AIM: Transbronchial cryobiopsies are increasingly used for the diagnosis of interstitial lung disease (ILD), but there is a lack of published information on the features of specific ILD in cryobiopsies. Here we attempt to provide pathological guidelines for separating usual interstitial pneumonia (UIP) of idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease-associated ILD (CTD-ILD) in cryobiopsies. METHODS: We examined 120 cryobiopsies from patients with multidisciplinary discussion (MDD)-established CTD-ILD and compared them to a prior series of 121 biopsies from patients with MDD-established IPF or FHP. RESULTS: A non-specific interstitial pneumonia (NSIP) pattern alone was seen in 36 of 120 (30%) CTD-ILD, three of 83 (3.6%) FHP and two of 38 (5.2%) IPF cases, statistically favouring a diagnosis of CTD-ILD. The combination of NSIP + OP was present in 29 of 120 (24%) CTD-ILD, two of 83 (2.4%) FHP and none of 38 (0%) IPF cases, favouring a diagnosis of CTD-ILD. A UIP pattern, defined as fibroblast foci plus any of patchy old fibrosis/fibrosis with architectural distortion/honeycombing, was identified in 28 of 120 (23%) CTD-ILD, 45 of 83 (54%) FHP and 27 of 38 (71%) IPF cases and supported a diagnosis of FHP or IPF. The number of lymphoid aggregates/mm2 and fibroblast foci/mm2 was not different in IPF, CTD-ILD or FHP cases with a UIP pattern. Interstitial giant cells supported a diagnosis of FHP or CTD-ILD over IPF, but were infrequent. CONCLUSIONS: In the correct clinical/radiological context the pathological findings of NSIP, and particularly NSIP plus OP, favour a diagnosis of CTD-ILD in a cryobiopsy, but CTD-ILD with a UIP pattern, FHP with a UIP pattern and IPF generally cannot be distinguished.
- MeSH
- biopsie metody MeSH
- dospělí MeSH
- idiopatická plicní fibróza patologie komplikace diagnóza MeSH
- intersticiální plicní nemoci * patologie diagnóza komplikace MeSH
- lidé středního věku MeSH
- lidé MeSH
- nemoci pojiva * komplikace patologie diagnóza MeSH
- plíce patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Despite many technological advances, the diagnostic yield of bronchoscopic peripheral lung nodule analysis remains limited due to frequent mispositioning. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic feedback on needle positioning, potentially improving the sampling location and diagnostic yield. Previous studies have defined and validated nCLE criteria for malignancy, airway and lung parenchyma. Larger studies demonstrating the effect of nCLE on diagnostic yield are lacking. We aim to investigate if nCLE-imaging integrated with conventional bronchoscopy results in a higher diagnostic yield compared with conventional bronchoscopy without nCLE. METHODS AND ANALYSIS: This is a parallel-group randomised controlled trial. Recruitment is performed at pulmonology outpatient clinics in universities and general hospitals in six different European countries and one hospital in the USA. Consecutive patients with a for malignancy suspected peripheral lung nodule (10-30 mm) with an indication for diagnostic bronchoscopy will be screened, and 208 patients will be included. Web-based randomisation (1:1) between the two procedures will be performed. The primary outcome is diagnostic yield. Secondary outcomes include diagnostic sensitivity for malignancy, needle repositionings, procedure and fluoroscopy duration, and complications. Pathologists will be blinded to procedure type; patients and endoscopists will not. ETHICS AND DISSEMINATION: Primary approval by the Ethics Committee of the Amsterdam University Medical Center. Dissemination involves publication in a peer-reviewed journal. SUPPORT: Financial and material support from Mauna Kea Technologies. TRIAL REGISTRATION NUMBER: NCT06079970.
- MeSH
- bronchoskopie * metody MeSH
- jehly MeSH
- konfokální mikroskopie * metody MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- nádory plic * patologie diagnóza diagnostické zobrazování MeSH
- plíce patologie diagnostické zobrazování MeSH
- randomizované kontrolované studie jako téma MeSH
- solitární plicní uzel * patologie diagnostické zobrazování diagnóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- protokol klinické studie MeSH
- randomizované kontrolované studie MeSH
INTRODUCTION: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. METHODS: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. RESULTS: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. DISCUSSION: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.
- Publikační typ
- časopisecké články MeSH
Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.
Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
- MeSH
- ABC transportéry genetika MeSH
- celogenomová asociační studie MeSH
- DNA-helikasy genetika MeSH
- exoribonukleasy genetika MeSH
- genetická predispozice k nemoci MeSH
- genetická variace MeSH
- idiopatická plicní fibróza genetika MeSH
- interakce hostitele a patogenu genetika MeSH
- lidé MeSH
- logistické modely MeSH
- mucin 5B genetika MeSH
- promotorové oblasti (genetika) genetika MeSH
- protein A asociovaný s plicním surfaktantem genetika MeSH
- protein C asociovaný s plicním surfaktantem genetika MeSH
- proteiny aktivující GTPasu genetika MeSH
- proteiny vázající telomery genetika MeSH
- RNA genetika MeSH
- sekvenční analýza DNA MeSH
- stárnutí buněk genetika MeSH
- studie případů a kontrol MeSH
- telomerasa genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.
- MeSH
- akutní nemoc MeSH
- běloši MeSH
- břicho MeSH
- dospělí MeSH
- fenotyp * MeSH
- genotyp MeSH
- kožní nemoci patofyziologie MeSH
- kůže patofyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické uzliny patofyziologie MeSH
- nemoci kloubů patofyziologie MeSH
- oči patofyziologie MeSH
- oční nemoci patofyziologie MeSH
- plíce patofyziologie MeSH
- plicní nemoci patofyziologie MeSH
- sarkoidóza diagnóza patofyziologie MeSH
- senioři MeSH
- terciární zdravotní péče MeSH
- usilovný výdechový objem MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
Fibrosing interstitial lung diseases (ILDs) are a large group of diseases triggered by external or internal stimuli that can have similar outcomes, i.e. lung fibrosis. Some ILDs are primarily fibro-proliferative disorders in which alveolar loss and epithelial/fibroblastic proliferation and dysplasia lead to lung fibrosis and architectural derangement, while other ILDs are considered inflammatory disorders in which specific underlying conditions (with either an external or an internal origin) can shift the pathogenic process to the fibro-proliferative pathway. The treatment of primarily inflammatory ILDs, regardless of their tendency to switch to lung fibrosis usually consists of anti-inflammatory drugs (e.g. corticosteroids, cytostatic + immunosuppressive agents), targeted 'biologic treatment' (e.g. anti TNF-alpha, anti CD20) and combinations thereof. However, we have entered an era in which new drugs that specifically target fibrosing ILDs, namely IPF, have emerged. Continuing laboratory research and clinical studies will hopefully provide us with a more complete understanding of the pathogenesis of fibrosing ILDs. Additionally, we are optimistic about the discovery of new pharmacological targets for the treatment of these serious diseases.The complex issues concerning fibrosing ILDs were addressed and passionately discussed during the Prague postgraduate course and conference devoted to these diseases (June 19th - 21th, 2014).
- MeSH
- antiflogistika terapeutické užití MeSH
- imunosupresiva terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- plíce účinky léků patologie MeSH
- plicní fibróza diagnóza farmakoterapie etiologie patologie MeSH
- prediktivní hodnota testů MeSH
- rizikové faktory MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
