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Wilfong EM, Crofford LJ, Kropski JA
(2019) Arthritis Rheumatol 71: 2133-2134
MeSH Terms: Humans, Lung Diseases, Interstitial, Pulmonary Medicine, Rheumatology
Added March 25, 2020
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Reply.
Wilfong EM, Bayram KW, Crofford LJ
(2019) Arthritis Rheumatol 71: 652-653
MeSH Terms: Humans, Lung Diseases, Interstitial, Pulmonary Medicine, Rheumatology
Added March 25, 2020
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Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes.
McCall AS, Bhave G, Pedchenko V, Hess J, Free M, Little DJ, Baker TP, Pendergraft WF, Falk RJ, Olson SW, Hudson BG
(2018) J Am Soc Nephrol 29: 2619-2625
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Anti-Glomerular Basement Membrane Disease, Antibodies, Antineutrophil Cytoplasmic, Antibody Specificity, Autoantibodies, Autoantigens, Child, Cohort Studies, Collagen Type IV, Extracellular Matrix Proteins, Female, Glomerulonephritis, Hemorrhage, Humans, Lung Diseases, Male, Middle Aged, Models, Immunological, Peroxidase, Peroxidases, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - Goodpasture syndrome (GP) is a pulmonary-renal syndrome characterized by autoantibodies directed against the NC1 domains of collagen IV in the glomerular and alveolar basement membranes. Exposure of the cryptic epitope is thought to occur disruption of sulfilimine crosslinks in the NC1 domain that are formed by peroxidasin-dependent production of hypobromous acid. Peroxidasin, a heme peroxidase, has significant structural overlap with myeloperoxidase (MPO), and MPO-ANCA is present both before and at GP diagnosis in some patients. We determined whether autoantibodies directed against peroxidasin are also detected in GP.
METHODS - We used ELISA and competitive binding assays to assess the presence and specificity of autoantibodies in serum from patients with GP and healthy controls. Peroxidasin activity was fluorometrically measured in the presence of partially purified IgG from patients or controls. Clinical disease severity was gauged by Birmingham Vasculitis Activity Score.
RESULTS - We detected anti-peroxidasin autoantibodies in the serum of patients with GP before and at clinical presentation. Enriched anti-peroxidasin antibodies inhibited peroxidasin-mediated hypobromous acid production . The anti-peroxidasin antibodies recognized peroxidasin but not soluble MPO. However, these antibodies did crossreact with MPO coated on the polystyrene plates used for ELISAs. Finally, peroxidasin-specific antibodies were also found in serum from patients with anti-MPO vasculitis and were associated with significantly more active clinical disease.
CONCLUSIONS - Anti-peroxidasin antibodies, which would previously have been mischaracterized, are associated with pulmonary-renal syndromes, both before and during active disease, and may be involved in disease activity and pathogenesis in some patients.
Copyright © 2018 by the American Society of Nephrology.
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Interstitial Pneumonia With Autoimmune Features: An Emerging Challenge at the Intersection of Rheumatology and Pulmonology.
Wilfong EM, Lentz RJ, Guttentag A, Tolle JJ, Johnson JE, Kropski JA, Kendall PL, Blackwell TS, Crofford LJ
(2018) Arthritis Rheumatol 70: 1901-1913
MeSH Terms: Autoimmune Diseases, Connective Tissue Diseases, Female, Humans, Lung Diseases, Interstitial, Male, Pulmonary Medicine, Rheumatology
Show Abstract · Added March 25, 2020
Interstitial lung disease (ILD) remains a cause of significant morbidity and mortality in patients with connective tissue disease (CTD)-associated ILD. While some patients meet clear classification criteria for a systemic rheumatic disease, a subset of patients do not meet classification criteria but still benefit from immunosuppressive therapy. In 2015, the American Thoracic Society and European Respiratory Society described classification criteria for interstitial pneumonia with autoimmune features (IPAF) to identify patients with lung-predominant CTD who lack sufficient features of a systemic rheumatic disease to meet classification criteria. Although these criteria are imperfect, they are an important attempt to classify the patient with undifferentiated disease for future study. Rheumatologists play a key role in the evaluation of potential IPAF in patients, especially as many patients with a myositis-spectrum disease (e.g., non-Jo-1 antisynthetase syndrome, anti-melanoma differentiation-associated protein 5 antibody inflammatory myositis, or anti-PM/Scl antibody-associated inflammatory myositis) would be classified under IPAF using the currently available criteria for inflammatory myositis, and would therefore benefit from rheumatologic comanagement. The aim of this review was to describe the historical context that led to the development of these criteria and to discuss the limitations of the current criteria, diagnostic challenges, treatment options, and strategies for disease monitoring.
© 2018, American College of Rheumatology.
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Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.
Sivley RM, Sheehan JH, Kropski JA, Cogan J, Blackwell TS, Phillips JA, Bush WS, Meiler J, Capra JA
(2018) BMC Bioinformatics 19: 18
MeSH Terms: Algorithms, Area Under Curve, DNA Helicases, Humans, Lung Diseases, Interstitial, Mutation, Missense, Protein Structure, Tertiary, ROC Curve, Spatial Analysis
Show Abstract · Added March 14, 2018
BACKGROUND - Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease.
RESULTS - To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function.
CONCLUSIONS - Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating spatial proximity analyses into other pathogenicity prediction tools may improve accuracy for other genes and genetic diseases.
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9 MeSH Terms
Utility of Flexible Bronchoscopic Cryobiopsy for Diagnosis of Diffuse Parenchymal Lung Diseases.
Lentz RJ, Taylor TM, Kropski JA, Sandler KL, Johnson JE, Blackwell TS, Maldonado F, Rickman OB
(2018) J Bronchology Interv Pulmonol 25: 88-96
MeSH Terms: Adult, Aged, Aged, 80 and over, Biopsy, Bronchoscopy, Female, Humans, Lung Diseases, Interstitial, Male, Middle Aged, Postoperative Complications, Predictive Value of Tests, Retrospective Studies, Young Adult
Show Abstract · Added March 21, 2018
BACKGROUND - Initial reports of transbronchial cryobiopsy for diffuse parenchymal lung disease (DPLD) suggest the diagnostic yield approaches that of surgical lung biopsy (SLB) with an excellent safety profile. Centers performing cryobiopsy differ significantly in procedure technique; an optimal technique minimizing complications but still capable of diagnosing a wide range of DPLDs has not been established. We evaluated our practice of flexible bronchoscopic cryobiopsy in a primarily outpatient setting for patients who required a tissue diagnosis for DPLD of uncertain etiology.
METHODS - Consecutive patients with indeterminate DPLD who underwent bronchoscopic cryobiopsy at a large academic medical center from January 2012 to August 2015 were retrospectively analyzed. Rates of confident histopathologic diagnosis, confident multidisciplinary consensus diagnosis, management change, and complications were determined.
RESULTS - One hundred four cases were identified. Confident histopathologic diagnoses were established in 44% (46/104) and confident multidisciplinary consensus diagnoses in 68% (71/104). Usual interstitial pneumonia (19/104) and idiopathic pulmonary fibrosis (22/104) were the most common histopathologic and consensus diagnoses, respectively. Five subjects proceeded to SLB after cryobiopsy which was diagnostic in 3. Results of cryobiopsies changed management in 70% (73/104). Complications occurred in 8 cases with no death.
CONCLUSIONS - Cryobiopsy during outpatient flexible bronchoscopy facilitated confident multidisciplinary consensus diagnosis of DPLD in more than two thirds of cases, and appears sufficient to establish the histopathologic diagnosis of usual interstitial pneumonia, with a complication rate that compares favorably to that reported for SLB.
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14 MeSH Terms
Reply: The Genetic Diagnosis of Interstitial Lung Disease: A Need for an International Consensus.
Kropski JA, Young LR, Blackwell TS, Loyd JE
(2017) Am J Respir Crit Care Med 195: 1539-1540
MeSH Terms: Consensus, Diagnosis, Differential, Humans, Lung, Lung Diseases, Interstitial
Added March 21, 2018
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5 MeSH Terms
Cholesterol, lipoproteins and subclinical interstitial lung disease: the MESA study.
Podolanczuk AJ, Raghu G, Tsai MY, Kawut SM, Peterson E, Sonti R, Rabinowitz D, Johnson C, Barr RG, Hinckley Stukovsky K, Hoffman EA, Carr JJ, Ahmed FS, Jacobs DR, Watson K, Shea SJ, Lederer DJ
(2017) Thorax 72: 472-474
MeSH Terms: Aged, Aged, 80 and over, Biomarkers, Cholesterol, HDL, Coronary Artery Disease, Cross-Sectional Studies, Female, Humans, Lipoproteins, Lung Diseases, Interstitial, Male, Matrix Metalloproteinase 7, Middle Aged, Prospective Studies, Pulmonary Surfactant-Associated Protein A, Tomography, X-Ray Computed
Show Abstract · Added September 11, 2017
We investigated associations of plasma lipoproteins with subclinical interstitial lung disease (ILD) by measuring high attenuation areas (HAA: lung voxels between -600 and -250 Hounsfield units) in 6700 adults and serum MMP-7 and SP-A in 1216 adults age 45-84 without clinical cardiovascular disease in Multi-Ethnic Study of Atherosclerosis. In cross-sectional analyses, each SD decrement in high density lipoprotein cholesterol (HDL-C) was associated with a 2.12% HAA increment (95% CI 1.44% to 2.79%), a 3.53% MMP-7 increment (95% CI 0.93% to 6.07%) and a 6.37% SP-A increment (95% CI 1.35% to 11.13%), independent of demographics, smoking and inflammatory biomarkers. These findings support a novel hypothesis that HDL-C might influence subclinical lung injury and extracellular matrix remodelling.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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16 MeSH Terms
Lung cancer risk test trial: study design, participant baseline characteristics, bronchoscopy safety, and establishment of a biospecimen repository.
Crawford EL, Levin A, Safi F, Lu M, Baugh A, Zhang X, Yeo J, Khuder SA, Boulos AM, Nana-Sinkam P, Massion PP, Arenberg DA, Midthun D, Mazzone PJ, Nathan SD, Wainz R, Silvestri G, Tita J, Willey JC
(2016) BMC Pulm Med 16: 16
MeSH Terms: Aged, Aged, 80 and over, Agriculture, Asbestos, Biological Specimen Banks, Bronchi, Bronchoscopy, Cohort Studies, Early Detection of Cancer, Epithelial Cells, Female, Forced Expiratory Volume, Genetic Predisposition to Disease, Humans, Incidence, Lung Diseases, Obstructive, Lung Neoplasms, Male, Middle Aged, Occupational Exposure, Prospective Studies, Respiratory Mucosa, Risk Assessment, Smoking, Tomography, Spiral Computed, Vital Capacity
Show Abstract · Added February 16, 2016
BACKGROUND - The Lung Cancer Risk Test (LCRT) trial is a prospective cohort study comparing lung cancer incidence among persons with a positive or negative value for the LCRT, a 15 gene test measured in normal bronchial epithelial cells (NBEC). The purpose of this article is to describe the study design, primary endpoint, and safety; baseline characteristics of enrolled individuals; and establishment of a bio-specimen repository.
METHODS/DESIGN - Eligible participants were aged 50-90 years, current or former smokers with 20 pack-years or more cigarette smoking history, free of lung cancer, and willing to undergo bronchoscopic brush biopsy for NBEC sample collection. NBEC, peripheral blood samples, baseline CT, and medical and demographic data were collected from each subject.
DISCUSSION - Over a two-year span (2010-2012), 403 subjects were enrolled at 12 sites. At baseline 384 subjects remained in study and mean age and smoking history were 62.9 years and 50.4 pack-years respectively, with 34% current smokers. Obstructive lung disease (FEV1/FVC <0.7) was present in 157 (54%). No severe adverse events were associated with bronchoscopic brushing. An NBEC and matched peripheral blood bio-specimen repository was established. The demographic composition of the enrolled group is representative of the population for which the LCRT is intended. Specifically, based on baseline population characteristics we expect lung cancer incidence in this cohort to be representative of the population eligible for low-dose Computed Tomography (LDCT) lung cancer screening. Collection of NBEC by bronchial brush biopsy/bronchoscopy was safe and well-tolerated in this population. These findings support the feasibility of testing LCRT clinical utility in this prospective study. If validated, the LCRT has the potential to significantly narrow the population of individuals requiring annual low-dose helical CT screening for early detection of lung cancer and delay the onset of screening for individuals with results indicating low lung cancer risk. For these individuals, the small risk incurred by undergoing once in a lifetime bronchoscopic sample collection for LCRT may be offset by a reduction in their CT-related risks. The LCRT biospecimen repository will enable additional studies of genetic basis for COPD and/or lung cancer risk.
TRIAL REGISTRATION - The LCRT Study, NCT 01130285, was registered with Clinicaltrials.gov on May 24, 2010.
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26 MeSH Terms
Pulmonary Abscess as a Complication of Transbronchial Lung Cryobiopsy.
Skalski JH, Kern RM, Midthun DE, Edell ES, Maldonado F
(2016) J Bronchology Interv Pulmonol 23: 63-6
MeSH Terms: Anti-Bacterial Agents, Biopsy, Bronchoscopy, Humans, Levofloxacin, Lung, Lung Abscess, Lung Diseases, Male, Metronidazole, Middle Aged, Tomography, X-Ray Computed
Show Abstract · Added February 1, 2016
We present the case of a 49-year-old man who developed pulmonary abscess as a complication of transbronchial lung cryobiopsy. He had been receiving prednisone therapy, but otherwise had no specific risk factors for lung abscess. Cryobiopsy is a novel technique for obtaining peripheral lung parenchymal tissue for the evaluation of diffuse parenchymal lung diseases. Cryobiopsy is being increasingly proposed as an alternative to surgical lung biopsy or conventional bronchoscopic transbronchial forceps biopsy, but the safety profile of the procedure has not been fully appreciated. Pulmonary abscess has been rarely reported as a complication of other bronchoscopic procedures such as endobronchial ultrasound-guided needle biopsy, however, to our knowledge this is the first reported case of pulmonary abscess complicating peripheral lung cryobiopsy.
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12 MeSH Terms