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Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease with the histology of usual interstitial pneumonia (UIP). Although the pathologist's visual inspection is central in histologic assessments, three-dimensional microcomputed tomography (microCT) assessment may complement the pathologist's scoring. We examined associations between the histopathologic features of UIP and IPF in explanted lungs and quantitative microCT measurements, including alveolar surface density, total lung volume taken up by tissue (%), and terminal bronchiolar number. Sixty frozen samples from 10 air-inflated explanted lungs with severe IPF and 36 samples from 6 donor control lungs were scanned with microCT and processed for histologic analysis. An experienced pathologist scored three major UIP criteria (patchy fibrosis, honeycomb, and fibroblastic foci), five additional pathologic changes, and immunohistochemical staining for CD68-, CD4-, CD8-, and CD79a-positive cells, graded on a 0 to 3+ scale. The alveolar surface density and terminal bronchiolar number decreased and the tissue percentage increased in lungs with IPF compared with controls. In lungs with IPF, lower alveolar surface density and higher tissue percentage were correlated with greater scores of patchy fibrosis, fibroblastic foci, honeycomb, CD79a-positive cells, and lymphoid follicles. A decreased number of terminal bronchioles was correlated with honeycomb score but not with the other scores. The three-dimensional microCT measurements reflect the pathological UIP and IPF criteria and suggest that the reduction in the terminal bronchioles may be associated with honeycomb cyst formation., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Transbronchial lung cryobiopsy (TBLC) has been introduced recently in the diagnosis of interstitial lung diseases. We aimed to evaluate the prognostic significance of the distinction between idiopathic pulmonary fibrosis and other interstitial lung diseases with the use of TBLC data in multidisciplinary team (MDT) diagnosis., Methods: In this single-centre, retrospective, investigator-initiated comparative study, we evaluated consecutive patients without a definite usual interstitial pneumonia pattern on high-resolution CT, who presented to the GB Morgagni Hospital (Forlì, Italy), and who underwent TBLC (Jan 1, 2011, to Dec 31, 2014) or surgical lung biopsy (SLB; Jan 1, 2002, to Dec 31, 2016). Three pathologists reviewed the specimens, masked to clinical information. MDT evaluation was done before and after biopsy. The primary endpoint was the prognostic significance of the MDT diagnostic separation between idiopathic pulmonary fibrosis and other interstitial lung diseases in patients undergoing TBLC. Mortality was evaluated by means of Cox regression analysis., Findings: We evaluated 500 consecutive cases, 426 of which were included: 266 had TBLC and 160 had SLB. 189 patients had idiopathic pulmonary fibrosis, 143 had other fibrotic interstitial lung diseases, and 94 had non-fibrotic interstitial lung diseases. Patients undergoing TBLC had more comorbidities and better preserved lung function compared with those undergoing SLB; among patients with a final MDT diagnosis of idiopathic pulmonary fibrosis, patients undergoing TBLC were older, had more comorbidities, and had a different post-biopsy treatment profile than those who received SLB. The distinction between idiopathic pulmonary fibrosis and other interstitial lung diseases made by MDT diagnosis on the basis of TBLC biopsy had clear prognostic significance, with a 5-year transplant-free survival of 68% (95% CI 57-76) in patients with an MDT idiopathic pulmonary fibrosis diagnosis based on TBLC compared with 93% (87-96) in patients without an idiopathic pulmonary fibrosis diagnosis based on TBLC (hazard ratio 5·28, 95% CI 2·72-10·04; p<0·0001). This distinction remained statistically significant in a multivariate analysis controlling for age, sex, smoking status, comorbidities, pulmonary function, and high-resolution CT patterns (p=0·02)., Interpretation: TBLC makes an important diagnostic contribution in interstitial lung disease, on the basis of the prognostic distinction between idiopathic pulmonary fibrosis and other interstitial lung diseases when TBLC findings are included in multidisciplinary diagnosis., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The observation that patients with idiopathic pulmonary fibrosis (IPF) can have higher than normal expiratory flow rates at low lung volumes led to the conclusion that the airways are spared in IPF. This study aimed to re-examine the hypothesis that airways are spared in IPF using a multiresolution imaging protocol that combines multidetector CT (MDCT), with micro-CT and histology., Methods: This was a retrospective cohort study comparing explanted lungs from patients with severe IPF treated by lung transplantation with a cohort of unused donor (control) lungs. The donor control lungs had no known lung disease, comorbidities, or structural lung injury, and were deemed appropriate for transplantation on review of the clinical files. The diagnosis of IPF in the lungs from patients was established by a multidisciplinary consensus committee according to existing guidelines, and was confirmed by video-assisted thoracic surgical biopsy or by pathological examination of the contralateral lung. The control and IPF groups were matched for age, sex, height, and bodyweight. Samples of lung tissue were compared using the multiresolution imaging approach: a cascade of clinical MDCT, micro-CT, and histological imaging. We did two experiments: in experiment 1, all the lungs were randomly sampled; in experiment 2, samples were selected from regions of minimal and established fibrosis. The patients and donors were recruited from the Katholieke Universiteit Leuven (Leuven, Belgium) and the University of Pennsylvania Hospital (Philadelphia, PA, USA). The study took place at the Katholieke Universiteit Leuven, and the University of British Columbia (Vancouver, BC, Canada)., Findings: Between Oct 5, 2009, and July 22, 2016, explanted lungs from patients with severe IPF (n=11), were compared with a cohort of unused donor (control) lungs (n=10), providing 240 samples of lung tissue for comparison using the multiresolution imaging approach. The MDCT specimen scans show that the number of visible airways located between the ninth generation (control 69 [SD 22] versus patients with IPF 105 [33], p=0·0023) and 14th generation (control 9 [6] versus patients with IPF 49 [28], p<0·0001) of airway branching are increased in patients with IPF, which we show by micro-CT is due to thickening of their walls and distortion of their lumens. The micro-CT analysis showed that compared with healthy (control) lung anatomy (mean 5·6 terminal bronchioles per mL [SD 1·6]), minimal fibrosis in IPF tissue was associated with a 57% loss of the terminal bronchioles (mean 2·4 terminal bronchioles per mL [SD 1·0]; p<0·0001), the appearance of fibroblastic foci, and infiltration of the tissue by inflammatory immune cells capable of forming lymphoid follicles. Established fibrosis in IPF tissue had a similar reduction (66%) in the number of terminal bronchioles (mean 1·9 terminal bronchioles per mL [SD 1·4]; p<0·0001) and was dominated by increased airspace size, Ashcroft fibrosis score, and volume fractions of tissue and collagen., Interpretation: Small airways disease is a feature of IPF, with significant loss of terminal bronchioles occuring within regions of minimal fibrosis. On the basis of these findings, we postulate that the small airways could become a potential therapeutic target in IPF., Funding: Katholieke Universiteit Leuven, US National Institutes of Health, BC Lung Association, and Genentech., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Transbronchial cryobiopsy (TBC) is increasingly recognized as a potential alternative to surgical lung biopsy (SLB) for the diagnosis of interstitial lung disease (ILD). The goal of this analysis was to examine the literature on TBC as it relates to diagnostic utility and safety to provide evidence-based and expert guidance to clinicians., Methods: Approved panelists developed key questions regarding the diagnostic utility and safety of TBC for the evaluation of ILD using the PICO (Population, Intervention, Comparator, Outcome) format. MEDLINE (via PubMed) and the Cochrane Library were systematically searched for relevant literature, which was supplemented by manual searches. References were screened for inclusion, and vetted evaluation tools were used to assess the quality of included studies, to extract data, and to grade the level of evidence supporting each recommendation or statement. Graded recommendations and ungraded consensus-based statements were drafted and voted on using a modified Delphi technique to achieve consensus., Results: The systematic review and critical analysis of the literature based on four PICO questions resulted in six statements: two evidence-based graded recommendations and four ungraded consensus-based statements., Conclusions: Evidence of the utility and safety of TBC for the diagnosis of ILD is limited but suggests TBC is safer than SLB, and its contribution to the diagnosis obtained via multidisciplinary discussion is comparable to that of SLB, although the histological diagnostic yield appears higher with SLB (approximately 80% for TBC vs 95% for SLB). Additional research is needed to enhance knowledge regarding utility and safety of TBC, its role in the diagnostic algorithm of ILD, and the impact of technical aspects of the procedure on diagnostic yield and safety., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Transbronchial cryobiopsy, a new diagnostic procedure in patients with diffuse lung disease, provides larger and better-preserved lung specimens compared to forceps biopsy. The diagnostic yield of cryobiopsy is much better than that of forceps biopsy and slightly lower than that of surgical lung biopsy, but with a lower complication rate compared to the latter. Literature suggests that in the multidisciplinary approach to patients with diffuse lung disease cryobiopsy provides diagnostic and prognostic information similar to surgical lung biopsy. Cryobiopsy can also be performed in some patients unsuitable for surgical biopsy, yet in whom histologic input is needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Case Presentation: A 52-year-old, nonsmoking, African-American woman with a history of obesity, hypertension, and rheumatoid arthritis was referred for workup of multiple bilateral pulmonary nodules. The pulmonary nodules were discovered incidentally while undergoing a CT scan for an abdominal mass that was radiographically diagnosed as a uterine leiomyoma. She was asymptomatic from a pulmonary standpoint without unintentional weight loss, fevers, or night sweats. Her mother and sister had a history of lung cancer. She was diagnosed with rheumatoid arthritis 5 years earlier that was controlled with adalimumab for approximately 3 years when she stopped being seen by her rheumatologist and discontinued adalimumab. During evaluation for the abdominal mass, she re-established care with a rheumatologist and was started on 40 mg prednisone daily with plans to restart adalimumab once the workup for the abdominal mass and pulmonary nodules was completed. She had undergone bariatric surgery with cholecystectomy approximately 5 years earlier, after which she experienced intentional postsurgical weight loss., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: In the appropriate clinical setting, the diagnosis of idiopathic pulmonary fibrosis (IPF) requires a pattern of usual interstitial pneumonia to be present on high-resolution chest CT (HRCT) or surgical lung biopsy. A molecular usual interstitial pneumonia signature can be identified by a machine learning algorithm in less-invasive transbronchial lung biopsy samples. We report prospective findings for the clinical validity and utility of this molecular test., Methods: We prospectively recruited 237 patients for this study from those enrolled in the Bronchial Sample Collection for a Novel Genomic Test (BRAVE) study in 29 US and European sites. Patients were undergoing evaluation for interstitial lung disease and had had samples obtained by clinically indicated surgical or transbronchial biopsy or cryobiopsy for pathology. Histopathological diagnoses were made by experienced pathologists. Available HRCT scans were reviewed centrally. Three to five transbronchial lung biopsy samples were collected from all patients specifically for this study, pooled by patient, and extracted for transcriptomic sequencing. After exclusions, diagnostic histopathology and RNA sequence data from 90 patients were used to train a machine learning algorithm (Envisia Genomic Classifier, Veracyte, San Francisco, CA, USA) to identify a usual interstitial pneumonia pattern. The primary study endpoint was validation of the classifier in 49 patients by comparison with diagnostic histopathology. To assess clinical utility, we compared the agreement and confidence level of diagnosis made by central multidisciplinary teams based on anonymised clinical information and radiology results plus either molecular classifier or histopathology results., Findings: The classifier identified usual interstitial pneumonia in transbronchial lung biopsy samples from 49 patients with 88% specificity (95% CI 70-98) and 70% sensitivity (47-87). Among 42 of these patients who had possible or inconsistent usual interstitial pneumonia on HRCT, the classifier showed 81% positive predictive value (95% CI 54-96) for underlying biopsy-proven usual interstitial pneumonia. In the clinical utility analysis, we found 86% agreement (95% CI 78-92) between clinical diagnoses using classifier results and those using histopathology data. Diagnostic confidence was improved by the molecular classifier results compared with histopathology results in 18 with IPF diagnoses (proportion of diagnoses that were confident or provisional with high confidence 89% vs 56%, p=0·0339) and in all 48 patients with non-diagnostic pathology or non-classifiable fibrosis histopathology (63% vs 42%, p=0·0412)., Interpretation: The molecular test provided an objective method to aid clinicians and multidisciplinary teams in ascertaining a diagnosis of IPF, particularly for patients without a clear radiological diagnosis, in samples that can be obtained by a less invasive method. Further prospective clinical validation and utility studies are planned., Funding: Veracyte., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Several drugs have been associated with druginduced sarcoidosis-like reactions (DISRs) that are clinically indistinguishable from sarcoidosis. Daclizumab is a humanized monoclonal IgG1 antibody that binds to CD25 that has been studied for the treatment of multiple sclerosis (MS). During MS clinical trials of daclizumab, 12 subjects developed clinical conditions potentially consistent with sarcoidosis. Therefore, an independent adjudication committee of individuals with expertise in sarcoidosis was organized to determine the likelihood of these cases representing sarcoidosis., Methods: The adjudication committee consisted of a pulmonologist, pathologist, and radiologist with clinical experience in sarcoidosis. The committee had access to the subjects' laboratory data, narratives of all suspect adverse reaction reports, radiographic imaging and histology from biopsies. A priori, a grading system was developed to determine criteria to establish the likelihood that the patient had developed sarcoidosis., Results: The adjudication confirmed sarcoidosis in 11/12 subjects. The committee's decisions were unanimous in all cases. Biopsies were available in 7/11 of these. In the 4 subjects who did not have a biopsy, they all had presentations, clinical findings, and/or laboratory findings that were highly specific for sarcoidosis. Alternative causes for these clinical findings were reasonably excluded in all cases. The lung (8/11) and skin (6/11) were the most common organs involved. The mean daclizumab dose given when signs or symptoms of sarcoidosis occurred was 5413 ± 2704 mg and the median time from first daclizumab dose was 996 days. The incidence rate of developing sarcoidosis in those participating in these daclizumab trials was 154/100,000 patient-years compared with incidence rates of sarcoidosis in the United States of 3.2-17.8/100,000/year. These data suggest that these sarcoidosis cases may have represented DISRs related to daclizumab therapy., Conclusions: Given the clinical presentation and subsequent evaluation of these 11 subjects, we suspect that they had DISRs from daclizumab., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Exposure to cigarette smoke can lead to a variety of parenchymal lung diseases, including diffuse cystic lung diseases (DCLDs). Lymphangioleiomyomatosis (LAM) is the prototypical DCLD and has a characteristic appearance on high-resolution CT (HRCT). We present a series of four patients with DCLD on HRCT who were referred to our institution with a presumed diagnosis of LAM and who were found instead to have smoking-related injury of the small airways on histopathological analysis. We submit that cigarette smoke-induced small airway injury can present as DCLD on HRCT in a pattern that can mimic LAM. A detailed history of cigarette smoke exposure should be obtained in patients presenting with DCLD, and imaging features should not be used in isolation to establish a firm diagnosis of LAM., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Interstitial lung diseases are heterogeneous, and patients with chronic fibrosing interstitial pneumonia (CFIP) often have clinical, serologic, and morphologic features suggestive but not diagnostic of connective tissue disease. Recently, the concept of interstitial pneumonia with autoimmune features (IPAF) has been proposed as a platform for such patients. However, the prognostic role of IPAF, including the cumulative incidence of acute exacerbations (AEs), is not fully clear. The aim of this study was to elucidate the clinical features and prognostic significance of IPAF., Methods: The clinical characteristics and prognostic relevance of a diagnosis of IPAF were retrospectively explored in 194 patients with CFIP, including 163 with idiopathic pulmonary fibrosis (IPF) and 31 with nonspecific interstitial pneumonia (NSIP), in our interstitial lung disease database., Results: Sixteen percent of patients with CFIP (8% of IPF, 61% of NSIP) met the criteria for IPAF. Patients with IPAF were significantly younger and included a higher proportion of women, never-smokers, and patients with NSIP than those without IPAF. The morphologic domain was the most common in patients with IPAF (97%), followed by the serologic domain (72%) and clinical domain (53%). CFIP patients with IPAF had a more favorable prognosis with regard to overall survival (OS; P < 0.001, log-rank test) and incidence of AEs (P = 0.029, Gray's test) than those without IPAF. In the subgroup analysis, NSIP patients with IPAF had significantly better survival than those without IPAF (P = 0.031, log-rank test), and IPF patients with IPAF tended to have better OS than those without IPAF (P = 0.092, log-rank test). However, there were no significant differences in the incidence of AEs between patients with IPAF and those without IPAF in the IPF and NSIP subgroups. Furthermore, fulfilment of the IPAF criteria was an independent predictor of OS (hazard ratio (HR) 0.127; 95% confidence interval (CI) 0.017-0.952; P = 0.045) and incidence of AEs (HR 0.225: 95% CI 0.054-0.937; P = 0.040)., Conclusions: A diagnosis of IPAF might predict a favorable prognosis and less risk of AEs in patients with CFIP., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This Review provides an updated approach to the diagnosis of idiopathic pulmonary fibrosis (IPF), based on a systematic search of the medical literature and the expert opinion of members of the Fleischner Society. A checklist is provided for the clinical evaluation of patients with suspected usual interstitial pneumonia (UIP). The role of CT is expanded to permit diagnosis of IPF without surgical lung biopsy in select cases when CT shows a probable UIP pattern. Additional investigations, including surgical lung biopsy, should be considered in patients with either clinical or CT findings that are indeterminate for IPF. A multidisciplinary approach is particularly important when deciding to perform additional diagnostic assessments, integrating biopsy results with clinical and CT features, and establishing a working diagnosis of IPF if lung tissue is not available. A working diagnosis of IPF should be reviewed at regular intervals since the diagnosis might change. Criteria are presented to establish confident and working diagnoses of IPF., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Although the accurate diagnosis of pleuroparenchymal fibroelastosis (PPFE) requires pathologic evaluation, this diagnosis is often suggested when the radiologic findings are consistent with typical PPFE and when pulmonary apical cap, which radiologically and pathologically mimics PPFE, can be excluded by confirming disease progression. The aim of this study was to evaluate the validity of the clinical diagnosis of idiopathic PPFE., Methods: We recruited 44 patients with idiopathic PPFE according to our modified diagnostic criteria: 1) a radiologic PPFE pattern (i.e., bilateral subpleural dense consolidation with or without pleural thickening in the upper lobes and less marked or absent involvement of the lower lobes), 2) radiologic confirmation of disease progression, and 3) exclusion of other lung diseases with identifiable etiologies. The patients' baseline characteristics and clinical course were reviewed., Results: The median age was 70 years, and 28 patients were males. The majority revealed emaciation, hypercapnia, and a high ratio of residual volume to total lung capacity. On chest computed tomography, 39 patients showed abnormal shadows in the lower lobes; more than half were classified as having usual interstitial pneumonia (UIP)/possible UIP pattern. Pneumothorax was the most frequent complication (33/44). The median overall survival time after diagnosis was 35.3 months. The presence of lower lobe UIP/possible UIP pattern did not show a significant prognostic impact., Conclusions: Using our diagnostic criteria, we could recruit relatively many patients with similar characteristics to those of idiopathic PPFE patients in the literature. The possibility of clinical diagnosis of idiopathic PPFE should be further discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to evaluate the incidence and clinical features of patients who developed collagen vascular disease (CVD) after an initial diagnosis of idiopathic nonspecific interstitial pneumonia (NSIP)., Methods: We conducted a retrospective review of 72 consecutive patients with NSIP who were diagnosed by surgical lung biopsy in our institution (idiopathic NSIP, n = 35; CVD-NSIP, n = 37 at initial diagnosis). No patients fulfilled the American College of Rheumatology criteria for a diagnosis with CVD within six months after the diagnosis of idiopathic NSIP., Results: Of 35 patients initially diagnosed with idiopathic NSIP, six patients (17.1%) developed CVD during the follow-up period (5.5 ± 5.0 years); three patients were diagnosed with dermatomyositis (DM), two patients with overlap syndrome (DM and Sjogren's syndrome), and one patient with rheumatoid arthritis. The mean time until CVD diagnosis was 2.0 years (six months - 3.5 years), and the one-, two- and three-year incidences of CVD development were 3.6%, 15.2% and 20.0%, respectively. There was no significant difference in clinical characteristics and survival among patients with NSIP preceding CVD diagnosis, those with idiopathic NSIP, or those with CVD-NSIP. In addition, at the time of initial diagnosis, there was no significant difference for the fulfillment of previous criteria such as interstitial pneumonia with autoimmune feature (IPAF) between patients with NSIP preceding CVD diagnosis and those with idiopathic NSIP., Conclusions: It is difficult to predict CVD occurrence and careful attention is needed to detect the development of CVD in patients with idiopathic NSIP., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Mac-2 binding protein (M2BP) is a cell-adhesive glycoprotein of the extracellular matrix secreted as a ligand of galectin-3 (Mac-2). Recently, a Wisteria floribunda agglutinin positive-M2BP (WFA(+)-M2BP) assay developed using a lectin-antibody sandwich immunoassay has shown promise as a new fibrotic marker in liver fibrosis to detect unique fibrosis-related glycoalteration. The aim of this study is to evaluate the utility of serum WFA(+)-M2BP levels in patients with idiopathic pulmonary fibrosis (IPF)., Methods: We measured serum WFA(+)-M2BP levels in 116 patients with IPF and 42 healthy volunteers. We examined the relationship between serum WFA(+)-M2BP levels and clinical parameters and further investigated the prognostic significance of serum WFA(+)-M2BP levels in patients with IPF., Results: Serum WFA(+)-M2BP levels were significantly higher in patients with IPF than in healthy controls (1.09 ± 0.89 cutoff index [COI], 0.57 ± 0.24 COI, respectively; P < 0.001). In patients with IPF, a significant positive correlation was found between serum WFA(+)-M2BP levels and age, KL-6, neutrophils in BAL, reticulation and honeycombing scores in HRCT, and fibrotic foci scores in pathological findings, and a significant negative correlation was found between serum WFA(+)-M2BP levels and FVC, %DLco and macrophages in BAL. Furthermore, patients with high serum WFA(+)-M2BP levels had a significantly worse prognosis than those with low levels (log-rank test, P = 0.0209), and a high serum WFA(+)-M2BP level was a significant prognostic factor in Cox proportional hazards regression analysis., Conclusions: Our results suggest that the serum WFA(+)-M2BP level is a potential biomarker in patients with IPF., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The National Heart, Lung, and Blood Institute-sponsored IPF Clinical Research Network (IPFnet) studies enrolled subjects with idiopathic pulmonary fibrosis (IPF) to evaluate drug therapies in treatment trials. An adjudication committee (AC) provided a structured review of cases in which there was uncertainty or disagreement regarding diagnosis or clinical event classification. This article describes the diagnosis and adjudication processes., Methods: The diagnostic process was based on review of clinical data and high-resolution CT scans with central review of lung biopsies when available. The AC worked closely with the data coordinating center to obtain clinical, radiologic, and histologic data and to communicate with the clinical centers. The AC used a multidisciplinary discussion model with four clinicians, one radiologist, and one pathologist to adjudicate diagnosis and outcome measures., Results: The IPFnet trials screened 1,015 subjects; of these, 23 cases required review by the AC to establish eligibility. The most common diagnosis for exclusion was suspected chronic hypersensitivity pneumonitis. The AC reviewed 88 suspected acute exacerbations (AExs), 93 nonelective hospitalizations, and 16 cases of bleeding. Determination of AEx presented practical challenges to adjudicators, as necessary clinical data were often not collected, particularly when subjects were evaluated outside of the primary study site., Conclusions: The IPFnet diagnostic process was generally efficient, but a multidisciplinary adjudication committee was critical to assure correct phenotype for study enrollment. The AC was key in adjudicating all adverse outcomes in two IPFnet studies terminated early because of safety issues. Future clinical trials in IPF should consider logistical and cost issues as they incorporate AExs and hospitalizations as outcome measures., Trial Registry: ClinicalTrials.gov; No.: NCT00517933, NCT00650091, NCT00957242; URL: www.clinicaltrials.gov.

Background: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease that distorts pulmonary architecture, leading to hypoxia, respiratory failure, and death. Diagnosis is difficult because other interstitial lung diseases have similar radiological and histopathological characteristics. A usual interstitial pneumonia pattern is a hallmark of idiopathic pulmonary fibrosis and is essential for its diagnosis. We aimed to develop a molecular test that distinguishes usual interstitial pneumonia from other interstitial lung diseases in surgical lung biopsy samples. The eventual goal of this research is to develop a method to diagnose idiopathic pulmonary fibrosis without the patient having to undergo surgery., Methods: We collected surgical lung biopsy samples from patients with various interstitial lung diseases at 11 hospitals in North America. Pathology diagnoses were confirmed by an expert panel. We measured RNA expression levels for 33 297 transcripts on microarrays in all samples. A classifier algorithm was trained on one set of samples and tested in a second set. We subjected a subset of samples to next-generation RNA sequencing (RNAseq) generating expression levels on 55 097 transcripts, and assessed a classifier trained on RNAseq data by cross-validation., Findings: We took 125 surgical lung biopsies from 86 patients. 58 samples were identified by the expert panel as usual interstitial pneumonia, 23 as non-specific interstitial pneumonia, 16 as hypersensitivity pneumonitis, four as sarcoidosis, four as respiratory bronchiolitis, two as organising pneumonia, and 18 as subtypes other than usual interstitial pneumonia. The microarray classifier was trained on 77 samples and was assessed in a test set of 48 samples, for which it had a specificity of 92% (95% CI 81-100) and a sensitivity of 82% (64-95). Based on a subset of 36 samples, the RNAseq classifier had a specificity of 95% (84-100) and a sensitivity of 59% (35-82)., Interpretation: Our results show that the development of a genomic signature that predicts usual interstitial pneumonia is feasible. These findings are an important first step towards the development of a molecular test that could be applied to bronchoscopy samples, thus avoiding surgery in the diagnosis of idiopathic pulmonary fibrosis., Funding: Veracyte., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Undifferentiated connective tissue disease (UCTD) involves conditions characterized by both having symptoms of connective tissue disease (CTD) and autoantibodies but not fulfilling the criteria of a specific CTD. The frequency or prognosis of the usual interstitial pneumonia (UIP) pattern in UCTD is unknown, which may be confused with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the frequency of the UIP pattern in interstitial pneumonia related to UCTD and compare its prognosis with that of IPF and UCTD-nonspecific interstitial pneumonia (UCTD-NSIP)., Methods: The medical records of 788 patients presumptively diagnosed with idiopathic interstitial pneumonia at Asan Medical Center from January 2005 to December 2012 were retrospectively reviewed. UCTD was diagnosed according to the criteria by Corte and colleagues, and the prognoses were compared between UCTD-UIP and UCTD-NSIP and between UCTD-UIP and IPF., Results: Among 105 patients with UCTD (13.3% of total subjects), 44 had a UIP pattern (by surgical lung biopsy: 24; by high-resolution CT scan: 20), 29 had a nonspecific interstitial pneumonia pattern (by surgical lung biopsy), and nine had an organizing pneumonia pattern (by biopsy). The overall survival of the UCTD-UIP group was shorter than that of the UCTD-NSIP group (P = .021) but significantly better than that of the IPF group (P = .042)., Conclusions: A UIP pattern, which seems to be frequent in UCTD, showed a poorer prognosis than that of UCTD-NSIP. However, the prognosis of UCTD-UIP was significantly better than that of IPF, highlighting the importance of searching for underlying UCTD in suspected IPF cases.

Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.

Background: Present guidelines for the diagnosis of idiopathic pulmonary fibrosis require histological confirmation of surgical lung biopsy samples when high-resolution CT images are not definitive for usual interstitial pneumonia. We aimed to assess the predictive value of high-resolution CT in a cohort of patients with suspected idiopathic pulmonary fibrosis from a previous randomised trial., Methods: ARTEMIS-IPF was a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial of ambrisentan for adults aged 40-80 years with well-defined idiopathic pulmonary fibrosis and 5% or less honeycombing on high-resolution CT. In December, 2010, an interim analysis showed lack of efficacy and the trial was stopped. In the present follow-on analysis, we assessed patients who were screened for ARTEMIS-IPF who underwent high-resolution CT as part of screening and surgical lung biopsy as part of standard clinical care. A radiologist and a pathologist from a central panel independently assessed anonymised CT scans and biopsy samples. We calculated the positive and negative predictive value of high-resolution CT (classified as usual interstitial pneumonia, possible usual interstitial pneumonia, and inconsistent with usual interstitial pneumonia) for confirmation of histological patterns of usual interstitial pneumonia. This study is registered with ClinicalTrials.gov, number NCT00768300., Findings: 315 (29%) of 1087 consecutively screened patients in ARTEMIS-IPF had both high-resolution CT and surgical lung biopsy samples. 108 of 111 patients who met high-resolution CT criteria for usual interstitial pneumonia had histologically confirmed usual interstitial pneumonia (positive predictive value 97·3%, 95% CI 92·3-99·4), as did 79 of 84 patients who met high-resolution CT criteria for possible usual interstitial pneumonia (94·0%, 86·7-98·0). 22 of 120 patients had an inconsistent high-resolution CT pattern for usual interstitial pneumonia that was histologically confirmed as not or possible usual interstitial pneumonia (negative predictive value 18·3%, 95% CI 11·9-26·4)., Interpretation: In the appropriate clinical setting, for patients with possible usual interstitial pneumonia pattern on high resolution CT, surgical lung biopsy sampling might not be necessary to reach a diagnosis of idiopathic pulmonary fibrosis if high-resolution CT scans are assessed by experts at regional sites familiar with patterns of usual interstitial pneumonia and management of idiopathic interstitial pneumonia., Funding: Gilead Sciences., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Currently, there is no reliable tool to predict response to intravesical bacillus Calmette-Guérin (BCG). Based on the fact that BCG is a Th1-polarizing immunotherapy, we attempt to correlate the pretreatment immunologic tumor microenvironment (Th1 or Th2) with response to therapy., Materials and Methods: Bladder cancer patients with initial diagnosis of carcinoma in situ (Tis) were stratified based on their response to BCG treatment. A total of 38 patients met inclusion criteria (20 patients who responded and 18 patients who did not respond). Immunohistochemical (IHC) methods known to assess the type of immunologic microenvironment (Th1 vs. Th2) were performed on tumor tissue obtained at initial biopsy/resection: the level of tumor eosinophil infiltration and degranulation (Th2 response); the number of tumor-infiltrating GATA-3(+) (Th2-polarized) lymphocytes; and the number of tumor-infiltrating T-bet(+) (Th1-polarized) lymphocytes. Results obtained from these metrics were correlated with response to treatment with BCG immunotherapy., Results: The IHC metrics of the tumor immune microenvironment prior to BCG treatment were each statistically significant predictors of responders (R) vs. nonresponders (NR). Eosinophil infiltration and degranulation was higher for R vs. NR: 1.02 ± 0.17 vs. 0.5 ± 0.12 (P = 0.01) and 1.1 ± 0.15 vs. 0.56 ± 0.15 (P = 0.04), respectively. Ratio of GATA-3(+) (Th2-polarized) lymphocytes to T-bet(+) (Th1-polarized) lymphocytes was higher for R vs. NR: 4.85 ± 0.94 vs. 0.98 ± 0.19 (P<0.001). The 3 markers were combined to create a Th2 signature biomarker, which was a statistically significant (P<0.0001) predictor of R vs. NR. All IHC markers demonstrated that a preexisting Th1 immunologic environment within the tumor was predictive of BCG failure., Conclusion: The Th1 vs. Th2 polarization of bladder tumor immune microenvironment prior to treatment with BCG represents a prognostic metric of response to therapy. If a patient has a preexisting Th1 immunologic response within the tumor, there is no value in using a therapy intended to create a Th1 immunologic response. An algorithm integrating 3 IHC methods provided a sensitive and specific technique that may become a useful tool for pathologists and urologists to predict response to BCG in patients with carcinoma in situ of the bladder., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The clinical features of idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis can be indistinguishable; the need to eliminate occult environmental factors known to cause pulmonary fibrosis in patients suspected to have IPF during diagnostic evaluation is evident. We aimed to investigate occult, putative causes in the environments of patients diagnosed with IPF using tests beyond those conventionally used., Methods: In this case-cohort study, 60 consecutive patients diagnosed with IPF on the basis of the 2000 American Thoracic Society (ATS) and the European Respiratory Society (ERS) criteria were prospectively followed up every 4 months for 6 years between Jan 1, 2004, and Dec 31, 2009. At each visit a uniformly applied questionnaire was administered to these 60 patients to identify occult antigen exposure known to cause hypersensitivity pneumonitis. Patients underwent specific IgG determination, bronchoalveolar lavage, bronchial challenge testing with suspected antigens, and re-review of histopathological features in existing and subsequently obtained surgical lung biopsy samples and from lung explants. Specimens obtained from suspected sources from the patient's environment were subjected to cultures in microbiology laboratory. These clinical data and discussions among pulmonologists and radiologists familiar with IPF were used to confirm the diagnosis in accordance with 2011 ATS, ERS, Japanese Respiratory Society, and Latin American Thoracic Association guidelines; 46 of the 60 patients had IPF according to the 2011 guidelines, and our analyses in this study were focused on these 46 patients., Findings: 20 of the 46 (43%, 95% CI 29-58) patients with IPF according to 2011 guidelines had a subsequent diagnosis of chronic hypersensitivity pneumonitis: nine patients had positive bronchial challenge testing (eight of whom were also IgG positive and six of these patients also had surgical lung biopsy showing a pattern consistent with chronic hypersensitivity pneumonitis); seven were IgG positive plus had histopathology on surgical lung biopsy that was consistent with hypersensitivity pneumonitis; one was IgG positive plus had greater than 20% lymphocytes in bronchoalveolar lavage fluid; and three had findings on surgical lung biopsy that were consistent with subacute hypersensitivity pneumonitis (and IgG positive). Altogether, 29 of 46 patients diagnosed with IPF who had met the 2011 criteria had lung tissue available for histopathology (surgical lung biopsy in 28 patients and explanted lung in two patients, one of whom also had surgical biopsy) during the study period, and 16 of the 20 patients with chronic hypersensitivity pneumonitis had histopathological features on surgical lung biopsy that were consistent with this diagnosis. 26 of the 46 patients remained with a diagnosis of IPF., Interpretation: Almost half of patients diagnosed with IPF on the basis of 2011 criteria were subsequently diagnosed with chronic hypersensitivity pneumonitis, and most of these cases were attributed to exposure of occult avian antigens from commonly used feather bedding. Our results reflect findings in one centre with recognised expertise in chronic hypersensitivity pneumonitis, and further research and studies at other centres are warranted., Funding: Fondo de Investigaciones Sanitarias; Fundació Privada Cellex; SEPAR 2010., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Because of the variable course of idiopathic pulmonary fibrosis (IPF), it is important to generate an accurate prognosis at the time of diagnosis. The aim of this study was to investigate the prognostic value of blood biomarkers in IPF., Methods: The plasma level of the biomarkers, matrix metalloproteinase-7 (MMP-7), Krebs von den Lungen-6 antigen, and surfactant protein (SP)-A and SP-D were retrospectively compared with the clinical course of 118 patients with IPF, 68 of whom had biopsy-proven IPF., Results: The median follow-up period was 24 months. Multivariate Cox analysis showed MMP-7 (HR, 1.056; P = .0063) and SP-A (HR, 1.011; P = .0001) were significant predictors of survival along with age, FVC, and extent of honeycombing. The patients with high levels of both MMP-7 (≥ 12.1 ng/mL) and SP-A (≥ 80.3 ng/mL) had shorter survival (1-year survival rate: 59%) and higher frequency (42%) of lung function decline (&gt; 10% reduction in FVC in 6 months) compared with those with high levels of one biomarker (1-year survival rate: 81%; FVC decline: 27%) or low levels of both (1-year survival rate: 83.3%; FVC decline: 9%). Multivariate models demonstrated marginal improvement in the prediction of mortality (concordance index [C-index]: 0.731; P = .061) when MMP-7 and SP-A were included and compared with standard clinical predictors only (C-index: 0.686); however, it became significant with addition of MMP-7, SP-A, and Krebs von den Lungen-6 antigen (C-index: 0.730; P = .037)., Conclusions: Our retrospective study suggested that at least three biomarkers are necessary to improve predictability of mortality in IPF compared with clinical parameters. Further study in a greater number of patients is warranted.

Objective: To investigate the prognostic significance of histopathological characteristics in patients with biopsy-proven rheumatoid lung disease (RLD)., Materials and Methods: Retrospective analysis was conducted on samples from 54 RLD patients who underwent surgical lung biopsies (SLBs) at Hamamatsu University Hospital and affiliated hospitals between 1980 and 2009. The overall survival rate, the spectrum of histopathological diagnosis and their associated prognostic significance were investigated., Results: The study group consisted of 30 men and 24 women with a median age of 60.3 years. Histopathological analysis revealed the following: usual interstitial pneumonia (UIP), 15 cases; nonspecific interstitial pneumonia/fibrosis, 16 cases; organizing pneumonia, 4 cases; unclassifiable, 2 cases; desquamative interstitial pneumonia, 1 case; and bronchiolar disease, 16 cases. In survival outcome, 10 yr survival rate was 76.6%. Patients with UIP had significantly worse prognosis than those with non-UIP (RLD cases except those with UIP) (p = 0.0452)., Conclusion: RLD includes several histopathological groups. Patients with UIP have worse survival than those with other types of RLD. Histopathological diagnosis may have a major impact on prognostication in patients with RLD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Although idiopathic nonspecific interstitial pneumonia (NSIP) was initially identified as a provisional diagnosis, the 2008 American Thoracic Society Project concluded that idiopathic NSIP is a distinct form of idiopathic interstitial pneumonia. However, an association between idiopathic NSIP and autoimmune diseases still attracts interest. In this context, a recent study proposed an intriguing concept that idiopathic NSIP is the pulmonary manifestation of undifferentiated connective tissue disease (UCTD). However, this has not been confirmed in a large number of patients with idiopathic NSIP. The present study was conducted to investigate the proportion and characteristics of patients with idiopathic NSIP who meet the criteria for UCTD., Methods: We reviewed 47 consecutive patients with idiopathic NSIP and examined whether they met prespecified criteria for UCTD. Furthermore, we compared the clinical characteristics between patients fulfilling the UCTD criteria (UCTD-NSIP) and those not meeting them (Non-UCTD-NSIP)., Results: Of 47 patients with idiopathic NSIP, 22 (47%) met the UCTD criteria. Common symptoms associated with connective tissue diseases (CTDs) were skin change (50%) and Raynaud's phenomenon (41%) in UCTD-NSIP. UCTD-NSIP showed a female predominance and significantly higher percentages of lymphocytes with a lower CD4/CD8 ratio in bronchoalveolar lavage than Non-UCTD-NSIP. Interestingly, UCTD-NSIP had a significantly better survival than Non-UCTD-NSIP., Conclusions: Idiopathic NSIP included subjects who fulfilled the UCTD criteria, and these subjects had different clinical characteristics with significantly better outcome than those who did not meet the criteria. These data suggest that a part, but not all, of patients with idiopathic NSIP show CTD-like features with a distinct prognosis.

Hyper IgG4 disease is a recently described inflammatory disease characterized by lymphoplasmacytic infiltration leading to fibrosis and tissue destruction. Whereas most cases have been successfully treated with corticosteroids, recurrent or refractory cases may benefit from alternative therapies. Bortezomib has proven to be successful in the treatment of multiple myeloma, and its mechanism indicates that it may have merit in autoimmune or other plasmacytic disorders. We report a patient with recurrent pulmonary infiltration with IgG4 plasma cells, consistent with hyper IgG4 disease, who was successfully treated using a bortezomib-based combination with minimal therapy-related toxicities.

Background: Patients with usual interstitial pneumonia (UIP) associated with collagen vascular disease (CVD) have been reported to have a better prognosis than those with idiopathic pulmonary fibrosis with a UIP pattern (IPF/UIP) seen on histology. The aim of this study was to evaluate the pathologic and radiologic differences between the two conditions and their relationship with clinical outcome., Methods: A retrospective review of 100 patients (CVD-UIP, 39 patients; IPF/UIP, 61 patients) with UIP pattern diagnosed by surgical lung biopsy at one tertiary referral center., Results: The median follow-up period was 34.4 months. The CVD-UIP group was younger, included more women and nonsmokers, and showed better survival than the IPF/UIP group. Pathologically, CVD-UIP patients had fewer fibroblastic foci and smaller honeycombing (HC) spaces with higher germinal centers and total inflammation scores than IPF/UIP patients. Radiologically, CVD-UIP patients had a lower emphysema score and more likely a nontypical UIP pattern without HC. The germinal centers score was the best distinguishing feature between CVD-UIP and IPF/UIP patients (odds ratio, 2.948; p = 0.001) and was marginally related to survival (p = 0.076). The HC score (hazard ratio [HR], 1.134; p < 0.001), total lung capacity (TLC) [HR, 0.932; p = 0.004], and age (HR, 1.052; p = 0.017) were significant predictors of survival in all patients with UIP histology, regardless of the presence of CVD. Among IPF/UIP patients, those with positive autoantibodies were pathologically more similar to CVD-UIP than to IPF/UIP without autoantibodies, despite no difference in survival between them., Conclusions: The germinal centers score was the best discriminative between CVD-UIP and IPF/UIP patients; it was of marginal prognostic significance. Age, TLC, and HC score were independent prognostic factors in all patients with UIP histology.

Background: Acute exacerbation (AE) is currently established as a distinct condition with acute deterioration of respiratory status in idiopathic pulmonary fibrosis (IPF). Recently, several studies have reported that AE also occurred in interstitial pneumonias other than IPF, such as collagen vascular disease-associated interstitial pneumonia (CVD-IP). However, the incidence of AE in CVD-IP and its clinical characteristics remain to be fully determined. This study was conducted to elucidate cumulative incidence of AE in CVD-IP and its clinical features., Methods: We reviewed 83 biopsy-proven CVD-IP patients, estimated cumulative incidence of AE, and examined its clinical characteristics., Results: Among 83 CVD-IP patients, six patients with a mean age of 65.7 years developed AE (overall incidence, 7.2%; 1-year incidence, 1.25%). Underlying CVDs included rheumatoid arthritis (RA) (n=5; overall incidence, 20.0%) and primary Sjögren syndrome (n=1; overall incidence, 5.9%). Patients with AE showed acute respiratory deterioration with severe hypoxemia (mean PaO(2)/FiO(2) ratio, 131). Radiologically, ground-glass opacity was superimposed on the underlying reticular abnormalities. Preexisting histological patterns included three usual interstitial pneumonia (UIP) and two non-specific interstitial pneumonia (NSIP). Five (83.3%) of six patients died of respiratory failure despite intensive therapy. Univariate Cox's proportional hazards analysis showed that age and RA diagnosis were significantly associated with AE. Multivariate Cox's proportional hazards analysis indicated that age was an independent significant factor predicting AE., Conclusions: These data suggest that AE can occur in CVD-IP, and this condition is closely similar to that of IPF with poor prognosis. AE is most common in RA, and associated with higher ages.

Placental transmogrification of the lung is a rare cystic lesion of the lung, which has some histologic resembling to placental tissue. Placental transmogrification of the lung has been considered a variant of unilateral bullous emphysema, but in our case, the patient was a 47-year-old man who had no coexisting emphysema of the lung. Histologically our case showed an interstitial proliferation of clear cells with cystic change interpreted as secondary; we also agree with our colleagues that this proliferation may be the primary event pathogenetically. Surgical resection of this lesion seems to be curative.

Many diverse and frequently idiopathic disorders cause interstitial lung disease (ILD) in children. Although the histologic patterns of ILD in children and adults share similar features, important differences exist in etiology, clinical manifestations, and outcome. Usual interstitial pneumonia (UIP) is the most frequent histologic pattern in adult ILD; however, the characteristic histologic features of UIP have yet to be demonstrated in a child. We report a 15-year-old boy with the UIP pattern of pulmonary fibrosis who had mutations in the adenosine triphosphate-binding-cassette-A3 gene. Discovery of how genetic mutations of proteins involved in surfactant biosynthesis lead to progressive fibrosis will have implications for the understanding of the pathogenesis and clinical manifestations of ILD in both adults and children.

Most patients with interstitial lung disease (ILD) associated with collagen vascular diseases (CVD) have a chronic indolent course with a relatively favorable prognosis; however, acute progression has been reported in some polymyositis-dermatomyositis patients. This study evaluated the prevalence, clinical features, and outcome relative to the presentation type of ILD in polymyositis-dermatomyositis (PM-DM). Ninety-nine patients with newly diagnosed polymyositis-dermatomyositis seen at the Asan Medical Center in Korea between January 1990 and December 2004 were enrolled. The clinical, radiological, and pathological findings were retrospectively reviewed. ILD were divided into acute (dyspnea within 1 month before diagnosis) or chronic types. ILD was found on chest radiographs in 33 patients (33.3%), and 11 (33.3%) of these were considered acute. The acute group presented with more severe respiratory symptoms, hypoxemia, and poorer lung function. Patients with an acute presentation had ground glass opacity and consolidation on high-resolution computed tomography (HRCT), in contrast to reticulation and honeycombing in the chronic type. Surgical lung biopsy of one acute-type patient revealed diffuse alveolar damage, whereas biopsies in the chronic type showed usual interstitial pneumonia (UIP) in four cases and nonspecific interstitial pneumonia (NSIP) in another four. Eight acute-type patients (72.7%) died of respiratory failure within 1-2 months despite steroid therapy. The 3-year mortality rate of the chronic-type patients (21.2%) was not statistically significantly different from that of the patients without ILD (10.2%). In polymyositis-dermatomyositis, the acute, severe form of ILD was not infrequent.

Background: Acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) is increasingly recognized as a relatively common and highly morbid clinical event. However, clinical data on AE in non-IPF interstitial pneumonia are sparse. This study was performed to find the frequency, clinical features, and outcome of AE in non-IPF interstitial pneumonia., Methods: Retrospective analysis of 10 patients who satisfied the modified Akira criteria for AE during follow-up of 74 patients with surgical lung biopsy-confirmed idiopathic nonspecific interstitial pneumonia (I-NSIP) and 93 patients with biopsy-confirmed interstitial pneumonia associated with collagen vascular disease (CVD-IP)., Results: AE occurred in six patients with I-NSIP (1-year frequency, 4.2%) and in four patients with CVD-IP (rheumatoid arthritis [RA], n = 3; scleroderma, n = 1), with 1-year frequency of 3.3%. Median age was 58 years (range, 47 to 75); six patients were female. AE occurred in two patients immediately after surgical biopsy. Median duration of acute symptom before hospital admission was 10 days (range, 1 to 30). Median ratio of Pao(2) to the fraction of inspired oxygen (Fio(2)) was 172 (range, 107 to 273), and Pao(2)/Fio(2) ratio was < 200 in six patients. Surgical lung biopsy performed at the time of AE in two patients revealed diffuse alveolar damage superimposed on nonspecific interstitial pneumonia pattern. Four patients with I-NSIP survived to discharge and were followed up for 24 months (range, 6 to 121)., Conclusion: AE occurred in the patients with I-NSIP with apparently better prognosis. In patients with CVD-IP, AE occurred mostly with RA-usual interstitial pneumonia in our small series with poor outcome.

The purpose of this study was to assess the role of bronchoalveolar lavage (BAL) in differentiating usual interstitial pneumonia (UIP) from non-specific interstitial pneumonia (NSIP) and in predicting the prognosis in fibrotic idiopathic interstitial pneumonia (IIP). A retrospective review of 122 patients (age 58+/-8 years, 70 male) with UIP (n=87) and NSIP (n=35) was carried out. Prior to surgical lung biopsy, all of them underwent BAL and high-resolution-computed tomography (HRCT) of the chest. Neutrophil count in BAL fluid was higher in UIP (7.0%) than NSIP (3.0%) (P=0.027). In contrast, BAL lymphocyte count was significantly higher in NSIP (29.0%) than UIP (5.5%) (P<0.0001). In 62 patients whose HRCT findings were atypical for UIP, BAL lymphocytosis was more frequently observed in NSIP (20/33) than UIP (4/29) (P<0.001) and the absence of BAL lymphocytosis suggested a diagnosis of UIP rather than NSIP (odds ratio 12.7, P<0.001). Pathologic diagnosis of NSIP was the only independent factor predicting a longer survival of our patients (median follow-up 21 months) (hazard ratio (HR) 0.035, P=0.005). When NSIP was not included in the survival analysis, higher BAL lymphocyte count was the only independent predictor of a longer survival (HR 0.909, P=0.029). BAL is an useful non-invasive tool in fibrotic IIP, not only for excluding a variety of specific non-IIP diseases but also for narrowing the differential diagnosis and predicting the prognosis in the absence of the histopathologic diagnosis.

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (EMZL/MALT-type) occurs in a wide variety of body sites; it is well recognized as a form of primary lung lymphoma. However, until recently, pleural presentation of this form of low-grade lymphoma has not been documented. A small series of case reports has brought to attention the potential for primary occurrence or initial presentation in the pleura of EMZL/MALT-type. In this report, we describe an additional patient with EMZL/MALT-type with initial pleural presentation and review the literature. Clinicians and pathologists dealing with lymphoproliferative disorders involving the pleura should be aware of this rare entity.

The male gametophyte (or pollen) plays an obligatory role during sexual reproduction of higher plants. The extremely reduced complexity of this organ renders pollen a valuable experimental system for studying fundamental aspects of plant biology such as cell fate determination, cell-cell interactions, cell polarity, and tip-growth. Here, we present the first reference map of the mature pollen proteome of the dicotyledonous model plant species, Arabidopsis thaliana. Based on two-dimensional gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight, and electrospray quadrupole time-of-flight mass spectrometry, we reproducibly identified 121 different proteins in 145 individual spots. The presence, subcellular localization, and functional classification of the identified proteins are discussed in relation to the pollen transcriptome and the full protein complement encoded by the nuclear Arabidopsis genome.

Study Objectives: To investigate the histopathologic pattern and clinical features of patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) according to the American Thoracic Society (ATS)/European Respiratory Society consensus classification of idiopathic interstitial pneumonia., Design: Retrospective review., Setting: Two thousand-bed, university-affiliated, tertiary referral center., Patients: Eighteen patients with RA who underwent surgical lung biopsy (SLBx) for suspected ILD., Method: SLBx specimens were reviewed and reclassified by three lung pathologists according to the ATS/European Respiratory Society classification. Clinical features and follow-up courses for the usual interstitial pneumonia (UIP) pattern and the nonspecific interstitial pneumonia (NSIP) pattern were compared., Results: The histopathologic patterns were diverse: 10 patients with the UIP pattern, 6 patients with the NSIP pattern, and 2 patients with inflammatory airway disease with the organizing pneumonia pattern. RA preceded ILD in the majority of patients (n = 12). In three patients, ILD preceded RA; in three patients, both conditions were diagnosed simultaneously. The majority (n = 13) of patients had a restrictive defect with or without low diffusion capacity of the lung for carbon monoxide (D(LCO)) on pulmonary function testing; 2 patients had only low (D(LCO)). The UIP and NSIP groups were significantly different in their male/female ratios (8/2 vs 0/6, respectively; p = 0.007) and smoking history (current/former or nonsmokers, 8/2 vs 0/6; p = 0.007). Many of the patients with the UIP pattern had typical high-resolution CT features of UIP. Five patients with the UIP pattern died, whereas no deaths occurred among patients with the NSIP pattern during median follow-up durations of 4.2 years and 3.7 years, respectively., Conclusions: The histopathologic type of RA-ILD was diverse; in our study population, the UIP pattern seemed to be more prevalent than the NSIP pattern.

Antineutrophil cytoplasmic autoantibodies (ANCAs) recognizing human proteinase 3 of neutrophil granules are a diagnostic hallmark of Wegener granulomatosis, an autoimmune systemic vasculitis with predilection for the respiratory tract and kidneys. In vitro experiments have implicated several mechanisms by which ANCAs may lead to tissue injury. However, little is known about the pathogenic significance of proteinase 3-specific antibodies in vivo. In vivo models for ANCA-mediated proinflammatory effects have not been forthcoming, primarily because ANCA epitopes on human proteinase 3 are not shared by the murine homolog. In this study we generated ANCAs against recombinant murine proteinase 3 in proteinase 3/neutrophil elastase-deficient mice that recognized the murine antigen on the surface of neutrophils. Local inflammation induced by intradermal injection of tumor necrosis factor alpha triggered a stronger subcutaneous panniculitis in the presence of passively transferred systemic proteinase 3-ANCAs than in the presence of mock immune serum. When we transferred mouse proteinase 3-ANCA serum to systemically lipopolysaccharide-primed wild-type mice, mice treated with proteinase 3-ANCAs did not develop significantly stronger signs of inflammation of the lungs or kidneys than the respective mock immune serum-treated animals. In conclusion, our in vivo study provides the first evidence for a pathogenic effect of proteinase 3-specific ANCAs at local sites of inflammation.

Abnormal proliferation of pulmonary fibroblasts is a prominent feature of chronic pulmonary fibrotic diseases such as idiopathic interstitial pneumonia (IIP), but it is not presently clear how this proliferative response by lung fibroblasts can be therapeutically modulated. In the present study, we examined whether it was possible to selectively target primary human pulmonary fibroblasts grown out of surgical lung biopsies (SLBs) from IIP patients based on their expression of interleukin-4 receptor (IL-4R) and IL-13R subunits. Pulmonary fibroblast lines cultured from patients with the severest form of IIP, namely usual interstitial pneumonia, exhibited the greatest gene and protein expression of IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2 compared with primary pulmonary fibroblast lines grown from other IIP SLBs and normal SLBs. When exposed to increasing concentrations of a chimeric protein comprised of human IL-13 and a truncated version of Pseudomonas exotoxin (IL13-PE), the proliferation of primary usual interstitial pneumonia fibroblasts was inhibited to a much greater extent compared with fibroblast lines from nonspecific interstitial pneumonia and respiratory bronchiolitis/interstitial lung disease patient groups. Fibroblasts from normal patients exhibited minimal susceptibility to the cytotoxic effect of IL13-PE. IL13-PE-mediated targeting of IIP fibroblasts was dependent on their expression of IL-4Ralpha and IL-13Ralpha2. Thus, these data suggest that the abnormal proliferative properties of human lung fibroblasts from certain IIP patient groups can be modulated in a manner that is dependent on the IL-4 and IL-13 receptor subunit expression by these cells.

Study Objectives: Lymphangioleiomyomatosis (LAM) is a rare disorder of unknown etiology, affecting almost exclusively women of childbearing age, that is associated with the proliferation of spindle cells and cystic changes in the affected lung. The underlying processes that contribute to this disease are poorly understood. Transforming growth factor (TGF)-beta(1) is a potent cytokine that promotes mesenchymal cell proliferation and regulates the synthesis of extracellular matrix (ECM) components, particularly fibronectins. Herein, we evaluate the expression of TGF beta(1) and matrix-associated fibronectin in lung specimens demonstrating LAM., Design: Lung biopsy specimens that were confirmed to contain pathologic LAM cells were obtained from 13 patients. The specimens were submitted to immunohistochemical evaluation for TGF beta(1) and fibronectin, as well as the typical markers of LAM cells. Healthy lung parenchyma surrounding resected neoplasms was studied in a parallel fashion as control tissues., Measurements and Results: In all 13 LAM cases and in healthy lung parenchyma, we demonstrated that TGF beta(1) localized consistently to airway epithelial cells. However, in LAM tissues, matrix-associated TGF beta(1) was also consistently found in regions containing pathologic LAM cells. Notably, more abundant TGF beta(1) was observed in highly cellular areas compared to the walls of chronic cystic regions in LAM tissues. Fibronectin, a matrix component that is strongly expressed in response to active TGF beta(1) was found to consistently colocalize with this protein in these highly cellular regions, supporting TGF beta(1) activity in these regions. The markers of proliferating LAM cells, including proliferating cell nuclear antigen, were also markedly present in these highly cellular LAM regions., Conclusion: These studies suggest that the proliferation of aberrant LAM cells may be associated with altered regional expression of TGF beta(1) and related ECM proteins.

Study Objectives: To determine the prevalence and prognostic significance of histologic discordance in multiple lung biopsy specimens obtained from patients investigated for suspected cryptogenic fibrosing alveolitis (CFA)/idiopathic pulmonary fibrosis (IPF)., Methods: and results: Between 1984 and 2001, 64 patients undergoing investigation for CFA/IPF were identified in whom multiple biopsies were performed that showed either a pattern of usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP). These cases were classified into three groups: concordant UIP-UIP (n = 25, 39.1%), discordant UIP-NSIP (n = 8,12.5%), and concordant NSIP-NSIP (n = 31, 48.4%). The discordant UIP group had survival, clinical, and physiologic features similar to those of the concordant UIP group, and prognosis in both concordant and discordant UIP groups was significantly worse than that of the concordant NSIP group (p = 0.02 and p = 0.04, respectively). The age of the concordant UIP group was higher than that of the concordant NSIP group, with the mean age of the discordant group being intermediate. There were no significant differences among the three groups in smoking history, duration of dyspnea, presence or absence of crackles, FVC, diffusion capacity of the lung for carbon monoxide, or PaO(2)., Conclusions: Patients with discordant UIP-NSIP results on multiple biopsies show clinical behavior similar to those with concordant UIP-UIP and should be regarded as having CFA/IPF in the correct clinical context, rather than "idiopathic NSIP" for the purposes of management. Multiple biopsies should be considered in all patients in order to improve the prognostic information provided by lung biopsy.

Objectives: To characterize the histologic, high-resolution CT (HRCT), and functional correlates of respiratory bronchiolitis (RB)/desquamative interstitial pneumonia (DIP)-like changes in biopsy specimens of adults with pulmonary Langerhans cell histiocytosis (PLCH)., Methods: We retrospectively identified 14 adult patients with histologically proven PLCH (all smokers) in whom both biopsy specimens and HRCT were available for review. The presence and extent of RB/DIP-like changes on lung biopsy specimens of patients with PLCH were correlated with total pack-years of smoking, lung function variables, and the presence of ground-glass attenuation on HRCT., Results: Varying degrees of RB/DIP-like changes were identified in all biopsy specimens. The extent of involvement with RB/DIP-like changes correlated with the cumulative exposure to cigarettes smoked at the time of biopsy (r = 0.61, p = 0.03). Ground-glass attenuation was detected in three HRCTs, two of which had extensive RB/DIP-like changes (> or = 70% involvement) on histology, suggesting that substantial smoking-induced RB/DIP-like changes may be the cause of ground-glass attenuation on the HRCT of patients with PLCH. No correlation was found between the extent of RB/DIP-like changes and total lung capacity, FEV(1), or diffusion capacity of the lung for carbon monoxide., Conclusions: RB/DIP-like changes are exceedingly common in PLCH, may be sufficiently severe to cause the appearance of ground-glass attenuation on HRCT, and correlate with the cumulative exposure to cigarettes smoked. This study provides additional evidence that PLCH, RB, and DIP form a spectrum of interstitial patterns of lung injury to cigarette smoke.

Purpose: To determine which clinical and radiologic findings are independently associated with a pathologic diagnosis of usual interstitial pneumonia (UIP)., Methods: We recently reported, using a prospective, multicenter study of patients suspected of having idiopathic interstitial pneumonia (IIP), that a confident diagnosis of UIP made by experienced radiologists was correct in 95% of cases. In the current article, we further analyzed data from this study. Ninety-one patients were entered into the study. Clinical, physiologic, chest radiographic, and CT features were prospectively recorded, and analyzed using univariate and multivariate logistic regression analysis to compare the patients with a histologic diagnosis of UIP with those who received other pathologic diagnoses., Results: Fifty-four of 91 patients (59%) received a pathologic diagnosis of UIP. The following features recorded at the referring clinical centers were associated with a pathologic diagnosis of UIP on multivariate analysis: lower-lobe honeycombing on high-resolution CT (HRCT) [odds ratio, 11.45], radiographic findings consistent with UIP (odds ratio, 5.73), elevated ratio of FEV(1) to FVC (odds ratio, 4.8), and absence of smoking history (odds ratio, 0.19). On multivariate analysis of specific HRCT features recorded by four experienced chest radiologists, lower-lung honeycombing (odds ratio, 5.36) and upper-lung irregular lines (odds ratio, 6.28) were the only independent predictors of UIP. Using only these two factors, a diagnosis of UIP could be established with a sensitivity of 74%, a specificity of 81%, and a positive predictive value of 85%., Conclusion: In patients presenting with a clinical syndrome suggestive of IIP, CT findings of lower-lung honeycombing and upper-lung irregular lines are most closely associated with a pathologic diagnosis of UIP.