Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics

The research of rare and devastating orphan diseases, such as idiopathic pulmonary fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor—the prevalence of IPF is only approximately four times the incidence, limiting the recruitment of patients to trials and studies of the underlying biology. Global biobanking efforts can dramatically alter the future of IPF research. We describe a large-scale meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine this meta-analysis with the largest available meta-analysis of IPF, reaching 11,160 patients and 1,364,410 population controls. We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection and note an unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B.publishedVersionPeer reviewe

Tenascin expression and distribution in pulmonary and pleural fibrotic disorders

Abstract Fibrotic pulmonary and pleural disorders represent a group of intrathoracic disorders with different etiologies and prognoses. A prominent part of both pulmonary and pleural fibrotic disorders remains etiologically unknown. An essential feature for all these disorders is an increase and disarray of many extracellular matrix proteins which take part in the remodeling of the fibrotic tissue. Further, the injury in pulmonary as well as in pleural fibrosis occurs often at the border between the epithelial or mesothelial and the mesenchymal cells breaking the epithelial basement membrane. Tenascin is an oligomeric matrix glycoprotein of the extracellular matrix. The best known isoforms are tenascin -C, -X, -R, -Y and -W. Tenascin-C is synthesized during embryonic development, expressed in a variety of tumors, being absent or scantily expressed in most adult tissues. The function of tenascin-C is still unclear. In lung, tenascin-C has been shown to be expressed in fetal lung during branching morphogenesis, benign and malignant lung tumors, idiopathic pulmonary fibrosis, sarcoidosis and asthma. The aim of the present study was to study tenascin-C (later called tenascin) expression in various types of pulmonary fibrosis such as usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), bronchiolitis obliterans organizing pneumonia (BOOP), sarcoidosis and extrinsic allergic alveolitis as well as in fibrotic and inflammatory disorders of the pleura of different etiologies. Further, the aims were to compare the accumulation of tenascin with the prognosis in UIP, to confirm the immunohistochemical findings in UIP by Western blotting and immunoelectron miscroscopic (immuno-EM) studies, to investigate which cells synthesize tenascin in UIP and in pleural fibrosis by mRNA in situ hybridization, and to determine whether epithelial lining fluid (ELF) and serum tenascin concentration are increased in patients with UIP, sarcoidosis and extrinsic allergic alveolitis. Tenascin was shown to be increased by immunohistochemical studies in all types of pulmonary and pleural fibrotic disorders included in the study. In UIP, increased tenascin expression was associated with a shortened survival time of the patients. In immuno-EM, labeling for tenascin was seen within type II pneumocytes. UIP cases showed reactivity for a polypeptide of Mr = 200 000 by Western blotting. Myofibroblasts and type II pneumocytes were mainly shown to synthesize tenascin in UIP. Also in pleural fibrosis myofibroblasts, and in addition possibly mesothelial cells, were observed to be responsible for its synthesis. ELF and serum tenascin concentrations were increased in UIP, sarcoidosis and extrinsic allergic alveolitis. In conclusion, tenascin expression is increased in pulmonary and pleural fibrotic disorders, especially in newly formed fibrosis. In UIP, tenascin is actively synthesized at the sites of recent epithelial injury, suggesting that it plays an important role in the fibrogenesis in the lung

Keuhkofibroosien äkilliset pahenemisvaiheet ovat haastavia diagnosoida ja hoitaa

Tiivistelmä Keuhkofibroosin äkillisiin pahenemisvaiheisiin (AE-ILD) liittyy suuri ­kuolleisuus. Diagnoosi edellyttää keuhkojen ohutleiketietokonetomografiatutkimusta ja huolellista erotusdiagnostista arviota erikoissairaanhoidossa. Tehokasta lääkehoitoa ei tunneta, mutta kliininen käytäntö on hoito ­antibiooteilla ja glukokortikoideilla. Keuhkofibroosilääkkeet pirfenidoni ja nintedanibi vaikuttavat ehkäisevän pahenemisvaiheita ja parantavan niiden ennustetta

Prognosis and causes of death of patients with acute exacerbation of fibrosing interstitial lung diseases

Abstract Background: The aim of this study was to compare the clinical characteristics, causes of death and factors impacting on the prognosis of patients with idiopathic pulmonary fibrosis (IPF) and other fibrosing interstitial lung disease (FILD) with a history of acute exacerbation (AE) of IPF or FILD. Methods: Retrospective data of hospital treatment periods caused by AE-IPF and AE-FILD were collected from medical records. Clinical features and survival data of IPF and non-IPF cases were evaluated and compared. The underlying and immediate causes of death were gathered from death certificates. Results: A total of 128 patients fulfilled the criteria for inclusion. IPF (n=79/62%), rheumatoid arthritis-associated interstitial lung disease (RA-ILD; n=17/14%) and asbestosis (n=11/8.6%) were the most common FILD subgroups in the study. The median survival after hospitalisation in AE-IPF was 2.6 months compared with 21 months in other AE-FILDs (p<0.001). The survival difference was not explained by age, gender or pulmonary function test results at the time of hospitalisation. Patients with non-specific interstitial pneumonia and RA-ILD had the most favourable prognosis. ILD was the most common underlying cause of death in both patients with IPF and with other FILD accounting for 87% and 78% of deaths, respectively. Conclusions: We detected a significantly longer survival in AE of patients with non-IPF compared with that of AE-IPFs. The prognosis of patients was affected by the underlying lung disease since pulmonary fibrosis was the underlying cause of death in the majority of all patients with FILD having experienced an AE

Causes of acute respiratory hospitalizations predict survival in fibrosing interstitial lung diseases

Abstract Acute exacerbation of ILD (AE-ILD) is a common reason for hospitalization; it is also associated with significant mortality. Less is known about the prognostic significance of other events causing acute, non-elective hospitalizations in ILD patients. ILD patients hospitalized due to acute respiratory worsening were collected from medical records. Reasons for respiratory deterioration were classified into AE-ILDs and other causes. Clinical features and survival data of idiopathic pulmonary fibrosis (IPF) and other types of ILDs were evaluated and compared. In all, 237 patients (138 with IPF and 99 with other ILD) fulfilled the inclusion criteria. Of the non-IPF ILD types, the most prevalent subgroups were connective tissue disease-associated ILD (n = 33) and asbestosis (n = 22). The most common cause for hospitalization was AE-ILD explaining 41% of hospitalizations. Lower respiratory tract infection (22%), subacute progression of ILD (12%) and cardiovascular causes (7.2%) were other common reasons for hospital treatment. Patients with a lower respiratory tract infection had a more favorable prognosis compared with patients with AE-ILD. AE-ILDs were less fatal than cardiovascular or concurrent non-ILD-related causes for hospitalizations in non-IPF patients. High Gender-Age-Physiology (GAP) index was a marker for shortened survival and earlier AE-ILDs in all patients. IPF patients had a significantly shorter overall and post-hospitalization survival time compared with other ILDs. Most respiratory hospitalizations in ILD patients were related to causes other than AE-ILD, which highlights the importance of accurate differential diagnosis in order to target the appropriate treatment for each ILD patient

Survival of patients with asbestosis can be assessed by risk-predicting models

Abstract Objectives: Our aim was to investigate the pulmonary function test (PFT) results of patients with asbestosis and determine whether baseline PFTs and the risk-predicting models such as gender, age and physiologic (GAP) variables model and composite physiologic index (CPI) would be useful in predicting survival in these patients. Methods: Demographics and PFTs of 100 patients with asbestosis were evaluated. The survival difference between the GAP stages was determined with Kaplan-Meier survival curves with statistical significance analysed with log-rank test. The suitability of the risk-predicting models and baseline PFTs to predict the survival of patients was analysed with Cox regression. Results: At baseline, the mean value of diffusion capacity for carbon monoxide (DLCO) was 65%; for forced vital capacity it was 81%, with restrictive lung function being the most common impairment. The median estimated survival of the patients was 124 months, that is, 171 months in GAP stage I, 50 months in stage II and 21 months in stage III (p<0.001). CPI, DLCO% predicted, age at baseline and GAP stage were significant predictors of mortality (all p values under 0.001). Conclusions: GAP and CPI as well as baseline DLCO% predicted were significant parameters in the evaluation of the prognosis of the patients with asbestosis; they may be useful in clinical practice when considering treatment strategies of individual patients

Re-hospitalisation predicts poor prognosis after acute exacerbation of interstitial lung disease

Abstract Background: Several markers have been identified to increase the risk for acute exacerbation of interstitial lung disease (AE-ILD) or mortality related to AE-ILD. However, less is known about the risk predictors of ILD patients who have survived AE. The aim of the study was to characterise AE-ILD survivors and investigate prognostic factors in this subpopulation. Methods: All AE-ILD patients (n = 95) who had been discharged alive from two hospitals located in Northern Finland were selected from a population of 128 AE-ILD patients. Clinical data related to the hospital treatment and six-month follow-up visit were collected retrospectively from medical records. Results: Fifty-three patients with idiopathic pulmonary fibrosis (IPF) and 42 patients with other ILD were identified. Two thirds of the patients had been treated without invasive or non-invasive ventilation support. The clinical features of six-month survivors (n = 65) and non-survivors (n = 30) did not differ in terms of medical treatment or oxygen requirements. Of the patients, 82.5% used corticosteroids at the six-month follow-up visit. Fifty-two patients experienced at least one non-elective respiratory re-hospitalisation before the six-month follow-up visit. In a univariate model, IPF diagnosis, high age and a non-elective respiratory re-hospitalisation increased the risk of death, although re-hospitalisation was the only independent risk factor in a multivariate model. In six-month survivors, there was no statistically significant decrease in pulmonary function test results (PFT) examined at the follow-up visit compared with earlier PFT examined near the time of AE-ILD. Conclusions: The AE-ILD survivors were a heterogeneous group of patients both clinically and in terms of their outcome. A non-elective respiratory re-hospitalisation was identified as a marker of poor prognosis among AE-ILD survivors

Extracellular matrix proteins produced by stromal cells in idiopathic pulmonary fibrosis and lung adenocarcinoma

Abstract Idiopathic pulmonary fibrosis (IPF) and lung cancer share common risk factors, epigenetic and genetic alterations, the activation of similar signaling pathways and poor survival. The aim of this study was to examine the gene expression profiles of stromal cells from patients with IPF and lung adenocarcinoma (ADC) as well as from normal lung. The gene expression levels of cultured stromal cells derived from non-smoking patients with ADC from the tumor (n = 4) and the corresponding normal lung (n = 4) as well as from patients with IPF (n = 4) were investigated with Affymetrix microarrays. The expression of collagen type IV alpha 1 chain, periostin as well as matrix metalloproteinase-1 and -3 in stromal cells and lung tissues were examined with quantitative real-time reverse transcriptase polymerase chain reaction and immunohistochemistry, respectively. Twenty genes were similarly up- or down-regulated in IPF and ADC compared to control, while most of the altered genes in IPF and ADC were differently expressed, including several extracellular matrix genes. Collagen type IV alpha 1 chain as well as matrix metalloproteinases-1 and -3 were differentially expressed in IPF compared to ADC. Periostin was up-regulated in both IPF and ADC in comparison to control. All studied factors were localized by immunohistochemistry in stromal cells within fibroblast foci in IPF and stroma of ADC. Despite the similarities found in gene expressions of IPF and ADC, several differences were also detected, suggesting that the molecular changes occurring in these two lung illnesses are somewhat different

Claudin-1, -2, -3, -4, -5, and -7 in Usual Interstitial Pneumonia and Sarcoidosis

The aim of this study was to study the expression of various claudins in sarcoidosis, usual interstitial pneumonia (UIP), and normal human lung. The expression and cell-specific localization of claudin-1, -2, -3, -4, -5, and -7 was analyzed by IHC. Bronchiolar epithelial cells showed mostly strong expression for claudin-1, -2, -3, -4, and -7 and mainly weak expression for claudin-5 in UIP, sarcoidosis, and normal lung. Three claudins, claudin-3, -4, and -7, were expressed in normal alveolar epithelium, mainly in type II pneumocytes. Claudin-5 was expressed strongly in endothelium of normal lung, and its staining was extremely intense in endothelium of UIP. Moderate or strong expression for claudin-1, -2, -3, -4, and -7 was observed in metaplastic alveolar- and bronchiolar-type epithelium in UIP and also in metaplastic alveolar-type epithelium in sarcoidosis. Expression of claudin-5 was mainly weak in metaplastic alveolar- and bronchiolar-type epithelium in UIP. We conclude that claudin-1, -2, -3, -4, -5, and -7 are expressed in UIP and sarcoidosis, and furthermore, the most prominent enhancement of staining is localized in metaplastic alveolar- and bronchiolar-type epithelium in UIP compared with the healthy lung. (J Histochem Cytochem 57:187–195, 2009