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The NHLBI convened a working group on October 23, 2019, to identify the most relevant and urgent research priorities and prevailing challenges in e-cigarette or vaping product use-associated lung injury (EVALI). Experts across multiple disciplines discussed the complexities of the EVALI outbreak, identified research priorities, and recommended strategies to address most effectively its causal factors and improve diagnosis, treatment, and prevention of this disease. Many research priorities were identified, including the need to create national and international registries of patients with EVALI, to track accurately those affected and assess outcomes. The group concluded that biospecimens from subjects with EVALI are urgently needed to help define EVALI pathogenesis and that vaping has disease risks that are disparate from smoking, with the occurrence of EVALI highlighting the importance of broadening e-cigarette research beyond comparators to smoking-related diseases.

InterMune Inc. (Brisbane, California, USA) Background The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. Methods The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson's correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a >= 10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a >= 10% decline in FVC or death during the subsequent 6 months. Results A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, -0.146, p= 10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a >= 10% decline in FVC or death (5.9% vs 27.9% relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). Conclusions Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. Inova Fairfax Hosp, Heart & Lung Transplant Ctr, Falls Church, VA 22042 USA Univ Turin, Dept Clin & Biol Sci, Turin, Italy InterMune Inc, Brisbane, CA USA Ruhrlandklin, Dept Pneumol Allergy, Essen, Germany Univ London Imperial Coll Sci Technol & Med, London, England Alfred Hosp, Melbourne, Australia Monash Univ, Melbourne, Australia Univ Miami, Miller Sch Med, Miami, FL 33136 USA Univ Calif San Francisco, San Francisco, CA 94143 USA Vanderbilt Univ, Med Ctr, Nashville, TN USA Columbia Univ, Med Ctr, New York, NY USA Univ Fed Sao Paulo, Paulista Sch Med, Sao Paulo, Brazil Natl Jewish Hlth, Interstitial Lung Dis Program, Denver, CO USA Avicenne Univ Hosp, AP HP, Bobigny, France Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA Royal Brompton Hosp, London SW3 6LY, England Univ Fed Sao Paulo, Paulista Sch Med, Sao Paulo, Brazil| Web of Science

While students entering medical schools are becoming more diverse, trainees in residency programs in competitive specialties and academic medicine faculty have not increased in diversity. As part of an educational continuous quality improvement process at the University of California, San Francisco, School of Medicine, the authors examined data for the classes of 2013-2016 to determine whether differences existed between underrepresented in medicine (UIM) and not-UIM students' clinical performance (clerkship director ratings and number of clerkship honors grades awarded) and honor society membership-all of which influence residency selection and academic career choices.This analysis demonstrated differences that consistently favored not-UIM students. Whereas the size and magnitude of differences in clerkship director ratings were small, UIM students received approximately half as many honors grades as not-UIM students and were three times less likely to be selected for honor society membership.The authors use these findings to illustrate the amplification cascade, a phenomenon in which small differences in assessed performance lead to larger differences in grades and selection for awards. The amplification cascade raises concerns about opportunities for UIM students to compete successfully for competitive residency programs and potentially enter academic careers. Using a fishbone diagram, a continuous quality improvement root cause analysis tool, the authors contextualize their institutional results. They describe potential causes of group differences, drawing from the education disparities literature, and propose interventions and future research. They also share countermeasures adopted at their institution and encourage other medical schools to consider similar exploration of their institutional data.

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg·day−1 or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3–55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0–96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF.

In the updated American Thoracic Society-European Respiratory Society classification of the idiopathic interstitial pneumonias (IIPs), the major entities have been preserved and grouped into (a) "chronic fibrosing IIPs" (idiopathic pulmonary fibrosis and idiopathic nonspecific interstitial pneumonia), (b) "smoking-related IIPs" (respiratory bronchiolitis-associated interstitial lung disease and desquamative interstitial pneumonia), (c) "acute or subacute IIPs" (cryptogenic organizing pneumonia and acute interstitial pneumonia), and (d) "rare IIPs" (lymphoid interstitial pneumonia and idiopathic pleuroparenchymal fibroelastosis). Furthermore, it has been acknowledged that a final diagnosis is not always achievable, and the category "unclassifiable IIP" has been proposed. The diagnostic interpretation of the IIPs is often challenging because other diseases with a known etiology (most notably, connective tissue disease and hypersensitivity pneumonitis) may show similar morphologic patterns. Indeed, more emphasis has been given to the integration of clinical, computed tomographic (CT), and pathologic findings for multidisciplinary diagnosis. Typical CT-based morphologic patterns are associated with the IIPs, and radiologists play an important role in diagnosis and characterization. Optimal CT quality and a systematic approach are both pivotal for evaluation of IIP. Interobserver variation for the various patterns encountered in the IIPs is an issue. It is important for radiologists to understand the longitudinal behavior of IIPs at serial CT examinations, especially for providing a framework for cases that are unclassifiable or in which a histologic diagnosis cannot be obtained.

Summary CT is increasingly being used to stage and quantify the extent of diffuse lung diseases both in clinical practice and in treatment trials. The role of CT in the assessment of patients entering treatment trials has greatly expanded as clinical researchers and pharmaceutical companies have focused their efforts on developing safe and effective drugs for interstitial lung diseases, particularly for idiopathic pulmonary fibrosis. These efforts have culminated in the simultaneous approval by the US Food and Drug Administration of two new drugs for the treatment of idiopathic pulmonary fibrosis. CT features are a key part of the inclusion criteria in many drug trials and CT is now being used to refine the type of patients enrolled. Interest in the potential use of serial CT as an effectiveness endpoint is increasing. For chronic progressive diseases, mortality may not be a feasible endpoint and many surrogate markers have been explored, ranging from pulmonary function decline to biomarkers. However, these surrogate markers are not entirely reliable and combinations of endpoints, including change in disease extent on CT, are being investigated. Methods to assess disease severity with CT range from simple visual estimates to sophisticated quantification by use of software. In this Position Paper, which cannot be regarded as a comprehensive set of guidelines in view of present knowledge, we examine the uses of serial CT in clinical practice and in drug trials and draw attention to uncertainties and challenges for future research.

To investigate the prognostic value of quantitative computed tomographic (CT) scoring for the extent of fibrosis or emphysema in the context of a clinical model that includes the gender, age, and physiology ( GAP gender, age, and physiology model) of the patient.Study cohorts were approved by local institutional review boards, and all patients provided written consent. This was a retrospective cohort study that included 348 patients (246 men, 102 women; mean age, 69 years ± 9) with idiopathic pulmonary fibrosis from two institutions. Fibrosis and emphysema visual scores were independently determined by two radiologists. Models were based on competing risks regression for death and were evaluated by using the C index and reclassification improvement.The CT- GAP gender, age, and physiology model (a modification of the original GAP gender, age, and physiology model that replaces diffusion capacity of carbon monoxide with CT fibrosis score) had accuracy comparable to that of the original GAP gender, age, and physiology model, with a C index of 70.3 (95% confidence interval: 66.4, 74.0); difference in C index compared with the GAP gender, age, and physiology model of -0.4 (95% confidence interval: -2.2, 3.4). The performance of the original GAP gender, age, and physiology model did not change significantly with the simple addition of fibrosis score, with a change in C index of 0.0 (95% confidence interval: -1.8, 0.5) or of emphysema score, with a change in C index of 0.0 [95% confidence interval: -1.3, 0.4]).CT fibrosis score can replace diffusion capacity of carbon monoxide test results in a modified GAP gender, age, and physiology model (the CT- GAP gender, age, and physiology model) with comparable performance. This may be a useful alternative model in situations where CT scoring is more reliable and available than diffusion capacity of carbon monoxide.

Acetylcysteine has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis, although data from placebo-controlled studies are lacking.In our initial double-blind, placebo-controlled trial, we randomly assigned patients who had idiopathic pulmonary fibrosis with mild-to-moderate impairment in pulmonary function to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo. The study was interrupted owing to safety concerns associated with the three-drug regimen. The trial continued as a two-group study (acetylcysteine vs. placebo) without other changes; 133 and 131 patients were enrolled in the acetylcysteine and placebo groups, respectively. The primary outcome was the change in forced vital capacity (FVC) over a 60-week period.At 60 weeks, there was no significant difference in the change in FVC between the acetylcysteine group and the placebo group (-0.18 liters and -0.19 liters, respectively; P=0.77). In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, P=0.30 by the log-rank test) or acute exacerbation (2.3% in each group, P0.99).As compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00650091.).

It is unknown if the radiographic fibrosis score predicts mortality in persistent hypersensitivity pneumonitis (HP) and if survival is similar to that observed in idiopathic pulmonary fibrosis (IPF) when adjusting for the extent of radiographic fibrosis.We reviewed records from 177 patients with HP and 224 patients with IPF whose diagnoses were established by multidisciplinary consensus. Two thoracic radiologists scored high-resolution CT (HRCT) scan lung images. Independent predictors of transplant-free survival were determined using a Cox proportional hazards analysis. Kaplan-Meier survival curves were constructed, stratified by disease as well as fibrosis score.HRCT scan fibrosis score and radiographic reticulation independently predicted time to death or lung transplantation. Clinical predictors included a history of cigarette smoking, auscultatory crackles on lung examination, baseline FVC, and FEV1/FVC ratio. The majority of HP deaths occurred in patients with both radiographic reticulation and auscultatory crackles on examination, compared with patients with only one of these manifestations (Plt; .0001). Patients with IPF had worse survival than those with HP at any given degree of radiographic fibrosis (hazard ratio 2.31; Plt; .01).Survival in patients with HP was superior to that of those with IPF with similar degrees of radiographic fibrosis. The combination of auscultatory crackles and radiographic reticulation identified patients with HP who had a particularly poor outcome.

Background Recent studies have suggested that non-definitive patterns on high-resolution CT (HRCT) scan provide sufficient diagnostic specificity to forgo surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine test characteristics of non-definitive HRCT patterns for identifying histopathological usual interstitial pneumonia (UIP). Methods Patients with biopsy-proven interstitial lung disease (ILD) and non-definitive HRCT scans were identified from two academic ILD centres. Test characteristics for HRCT patterns as predictors of UIP on surgical lung biopsy were derived and validated in independent cohorts. Results In the derivation cohort, 64/385 (17%) had possible UIP pattern on HRCT; 321/385 (83%) had inconsistent with UIP pattern. 113/385 (29%) patients had histopathological UIP pattern in the derivation cohort. Possible UIP pattern had a specificity of 91.2% (95% CI 87.2% to 94.3%) and a positive predictive value (PPV) of 62.5% (95% CI 49.5% to 74.3%) for UIP pattern on surgical lung biopsy. The addition of age, sex and total traction bronchiectasis score improved the PPV. Inconsistent with UIP pattern demonstrated poor PPV (22.7%, 95% CI 18.3% to 27.7%). HRCT pattern specificity was nearly identical in the validation cohort (92.7%, 95% CI 82.4% to 98.0%). The substantially higher prevalence of UIP pattern in the validation cohort improved the PPV of HRCT patterns. Conclusions A possible UIP pattern on HRCT has high specificity for UIP on surgical lung biopsy, but PPV is highly dependent on underlying prevalence. Adding clinical and radiographic features to possible UIP pattern on HRCT may provide sufficient probability of histopathological UIP across prevalence ranges to change clinical decision-making.

Academic medical centers (AMCs) and their academic departments are increasingly assuming leadership in the education, science, and implementation of quality improvement (QI) and patient safety efforts. Fostering, recognizing, and promoting faculty leading these efforts is challenging using traditional academic metrics for advancement.The authors adapted a nationally developed QI portfolio, adopted it into their own department's advancement process in 2012, and tracked its utilization and impact over the first two years of implementation.Sixty-seven QI portfolios were submitted with 100% of faculty receiving their requested academic advancement. Women represented 60% of the submitted portfolios, while the Divisions of General Internal Medicine and Hospital Medicine accounted for 60% of the submissions. The remaining 40% were from faculty in 10 different specialty divisions. Faculty attitudes about the QI portfolio were overwhelmingly positive, with 83% agreeing that it "was an effective tool for helping to better recognize faculty contributions in QI work" and 85% agreeing that it "was an effective tool for elevating the importance of QI work in our department."The QI portfolio was one part of a broader effort to create opportunities to recognize and support faculty involved in improvement work. Further adapting the tool to ensure that it complements-rather than duplicates-other elements of the advancement process is critical for continued utilization by faculty. This will also drive desired dissemination to other departments locally and other AMCs nationally who are similarly committed to cultivating faculty career paths in systems improvement.

The objective of this study was to develop a diagnostic model that allows for a highly specific diagnosis of chronic hypersensitivity pneumonitis using clinical and radiological variables alone. Chronic hypersensitivity pneumonitis and other interstitial lung disease cases were retrospectively identified from a longitudinal database. High-resolution CT scans were blindly scored for radiographic features (eg, ground-glass opacity, mosaic perfusion) as well as the radiologist's diagnostic impression. Candidate models were developed then evaluated using clinical and radiographic variables and assessed by the cross-validated C-statistic. Forty-four chronic hypersensitivity pneumonitis and eighty other interstitial lung disease cases were identified. Two models were selected based on their statistical performance, clinical applicability and face validity. Key model variables included age, down feather and/or bird exposure, radiographic presence of ground-glass opacity and mosaic perfusion and moderate or high confidence in the radiographic impression of chronic hypersensitivity pneumonitis. Models were internally validated with good performance, and cut-off values were established that resulted in high specificity for a diagnosis of chronic hypersensitivity pneumonitis.

Background Decline in forced vital capacity (FVC) over time reliably predicts mortality in patients with idiopathic pulmonary fibrosis. The use of this measure in clinical practice is recommended by current evidence-based guidelines. It is unknown if the method of calculating decline in FVC (relative vs absolute change) impacts its frequency or its ability to predict mortality. Methods Patients with idiopathic pulmonary fibrosis from two prospective cohorts were included if they had a baseline and 12-month follow-up FVC. A ≥10% decline in FVC from baseline was calculated in two ways: a relative decline of 10% (eg, from 60% predicted to 54% predicted) and an absolute decline of 10% (eg, from 60% predicted to 50% predicted). The frequency of a ≥10% decline in FVC and its ability to predict 2-year transplant-free survival were compared between these two methods. Declines in FVC of ≥5% and ≥15% were similarly compared. Analyses were performed unadjusted and adjusted for age, gender, use of oxygen, baseline FVC and baseline diffusion capacity for carbon monoxide. Results The frequency of any given FVC decline was significantly greater using the relative change in FVC method. For ≥10% decline, both methods predicted 2-year transplant-free survival with similar accuracy, and remained significant predictors after adjusting for baseline characteristics. The absolute change method appeared more predictive for ≥5% decline. Conclusions Using the relative change in FVC maximises the chance of identifying a ≥10% decline in FVC without sacrificing prognostic accuracy. This may not hold true for ≥5% decline in FVC. These findings have important implications for clinical practice and the design of clinical trials.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening, interstitial lung disease of unknown etiology. The median survival of patients with IPF is only 2 to 3 years, yet some patients live much longer. Respiratory failure resulting from disease progression is the most frequent cause of death. To date we have limited information as to predictors of mortality in patients with IPF, and research in this area has failed to yield prediction models that can be reliably used in clinical practice to predict individual risk of mortality. The goal of this concise clinical review is to examine and summarize the current data on the clinical course, individual predictors of survival, and proposed clinical prediction models in IPF. Finally, we will discuss challenges and future directions related to predicting survival in IPF.

Little is known about the pathobiology of acute exacerbation of idiopathic pulmonary fibrosis (IPF), a condition that shares clinical and histopathological features with acute lung injury. Plasma biomarkers have been well studied in acute lung injury and have provided insight into the underlying disease mechanism. The objective of this study was to determine the plasma biomarker profile of acute exacerbation of IPF and compare this profile with that of stable IPF and acute lung injury. Plasma was collected from patients with stable IPF, acute exacerbation of IPF, and acute lung injury for measurement of biomarkers of cellular activity/injury (receptor for advanced glycation endproducts, surfactant protein D, KL-6, von Willebrand factor), systemic inflammation (IL-6), and coagulation/fibrinolysis (protein C, thrombomodulin, plasminogen activator inhibitor-1). Plasma from patients with acute exacerbation of IPF showed significant elevations in markers of type II alveolar epithelial cell injury and/or proliferation, endothelial cell injury, and coagulation. This profile differed from the biomarker profile in patients with acute lung injury. These findings support the hypothesis that type II alveolar epithelial cells are centrally involved in the pathobiology of acute exacerbation of IPF. Furthermore, they suggest that acute exacerbation of IPF has a distinct plasma biomarker profile from that of acute lung injury.

Summary Rationale Health-related quality of life (HRQL) is an important outcome in drug trials. Little is known about how the Short Form-36 (SF-36) and Saint George's Respiratory Questionnaire (SGRQ) perform in idiopathic pulmonary fibrosis (IPF). Objectives To examine the validity of the SF-36 and SGRQ and to determine scores from each that would constitute a minimum important difference (MID). Methods We analyzed data from a recently completed trial that enrolled subjects with well-defined IPF who completed the SF-36, SGRQ, and Baseline/Transition Dyspnea Index at baseline and six months. We compared mean changes in HRQL scores between groups of subjects whose disease severity changed over six months according to clinical anchors (FVC, DLCO, and dyspnea). We estimated the MID for each domain by using both anchor- and distribution-based approaches. Main results Results supported the validity of the SF-36 and SGRQ for use in longitudinal studies. Mean changes in domain scores differed significantly between subjects whose clinical status improved and those whose clinical status declined according to the anchors. MID estimates for the SF-36 ranged from 2–4 points and from 5–8 points for the SGRQ. Conclusion In IPF, the SF-36 and SGRQ possess reasonable validity for differentiating subjects whose disease severity changes over time. More studies are needed to continue the validation process, to refine estimates of the MIDs for the SF-36 or SGRQ, and to determine if a disease-specific instrument will perform better than either of these.

Numerous accrediting organizations are calling for competency-based medical education that would help define specific specialties and serve as a foundation for ongoing assessment throughout a practitioner's career. Pulmonary Medicine and Critical Care Medicine are two distinct subspecialties, yet many individual physicians have expertise in both because of overlapping content. Establishing specific competencies for these subspecialties identifies educational goals for trainees and guides practitioners through their lifelong learning.To define specific competencies for graduates of fellowships in Pulmonary Medicine and Internal Medicine-based Critical Care.A Task Force composed of representatives from key stakeholder societies convened to identify and define specific competencies for both disciplines. Beginning with a detailed list of existing competencies from diverse sources, the Task Force categorized each item into one of six core competency headings. Each individual item was reviewed by committee members individually, in group meetings, and conference calls. Nominal group methods were used for most items to retain the views and opinions of the minority perspective. Controversial items underwent additional whole group discussions with iterative modified-Delphi techniques. Consensus was ultimately determined by a simple majority vote.The Task Force identified and defined 327 specific competencies for Internal Medicine-based Critical Care and 276 for Pulmonary Medicine, each with a designation as either: (1) relevant, but competency is not essential or (2) competency essential to the specialty.Specific competencies in Pulmonary and Critical Care Medicine can be identified and defined using a multisociety collaborative approach. These recommendations serve as a starting point and set the stage for future modification to facilitate maximum quality of care as the specialties evolve.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease lacking effective treatment.To determine the effects of bosentan on exercise capacity and time to disease progression in patients with IPF.In a double-blind, multicenter trial, patients with IPF were randomized to receive oral bosentan 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily thereafter, or placebo, for 12 months or longer. The primary efficacy endpoint was change from baseline up to Month 12 in exercise capacity, as measured by a modified six-minute-walk test. Secondary endpoints were time to death or disease progression (worsening pulmonary function tests [PFTs] or acute decompensation), change in PFT scores, and quality of life (QOL) assessed using Short-Form 36 and St. George's Respiratory Questionnaire.A total of 158 patients randomly received bosentan (n = 74) or placebo (n = 84). Bosentan showed no superiority over placebo in six-minute-walk distance (6MWD) up to Month 12, the primary efficacy endpoint. A trend in favor of bosentan was observed in the secondary endpoint of time to death or disease progression (hazard ratio [HR], 0.613; 95% confidence interval [CI], 0.328-1.144; P = 0.119), which was more pronounced in a patient subgroup diagnosed using surgical lung biopsy (post hoc analysis; HR, 0.315; 95% CI, 0.126-0.789; P = 0.009). Changes from baseline up to Month 12 in assessments of dyspnea and QOL favored treatment with bosentan. No unexpected adverse events were reported.Bosentan treatment in patients with IPF did not show superiority over placebo on 6MWD. A trend in delayed time to death or disease progression, and improvement in QOL, was observed with bosentan. The more pronounced treatment effect in patients with biopsy-proven IPF warrants further investigation. Clinical trial registered with www.clinicaltrials.gov (NCT 00071461).

Background The prognostic value of BAL fluid cell count differential in patients with idiopathic pulmonary fibrosis (IPF) is unknown. We hypothesized that baseline BAL fluid cell count differential (ie, elevated levels of neutrophils and eosinophils, or reduced levels of lymphocytes) would predict higher mortality among persons with IPF. Methods We evaluated the association of BAL fluid cell count differential and mortality among 156 persons with surgical lung biopsy-proven IPF who underwent bronchoscopy with BAL and cell count differential measurements at presentation. Vital status was obtained among all participants. Cox regression analysis evaluated the association of BAL fluid cell count differential and mortality. Results After controlling for known clinical predictors of mortality, we found that each doubling of baseline BAL fluid neutrophil percentage was associated with a 30% increased risk of mortality (adjusted hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.01 to 1.62; adjusted p=0.04) in the first year after presentation. We observed no association with BAL fluid lymphocyte percentage and mortality (adjusted HR per doubling, 0.99; 95% CI, 0.76 to 1.29; p=0.93) or eosinophil percentage and mortality (adjusted HR per doubling, 0.99; 95% CI, 0.69 to 1.40; p=0.95). Conclusions Increased BAL fluid neutrophil percentage is an independent predictor of early mortality among persons with IPF. Alternatively, BAL fluid lymphocyte and eosinophil percentages were not associated with mortality. The clinical utility of BAL at the time of diagnosis of IPF should be reconsidered.

High resolution CT (HRCT) scanning has contributed significantly to the evaluation of patients with interstitial lung disease and is particularly useful in the diagnosis of idiopathic pulmonary fibrosis (IPF). The characteristic radiographic features of the idiopathic interstitial pneumonias on HRCT scans have been increasingly analysed and are now fairly well described. Based on current data, HRCT scanning can provide a confident, highly specific diagnosis of IPF in many patients with diffuse lung disease. This article reviews an organised approach to HRCT scanning and identifies the features that allow an accurate diagnosis of the idiopathic interstitial pneumonias to be made. The role of surgical lung biopsy is discussed in the diagnosis of cases when a definite HRCT diagnosis cannot be made.

Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult.Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers.Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days.Each observer's diagnosis was coded into one of eight categories. A kappa statistic allowing for multiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (kappa = 0.55-0.71) than within community centers (kappa = 0.32-0.44). Clinically significant disagreement was present between academic and community-based physicians (kappa = 0.11-0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians.Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options.

BackgroundForced vital capacity (FVC) is a key measure of disease severity in patients with idiopathic pulmonary fibrosis (IPF) and is an important clinical trial endpoint. We hypothesize that reversible airflow limitation co-exists in a subgroup of patients with IPF, and that bronchodilator use will improve the performance characteristics of FVC.MethodsIPF patients with pre and post-bronchodilator spirometry testing performed were identified from two tertiary referral cohorts. The difference between pre and post-bronchodilator FVC (intra-test difference) was calculated. The test characteristics of pre and post-bronchodilator FVC change over time (inter-test difference) were assessed in patients with sequential spirometry, and were used to generate sample size estimates for hypothetical clinical trials using change in FVC as the primary endpoint.ResultsThere were 551 patients, contributing 967 unique spirometry tests. The mean intra-test increase in FVC with bronchodilator use was 0.04L (2.71 vs. 2.75L, p&nbsp

BACKGROUND FVC outcomes in clinical trials on idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary end point of FVC change in a phase 3 trial evaluating pirfenidone in adults with IPF. METHODS Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary end point of change from baseline to week 52 in FVC. RESULTS The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis. CONCLUSIONS Our results confirm the robustness of the statistical finding on the primary end point of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01366209; URL: www.clinicaltrials.gov

Background Some patients with chronic fibrosing interstitial pneumonia (IP) have clinical, serological, and morphological features suggestive of, but not diagnostic for, a connective tissue disease. Several names and diagnostic criteria for this entity have been proposed. The objective of this study was to compare the clinical characteristics and behavior of each of the proposed diagnostic criteria. Methods Patients with chronic fibrosing IP were identified from an ongoing, longitudinal cohort. Four published diagnostic criteria for what we generically label as "IP with features of autoimmunity" were applied to all patients to identify four unique cohorts (Kinder, Vij, Corte, and Fischer). Kaplan–Meier survival functions compared differences in survival in each cohort between patients meeting and not meeting criteria. Unadjusted and adjusted Cox proportional hazard regression models identified predictors of survival. Results The study cohort included 119 patients, 40% of whom were female. The mean age was 65.5 years. There was overlap between the four different criteria, identifying patients with similar clinical characteristics. Interstitial pneumonia patients with features of autoimmunity tended to have improved survival compared to those without these features (p-value range 0.03–0.10) on univariate analysis. After adjusting for disease severity using the gender-age-physiology score, only the Corte criteria was an independent predictor of survival (p-value 0.04). Conclusion Interstitial pneumonia with features of autoimmunity may be associated with improved survival compared to those patients without these features depending on which criteria is used to define the population. These data support the efforts being made to standardize the definition.

Summary Background Mortality is an impractical primary endpoint for clinical trials in patients with idiopathic pulmonary fibrosis who have mild-to-moderate physiological impairment because event rates are low. Change in forced vital capacity (FVC) is widely accepted as a surrogate for mortality and is the most common primary endpoint in clinical trials for this disorder. Use of hospital admission as a predictor for mortality, independent of FVC decline, has not been well defined. We aimed to ascertain the independent and combined association of hospital admission and at least a 10% decrease in FVC with all-cause mortality. Methods We did a pooled cohort study of 517 patients with idiopathic pulmonary fibrosis from three IPFnet multicentre randomised controlled trials. We compared the incidence of non-elective hospital admission and a 10% or greater reduction in FVC across strata of baseline physiological impairment. We used Cox proportional-hazards models to assess the risk of all-cause mortality associated with these surrogate events, occurring up to a predefined landmark timepoint. The three studies are registered at ClinicalTrials.gov, numbers NCT00650091, NCT00517933, and NCT00957242. Findings Seven patients died before the landmark timepoint. Of the 510 patients remaining, 38 (7%) were admitted to hospital up to the predefined timepoint and 58 (11%) had a categorical decrease in FVC of at least 10%. Most patients admitted to hospital did not have a 10% or greater decrease in FVC (30 vs eight). Both surrogate events were associated with subsequent time to death from any cause (hazard ratio [HR] for admission 4·05, 95% CI 1·36–12·11 vs HR for 10% or greater decline in FVC 4·68, 1·83–11·99). When causes of hospital admission were considered, only respiratory events were associated with mortality (5·97, 1·81–19·74). Interpretation Hospital admission might be an appropriate component of a clinically meaningful composite endpoint that improves the feasibility of clinical trials in idiopathic pulmonary fibrosis. Further studies are needed to refine the most appropriate definition of hospital admission for future trials. Funding US National Heart, Lung, and Blood Institute (NHLBI), and The Cowlin Family Fund at the Chicago Community Trust.

In the American Thoracic Society/European Respiratory Society consensus classification, idiopathic interstitial pneumonias are classified into seven clinicopathologic entities. The classification is largely based on histopathology, but depends on the close interaction of clinician, radiologist, and pathologist. An accurate diagnosis can be very difficult, especially when deciding between idiopathic pulmonary fibrosis and fibrotic nonspecific interstitial pneumonia; better diagnostic markers are needed. The prognosis of idiopathic pulmonary fibrosis is very poor, with median survival of 2–4 yr after the diagnosis, yet the course of individual patients is highly variable. Predicting prognosis in the individual patient is challenging but various clinical and radiologic variables have been identified. According to several recent clinical trials, the natural history of this disease may involve periods of relative stability punctuated by acute exacerbations of disease that result in substantial morbidity or death. Nonspecific interstitial pneumonia is characterized by a distinct histopathologic appearance and a better prognosis than idiopathic pulmonary fibrosis. However, there is still confusion and controversy over the relationship between idiopathic pulmonary fibrosis and fibrotic nonspecific interstitial pneumonia.

Background: Abnormalities of lung coagulation and fibrinolysis in sarcoidosis are thought to play a role in the pathogenesis of this disease. Objective: We previously showed that bronchoalveolar lavage fluid (BALF) D dimer directly correlated with various measures of severity in sarcoidosis. Here, we analyze our observation that BALF D dimer was more frequently found at higher levels in African-American patients with pulmonary sarcoidosis. Methods: BALF D dimer was measured in 55 subjects with pulmonary sarcoidosis and 31 healthy volunteers by enzyme immunoassay. The healthy group established a normal range of BALF D dimer with 71 ng/ml as the highest measured level. This was the cut point for comparisons among the patients with sarcoidosis. Results: High BALF D dimer levels (>71 ng/ml) were found in younger patients with sarcoidosis and were associated with a significantly lower percent predicted forced expiratory volume in 1 s and greater numbers of BAL lymphocytes. Black patients with sarcoidosis had higher BALF D dimer levels (median 131, range 0–2,040 ng/ml) than white patients (median 18, range 0–605 ng/ml; p = 0.011). Higher than normal BALF D dimer levels were found in 61% of the black subjects with sarcoidosis, but in only 20% of the white individuals (χ2 = 5.539, p = 0.019). BALF D dimer was the only disease measure that discriminated black from white individuals with sarcoidosis. Conclusion: BALF D dimer is an indicator of lung fibrin formation and degradation in sarcoidosis. The relationship of high D dimer levels with greater BAL lymphocytosis and worse lung function may be a marker of active sarcoidosis, especially in African-Americans who tend to suffer a more serious form of the disease.

High-resolution computed tomography (HRCT) is an integral aspect of the evaluation of patients with suspected idiopathic pulmonary fibrosis (IPF). However, few studies have evaluated its use in a large cohort.To describe HRCT features in patients with mild to moderate IPF, compare diagnostic evaluations by a radiology core (three thoracic radiologists) with those by study-site radiologists, correlate baseline clinical and physiologic variables with HRCT findings, and evaluate their association with mortality.We assessed HRCT scans from patients with IPF (n = 315) enrolled in a randomized controlled study evaluating IFN-gamma1b.There was concordance between study-site and core radiologists regarding the diagnosis of IPF in 86% of cases. Diffusing capacity of carbon monoxide (DLCO) was the physiologic characteristic most highly correlated with HRCT findings. Multivariate analysis identified three independent predictors of mortality: a higher extent of fibrosis score increased the risk of death (p0.0001), whereas a higher percent-predicted DLCO (p = 0.004) and treatment assignment to IFN-gamma1b rather than placebo (p = 0.04) reduced the risk of death.A study-site diagnosis of IPF on HRCT was regularly confirmed by core radiologists. Extent of reticulation and honeycombing on HRCT is an important independent predictor of mortality in patients with IPF.

Idiopathic interstitial pneumonias comprise usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), and lymphoid interstitial pneumonia (LIP). Each of these entities has a typical imaging and histologic pattern, although in practice the imaging patterns may be variable. Each entity may be idiopathic or may be secondary to a recognizable cause such as collagen vascular disease or inhalational exposure. The diagnosis of idiopathic interstitial pneumonia is made by means of correlation of clinical, imaging, and pathologic features. The characteristic computed tomographic (CT) features of UIP are predominantly basal and peripheral reticular pattern with honeycombing and traction bronchiectasis. NSIP is characterized by predominantly basal ground-glass opacity and/or reticular pattern, often with traction bronchiectasis. DIP and RB-ILD are smoking-related lung diseases characterized by ground-glass opacity and centrilobular nodules. COP is characterized by patchy peripheral or peribronchovascular consolidation. AIP manifests as diffuse lung consolidation and ground-glass opacity. LIP is associated with a CT pattern of ground-glass opacity sometimes associated with perivascular cysts.

Background Idiopathic pulmonary fibrosis (IPF) is a devastating disease, yet validated, reliable criteria for evaluating patient response to therapies in clinical trials are lacking. Methods To optimize selection of end point criteria for the study of interferon (IFN)-γ1b in patients with IPF, we retrospectively analyzed the components of the primary efficacy end point used in a large, controlled study of 330 patients for reliability, validity, and sensitivity to treatment effect. The primary end point components were death, disease progression defined as a ≥ 5 mm Hg increase in resting alveolar-arterial oxygen pressure gradient (P[A-a]O2), and disease progression defined as a ≥ 10% decrease in percentage of predicted FVC. Results We found that the P(A-a)O2 criterion was not reliable and was not associated with mortality. In contrast, the FVC criterion was reliable and was associated with a 2.4-fold increase in the risk of death. Of the three measures, only mortality was sensitive to a treatment effect of IFN-γ1b. Additionally, the tendency for mortality benefit was observed in nearly all patient subgroups defined by baseline physiology. The effect of IFN-γ1b on mortality was strongest in patients with baseline percentage of predicted FVC ≥ 55% (p = 0.004) or percentage of predicted diffusing capacity of the lung for carbon monoxide ≥ 30% (p = 0.008). Conclusion We conclude that mortality is the most inclusive end point for future trials of IFN- γ1b in patients with IPF, and that a > 10% decrement in the percentage of predicted FVC represents a valid measure of disease progression.

Idiopathic pulmonary fibrosis is a progressive, fatal disease with no known efficacious therapy.In a double-blind, multinational trial, we randomly assigned 330 patients with idiopathic pulmonary fibrosis that was unresponsive to corticosteroid therapy to receive subcutaneous interferon gamma-1b or placebo.Over a median of 58 weeks, interferon gamma-1b therapy did not significantly affect the primary end point of progression-free survival, defined as the time to disease progression or death, and no significant treatment effect was observed on measures of lung function, gas exchange, or the quality of life. Ten percent of patients in the interferon gamma-1b group died, as compared with 17 percent of patients in the placebo group (P=0.08). Treatment with interferon gamma-1b was associated with more frequent constitutional symptoms. However, the rates of treatment adherence and premature discontinuation of treatment were similar in the two groups. More pneumonias were reported among patients in the interferon gamma-1b group, but the incidence of severe or life-threatening respiratory tract infections was similar in the two groups.In a well-defined population of patients with idiopathic pulmonary fibrosis, interferon gamma-1b did not affect progression-free survival, pulmonary function, or the quality of life. Owing to the size and duration of the trial, a clinically significant survival benefit could not be ruled out.

There is significant heterogeneity in survival time among patients with idiopathic pulmonary fibrosis. Studies of baseline clinical and physiologic variables as predictors of survival time have reported inconsistent results. We evaluated the predictive value of changes in clinical and physiologic variables over time for survival time in 81 patients with biopsy-proven idiopathic pulmonary fibrosis. Six-month changes in dyspnea score, total lung capacity, thoracic gas volume, FVC, FEV1, diffusing capacity of carbon monoxide, partial pressure of arterial oxygen, oxygen saturation, and alveolar-arterial oxygen gradient were predictive of survival time even after adjustment for baseline values. Analyses were repeated on 51 patients with 12-month change data. Twelve-month changes in dyspnea score, total lung capacity, FVC, partial pressure of arterial oxygen, oxygen saturation, and alveolar-arterial oxygen gradient were predictive of survival time after adjustment for baseline values. Evaluation of changes in clinical and physiological variables over 6 and 12 months may provide clinicians with more accurate prognostic information than baseline values alone.

Idiopathic pulmonary fibrosis (IPF) is an insidious inflammatory fibroproliferative disease whose cause and course before diagnosis are unknown, and for which existing treatments are of limited benefit. The National Heart, Lung, and Blood Institute convened a working group to develop specific recommendations for future IPF research. Inflammatory and immune processes are involved in IPF pathogenesis, and current therapeutic strategies are aimed at suppressing the inflammation. Recent data suggest that the molecular processes underlying the fibrogenesis may provide new opportunities for therapeutic intervention. Specific areas of future research recommended by the working group include studies to elucidate the etiology of IPF, to develop novel diagnostic techniques and molecular diagnostics, to establish a program for identification of molecular targets for IPF treatment and identification and generation of agonists or antagonists that inhibit fibrogenesis, to foster investigations that couple the use of new technologies (e.g., laser capture microdissection, microarrays, and mass spectroscopic analysis of proteins) with data from the human genome project, to establish a national consortium of Clinical Centers of Excellence to conduct coordinated clinical and laboratory studies of well-characterized patients and patient-derived materials, and to stimulate research to develop animal models of persistent and progressive pulmonary fibrosis for evaluation of new intervention approaches.

Idiopathic pulmonary fibrosis (IPF) has a high mortality rate, and current therapies are only marginally effective. A serum biomarker that predicts clinical outcome would be useful to stage disease, indicate prognosis and the need for aggressive therapy, and help stratify patients for clinical trials. The goals of this study were to determine whether serum levels of surfactant protein-A (SP-A) or surfactant protein-D (SP-D) would distinguish between IPF and other types of interstitial lung disease and whether serum SP-A or SP-D levels predict outcome in patients with IPF. The authors found that serum SP-A and SP-D levels were significantly elevated in patients with IPF and systemic sclerosis compared to sarcoidosis, beryllium disease and normal controls, and that SP-D correlated with radiographic abnormalities in patients with IPF. In addition, the authors found that both serum SP-A and SP-D levels were highly predictive of survival in patients with IPF. This is the largest North American data set of surfactant protein measurements in idiopathic pulmonary fibrosis and the first report using multivariate analysis comparing serum surfactant proteins-A and -D to other commonly measured predictors of survival in idiopathic pulmonary fibrosis. Based on these results, the authors propose that serum surfactant proteins may prove to be useful biomarkers in patients with idiopathic pulmonary fibrosis.

The purpose of this work was to describe the radiographic and CT findings in patients with respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and to correlate them with clinical, physiologic, and pathologic features.RB-ILD was proved pathologically in all 21 patients. Sixteen (76%) patients were current smokers, and five (24%) patients were ex-smokers. The mean cigarette consumption was 38.7 pack-years. Chest radiographs and CT scans were semiquantitatively analyzed and correlated with clinical findings, physiologic measures, and a pathologic score of disease extent.The major radiographic findings were bronchial wall thickening in 16 patients (76%) and ground-glass opacity in 12 patients (57%). The predominant initial CT findings were central bronchial wall thickening (proximal to subsegmental bronchi) in 19 patients (90%), peripheral bronchial wall thickening (distal to subsegmental bronchi) in 18 patients (86%), centrilobular nodules in 15 patients (71%), and ground-glass opacity in 14 patients (67%), None of these CT findings had a significant zonal predominance. Other findings were upper lung predominant centrilobular emphysema (57%) and patchy areas of hypoattenuation (38%) with a lower lung predominance. Radiologic findings were similar in both current and ex-smokers. The amount of ground-glass opacity correlated inversely with arterial oxygen saturation ( r = -0.67, p = 0.04), and the areas of hypoattenuation correlated with alveolar-arterial oxygen gradient ( r = 0.56, p = 0.04). The extent of centrilobular nodules correlated with the extent of macrophages in respiratory bronchioles ( r = 0.53, p = 0.03) and with chronic inflammation of respiratory bronchioles ( r = 0.57, p = 0.02). The extent of ground-glass opacity correlated with the amount of macrophage accumulation in the alveoli and alveolar ducts ( r = 0.56, p0.01 and r = 0.54, p = 0.04, respectively). At follow-up CT after steroid treatment and smoking cessation, in nine patients, the extent of bronchial wall thickening, centrilobular nodules, and ground-glass opacity had decreased, but the areas of hypoattenuation had increased (p0.05).The CT findings of RB-ILD are centrilobular nodules, ground-glass opacity, and air trapping. These radiologic features, in patients with a history of heavy cigarette smoking, may differentiate RB-ILD from other interstitial lung diseases.

Idiopathic pulmonary fibrosis (IPF) is an incurable condition that is characterized by progressive pulmonary fibrosis, architectural distortion of the lung and loss of gas exchange units. Until recently, there was no effective treatment for this condition. However, there were two landmark trials published earlier this year, which have changed the management of this condition. Pirfenidone (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis trial) and nintedanib (Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis-1 and -2 trials) have both demonstrated positive outcomes in patients with IPF. In this perspective, we critically discuss the role of these agents in IPF and in the broader pulmonary fibrosis population.

The aim of this study was to determine the prevalence, characteristics and outcomes of patients with unclassifiable interstitial lung disease (ILD) and to develop a simple method of predicting disease behaviour. Unclassifiable ILD patients were identified from an ongoing longitudinal cohort. Unclassifiable ILD was diagnosed after a multidisciplinary review did not secure a specific ILD diagnosis. Clinical characteristics and outcomes were compared with idiopathic pulmonary fibrosis (IPF) and non-IPF ILDs. Independent predictors of mortality were determined using Cox proportional-hazards analysis to identify subgroups with distinct disease behaviour. Unclassifiable ILD was diagnosed in 10% of the ILD cohort (132 out of 1370 patients). The most common reason for being unclassifiable was missing histopathological assessment due to a high risk of surgical lung biopsy. Demographic and physiological features of unclassifiable ILD were intermediate between IPF and non-IPF disease controls. Unclassifiable ILD had longer survival rates when compared to IPF on adjusted analysis (hazard ratio 0.62, p = 0.04) and similar survival compared to non-IPF ILDs (hazard ratio 1.54, p = 0.12). Independent predictors of survival in unclassifiable ILD included diffusion capacity of the lung for carbon monoxide (p = 0.001) and a radiological fibrosis score (p = 0.02). Unclassifiable ILD represents approximately 10% of ILD cases and has a heterogeneous clinical course, which can be predicted using clinical and radiological variables.

Rheumatoid arthritis is a common inflammatory disease affecting about 1% of the population. Interstitial lung disease is a serious and frequent complication of rheumatoid arthritis. Rheumatoid arthritis associated interstitial lung disease (RA-ILD) is characterized by several histopathologic subtypes. This article reviews the proposed pathogenesis and risk factors for RA-ILD. We also outline the important steps involved in the work-up of RA-ILD and review the evidence for treatment and prognosis.

Purpose: To determine the accuracy of computed tomography (CT) in identifying the histopathologic usual interstitial pneumonia (UIP) pattern in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Materials and All patients were enrolled into institutional review board-Methods: approved longitudinal cohorts at their respective institution, and informed consent was obtained at the time of enrollment. Images of patients with surgical lung biopsyproved RA-ILD (n = 69) were collected from three tertiary care centers. Two experienced thoracic radiologists independently reviewed the CT scans. The CT pattern was categorized as definite UIP, possible UIP, or inconsistent with UIP in accordance with published criteria. Findings of biopsies were reviewed by an experienced lung pathologist. The sensitivity and specificity of definite CT UIP pattern to histopathologic UIP pattern were determined. The agreement between radiologists was assessed by calculating a k score. Results: The histopathologic UIP pattern was present in 42 of 69 (61%) patients. Men were more likely than women to have a histopathologic UIP pattern (P =.02). Twenty patients (29%, 20 of 69) had a definite UIP pattern on CT scans. The specificity of CT UIP pattern was 96% (26 of 27; 95% confidence interval [Cl]: 81%, 100%), with a negative predictive value of 53% (26 of 49). The sensitivity of CT UIP pattern was 45% (19 of 42; 95% Cl: 30%, 61%), with a positive predictive value of 95% (19 of 20). The agreement between radiologists for definite UIP pattern versus not was 87% (k = 0.67, P

FVC has emerged as a standard primary endpoint in clinical trials evaluating novel therapies for patients with idiopathic pulmonary fibrosis (IPF). However, it has recently been proposed that all-cause mortality or a composite comprised of all-cause mortality and all-cause nonelective hospitalization be adopted as the standard primary endpoint for IPF clinical trials.To conduct a comprehensive evaluation of mortality in three phase 3 clinical trials and evaluate the feasibility of mortality trials in patients with IPF.The study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (n = 347) or the INSPIRE study evaluating interferon-γ1b (n = 275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided α of 0.05. Modeling analyses were used to assess the effects of selected variables on sample size and study design.A total of 73 deaths occurred during the period of observation (mean duration of follow-up, 80.1 wk). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a two-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2,582 patients.The all-cause mortality rate is relatively low in patients with IPF with mild to moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of all-cause mortality trials in this population are substantial and likely prohibitive.

The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI. ©Published 2014 by the American Thoracic Society.

In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis ; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS: In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died ; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P

Background and objective Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF. Methods All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF (Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug. Results A total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week–7.7 years), and the cumulative total exposure was 2059 person exposure years (PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY. Conclusions This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated.

This study was designed to investigate the levels of IL-2 and its soluble receptor (sIL-2R) in bronchoalveolar lavage fluid (BALF) from patients with systemic sclerosis (SSc). We studied 18 patients with SSc and 10 healthy volunteers. Based on high-resolution computed tomography lung scans the patients were divided into two groups, those with (SSc-ILD group, n= 10) and those without (SSc group, n = 8) evidence of interstitial lung disease (ILD). Both groups showed significantly higher total cell and neutrophil counts in the BALF than controls. The SSc group also showed significantly higher levels of lymphocytes than controls. IL-2 was not detectable in BALF. The patients showed significantly higher levels of sIL-2R than controls (77.8% vs 20%, P=0.005). The median sIL-2R levels detected did not differ between the two patient groups (SSc-ILD 270 pg/ml, SSc 232 pg/ml). This study suggests that SSc patients with or without ILD have elevated levels of sIL-2R in BALF and that in some of these patients this finding could be explained by subclinical pulmonary inflammation.

It is hypothesized that the extent and severity of fibrosis and cellularity found on lung biopsy determine the prognosis and response to therapy in idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine which histopathologic features predict survival in IPF. We prospectively studied 87 patients with usual interstitial pneumonia (UIP) confirmed by surgical lung biopsy. Four pathologists independently graded the extent and severity of specific histopathologic features. We used Cox proportional-hazards models to assess the effect of histopathologic patterns on patients' survival. The effects of age, sex, and smoking were also included in the analysis. Sixty-three patients died during the 17-yr study period. Survival was longer in subjects with lesser degrees of granulation/connective tissue deposition (fibroblastic foci). The degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival. The extent of fibroblastic foci present on lung biopsy predicts survival in IPF. These findings support the hypothesis that the critical pathway to end-stage fibrosis is not "alveolitis" but rather the ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Controlling these processes, rather than stopping inflammation, appears most important in preventing progressive disease and the fatal outcome common in IPF.

Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells (IDHPNC) is a clinicopathological entity characterized by a diffuse hyperplasia of neuroendocrine cells involving distal bronchi and bronchioles. The pathogenesis of this syndrome remains unknown. The hyperplastic neuroendocrine (NE) cells contain multiple neuropeptides, including the bombesinlike peptides (BLP), which are likely important in the pathogenesis of the disorder by stimulating proliferation of fibroblasts in a paracrine fashion and the NE cells themselves in an autocrine manner. Neutral endopeptidase (NEP) is a cell-surface enzyme that hydrolyzes BLP and other bioactive peptides. Low or undetectable NEP is present in many primary lung cancers and cell lines. Low NEP expression could increase neuropeptide-induced autocrine effects by increasing local levels of neuropeptides. We hypothesized that IDHPNC was associated with low or absent NEP expression. NEP expression was assayed in patients with IDHPNC (n = 3) and was compared with expression in patients with idiopathic pulmonary fibrosis (n = 5), hypersensitivity pneumonitis (n = 5), and normal lung (n = 4) using immunohistochemistry, ELISA, activity assay, and Western blot analysis. By these assays, NEP expression was highest in lungs affected by IDHPNC. NEP mRNA, as assessed in IDHPNC lung tissue by RT-PCR, was the expected size and free of mutation between bp 238-2437. Therefore, IDHPNC is unlikely to be the result of a defect in NEP expression. The apparent increase in NEP expression in lung tissue from patients with IDHPNC may reflect a compensatory increase that partly counteracts abundant neuropeptides, including BLP, present in this disorder.

Idiopathic pulmonary fibrosis (IPF) and bronchiolitis obliterans with organizing pneumonia (BOOP) are interstitial lung diseases of unknown pathogenesis. Alveolar macrophages play a major role in the regulation of the inflammatory response in these diseases through their ability to produce cytokines that modify the inflammatory response. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) exhibit proinflammatory and anti-inflammatory actions, respectively, and thus an imbalance in the expression of these cytokines may contribute to the pathogenesis of IPF and BOOP. Therefore, we quantified IL-10 and TNF-alpha mRNA levels in alveolar macrophages obtained by bronchoalveolar lavage (BAL) from patients with IPF and BOOP and in normal healthy volunteers. The level of TNF-alpha mRNA in macrophages obtained from IPF and BOOP patients was not significantly different from normal healthy subjects. However, macrophages from patients with IPF and BOOP expressed increased levels of IL-10 mRNA compared with healthy controls. In addition, stimulation of alveolar macrophages with lipopolysaccharide in the presence of a neutralizing anti-IL-10 antibody augmented the production of TNF-alpha over that seen in the absence of anti-IL-10 antibody, suggesting that the increased expression of IL-10 by alveolar macrophages may act to control the expression of TNF-alpha. Paradoxically, measurement of IL-10 protein in cell-free BAL fluid revealed lower amounts of the protein in patients with IPF and BOOP compared with healthy controls.

Risk prediction is challenging in chronic interstitial lung disease (ILD) because of heterogeneity in disease-specific and patient-specific variables. Our objective was to determine whether mortality is accurately predicted in patients with chronic ILD using the GAP model, a clinical prediction model based on sex, age, and lung physiology, that was previously validated in patients with idiopathic pulmonary fibrosis.Patients with idiopathic pulmonary fibrosis (n=307), chronic hypersensitivity pneumonitis (n=206), connective tissue disease-associated ILD (n=281), idiopathic nonspecific interstitial pneumonia (n=45), or unclassifiable ILD (n=173) were selected from an ongoing database (N=1,012). Performance of the previously validated GAP model was compared with novel prediction models in each ILD subtype and the combined cohort. Patients with follow-up pulmonary function data were used for longitudinal model validation.The GAP model had good performance in all ILD subtypes (c-index, 74.6 in the combined cohort), which was maintained at all stages of disease severity and during follow-up evaluation. The GAP model had similar performance compared with alternative prediction models. A modified ILD-GAP Index was developed for application across all ILD subtypes to provide disease-specific survival estimates using a single risk prediction model. This was done by adding a disease subtype variable that accounted for better adjusted survival in connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, and idiopathic nonspecific interstitial pneumonia.The GAP model accurately predicts risk of death in chronic ILD. The ILD-GAP model accurately predicts mortality in major chronic ILD subtypes and at all stages of disease.