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Background: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts., Methods: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide ( D LCO ) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups., Results: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations., Conclusion: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients., Competing Interests: Conflict of interest: J. Jacob reports fees from Boehringer Ingelheim, Roche, NHSX, Takeda and GlaxoSmithKline, unrelated to the submitted work, and was supported by Wellcome Trust Clinical Research Career Development Fellowship 209553/Z/17/Z and the NIHR Biomedical Research Centre at University College London. N. Mogulkoc reports grant TUBITAK (EJP Rare Disease project “COCOS-IPF”), fees from Boehringer Ingelheim, Roche, and Nobel Turkey unrelated to the submitted work, and received support for travel to meetings from Roche and Actelion. T.J. Corte reports unrestricted educational grants from Boehringer Ingelheim, Roche, Biogen and Galapagos, fees from Roche, BMS, Boehringer Ingelheim, Vicore and DevPro, assistance for travel to meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board for Roche, BMS, Boehringer Ingelheim, Vicore, Ad Alta, Bridge Biotherapeutics and DevPro. P. Vasudev reports financial interests from Blackford Analysis. T. Goos is supported by Research Foundation Flanders (1S73921N). L.J. De Sadeleer is supported by Marie Sklodowska-Curie actions postdoctoral fellowship within the European Union's Horizon Europe research and innovation programme. H. Jo reports fees from Boehringer Ingelheim and Roche, and received assistance for travel to meetings from Boehringer Ingelheim and Roche. S. Verleden reports consultancy fees from Boehringer Ingelheim and Sanofi. M. Vermant is supported by an FWO (Research Flanders Foundation) fellowship. S.M. Janes reports fees from AstraZeneca, Bard1 Bioscience, Achilles Therapeutics and Jansen unrelated to the submitted work, received assistance for travel to meetings from AstraZeneca and Takeda, and is the investigator lead on grants from GRAIL Inc., GlaxoSmithKline plc and Owlstone. A.U. Wells reports personal fees and non-financial support from Boehringer Ingelheim, Bayer and Roche Pharmaceuticals, and personal fees from Blade, outside of the submitted work. The remaining authors report no relevant conflicts of interest., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Chronic lung allograft dysfunction (CLAD) encompasses three main phenotypes: bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS) and a Mixed phenotype combining both pathologies. How the airway structure in its entirety is affected in these phenotypes is still poorly understood., Methods: A detailed analysis of airway morphometry was applied to gain insights on the effects of airway remodelling on the distribution of alveolar ventilation in end-stage CLAD. Ex vivo whole lung μCT and tissue-core μCT scanning of six control, six BOS, three RAS and three Mixed explant lung grafts (9 male, 9 female, 2014-2021, Leuven, Belgium) were used for digital airway reconstruction and calculation of airway dimensions in relation to luminal obstructions., Findings: BOS and Mixed explants demonstrated airway obstructions of proximal bronchioles (starting at generation five), while RAS explants particularly had airway obstructions in the most distal bronchioles (generation >12). In BOS and Mixed explants 76% and 84% of bronchioles were obstructed, respectively, while this was 22% in RAS. Bronchiolar obstructions were mainly caused by lymphocytic inflammation of the airway wall or fibrotic remodelling, i.e. constrictive bronchiolitis. Proximal bronchiolectasis and imbalance in distal lung ventilation were present in all CLAD phenotypes and explain poor lung function and deterioration of specific lung function parameters., Interpretation: Alterations in the structure of conducting bronchioles revealed CLAD to affect alveolar ventilatory distribution in a regional fashion. The significance of various obstructions, particularly those associated with mucus, is highlighted., Funding: This research was funded with the National research fund Flanders (G060322N), received by R.V., Competing Interests: Declaration of interests JK and VG and MV are junior research fellows of the Research Foundation Flanders (FWO; 1198920N and 1102020N and 1SE433N). MV received compensation from Sanofi for attending the ERS 2023 congress. GPLA is a supported by an European Respirology Society Clinical Fellowship Grant. SB is supported by the Paul Corris International Clinical Research Training Scholarship. LJDS (De Sadeleer) is supported by the European Union's Horizon Europe research and innovation programme as a Marie Sklodowska-Curie actions postdoctoral fellowship (grant agreement No. 101066289)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Fibroblast to myofibroblast conversion is a major driver of tissue remodeling in organ fibrosis. Distinct lineages of fibroblasts support homeostatic tissue niche functions, yet, their specific activation states and phenotypic trajectories during injury and repair have remained unclear., Methods: We combined spatial transcriptomics, multiplexed immunostainings, longitudinal single-cell RNA-seq and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. Our findings were validated in IPF patient tissues in situ as well as in cell differentiation and invasion assays using patient lung fibroblasts. Cell differentiation and invasion assays established a function of SFRP1 in regulating human lung fibroblast invasion in response to TGFβ1., Measurements and Main Results: We discovered a transitional fibroblast state characterized by high Sfrp1 expression, derived from both Tcf21 -Cre lineage positive and negative cells. Sfrp1 + cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1 + transitional fibroblasts and Cthrc1 + myofibroblasts. TGFβ1 downregulated SFRP1 in non-invasive transitional cells and induced their switch to an invasive CTHRC1+ myofibroblast identity. Finally, using loss of function studies we showed that SFRP1 modulates TGFβ1 induced fibroblast invasion and RHOA pathway activity., Conclusions: Our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies SFRP1 as a modulator of TGFβ1 driven fibroblast phenotypes in fibrogenesis. These findings are relevant in the context of therapeutic interventions that aim at limiting or reversing fibroblast foci formation., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with single-cell RNA sequencing and induced a multilineage circuit of fibrogenic cell states in hPCLS. We showed that these cell states were highly similar to the in vivo cell circuit in a multicohort lung cell atlas from patients with pulmonary fibrosis. Using micro-CT-staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state, and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the hPCLS model provided evidence that the basaloid cell state was derived from alveolar type 2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in hPCLS, and antifibrotic drug treatments showed highly cell type-specific effects. Our work provides an experimental framework for perturbational single-cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration, and pathology. We further demonstrate that hPCLS offer an avenue for scalable, high-resolution drug testing to accelerate antifibrotic drug development and translation.

Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: W. A. W. received scientific grants from Roche, Boehringer Ingelheim, Galapagos, and Alentis. S. E. V. received consulting fees from Sanofi, Boehringer Ingelheim, and Therakos. E. D. L. received fees from Amgen, Argenx, GSK, Actelion, Lilly, Pfizer, Boehringer Ingelheim, MSD, AC Immune, Amgen, Astra Zeneca, Novartis, and Otsuka and is copresident of the Working Group Rare Diseases, Belgian Royal Society of Rheumatology. None declared (T. G., A. D., M. V., S. G., L. J. D. S., N. D. C., J. Y., B. W., M. S. C., J. V., S. V.).

Rationale: COPD is characterized by chronic airway inflammation, small airways changes, with disappearance and obstruction, and also distal/alveolar destruction (emphysema). The chronology by which these three features evolve with altered mucosal immunity remains elusive. This study assessed the mucosal immune defense in human control and end-stage COPD lungs, by detailed microCT and RNA transcriptomic analysis of diversely affected zones., Methods: In 11 control (non-used donors) and 11 COPD (end-stage) explant frozen lungs, 4 cylinders/cores were processed per lung for microCT and tissue transcriptomics. MicroCT was used to quantify tissue percentage and alveolar surface density to classify the COPD cores in mild, moderate and severe alveolar destruction groups, as well as to quantify terminal bronchioles in each group. Transcriptomics of each core assessed fold changes in innate and adaptive cells and pathway enrichment score between control and COPD cores. Immunostainings of immune cells were performed for validation., Results: In mildly affected zones, decreased defensins and increased mucus production were observed, along CD8+ T cell accumulation and activation of the IgA pathway. In more severely affected zones, CD68+ myeloid antigen-presenting cells, CD4+ T cells and B cells, as well as MHCII and IgA pathway genes were upregulated. In contrast, terminal bronchioles were decreased in all COPD cores., Conclusion: Spatial investigation of end-stage COPD lungs show that mucosal defense dysregulation with decreased defensins and increased mucus and IgA responses, start concomitantly with CD8+ T-cell accumulation in mild emphysema zones, where terminal bronchioles are already decreased. In contrast, adaptive Th and B cell activation is observed in areas with more advanced tissue destruction. This study suggests that in COPD innate immune alterations occur early in the tissue destruction process, which affects both the alveoli and the terminal bronchioles, before the onset of an adaptive immune response., Competing Interests: IG reports travel support from AstraZeneca, not related to the content of this work. MV reports travel support from Sanofi, not related to the content of this manuscript. SE reports consulting fees from GSK, lecture honoraria from GSK, Boehringer Ingelheim, Chiesi and AstraZeneca, travel support from GSK and Sanofi, not related to the content of this manuscript. WJ reports grants and lecture honoraria from AstraZeneca and Chiesi, consulting fees from AstraZeneca, Griffols, GSK and Chiesi and travel support from Chiesi and AstraZeneca; has a leadership or fiduciary role in Board of VRGT and Board of ArtiQ, and is a co-founder and shareholder of ArtiQ NV. NK served as consultant for Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Astra Zeneca, RohBar, Veracyte, Augmanity, CSL Behring, Thyron, BMS, Biotech, Gilead, Galapagos, Chiesi, Arrowhead, Sofinnova and GSK, reports equity in Pliant and Thyron, and has a patent in new therapies for IPF, new therapies for ARDS and new biomarkers for IPF, licensed to Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de Fays, Geudens, Gyselinck, Kerckhof, Vermaut, Goos, Vermant, Beeckmans, Kaes, Van Slambrouck, Mohamady, Willems, Aversa, Cortesi, Hooft, Aerts, Aelbrecht, Everaerts, McDonough, De Sadeleer, Gohy, Ambroise, Janssens, Ceulemans, Van Raemdonck, Vos, Hackett, Hogg, Kaminski, Gayan-Ramirez, Pilette and Vanaudenaerde.)

Background: Given the plethora of pathophysiologic mechanisms described in idiopathic pulmonary fibrosis (IPF), we hypothesize that the mechanisms driving fibrosis in IPF may be different from one patient to another., Research Question: Do IPF endotypes exist and are they associated with outcome?, Study Design and Methods: Using a publicly available gene expression dataset retrieved from BAL samples of patients with IPF and control participants (GSE70867), we clustered IPF samples based on a dimension reduction algorithm specifically designed for -omics data, called DDR Tree. After clustering, gene set enrichment analysis was performed for functional annotation, associations with clinical variables and prognosis were investigated, and differences in transcriptional regulation were determined using motif enrichment analysis. The findings were validated in three independent publicly available gene expression datasets retrieved from IPF blood samples., Results: One hundred seventy-six IPF samples from three centers were clustered in six IPF clusters, with distinct functional enrichment. Although clinical characteristics did not differ between the clusters, one cluster conferred worse sex-age-physiology score-corrected survival, whereas another showed a numeric trend toward worse survival (P = .08). The first was enriched for increased epithelial and innate and adaptive immunity signatures, whereas the other showed important telomere and mitochondrial dysfunction, loss of proteostasis, and increased myofibroblast signatures. The existence of these two endotypes, including the impact on survival of the immune endotype, was validated in three independent validation cohorts. Finally, we identified transcription factors regulating the expression of endotype-specific survival-associated genes., Interpretation: Gene expression-based endotyping in IPF is feasible and can inform clinical evolution. As endotype-specific pathways and survival-associated transcription factors are identified, endotyping may open up the possibility of endotype-tailored therapy., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung disease (ILD) and with prolonged pre-transplant survival in idiopathic pulmonary fibrosis (IPF), but no information is available regarding its prevalence in other respiratory diseases and its influence on post-transplant outcome. We included the Leuven lung transplantation cohort between 1991 and 2015 ( n = 801). We assessed the minor allele frequency (MAF) of the MUC5B variant in the entire study cohort and investigated the influence of recipient MUC5B promoter polymorphism on post-transplant outcome in patients who were transplanted after 2004. MUC5B was successfully genotyped in 746 patients. The MAF was significantly higher in ILD (17.6%) compared to chronic obstructive pulmonary disease (COPD)/emphysema (9.3%), cystic fibrosis (CF)/bronchiectasis (BRECT) (7.5%) and pulmonary hypertension (PHT) (7.4%) ( p < 0.001). No association was observed between rs35705950 and chronic lung allograft dysfunction (CLAD)/graft loss in the ILD population [CLAD: HR 1.37 95% CI (0.70-2.68); graft loss: HR 1.02 95% CI (0.55-1.89)], nor the entire study cohort [CLAD: HR 0.96 95% CI (0.69-1.34); graft loss: HR 0.97 95% CI (0.70-1.35)]. The MUC5B promoter polymorphism is a very specific predictive factor for the presence of pulmonary fibrosis as it is only associated with pulmonary fibrosis and not with other chronic respiratory diseases. While the MUC5B promoter variant is associated with better pre-transplant survival among IPF patients, recipient MUC5B promoter variant does not play a role in post-transplant outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goos, Verleden, De Sadeleer, Van Herck, Sacreas, Vanstapel, Kaes, Geudens, Aelbrecht, Ruttens, Lambrechts, Vermeer, Ceulemans, Van Raemdonck, Godinas, Yserbyt, Vanaudenaerde, Verleden, Vos and Wuyts.)

Rationale: Fibrotic hypersensitivity pneumonitis (fHP) is an interstitial lung disease caused by sensitization to an inhaled allergen. Objectives: To identify the molecular determinants associated with progression of fibrosis. Methods: Nine fHP explant lungs and six unused donor lungs (as controls) were systematically sampled (4 samples/lung). According to microcomputed tomography measures, fHP cores were clustered into mild, moderate, and severe fibrosis groups. Gene expression profiles were assessed using weighted gene co-expression network analysis, xCell, gene ontology, and structure enrichment analysis. Gene expression of the prevailing molecular traits was also compared with idiopathic pulmonary fibrosis (IPF). The explant lung findings were evaluated in separate clinical fHP cohorts using tissue, BAL samples, and computed tomography scans. Measurements and Main Results: We found six molecular traits that associated with differential lung involvement. In fHP, extracellular matrix and antigen presentation/sensitization transcriptomic signatures characterized lung zones with only mild structural and histological changes, whereas signatures involved in honeycombing and B cells dominated the transcriptome in the most severely affected lung zones. With increasing disease severity, endothelial function was progressively lost, and progressive disruption in normal cellular homeostatic processes emerged. All six were also found in IPF, with largely similar associations with disease microenvironments. The molecular traits correlated with i n vivo disease behavior in a separate clinical fHP cohort. Conclusions: We identified six molecular traits that characterize the morphological progression of fHP and associate with in vivo clinical behavior. Comparing IPF with fHP, the transcriptome landscape was determined considerably by local disease extent rather than by diagnosis alone.

Randomized placebo-controlled trials demonstrated the efficacy of antifibrotic treatment in non-IPF progressive fibrosing ILD (fILD). Currently, there is no consensus on how progression should be defined and clinical data of non-IPF fILD patients in a real-world setting are scarce. Non-IPF fILD patients presenting at the University Hospitals Leuven between 2012 and 2016 were included. Different definitions of progression according to the selection criteria of the INBUILD, RELIEF and the uILD study were retrospectively evaluated at every hospital visit. Univariate and multivariate analyses were performed to identify predictors of progression and mortality. The study cohort comprised 120 patients; 68.3%, 54.2% and 65.8% had progressive disease based on the INBUILD, RELIEF and uILD study, respectively. A large overlap of progressive fILD patients according to the different clinical trials was observed. Median transplant-free survival time of progressive fILD patients was 3.9, 3.9, 3.8 years and the median time-to-progression after diagnosis was 2.0, 3.1 and 2.3 years according to the INBUILD, RELIEF and uILD study, respectively. We identified several predictors of mortality, but only an underlying diagnosis of HP and uILD was independently associated with progression. Our data show a high prevalence of progressive fibrosis among non-IPF fILD patients and a discrepancy between predictors of mortality and progression. Mortality rate in fILD is high and the identification of progressive disease is only made late during the disease course. Moreover, future treatment decisions will be based upon disease behavior. Therefore, more predictors of progressive disease are needed to guide treatment decisions in the future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

This review aims to provide an overview of pre-transplant antifibrotic therapy on peri-transplant outcomes and to address the possible role of antifibrotics in lung transplant recipients with chronic lung allograft dysfunction.Lung transplantation is an established treatment modality for patients with various end-stage lung diseases, of which idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases are growing indications. Theoretically, widespread use of antifibrotics prior to lung transplantation may increase the risk of bronchial anastomotic complications and impaired wound healing.Long-term graft and patient survival are still hampered by development of chronic lung allograft dysfunction, on which antifibrotics may have a beneficial impact.Antifibrotics until the moment of lung transplantation proved to be safe, without increasing peri-transplant complications. Currently, best practice is to continue antifibrotics until time of transplantation. In a large multicentre randomised trial, pirfenidone did not appear to have a beneficial effect on lung function decline in established bronchiolitis obliterans syndrome. The results of antifibrotic therapy in restrictive allograft syndrome are eagerly awaited, but nonrandomised data from small case reports/series are promising., Competing Interests: Conflict of interest: S. Bos has nothing to disclose. Conflict of interest: L.J. De Sadeleer reports non-financial support from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: A. Vanstapel has nothing to disclose. Conflict of interest: H. Beeckmans has nothing to disclose. Conflict of interest: A. Sacreas has nothing to disclose. Conflict of interest: J. Yserbyt has nothing to disclose. Conflict of interest: W.A. Wuyts reports grants from Boehringer Ingelheim and Roche, paid to his institution, outside the submitted work. Conflict of interest: R. Vos reports grants from Research Foundation Flanders (FWO), outside the submitted work., (Copyright ©The authors 2021.)

Mammalian target of rapamycin inhibitors (mTORi) are increasingly used after lung transplantation as part of a calcineurin inhibitor sparing regimen, aiming to preserve renal function. The aim of our study was to determine whether immunosuppressive therapy using mTORi in lung transplant recipients (LTR) is feasible in practice, or limited by intolerance and adverse events. Data were retrospectively assessed for all LTR transplanted between July 1991 and January 2020. Patients ever receiving mTORi (monotherapy or in combination with calcineurin inhibitor) as treatment of physicians' choice were included. 149/1184 (13%) of the LTR ever received mTORi. Main reasons to start were renal insufficiency (67%) and malignancy (21%). In 52% of the patients, mTORi was stopped due to side effects or drug toxicity after a median time of 159 days. Apart from death, main reasons for discontinuation were infection (19%) and edema (14%). Early discontinuation (<90 days) was mainly due to edema or gastrointestinal intolerance. As mTORi was stopped due to adverse events or drug intolerance in 52% of LTR, cautious consideration of advantages and disadvantages when starting mTORi is recommended., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A significant proportion of patients with interstitial lung disease (ILD) may develop a progressive fibrosing phenotype characterized by worsening of symptoms and pulmonary function, progressive fibrosis on chest computed tomography and increased mortality. The clinical course in these patients mimics the relentless progressiveness of idiopathic pulmonary fibrosis (IPF). Common pathophysiological mechanisms such as a shared genetic susceptibility and a common downstream pathway-self-sustaining fibroproliferation-support the concept of a progressive fibrosing phenotype, which is applicable to a broad range of non-IPF ILDs. While antifibrotic drugs became the standard of care in IPF, immunosuppressive agents are still the mainstay of treatment in non-IPF fibrosing ILD (F-ILD). However, recently, randomized placebo-controlled trials have demonstrated the efficacy and safety of antifibrotic treatment in systemic sclerosis-associated F-ILD and a broad range of F-ILDs with a progressive phenotype. This review summarizes the current pharmacological management and highlights the unmet needs in patients with non-IPF ILD.

Background and Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial lung disease with poor prognosis despite the recent availability of two antifibrotic drugs. Patients are more susceptible to cardiovascular comorbidities. In this study, we aimed to determine the impact of concomitant cardiovascular drugs on disease progression and survival in a modern IPF cohort., Methods: The database of a tertiary referral centre for interstitial lung diseases in Belgium was reviewed for statin, antiaggregant, anticoagulant and metformin therapy. For a study period of four years, we noted both FVC% and DLCO% trajectories along with survival as outcome measurements., Results: 323 patients were included of which 45% had at least one cardiovascular comorbidity. 274 (86%) patients received antifibrotic therapy. Statin users (n = 171) displayed significantly slower annual FVC% (difference 2.9%, CI 1.6-4.4, p < 0.001) and DLCO% decline (difference 1.3%, CI 0.24-2.3, p = 0.013). Results for antiaggregant therapy (n = 152) were inconclusive: we found a trend for slower FVC decline (p = 0.098) and a numerically decrease in survival rates (HR 1.63, p = 0.074) in a multivariate Cox analysis. Anticoagulant use (n = 49) showed a trend towards worse DLCO decline (difference -1.3%, CI -2.6 - 0.02, p = 0.055).r Metformin (n = 28) therapy did not affect IPF progression in terms of pulmonary function test evolution or survival., Conclusion: This retrospective study demonstrated a benefit of statin therapy on IPF progression. Our observations emphasize the need for large clinical trials analysing the effect of statins, as well as other cardiovascular drugs, in the management of IPF patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose of Review: Lung transplantation (LTx) is increasingly used as ultimate treatment modality in end-stage interstitial lung diseases (ILDs). This review aims to give an overview of the latest evolutions in this field., Recent Findings: In the last two years, important new findings regarding LTx outcomes in specific ILD entities have been reported. More data are available on optimization of pre-LTx management of ILD patients especially with regard to pretransplant antifibrotic treatment., Summary: LTx is the only treatment option with curative intent for ILDs and is increasingly used for this indication. Several studies have now reported adequate outcomes in different ILD entities, although outcome is shown to be affected by underlying telomeropathies. As new studies could not replicate inferior survival with single compared with double LTx, both options remain acceptable. ILD specialists can beneficially impact on post-LTx outcome by optimizing pre-LTx management: corticosteroids should be avoided, antifibrotics should be initiated whenever possible and BMI and nutritional status optimized, rehabilitation and depression-screening strategies should be implemented in all LTx candidates, as these interventions may all improve postlung transplant survival.

It is generally assumed that allergic asthma originates primarily through sensitization via the respiratory mucosa, but emerging clinical observations and experimental studies indicate that skin exposure to low molecular weight (LMW) agents, i.e . "chemicals," may lead to systemic sensitization and subsequently develop asthma when the chemical is inhaled. This review aims to evaluate the accumulating experimental evidence that adverse respiratory responses can be elicited upon inhalation of an LMW chemical sensitizer after previous sensitization by dermal exposure. We systematically searched the PubMed and Embase databases up to April 15, 2017, and conducted forward and backward reference tracking. Animal studies involving both skin and airway exposure to LMW agents were included. We extracted 6 indicators of "selective airway hyper-responsiveness" (SAHR)- i.e . respiratory responses that only occurred in previously sensitized animals-and synthesized the evidence level for each indicator into strong, moderate or limited strength. The summarized evidence weight for each chemical agent was graded into high, middle, low or "not possible to assess." We identified 144 relevant animal studies. These studies involved 29 LMW agents, with 107 (74%) studies investigating the occurrence of SAHR. Indicators of SAHR included physiological, cytological/histological and immunological responses in bronchoalveolar lavage, lung tissue and airway-draining lymph nodes. Evidence for skin exposure-induced SAHR was present for 22 agents; for 7 agents the evidence for SAHR was inconclusive, but could not be excluded. The ability of a chemical to cause sensitization via skin exposure should be regarded as constituting a risk of adverse respiratory reactions., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2020 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Although only recently introduced in the ILD community, the concept of progressive fibrosing interstitial lung disease (PF-ILD) has rapidly acquired an important place in the management of non-idiopathic pulmonary fibrosis fibrosing ILD (nonIPF fILD) patients. It confirms a clinical gut feeling that an important subgroup of nonIPF fILD portends a dismal prognosis despite therapeutically addressing the alleged triggering event. Due to several recently published landmark papers showing a treatment benefit with currently available antifibrotic drugs in PF-ILD patients, endorsing a PF-ILD phenotype has vital therapeutic consequences. Importantly, defining progressiveness is based on former progression, which has proven to be a rather moderate predictor of future progression. As fibrosis extent >20% and the presence of honeycombing have superior predictive properties regarding future progression, we advocate immediate initiation of antifibrotic treatment in the presence of these risk factors. In this perspective, we describe the historical context wherein PF-ILD has emerged, determine the currently employed PF-ILD criteria and their inherent limitations and propose new directions to mature its definition. Finally, while ascertaining progression in a nonIPF fILD patient clearly demonstrates the need for (additional) therapy, in the future, therapeutic decisions should be taken after assessing which pathway is ultimately driving the progression. Although not readily available, pathophysiological insight and diagnostic means are emergent to go full steam ahead in this novel direction.

Background: Although the third most frequent interstitial lung disease, hypersensitivity pneumonitis (HP) remains an enigmatic disease without clear diagnostic and therapeutic guidelines. We assessed the effect of the commonly used therapeutic interventions (i.e. exposure avoidance and corticosteroid treatment) in an HP cohort., Methods: We collected clinical data of all HP patients followed at our centre between January 1, 2005, and December 31, 2016. HP patients were stratified according to the presence of fibrosis on chest CT. Survival was analysed using the multivariate Cox proportional hazards model. Forced vital capacity (percent predicted, FVC%) and diffusing capacity of the lung for carbon monoxide (percent predicted, DLCO%) evolution were analysed using linear mixed-effect models., Results: Two hundred and two HP patients were identified: 93 non-fibrotic HP (nfHP) and 109 fibrotic HP (fHP), experiencing a monthly FVC% decline before treatment of 0.93% and 0.56%, respectively. While nfHP had an excellent survival, fHP patients experienced a median survival of 9.2 years. Corticosteroid treatment and exposure avoidance did not result in survival differences. Although nfHP patients showed FVC% and DLCO% increase after corticosteroid initiation, no therapeutic effect was seen in fHP patients. FVC% and DLCO% increased in nfHP patients after exposure avoidance, while a positive numerical trend was seen for FVC% after exposure avoidance in fHP patients ( p = 0.15)., Conclusions: nfHP patients experienced an excellent survival with good therapeutic effect on pulmonary function tests with both corticosteroid initiation as well as antigen avoidance. In contrast, fHP patients experienced a dismal prognosis (median survival of 9.2 years) without any therapeutic effect of corticosteroid treatment. Whether antigen avoidance is useful in fHP patients is still unclear.

Background and Objective: Although idiopathic pulmonary fibrosis (IPF) patients experience a worse survival compared with chronic hypersensitivity pneumonitis (CHP), organic dust exposure is a known risk factor for both IPF and CHP., Methods: We divided patients diagnosed with IPF, based on their exposure to moulds/birds (absent: group A; present: group B). We retrospectively compared pulmonary function and survival between groups A and B, and a separate CHP cohort (group C)., Results: A total of 293 patients were included (group A: n = 171, group B: n = 73, group C: n = 49). Demographics and baseline pulmonary function did not differ between groups A and B, but significant differences were seen between groups B and C. Median survival of group B was 84 months, which was longer than group A (43 months, P = 0.002), but lower than group C (157 months, P = 0.04), in both univariate and multivariate analyses. Antifibrotic treatment resulted in a better outcome in group A (hazard ratio (HR): 0.44) and group B (HR: 0.12) without interaction between exposure and antifibrotic use (P = 0.20). Forced vital capacity (FVC) decline was not associated with mould/bird exposure in this cohort., Conclusion: Group B patients experienced a better outcome compared with (non-exposed) IPF patients, although worse compared with CHP patients. Antifibrotic treatment in group B resulted in a similar beneficial effect compared with group A. Further research is needed to ascertain the diagnostic designation in this exposed usual interstitial pneumonia (UIP) patient group without other CHP features., (© 2018 Asian Pacific Society of Respirology.)

Background: The advice of a dynamic multidisciplinary discussion (MDD) is believed to be important in the diagnosis of interstitial lung diseases (ILDs). However, to what extent MDD diagnoses differ from the preliminary diagnoses before formal workup and MDD (preMDD diagnoses) is still insufficiently studied., Methods: We compared preMDD and MDD diagnoses in patients discussed at the Leuven University Hospitals MDDs between January 2005 and December 2015., Results: Of 938 consecutive patients discussed in an MDD, 755 (80.5%) received a specific diagnosis. From the 183 patients with unclassifiable ILD, 150 patients (16.0%) received suggestions concerning further investigations to establish a definite diagnosis. In 191 patients (41.9% of patients with a preMDD diagnosis), the MDD changed the diagnosis. In 384 patients (79.5% of patients without preMDD diagnosis), MDD provided a diagnosis when the referring physician did not. MDD diagnosis showed a trend toward better prognostic discrimination between idiopathic pulmonary fibrosis and other ILDs compared with preMDD diagnosis (Harrell C-index, 0.666 vs 0.631; P = .08), which was particularly clear in patients with discordant MDD and preMDD diagnoses (hazard ratio, 2.68 vs 0.84; P = .012 vs .768)., Conclusions: The MDD provided a definite diagnosis in 80.5% of presented cases, suggesting further investigations in almost all others. Given the high number of patients without preMDD diagnosis, the rate of change in preMDD diagnoses (41.9% of patients with a preMDD diagnosis) probably is an underestimation. The better prognostic discrimination among ILDs by using MDD indicates the added value of MDD in ILD., (Copyright © 2018 American College of Chest Physicians. All rights reserved.)

Although included in the serological domain of the 'interstitial pneumonia with auto-immune features' (IPAF) research statement, the search for myositis-specific antibodies (MSA) is not incorporated in routine clinical practice. The objective of the study was to evaluate MSA prevalence in an idiopathic interstitial pneumonia (IIP) cohort (n = 68) with suggestive morphological interstitial lung disease patterns. Twelve of 68 patients (17.6%) carried MSA, whereof only two were anti-nuclear antibody-positive. Besides female gender, no demographic or pulmonary function parameter was predictive for MSA positivity. MSA were present in 32.4% of IPAF patients (n = 37), being essential for IPAF diagnosis in four of them (10.8%).

Background: Telomere shortening has been associated with several lung diseases. However, telomere length is generally measured in peripheral blood leucocytes rather than in lung tissue, where disease occurs. Consequently, telomere dynamics have not been established for the normal human lung nor for diseased lung tissue. We hypothesized an age- and disease-dependent shortening of lung tissue telomeres., Methods: At time of (re-)transplantation or autopsy, 70 explant lungs were collected: from unused donors (normal, n = 13) and patients with cystic fibrosis (CF, n = 12), chronic obstructive pulmonary disease (COPD, n = 11), chronic hypersensitivity pneumonitis (cHP, n = 9), bronchiolitis obliterans syndrome (BOS) after prior transplantation (n = 11) and restrictive allograft syndrome (RAS) after prior transplantation (n = 14). Lungs were inflated, frozen and then scanned using CT. Four tissue cores from distinct lung regions were sampled for analysis. Disease severity was evaluated using CT and micro CT imaging. DNA was extracted from the samples and average relative telomere length (RTL) was determined using real-time qPCR., Results: The normal lungs showed a decrease in RTL with age (p < 0.0001). Of the diseased lungs, only BOS and RAS showed significant RTL decrease with increasing lung age (p = 0.0220 and p = 0.0272 respectively). Furthermore, we found that RTL showed considerable variability between samples within both normal and diseased lungs. cHP, BOS and RAS lungs had significant shorter RTL in comparison with normal lungs, after adjustment for lung age, sex and BMI (p < 0.0001, p = 0.0051 and p = 0.0301 respectively). When investigating the relation between RTL and regional disease severity in CF, cHP and RAS, no association was found., Conclusion: These results show a progressive decline in telomere length with age in normal, BOS and RAS lungs. cHP, BOS and RAS lungs demonstrated shorter RTL compared to normal lungs. Lung tissue RTL does not associate with regional disease severity within the lung. Therefore, tissue RTL does not seem to fully reflect peripheral blood telomere length.