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Idiopathic pulmonary fibrosis (IPF) is a chronic, rare progressive lung disease, characterized by lung scarring and the irreversible loss of lung function. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been demonstrated to slow down disease progression, although IPF mortality remains a challenge and the patients die after a few years from diagnosis. Rare pathogenic variants in genes that are involved in the surfactant metabolism and telomere maintenance, among others, have a high penetrance and tend to co-segregate with the disease in families. Common recurrent variants in the population with modest effect sizes have been also associated with the disease risk and progression. Genome-wide association studies (GWAS) support at least 23 genetic risk loci, linking the disease pathogenesis with unexpected molecular pathways including cellular adhesion and signaling, wound healing, barrier function, airway clearance, and innate immunity and host defense, besides the surfactant metabolism and telomere biology. As the cost of high-throughput genomic technologies continuously decreases and new technologies and approaches arise, their widespread use by clinicians and researchers is efficiently contributing to a better understanding of the pathogenesis of progressive pulmonary fibrosis. Here we provide an overview of the genetic factors known to be involved in IPF pathogenesis and discuss how they will continue to further advance in this field. We also discuss how genomic technologies could help to further improve IPF diagnosis and prognosis as well as for assessing genetic risk in unaffected relatives. The development and validation of evidence-based guidelines for genetic-based screening of IPF will allow redefining and classifying this disease relying on molecular characteristics and contribute to the implementation of precision medicine approaches.

Approximately 12–13% of patients with interstitial lung disease (ILD) are diagnosed with unclassifiable ILD (uILD), often despite thorough evaluation. A recent Phase 2 study (NCT03099187) described a significant effect of pirfenidone vs. placebo on forced vital capacity (FVC) measured by site spirometry in patients with progressive fibrosing uILD (hereafter referred to as the pirfenidone in uILD study). Here, we present the results from a post-hoc analysis of this study to assess patient baseline characteristics and the efficacy of pirfenidone vs. placebo analyzed by surgical lung biopsy (SLB) status. Mean FVC (mL) change over 24 weeks was included as a post-hoc efficacy outcome. Of 253 randomized patients, 88 (34.8%) had a SLB and 165 (65.2%) did not. Baseline characteristics were generally similar between SLB subgroups; however, patients who had a SLB were slightly younger and had a higher 6-min walk distance than those without a SLB. Mean FVC change over 24 weeks for pirfenidone vs. placebo was −90.9 vs. −146.3 mL, respectively, in patients who had a SLB, and 8.2 vs. −85.3 mL, respectively, in patients without a SLB. Overall, the results from the post-hoc analysis identified that pirfenidone may be an effective treatment in progressive fibrosing uILD over 24 weeks, irrespective of SLB status; however, caution should be taken when interpreting these data due to several limitations. There are differences in the treatment effect of pirfenidone between the subgroups that require further pathological and radiological investigation. In this manuscript, we also descriptively compared baseline characteristics from the overall pirfenidone in uILD study population with other uILD populations reported in the literature, with the aim of understanding if there are any similarities or differences within these cohorts. Most baseline characteristics for patients in the pirfenidone in uILD study were within the ranges reported in the literature; however, ranges were wide, highlighting the heterogeneity of uILD populations.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT03099187.

Cross-analysis of clinical and pollution factors could help calculate the risk of fibrotic interstitial lung disease (ILD) development and progression. The intent of this study is to build a body of knowledge around early detection and diagnosis of lung disease, harnessing new data sets generated for other purposes. We cross-referenced exposure levels to particulate matter 2.5 (PM2.5) with telomere length of a cohort of 280 patients with fibrotic ILD to weigh impact and associations. There was no linear correlation between PM2.5 and telomere length in our data sets, as the value of the correlation coefficient was 0.08. This exploratory study offers additional insights into methodologies for investigating the development and prognosis of pulmonary fibrosis.

BackgroundPatients with coronavirus disease 2019 (COVID-19) can develop severe bilateral pneumonia leading to respiratory failure. Lung histological samples were scarce due to the high risk of contamination during autopsies. We aimed to correlate histological COVID-19 features with radiological findings through lung ultrasound (LU)-guided postmortem core needle biopsies (CNBs) and computerized tomography (CT) scans.MethodologyWe performed an observational prospective study, including 30 consecutive patients with severe COVID-19. The thorax was divided into 12 explorations regions to correlate LU and CT-scan features. Histological findings were also related to radiological features through CNBs.ResultsMean age was 62.56 ± 13.27 years old, with 96.7% male patients. Postmortem LU-guided CNBs were performed in 13 patients. Thirty patients were evaluated with both thoracic LU and chest CT scan, representing a total of 279 thoracic regions explored. The most frequent LU finding was B2-lines (49.1%). The most CT-scan finding was ground-glass opacity (GGO, 29%). Pathological CT-scan findings were commonly observed when B2-lines or C-lines were identified through LU (positive predictive value, PPV, 87.1%). Twenty-five postmortem echo-guided histological samples were obtained from 12 patients. Histological samples showed diffuse alveolar damage (DAD) (75%) and chronic interstitial inflammation (25%). The observed DAD was heterogeneous, showing multiple evolving patterns of damage, including exudative (33.3%), fibrotic (33.3%), and organizing (8.3%) phases. In those patients with acute or exudative pattern, two lesions were distinguished: classic hyaline membrane; fibrin “plug” in alveolar space (acute fibrinous organizing pneumonia, AFOP). C-profile was described in 33.3% and presented histological signs of DAD and lung fibrosis. The predominant findings were collagen deposition (50%) and AFOP (50%). B2-lines were identified in 66.7%; the presence of hyaline membrane was the predominant finding (37.5%), then organizing pneumonia (12.5%) and fibrosis (37.5%). No A-lines or B1-lines were observed in these patients.ConclusionLU B2-lines and C-profile are predominantly identified in patients with severe COVID-19 with respiratory worsening, which correspond to different CT patterns and histological findings of DAD and lung fibrosis.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication associated with a high mortality. However, evidence and guidance on management is sparse. The aim of this international survey was to assess differences in prevention, diagnostic and treatment strategies for AE-IPF in specialised and non-specialised ILD centres worldwide.Material and Methods: Pulmonologists working in specialised and non-specialised ILD centres were invited to participate in a survey designed by an international expert panel. Responses were evaluated in respect to the physicians' institutions.Results: Three hundred and two (65%) of the respondents worked in a specialised ILD centre, 134 (29%) in a non-specialised pulmonology centre. Similarities were frequent with regards to diagnostic methods including radiology and screening for infection, treatment with corticosteroids, use of high-flow oxygen and non-invasive ventilation in critical ill patients and palliative strategies. However, differences were significant in terms of the use of KL-6 and pathogen testing in urine, treatments with cyclosporine and recombinant thrombomodulin, extracorporeal membrane oxygenation in critical ill patients as well as antacid medication and anaesthesia measures as preventive methods.Conclusion: Despite the absence of recommendations, approaches to the prevention, diagnosis and treatment of AE-IPF are comparable in specialised and non-specialised ILD centres, yet certain differences in the managements of AE-IPF exist. Clinical trials and guidelines are needed to improve patient care and prognosis in AE-IPF.

Introduction: Many severe COVID-19 patients require respiratory support and monitoring. An intermediate respiratory care unit (IMCU) may be a valuable element for optimizing patient care and limited health-care resources management. We aim to assess the clinical outcomes of severe COVID-19 patients admitted to an IMCU.Methods: Observational, retrospective study including patients admitted to the IMCU due to COVID-19 pneumonia during the months of March and April 2020. Patients were stratified based on their requirement of transfer to the intensive care unit (ICU) and on survival status at the end of follow-up. A multivariable Cox proportional hazards method was used to assess risk factors associated with mortality.Results: A total of 253 patients were included. Of them, 68% were male and median age was 65 years (IQR 18 years). Ninety-two patients (36.4%) required ICU transfer. Patients transferred to the ICU had a higher mortality rate (44.6 vs. 24.2%; p < 0.001). Multivariable proportional hazards model showed that age ≥65 years (HR 4.14; 95%CI 2.31–7.42; p < 0.001); chronic respiratory conditions (HR 2.34; 95%CI 1.38–3.99; p = 0.002) and chronic kidney disease (HR 2.96; 95%CI 1.61–5.43; p < 0.001) were independently associated with mortality. High-dose systemic corticosteroids followed by progressive dose tapering showed a lower risk of death (HR 0.15; 95%CI 0.06–0.40; p < 0.001).Conclusions: IMCU may be a useful tool for the multidisciplinary management of severe COVID-19 patients requiring respiratory support and non-invasive monitoring, therefore reducing ICU burden. Older age and chronic respiratory or renal conditions are associated with worse clinical outcomes, while treatment with systemic corticosteroids may have a protective effect on mortality.

BackgroundRehabilitation in subjects with severe coronavirus disease 2019 (COVID-19) pneumonia has been widely recommended. However, data regarding the starting time of rehabilitation, subjects and healthcare workers’ safety, as well as rehabilitation program features are limited. We aimed to assess the safety and characterize the effect of early and non-early physiotherapy on severe COVID-19 pneumonia subjects.MethodsA retrospective cohort study, including a consecutive sample of surviving subjects admitted to an acute care hospital due to severe COVID-19 pneumonia from March 13th to May 15th of 2020, is made. Subjects were separated into three groups: non-physical therapy, early physiotherapy (onset

Introduction: Fibrotic interstitial lung diseases (ILDs) are the first indication for lung transplantation (LT). Telomere dysfunction has been associated with poor post-transplant outcomes. The aim of the study was to evaluate the morbi-mortality and quality of life in fibrotic ILDs after lung transplant depending on telomere biology.Methods: Fibrotic ILD patients that underwent lung transplant were allocated to two arms; with or without telomere dysfunction at diagnosis based on the telomere length and telomerase related gene mutations revealed by whole-exome sequencing. Post-transplant evaluation included: (1) short and long-term mortality and complications and (2) quality of life.Results: Fifty-five percent of patients that underwent LT carried rare coding mutations in telomerase-related genes. Patients with telomere shortening more frequently needed extracorporeal circulation and presented a higher rate of early post-transplant hematological complications, longer stay in the intensive care unit (ICU), and a higher number of long-term hospital admissions. However, post-transplant 1-year survival was higher than 80% regardless of telomere dysfunction, with improvement in the quality of life and oxygen therapy withdrawal.Conclusions: Post-transplant morbidity is higher in patients with telomere dysfunction and differs according to elapsed time from transplantation. However, lung transplant improves survival and quality of life and the associated complications are manageable.