Idiopathic Pulmonary Fibrosis Cases Research Articles

Physical activity and idiopathic pulmonary fibrosis: A prospective cohort study in UK Biobank and Mendelian randomization analyses

IntroductionThe impact of physical activity on the incidence of idiopathic pulmonary fibrosis (IPF) remains less well studied. This study aimed to investigate the relationship between moderate-to-vigorous physical activity (MVPA) and the risk of developing IPF. MethodsWe analyzed data from a prospective cohort study within the UK Biobank involving 502,476 participants. Participants were categorized as meeting or not meeting the 2017 UK Physical Activity Guidelines (150 min of moderate activity or 75 min of vigorous activity per week). The cumulative incidence and hazard ratios (HRs) for IPF were analyzed using the Kaplan–Meier method, log-rank test, and Cox regression. Two-sample Mendelian randomization (MR) analyses were performed to identify potential causal links between physical activity and IPF risk. ResultsOver a median of 12.2 y follow-up, we identified 1,639 incident IPF cases and 395,172 controls. Individuals who met the physical activity guidelines had a significantly lower risk of IPF than those who did not meet the guidelines (adjusted HR = 0.843, 95 % confidence interval [CI] = 0.765–0.930).The cumulative incidence of IPF was lower in the meeting guideline group than in the nonmeeting guideline group (Log-rank P = 0.0019). Two-sample MR analysis revealed that a 1-standard deviation increase in moderate-to-vigorous physical activity was linked to a reduced IPF risk (odds ratio [OR] = 0.17, 95 % CIs = 0.04 to 0.81, P = 0.026). Moreover, an increase in the number of days per week of moderate physical activity was genetically correlated with decreased IPF risk (OR = 0.32, 95 % CIs = 0.15–0.70, P = 0.003). ConclusionHigher levels of moderate-to-vigorous physical activity are causally associated with a significant reduction in the risk of developing IPF.

Pathological features of connective tissue disease-associated interstitial lung disease in transbronchial cryobiopsies.

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. 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. 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. 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.

The efficacy and safety of modified transbronchial cryobiopsy in the diagnosis of interstitial lung disease.

The objective of this study is to investigate the efficacy and safety of flexible transbronchial cryobiopsy (TBCB) in the diagnosis of diffuse parenchymal lung disease (DPLD) in a routine bronchoscopy examination room under analgesia and sedation, using neither endotracheal intubation or rigid bronchoscope nor fluoroscopy or general anesthesia. The data from 50 DPLD patients with unknown etiology who were treated in the Affiliated Hospital of Guilin Medical College from May 2018 to September 2020 were collected, and 43 were eventually included. The specimens obtained from these 43 patients were subjected to pathological examination, pathogenic microorganism culture, etc, and were analyzed in the clinical-radiological-pathological diagnosis mode to confirm the efficacy of TBCB in diagnosing the cause of DPLD. Subsequently, the intraoperative and postoperative complications of TBCB and their severity were closely observed and recorded to comprehensively evaluate the safety of TBCB. For the 43 patients included, a total of 85 TBCB biopsies were performed (1.98 [1, 4] times/case), and 82 valid tissue specimens were obtained (1.91 [1, 4] pieces/case), accounting for 96.5% (82/85) of the total sample. The average specimen size was 12.41 (1, 30) mm2. Eventually, 38 cases were diagnosed, including 11 cases of idiopathic pulmonary fibrosis, 5 cases of connective tissue-related interstitial lung disease, 5 cases of nonspecific interstitial pneumonia, 4 cases of tuberculosis, 4 cases of occupational lung injury, 3 cases of interstitial pneumonia with autoimmune characteristics, 1 case of lung cancer, 2 cases of interstitial lung disease (unclassified interstitial lung disease), 1 case of hypersensitivity pneumonitis, 1 case of pulmonary alveolar proteinosis, and 1 case of fungal infection. The remaining 5 cases were unclarified. For infectious diseases, the overall etiological diagnosis rate was 88.4% (38/43). With respect to complications, pneumothorax occurred in 4 cases (9.3%, 4/43, including 1 mild case and 3 moderate cases), of which 3 cases (75%) were closed by thoracic drainage and 1 case (25%) was absorbed without treatment. In addition, 22 cases experienced no bleeding (51.2%) and 21 cases suffered bleeding to varying degrees based on different severity assessment methods. TBCB is a minimally invasive, rapid, economical, effective, and safe diagnostic technique.

Understanding Patterns of Adherence to Antifibrotic Treatment in Idiopathic Pulmonary Fibrosis: Insights from an Italian Prospective Cohort Study.

Background: Pirfenidone and Nintedanib have significantly improved the prognosis of patients with idiopathic pulmonary fibrosis (IPF), reducing mortality risk and exacerbations. This study aimed to analyze antifibrotic treatment utilization and its association with clinical outcomes (i.e., acute exacerbation or death) during 2014-2021 in newly diagnosed IPF patients, using Healthcare Utilization Databases of the Marche Region, Italy. Methods: The first 12-month adherence to antifibrotic was estimated using the Proportion of Days Covered (PDC), defining adherence as PDC ≥ 75%. State Sequence Analysis over the initial 52 weeks of treatment was used to identify adherence patterns. The role of adherence patterns on acute exacerbations/death, adjusted by demographic, clinical features, and monthly adherence after the 52-week period (time-dependent variable), was assessed with Cox regression. Results: Among 667 new IPF cases, 296 received antifibrotic prescriptions, with 62.8% being adherent in the first year. Three antifibrotic utilization patterns emerged-high adherence (37.2%), medium adherence (42.5%), and low adherence (20.3%)-with median PDCs of 95.3%, 79.5%, and 18.6%, respectively. These patterns did not directly influence three-year mortality/exacerbation probability, but sustained adherence reduced risk over time. Conclusions: Good adherence was observed in in this population-based study, emphasizing the importance of continuous antifibrotics therapy over time to mitigate adverse outcomes.

Incidence, prevalence and mortality of idiopathic pulmonary fibrosis in England from 2008 to 2018: a cohort study

BackgroundOwing to discrepancies in methodologies and how idiopathic pulmonary fibrosis (IPF) is diagnosed it is challenging to establish a consistent understanding of the disease burden In the UK, over 10...

The causal relationship between genetically predicted blood metabolites and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study.

Numerous metabolomic studies have confirmed the pivotal role of metabolic abnormalities in the development of idiopathic pulmonary fibrosis (IPF). Nevertheless, there is a lack of evidence on the causal relationship between circulating metabolites and the risk of IPF. The potential causality between 486 blood metabolites and IPF was determined through a bidirectional two-sample Mendelian randomization (TSMR) analysis. A genome-wide association study (GWAS) involving 7,824 participants was performed to analyze metabolite data, and a GWAS meta-analysis involving 6,257 IPF cases and 947,616 control European subjects was conducted to analyze IPF data. The TSMR analysis was performed primarily with the inverse variance weighted model, supplemented by weighted mode, MR-Egger regression, and weighted median estimators. A battery of sensitivity analyses was performed, including horizontal pleiotropy assessment, heterogeneity test, Steiger test, and leave-one-out analysis. Furthermore, replication analysis and meta-analysis were conducted with another GWAS dataset of IPF containing 4,125 IPF cases and 20,464 control subjects. Mediation analyses were used to identify the mediating role of confounders in the effect of metabolites on IPF. There were four metabolites associated with the elevated risk of IPF, namely glucose (odds ratio [OR] = 2.49, 95% confidence interval [95%CI] = 1.13-5.49, P = 0.024), urea (OR = 6.24, 95% CI = 1.77-22.02, P = 0.004), guanosine (OR = 1.57, 95%CI = 1.07-2.30, P = 0.021), and ADpSGEGDFXAEGGGVR (OR = 1.70, 95%CI = 1.00-2.88, P = 0.0496). Of note, the effect of guanosine on IPF was found to be mediated by gastroesophageal reflux disease. Reverse Mendelian randomization analysis displayed that IPF might slightly elevate guanosine levels in the blood. Conclusively, hyperglycemia may confer a promoting effect on IPF, highlighting that attention should be paid to the relationship between diabetes and IPF, not solely to the diagnosis of diabetes. Additionally, urea, guanosine, and ADpSGEGDFXAEGGGVR also facilitate the development of IPF. This study may provide a reference for analyzing the potential mechanism of IPF and carry implications for the prevention and treatment of IPF.

External validation of Fibresolve, a machine-learning algorithm, to non-invasively diagnose idiopathic pulmonary fibrosis

BackgroundPrevious work has shown the ability of Fibresolve, a machine learning system, to non-invasively classify idiopathic pulmonary fibrosis (IPF) with a sensitivity of 41% and specificity of 87% versus other types of interstitial lung disease. Further external validation for the use of Fibresolve to classify IPF in patients with non-definite usual interstitial pneumonia (UIP) is needed. The aim of this study is to assess the sensitivity for Fibresolve to positively classify IPF in an external cohort of patients with a non-definite UIP radiographic pattern. MethodsThis is a retrospective analysis of patients (n=193) enrolled in two prospective phase two clinical trials that enrolled patients with IPF. We retrospectively identified patients with non-definite UIP on HRCT (n=51), 47 of whom required surgical lung biopsy for diagnosis. Fibresolve was used to analyze the HRCT chest imaging which was obtained prior to invasive biopsy and sensitivity for final diagnosis of IPF was calculated. ResultsThe sensitivity of Fibresolve for the non-invasive classification of IPF in patients with a non-definite UIP radiographic pattern by HRCT was 76.5% (95% CI 66.5-83.7). For the subgroup of 47 patients who required surgical biopsy to aid in final diagnosis of IPF, Fibresolve had a sensitivity of 74.5% (95% CI 60.5-84.7). ConclusionIn patients with suspected IPF with non-definite UIP on HRCT, Fibresolve can positively identify cases of IPF with high sensitivity. These results suggest that in combination with standard clinical assessment, Fibresolve has the potential to serve as a low-cost adjunct in the non-invasive diagnosis of IPF.

The diagnosis and treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease (ILD) of unknown cause. The prognosis of IPF is poor, respiratory failure is the most common cause of mortality. Velcro rales are typical on respiratory system examination. Clubbing is seen in 30-60% of IPF cases. There is no laboratory test specific to IPF. Usual interstitial pneumonia (UIP) pattern is seen in IPF. UIP features in high-resolution computed tomography (HRCT); peripheral subpleural bibasilar reticular opacities, honeycombing, traction bronchiectasis and interseptal thickening. It shows craniocaudal localization. Diagnosis of IPF; It is diagnosed by the combination of HRCT findings and clinical findings. Antifibrotic drugs (Pirfenidone and Nintedanib) slow down the progression of IPF and reduce the number of annual attacks and reduce the frequency of hospitalization.

A Test to Comprehensively Capture the Known Genetic Component of Familial Pulmonary Fibrosis.

The recent European Respiratory Society statement on familial pulmonary fibrosis supports the need for genetic testing in the care of patients and their relatives. However, no solution (i.e., a concrete test) was provided to implement genetic testing in daily practice. Herein, we tabulated and standardized the nomenclature of 128 genetic variants in 20 genes implicated in adult-onset pulmonary fibrosis. The objective was to develop a laboratory-developed test (LDT) on the basis of standard Sanger sequencing to capture all known familial pulmonary fibrosis-associated variants. Targeted DNA fragments were amplified using harmonized PCR conditions to perform the LDT in a single 96-well plate. The new genetic test was evaluated in 62 sporadic cases of idiopathic pulmonary fibrosis. As expected in this population, we observed a low yield of disease-causing mutations. More important, 100% of targeted variants by the LDT were successfully evaluated. Furthermore, four variants of uncertain significance with in silico-predicted deleterious scores were identified in three patients, suggesting novel pathogenic variants in genes known to cause idiopathic pulmonary fibrosis. Finally, the MUC5B promoter variant rs35705950 was strongly enriched in these patients with a minor allele frequency of 41.1% compared with 10.6% in a matched population-based cohort (n = 29,060), leading to an estimation that this variant may explain up to 35% of the population-attributable risk. This LDT provides a solution for rapid clinical translation. Technical laboratory details are provided so that specialized pulmonary centers can implement the LDT in house to expedite the clinical recommendations of expert panels.

Fibrotic lung diseases in children.

In children, pulmonary fibrosis (PF) is an extremely unusual entity that can be observed in some types of interstitial lung disease (ILD). Defining whether ILD is accompanied by PF is important for targeted therapy. Algorithm for the diagnosis of PF in children is not clearly established. Besides, the clinical, radiological, and histological definitions commonly used to diagnose particularly the cases of idiopathic PF in adult patients, is not applicable to pediatric cases. However, a few studies conducted in children offer good exemplarydiagnostic approach to fibrosing ILD. Thorax high resonance computed tomography and/or lung biopsy scanning can provide valuable information about PF. Another issue that has not been clearly established is when to start antifibrotic treatment in pediatric patients with PF. The objective of this current review is to provide a comprehensive overview of pediatric PF by drawing upon adult research, particularly focusing on the areas of uncertainty.

The Impact of Occupational Exposures on the Risk of Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic pulmonary disorder of unknown etiology that is characterized by a usual interstitial pneumonia pattern. Previous meta-analyses have reported associations between occupational exposures and IPF, but higher-quality studies have been published in recent years, doubling the number of studied patients. Objectives: To provide a contemporary and comprehensive assessment of the relationship between occupational exposures and IPF. Methods: We searched PubMed, Embase, and Web of Science through July 2023 to identify all publications on occupational exposure and IPF. We conducted a meta-analysis of the occupational burden, odds ratio (OR), and population attributable fraction (PAF) of exposures. Five exposure categories were analyzed: vapors, gas, dust, and fumes (VGDF); metal dust; wood dust; silica dust; and agricultural dust. A comprehensive bias assessment was performed. The study protocol was registered in the International Prospective Register of Systematic Reviews (identifier CRD42021267808). Results: Our search identified 23,942 publications. Sixteen publications contained relative risks needed to calculate pooled ORs and PAFs, and 12 additional publications reported an occupational burden within a case series. The proportion of cases with occupational exposures to VGDF was 44% (95% confidence interval [CI], 36-53%), with a range of 8-17% within more specific exposure categories. The pooled OR was increased for VGDF at 1.8 (95% CI, 1.3-2.4), with a pooled PAF of 21% (95% CI, 15-28%). ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust. The pooled ORs and PAFs within specific exposure categories ranged from 1.6 to 1.8 and from 4% to 14%, respectively. We identified some publication bias, but it was not sufficient to diminish the association between occupational exposures and IPF based on sensitivity analysis and bias assessment. Conclusions: Our findings indicate that 21% of IPF cases (or approximately one in five) could be prevented by removal of occupational exposure (alongside a pooled OR of 1.8). Additionally, 44% of patients with IPF report occupational exposure to VGDF. This meta-analysis suggests that a considerable number of cases of IPF are attributable to inhaled occupational exposures and warrant increased consideration in the clinical care of patients and future prevention efforts.

Surgical Treatment of Secondary Pneumothorax-Complicated Interstitial Lung Disease.

To investigate the feasibility of early surgical treatment and perioperative steroid use in patients with interstitial lung disease (ILD) complicated by pneumothorax. We retrospectively examined data, including patient characteristics, laboratory findings, surgical treatment details, postoperative complications, and deaths, of nine patients with ILD complicated by secondary pneumothorax. The patients had been treated at our hospital during the past 10 years. All nine patients were male (median age, 69.0 years). A total of nine patients had a histopathologic diagnosis of ILD after surgery. Of these, five were clinically diagnosed with ILD before surgery. Collagen disease was diagnosed in one case, drug-induced in one case, and idiopathic ILD (IILD) in three cases. All nine patients were diagnosed with postoperative ILD, including one case of collagen disease, one case of drug-induced, three cases of idiopathic pulmonary fibrosis (IPF)/cryptogenic fibrosing alveolitis, one case of nonspecific interstitial pneumonia (NSIP), and three cases of cryptogenic organizing pneumonia (COP). Regarding preoperative clinical characteristics, the performance status (PS) was 0 or 1 in all patients. Overall, three patients received oxygen (0-3 L/min), whereas steroids were administered to five patients. The mean drainage period was 23.5 days, and this was consistent with the time taken from pneumothorax occurrence to surgery. Video-assisted thoracic surgery (VATS) and thoracoscopic-assisted surgery were performed in seven and two patients, respectively. No postoperative recurrence or surgery-related deaths occurred. Early surgery for secondary pneumothorax complicated by ILD may be a viable option for patients in good preoperative condition. For patients who are preoperatively treated with steroids, continued use of steroids should be carefully considered.

Low-level ambient sulfur dioxide exposure and genetic susceptibility associated with incidence of idiopathic pulmonary fibrosis: A national prospective cohort study

BackgroundThe association between long-term air pollution exposure and the development of idiopathic pulmonary fibrosis (IPF) has been established, but the evidence regarding the effect of low levels of air pollution, especially ambient sulfur dioxide (SO2), is limited. Besides, the combined effect and interaction between genetic susceptibility and ambient SO2 on IPF remain uncertain. MethodsThis study retrieved data from 402,042 participants who were free of IPF at baseline in the UK Biobank. The annual mean concentration of ambient SO2 was estimated for each participant based on their residential addresses using a bilinear interpolation method. Cox proportional hazard models were used to examine the relationship between ambient SO2 and incident IPF. We further generated a polygenic risk score (PRS) for IPF and estimated the combined effects of genetic susceptibility and ambient SO2 on incident IPF. ResultsAfter a median follow-up of 11.78 years, 2562 cases of IPF were identified. The results indicated that each 1 μg/m3 increase in ambient SO2 was associated with a hazard ratio (HR) (95% confidence interval [CI]) of 1.67 (1.58, 1.76) for incident IPF. The study found statistically significant synergistic additive interaction between genetic susceptibility and ambient SO2. Individuals with high genetic risk and high ambient SO2 exposure had a higher risk of developing IPF (HR = 7.48, 95% CI:5.66, 9.90). ConclusionThe study suggests that long-term exposure to ambient SO2, even at concentrations lower than current air quality guidelines set by the Word Health Organization and European Union, may be an important risk factor for IPF. This risk is more pronounced among people with a high genetic risk. Therefore, these findings emphasize the need to consider the potential health effects of SO2 exposure and the necessity for stricter air quality standards.

Association between the use of statins and risk of interstitial lung disease/idiopathic pulmonary fibrosis: time-dependent analysis of population-based nationwide data.

We aimed to study whether statin use is associated with lowering the development of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). The study population was the Korean National Health Insurance Service-Health Screening Cohort. ILD and IPF cases were identified using diagnosis codes (J84.1 for ILD and J84.1A as a special code for IPF) based on the International Classification of Diseases, 10th Revision. The study participants were followed up from 1 January 2004 to 31 December 2015. Statin use was defined by the cumulative defined daily dose (cDDD) per 2-year interval and participants were categorised into never-users, <182.5, 182.5-365.0, 365.0-547.5 and ≥547.5 by cDDD. A Cox regression was used to fit models with time-dependent variables of statin use. Incidence rates for ILD with and without statin use were 20.0 and 44.8 per 100 000 person-years, respectively, and those for IPF were 15.6 and 19.3 per 100 000 person-years, respectively. The use of statins was independently associated with a lower incidence of ILD and IPF in a dose-response manner (p-values for trend <0.001). ILD showed respective adjusted hazard ratios (aHRs) of 1.02 (95% CI 0.87-1.20), 0.60 (95% CI 0.47-0.77), 0.27 (95% CI 0.16-0.45) and 0.24 (95% CI 0.13-0.42) according to the increasing category of statin use compared with never-users. IPF showed respective aHRs of 1.29 (95% CI 1.07-1.57), 0.74 (95% CI 0.57-0.96), 0.40 (95% CI 0.25-0.64) and 0.21 (95% CI 0.11-0.41). A population-based cohort analysis found that statin use is independently associated with a decreased risk of ILD and IPF in a dose-response manner.

Clinical outcomes and survival following lung transplantation for work-related lung disease: a single-center retrospective cohort study

BackgroundPatients with work-related lung disease (WRLD) are at increased risk of death caused by severe lung tissue damage and fibrosis. This study aimed to assess the clinical outcomes of lung transplantation (LTx) for WRLD and compare the results of LTx between WRLD and idiopathic pulmonary fibrosis (IPF).MethodsThis single-center retrospective cohort study reviewed the clinical data of patients who underwent LTx for WRLD or IPF at our hospital between January 2015 and December 2021. Cumulative survival rates after LTx were estimated using the Kaplan-Meier method.ResultsThe final analysis included 33 cases of WRLD and 91 cases of IPF. The 33 WRLD patients consisted of 19 (57.6%) cases of silicosis, 8 (24.2%) cases of coal workers’ pneumoconiosis, 3 (9.09%) cases of asbestosis, and 3 (9.09%) cases of other WRLD. Pneumothorax as an indication for LTx was significantly more common in the WRLD group than in the IPF group (51.5% vs. 2.2%, P < 0.001). There was no significant difference in the 5-year cumulative survival rate between the WRLD patients and the IPF patients (66.6% vs. 56.7%, P = 0.67). There was no significant difference in the best performance of exercise capacity and lung function between the two groups at 1 year post-transplant.ConclusionsLTx had similar survival outcomes and lung function for WRLD and IPF patients. Pneumothorax was the primary indication for lung transplantation in WRLD.

Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

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.

Nintedanib and pirfenidone for idiopathic pulmonary fibrosis in King Abdulaziz Medical City, Riyadh: Real-life data.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive age-related lung disease causing relentless fibrosis of the lung parenchyma. Currently, pirfenidone and nintedanib are the two antifibrotic drugs, approved for the treatment of IPF. Both are shown to slow progression by preserving lung functions from rapid decline compared to a placebo. We are reporting a real-life patient experience using these two antifibrotic medications (AFMs) in our tertiary care hospital. A retrospective cohort study was conducted for all IPF cases diagnosed in multidisciplinary meetings between 2015 and 2020 at KAMC, Riyadh (Saudi Arabia). We are reporting patients' demographics, lung function, survival, tolerance, side effects, or death in patients taking AFMs. A total of 81 cases were identified. The majority of patients aged 67 years (68%) were men with a median age of 68 years. Late presentation, severe disease, and definite usual interstitial pneumonia patterns were reported in 60% of our patients. The average number of hospital admissions before starting treatment was 1 (range: 0-3) in the nintedanib group and 1.4 (range: 1.2-5) in the pirfenidone group. There was an increase in the number of hospital admissions in the group started on pirfenidone 1.7 (range: 1.9-8) compared to nintedanib 0.5 (range: 0-3), P = 0.001. The observed mortality outcome in this cohort was 4 (11%) and 12 (27%) for nintedanib and pirfenidone, respectively. The predominant side effects were gastrointestinal symptoms for both the groups 18 (22%). Pirfenidone and nintedanib are the available approved antifibrotic agents used for many years to treat IPF patients. Real-life data showed better tolerability than reported in the West, good compliance, and a manageable side effect profile in this group of elderly and severe IPF patients.

Automated Classification of Idiopathic Pulmonary Fibrosis in Pathological Images Using Convolutional Neural Network and Generative Adversarial Networks.

Interstitial pneumonia of uncertain cause is referred to as idiopathic interstitial pneumonia (IIP). Among the various types of IIPs, the prognosis of cases of idiopathic pulmonary fibrosis (IPF) is extremely poor, and accurate differentiation between IPF and non-IPF pneumonia is critical. In this study, we consider deep learning (DL) methods owing to their excellent image classification capabilities. Although DL models require large quantities of training data, collecting a large number of pathological specimens is difficult for rare diseases. In this study, we propose an end-to-end scheme to automatically classify IIPs using a convolutional neural network (CNN) model. To compensate for the lack of data on rare diseases, we introduce a two-step training method to generate pathological images of IIPs using a generative adversarial network (GAN). Tissue specimens from 24 patients with IIPs were scanned using a whole slide scanner, and the resulting images were divided into patch images with a size of 224 × 224 pixels. A progressive growth GAN (PGGAN) model was trained using 23,142 IPF images and 7817 non-IPF images to generate 10,000 images for each of the two categories. The images generated by the PGGAN were used along with real images to train the CNN model. An evaluation of the images generated by the PGGAN showed that cells and their locations were well-expressed. We also obtained the best classification performance with a detection sensitivity of 97.2% and a specificity of 69.4% for IPF using DenseNet. The classification performance was also improved by using PGGAN-generated images. These results indicate that the proposed method may be considered effective for the diagnosis of IPF.

Prognosis and Survival in Idiopathic Pulmonary Fibrosis in the Era of Antifibrotic Therapy in Italy: Evidence from a Longitudinal Population Study Based on Healthcare Utilization Databases.

The aim was to evaluate the determinants of acute exacerbation (AE) and death in new cases of idiopathic pulmonary fibrosis (IPF) using administrative databases in the Marche Region. Adults at their first prescription of antifibrotics or hospitalization with a diagnosis of IPF occurring in 2014-2019 were considered as new cases. Multiple Cox regression was used to estimate the risk of AE and of all-cause mortality adjusted by demographic and clinical characteristics, stratifying patients according to antifibrotic treatment. Overall, 676 new cases of IPF were identified and 276 deaths and 248 AE events occurred. In never-treated patients, the risk of AE was higher in patients with poor health conditions at diagnosis; the risk of death was higher in males, in patients aged ≥75 and in those with poor health conditions at baseline. The increasing number of AEs increased the risk of death in treated and never-treated patients. Within the limits of an observational study based on secondary data, the combined use of healthcare administrative databases allows the accurate analysis of progression and survival of IPF from the beginning of the antifibrotic therapy era, suggesting that timely and early diagnosis is critical to prescribing the most suitable treatment to increase survival and maintain a healthy life expectancy.

The Genetic and Epigenetic Footprint in Idiopathic Pulmonary Fibrosis and Familial Pulmonary Fibrosis: A State-of-the-Art Review.

Idiopathic pulmonary fibrosis (IPF) is a rare disease of the lung with a largely unknown etiology and a poor prognosis. Intriguingly, forms of familial pulmonary fibrosis (FPF) have long been known and linked to specific genetic mutations. There is little evidence of the possible role of genetics in the etiology of sporadic IPF. We carried out a non-systematic, narrative literature review aimed at describing the main known genetic and epigenetic mechanisms that are involved in the pathogenesis and prognosis of IPF and FPF. In this review, we highlighted the mutations in classical genes associated with FPF, including those encoding for telomerases (TERT, TERC, PARN, RTEL1), which are also found in about 10-20% of cases of sporadic IPF. In addition to the Mendelian forms, mutations in the genes encoding for the surfactant proteins (SFTPC, SFTPA1, SFTPA2, ABCA3) and polymorphisms of genes for the mucin MUC5B and the Toll-interacting protein TOLLIP are other pathways favoring the fibrogenesis that have been thoroughly explored. Moreover, great attention has been paid to the main epigenetic alterations (DNA methylation, histone modification and non-coding RNA gene silencing) that are emerging to play a role in fibrogenesis. Finally, a gaze on the shared mechanisms between cancer and fibrogenesis, and future perspectives on the genetics of pulmonary fibrosis have been analyzed.