peak work rate <62 watts (P = .005), peak V̇O2 ≤13.8 mL/kg/min (P = .031), tidal volume reserve ≤0.48 L/breath (P = .010), minute ventilation to carbon dioxide (V̇E)/V̇CO2 ) ratio at the anaerobic threshold >34 (P = .02), and V̇E)/V̇O2 nadir >34 (P = .002) were detected as cut-off points associated with mortality. Non-survivor subjects were characterized by higher dyspnea levels, the presence of pulmonary hypertension assessed by echocardiography, pronounced inefficient ventilatory pattern, lower exercise capacity, and more severe desaturation during physical exertion. By the end of the study, 11 subjects (7 women and 4 men) died. Overall mean survival was 60%, 33.7 months (95% CI 30.2-37.2)., Conclusions: This study provides simple, practical, and novel cut-off points for CPET as predictors of prognosis to identify high-risk IPF subjects. Impairment in exercise capacity and abnormal ventilatory responses during CPET were associated with poorer survival in IPF subjects. The findings suggest considering the use of CPET for IPF risk stratification and prediction of prognosis. (ClinicalTrials.gov registration NCT01499745.)., (Copyright © 2016 by Daedalus Enterprises.)

Purpose: This study aimed to describe the physiological profile and limiting factors during exercise among patients with idiopathic pulmonary fibrosis., Methods: A descriptive study involving 34 patients with idiopathic pulmonary fibrosis (22 men) aged 68 ± 8 years was conducted. All patients completed a pulmonary function test, cardiopulmonary exercise test, Doppler echocardiography, 6-minute walk test, and modified Medical Research Council dyspnea evaluation., Results: Approximately 38% of patients (range, 15%-71%) presented with coexisting comorbidities including pulmonary hypertension and emphysema. Modified Medical Research Council grades 0-2 and 3-4 were assigned to 68% and 32% of patients, respectively. Median values for forced vital capacity and diffusion capacity for carbon monoxide percent (%) predicted were 68 (95% CI, 63-76) and 51 (95% CI, 46-55), respectively. Left ventricular systolic function was normal. Aerobic capacity ((Equation is included in full-text article.)O2peak = 13.4 mL/kg/min [95% CI, 12.6-14.9]; 62% predicted [95% CI, 56-67]) was moderately reduced with the presence of abnormalities in pulmonary gas exchange and desaturation, circulatory impairments, inefficient ventilation, and skeletal muscle dysfunction. Functional capacity was normal (6-minute walk test distance = 505 m [95% CI, 435-522]; 99% predicted [95% CI, 91-108])., Conclusions: The physiological profile demonstrated the presence of comorbidities in approximately 38% of patients with idiopathic pulmonary fibrosis and a moderate level of dyspnea. Resting cardiopulmonary function showed moderate pulmonary restriction and severe impairments in diffusion capacity with normal left ventricular systolic function. Multifactorial limitations for a moderately diminished aerobic capacity were revealed during the cardiopulmonary exercise test, although functional capacity was normal. These results emphasize the significance of a meticulous evaluation, including the cardiopulmonary exercise test for an accurate exercise tolerance evaluation, to aid in the diagnosis and prognosis and for developing effective targeted treatments.

Objective: To examine the effect of participating in a 12-week supervised exercise training (ET) program on physical activity and body composition in patients with idiopathic pulmonary fibrosis (IPF)., Design: Randomized controlled trial assessing physical activity and body composition at baseline, after 12-week intervention, and at 11 months follow-up., Setting: Outpatient hospital., Participants: Patients with IPF (N=34; mean age, 68±8y) recruited for this study; 32 patients completed the 12-week intervention (ET group: n=15; control group: n=17) and 28 patients (14 in each group) reassessed at 11-month follow-up from baseline., Interventions: Participation in a 12-week supervised ET program or regular medical treatment., Main Outcome Measures: Changes in physical activity levels as measured by the International Physical Activity Questionnaire., Results: After the 12-week intervention, physical activity levels were significantly increased in the ET group whereas the control group showed a trend toward deterioration (median difference between the groups, 2164MET-min/wk [interquartile range, 1576MET-min/wk]; MET = metabolic equivalent; P<.001). Body composition was also significantly improved in the ET group, whereas the control group showed an opposite trend. At 11-month follow-up, no significant differences were observed between the 2 groups in all variables. The ET group lost most of the achieved improvements in the outcomes and returned to near baseline levels, whereas the control group showed a trend toward worsened outcomes., Conclusions: Physical activity and body composition in patients with IPF were improved after a 12-week supervised ET program, although the benefits were not sustained at 11-month follow-up. These results may support the efficacy of participation in supervised ET to improve physical activity and body composition in patients with IPF; however, maintenance strategies are warranted to preserve the improved outcomes., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a chronic devastating interstitial lung disease associated with exercise intolerance, dyspnea, hypoxemia, diminished quality of life and poor prognosis. A growing body of evidence with respect to short-term effects of exercise training has demonstrated clinical benefits in IPF patients. A recent systematic review showed significant improvements in 6-min walking distance, peak aerobic capacity, reduced dyspnea and improved quality of life. However, aspects of training programs, maintenance and predictors of improvement and the impact on prognosis need to be further explored. The aim of this paper was to comprehensively review the existing scientific literature regarding exercise training in patients with IPF and identify important gaps that should be studied in the future.

Purpose: Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating, lung disease, with few therapeutic options. Data are limited with respect to the long-term effect of exercise training (ET) in IPF. This study sought to evaluate the long-term effects of a 12-week ET program on clinical outcomes in IPF patients., Methods: Thirty-four IPF patients were randomly allocated to ET or control groups. ET group participated in a 12-week supervised exercise program, while the control group continued with regular medical treatment alone. Exercise capacity, 30 s-chair-stand test for leg strength, dyspnea, and Saint George's Respiratory Questionnaire (SGRQ) for quality of life (QOL) were assessed at baseline and re-evaluated at 11 months from baseline. In addition, at 30-month time point from baseline, the impact of the 12-week intervention was analyzed with respect to survival and cardio-respiratory-related hospitalizations., Results: Thirty-two patients completed the 12-week intervention and 28 patients (14 in each group) were re-evaluated. At 11-month follow-up, no significant differences between the groups and time effect were demonstrated for most outcomes. ET group showed preserved values at the baseline level while the control group showed a trend of deterioration. Only the 30 s-chair-stand test (mean difference 3 stands, p = 0.01) and SGRQ (mean difference -6 units, p = 0.037) were significantly different between the groups. At 30 months, the survival analysis showed three deaths, eight hospitalizations occurred in the control group versus one death, one lung transplantation and seven hospitalizations in the ET group, with no significant differences between groups., Conclusions: At 11-month follow-up, the 12-week ET program showed clinical outcomes were preserved at baseline levels with some maintenance of improvements in leg strength and QOL in the ET group. The control group showed a trend of deterioration in the outcomes. At 30 months, the 12-week ET program did not show benefits in prognosis although the study was underpowered to detect such differences. We suggest including ET as a long-term continued treatment and as a core component of pulmonary rehabilitation programs for IPF patients.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating, interstitial lung disease, with few therapeutic options. IPF is characterized by pulmonary restriction, dyspnea, hypoxemia, exercise intolerance and poor quality of life (QOL)., Objectives: We aimed to examine the effect of exercise training (ET) on clinical outcomes in IPF patients., Methods: A randomized controlled study included thirty-two IPF patients (aged 68 ± 8 years) who were allocated either to the ET group (n = 15), participating in a 12-week, twice-weekly 60-min supervised ET-based pulmonary rehabilitation program, or to a control group (n = 17) continuing with regular medical treatment alone. Cardiopulmonary exercise test, 6-min walking distance (6MWD) test, 30-second chair-stand test, pulmonary function tests, dyspnea and QOL were assessed at baseline and at the end of the 12-week intervention., Results: Significant differences were observed between the ET and the control groups in raw mean deltas (Δ = post- - pre-intervention): Δ6MWD, 81 m, p < 0.001; ΔVO2 peak, 2.6 ml/kg/min, p = 0.002; Δwork rate, 22 W, p < 0.001; Δanaerobic threshold, 3.1 ml/kg/min, p < 0.001, and ΔFVC % predicted, 6%, p = 0.038. Dyspnea, QOL and 30-second chair-stand were also improved significantly following the program., Conclusions: ET improves exercise tolerance, functional capacity, pulmonary function, dyspnea and QOL in patients with IPF, suggesting a short-term treatment efficacy for clinical improvement, and should be considered the standard care for IPF.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a 3-year median survival. Lung volume and diffusion capacity at rest are usually used to monitor the clinical course. Because of high mortality, identification of patients at high risk is crucial for treatment strategies such as lung transplantation (LTX). This study was designed to determine if tumor markers could accurately characterize disease severity and survival in patients with IPF., Methods: The study population consisted of 61 patients with progressive IPF referred for LTX. Pulmonary function tests, cardiopulmonary exercise test, 6-min walk distance test, and Doppler echocardiogram were assessed at baseline and compared with tumor marker levels. Participants were prospectively followed for at least 25 months to determine the relationship between test parameters and survival. Tumor marker levels were reassessed in patients who underwent LTX. Forty-one age- and sex-matched patients (21 LTX recipients) with COPD served as control subjects., Results: In the IPF group, nine patients (14.7%) died during follow-up and 20 (32.8%) underwent LTX. Univariate analysis showed correlations between carbohydrate antigen (CA) 125 and FEV(1) % (P = .0001). CA 19-9 yielded the best correlations with exercise parameters and PAP. Significant correlation with survival was noted with CA 15-3 (P = .04) only. All tumor marker levels decreased significantly following LTX, except CA 125. CA 15-3 had the largest decrease (P = .001). Among the COPD group, tumor marker levels before LTX were significantly lower compared with the IPF and did not decrease following LTX. No patient in either group developed malignancy., Conclusions: CA 15-3 levels may predict disease severity in IPF. Levels decreased in patients with IPF but not with COPD following LTX and were not associated with malignancy. This preliminary observation suggests that mucin has a role in the pathogenesis of IPF and possibly is a marker for disease activity.

Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease (ILD) characterized by exertional dyspnea, hypoxemia and exercise intolerance. The pathophysiology of IPF usually presents restrictive physiology of lung volume and impaired gas exchange. Most of the research which supports the effectiveness of pulmonary rehabilitation (PR) comes from chronic obstructive pulmonary disease (COPD) patients' studies. However, in the past few years growing evidence has emerged to support the effectiveness and safety of PR programs in IPF patients. Exercise training in PR programs was shown to increase exercise and functional capacity, decreasing shortness of breath and improving quality of life in IPF patients. Nevertheless, PR guidelines for IPF patients have not yet been established. This review presents the current existing data on the effectiveness of PR programs in IPF patients. Large and well controlled trials are needed for the establishment of clinical guidelines of PR in IPF patients.

Background: Lung transplantation is a viable therapy for patients with end-stage lung disease and is being increasingly performed worldwide. The incidence of lung cancer after lung transplantation has increased concomitantly, although data are still sparse., Methods: The computerized medical records of the Pulmonary Institute of a tertiary care medical center were searched for patients who underwent lung transplantation from 1997 to 2009 and acquired lung cancer postoperatively. The prevalence, potential contributing factors, and outcome of bronchogenic cancer were determined, and the medical literature was reviewed., Results: Bronchogenic cancer developed in 7 of the 290 lung transplant recipients (2.4%). All had received a single lung transplant and in most cases, the cancer developed in the native lung. These findings were similar to reports in the literature. The indication for transplantation was chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis/interstitial lung disease. All had a history of smoking. The average interval from transplantation to development of lung cancer was 5 years (range 1-9). Five patients had stage 4 cancer at diagnosis and 2 had stage 1. Six patients died from 10 days to 1 year after diagnosis., Conclusion: Lung transplantation is associated with a relatively high prevalence of bronchogenic cancer, particularly in the native lung, in patients with primary chronic obstructive pulmonary disease/idiopathic pulmonary fibrosis, and a history of smoking. The cancer is usually diagnosed at an advanced stage with poor outcome. Efforts to improve screening are recommended, as aggressive management and treatment may be beneficial for earlier stage disease., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease with a median survival of approximately 3 years. Measurements of lung volumes and diffusion capacity at rest are generally used to monitor the clinical course of IPF. Due to its high mortality, identification of patients at high risk is crucial for treatment strategies such as lung transplantation. This study was design to determine whether the simple 15-step climbing exercise oximetry test accurately characterizes disease severity and survival in patients with IPF., Methods: The study population consisted of 51 patients with progressive IPF. Findings on the 15-step climbing test, pulmonary function tests, cardiopulmonary exercise test and 6-minute walk distance test were assessed at baseline. Participants were prospectively followed for >or=2 years to determine the relationship between the test parameters and survival., Results: On univariate analysis, there were strong correlations between the 15-stair climbing test parameters and survival. On stepwise linear regression analysis, independent significant predictors of mortality were lowest saturation levels on the 15-step test and the 6-minute walk distance test., Conclusions: The lowest saturation and desaturation areas on the 15-step oximetry test are significantly associated with long-term outcome in patients with IPF. We suggest that the 15-step test be used as a simple and reliable tool to predict severity and prognosis in IPF and to identify candidates for lung transplantation.