Because severe coronavirus disease 2019 (COVID-19) affects the respiratory system and develops into respiratory failure, patients with pre-existing chronic lung disorders, such as idiopathic pulmonary fibrosis (IPF), are thought to be at high risk of death. Patients with IPF often suffer from a lethal complication, acute exacerbation (AE), a significant part of which is assumed to be triggered by respiratory viral infection. However, whether mild to moderate COVID-19 can trigger AE in patients with IPF remains unknown. This is the case report of a 60-year-old man with a 4-year history of IPF who successfully recovered from moderate COVID-19 but subsequently developed more severe respiratory failure, which was considered to be a COVID-19-triggered acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). It is important to be aware of the risk of AE-IPF after COVID-19 and to properly manage this deadly complication of IPF. Recent literature reporting cases with chronic interstitial lung diseases which developed respiratory failure by complications with COVID-19 is also reviewed and discussed.

Objective: To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype.

Methods: The INBUILD trial enrolled subjects with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity (FVC) ≥45% predicted and diffusing capacity of the lungs for carbon monoxide ≥30%-<80% predicted. Subjects fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (mL/year) and adverse events over 52 weeks in the subgroup with autoimmune disease-related ILDs.

Results: Among 170 subjects with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 mL/year with nintedanib versus -178.6 mL/year with placebo (difference 102.7 mL/year [95% CI 23.2, 182.2]; nominal P=0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups by ILD diagnosis (P=0.91). The most frequent adverse event was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. Adverse events led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively.

Conclusion: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in subjects with progressive fibrosing autoimmune disease-related ILDs, with adverse events that were manageable for most subjects.

Background and objective: Patients with progressive fibrosing interstitial lung disease (PF-ILD) are prone to early mortality compared with other phenotypes of ILD. The possible effect of smoking on survival has not been investigated yet. Furthermore, it is unknown what the effect of quantity of smoking is in PF-ILD. In this study, it was determined if quantity of smoking is associated with worse survival in patients with PF-ILD.

Methods: Patients meeting the INBUILD trial-criteria for PF-ILD were included in this retrospective cohort study. Pack year (py) was tested as a prognostic variable with a multivariable Cox proportional hazard model. Also, median transplant-free survival was compared between heavy (≥20 pys) and mild-moderate smokers (0.1-19.9 pys).

Results: In PF-ILD (N = 377), the unadjusted and adjusted hazard ratio for py were significant, (1.014, 95% confidence interval (CI): 1.006-1.022, P < 0.001; 1.011, CI:1.002-1.021, P = 0.022 respectively). This translates to an 11%, 22%, or 44% higher risk for mortality for patients accumulating 10, 20 or 40 pys, respectively. Heavy smokers demonstrated a median transplant-free survival of 3.0 years, which was significantly reduced compared with mild-moderate smokers (3.8 years, P = 0.035). Additionally, more patients with emphysema were heavy smokers (N = 68) than never (N = 5, P < 0.001) or mild-moderate smokers (n = 21, p < 0.001).

Conclusion: In PF-ILD, a pack year is associated with an increased risk of mortality. Furthermore, quantity of smoking is associated with worse survival and higher prevalence of emphysema. Our data indicates that limiting amount of pys will provide a survival benefit in patients developing PF-ILD.

The PERSEIDS study aimed to estimate incidence/prevalence of interstitial lung diseases (ILDs), fibrosing interstitial lung diseases (F-ILDs), idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated ILD (SSc-ILD), other non-IPF F-ILDs and their progressive-fibrosing (PF) forms in six European countries, as current data are scarce. This retrospective, two-phase study used aggregate data (2014-2018). In Phase 1, incident/prevalent cases of ILDs above were identified from clinical databases through an algorithm based on codes/keywords, and incidence/prevalence was estimated. For non-IPF F-ILDs, the relative percentage of subtypes was also determined. In Phase 2, a subset of non-IPF F-ILD cases was manually reviewed to determine the percentage of PF behaviour and usual interstitial pneumonia-like (UIP-like) pattern. A weighted mean percentage of progression was calculated for each country and used to extrapolate incidence/prevalence of progressive-fibrosing ILDs (PF-ILDs). In 2018, incidence/105 person-years ranged between 9.4 and 83.6 (ILDs), 7.7 and 76.2 (F-ILDs), 0.4 and 10.3 (IPF), 6.6 and 71.7 (non-IPF F-ILDs), and 0.3 and 1.5 (SSc-ILD); and prevalence/105 persons ranged between 33.6 and 247.4 (ILDs), 26.7 and 236.8 (F-ILDs), 2.8 and 31.0 (IPF), 22.3 and 205.8 (non-IPF F-ILDs), and 1.4 and 10.1 (SSc-ILD). Among non-IPF F-ILDs, sarcoidosis was the most frequent subtype. PF behaviour and UIP-like pattern were present in a third of non-IPF F-ILD cases each and hypersensitivity pneumonitis showed the highest percentage of progressive behaviour. Incidence of PF-ILDs ranged between 2.1 and 14.5/105 person-years, and prevalence between 6.9 and 78.0/105 persons. To our knowledge, PERSEIDS is the first study assessing incidence, prevalence and rate of progression of ILDs across several European countries. Still below the threshold for orphan diseases, the estimates obtained were higher and more variable than reported in previous studies, but differences in study design/population must be considered.

Objective: To investigate the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) with and without cough or dyspnoea in the SENSCIS trial.

Methods: Patients in the SENSCIS trial were randomized to receive nintedanib or placebo. Subgroups with and without cough or dyspnoea at baseline were defined by responses to the St. George's Respiratory Questionnaire.

Results: At baseline, 114/575 patients (19.8%) did not have cough and 172/574 patients (30.0%) did not have dyspnoea. In the placebo group, the rate of FVC decline over 52 weeks was similar in patients with and without cough (-95.6 and -83.4 ml/year, respectively) or dyspnoea (-95.8 and -87.7 ml/year, respectively). The effect of nintedanib vs placebo on reducing the rate of FVC decline was numerically more pronounced in patients without than with cough (difference: 74.4 [95% CI -11.1, 159.8] vs 31.5 [-11.1, 74.1]) and without than with dyspnoea (79.8 [9.8, 149.7] vs 25.7 [-19.9, 71.3]), but interaction p-values did not indicate heterogeneity in the treatment effect between these subgroups (p= 0.38 and p= 0.20, respectively).

Conclusion: In the placebo group of the SENSCIS trial, the rate of FVC decline was similar irrespective of the presence of cough or dyspnoea at baseline. The effect of nintedanib on reducing the rate of FVC decline was numerically more pronounced in patients without than with cough or dyspnoea at baseline, but no statistically significant heterogeneity was observed between the subgroups.

Summary: The interstitial lung diseases are a heterogenous group of parenchymal lung disorders with a common feature-infiltration of the interstitial space with derangement of the normal capillary-alveolar anatomy. Diseases characterized by fibrosis of the interstitial space are referred to as the fibrosing interstitial lung diseases and often show progression over time: idiopathic pulmonary fibrosis is the most common fibrotic interstitial lung disease. Historically, therapies for fibrosing lung diseases have been limited in number, questionable in efficacy, and associated with potential harms. Food and Drug Administration (FDA) approval of the antifibrotic agents nintedanib and pirfenidone for idiopathic pulmonary fibrosis in 2014 heralded an era of reorganization of therapy for the fibrotic interstitial lung diseases. Subsequent investigations have led to FDA approval of nintedanib for systemic sclerosis-associated interstitial lung disease and interstitial lung diseases with a progressive phenotype. Although supportive care and pulmonary rehabilitation should be provided to all patients, the role(s) of immunomodulators and/or immune suppressing agents vary by the underlying disease state. Several agents previously used to treat fibrotic lung diseases (N-acetylcysteine, anticoagulation, and pulmonary vasodilators) lack efficacy or cause harm.

Conclusion: With the introduction of effective pharmacotherapy for fibrosing interstitial lung disease, pharmacists have an increasingly important role in the interdisciplinary team managing these patients

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease of unknown etiology. Different types of cells are involved in fibrogenesis, which is persistently physical and molecular stimulation, either directly or by interacting with bioactive molecules and extracellular vesicles (EVs). Current evidence suggests that EVs play an essential role in IPF development. EVs are released by a variety of cells, including fibroblasts, epithelial cells, and alveolar macrophages. In addition, EVs can transport bioactive molecules, such as lipids, proteins, and nucleic acids, which play a pivotal role in cellular communication. Several proposed mechanisms show that an acceptor cell can capture, absorb, or interact with EVs through direct fusion with the plasma membrane, ligand-receptor interaction, and endocytotic process, modifying the target cell. During fibrogenesis, the release of EVs is deregulated, increases the EVs amount, and the cargo content is modified. This alteration is closely associated with the maintenance of the fibrotic microenvironment. This review summarizes the current data on the participation of EVs secreted by the cells playing a critical role in IPF pathogenesis.

Rheumatoid arthritis is an autoimmune disease that primarily affects the joints. The emergence of highly effective anti-rheumatic drugs such as biologic agents and janus kinase inhibitors has dramatically improved the management of the disease by preventing irreversible joint destruction and disability. This disease can manifest the serious extra-articular involvements including interstitial lung disease, which has the significant impact on the patients' morbidity and mortality. However, treatment strategy specific for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has not been yet established. Therefore, understanding the pathogenesis and clinical features of RA-ILD is critical to provide the better management and improve the prognosis of the patients. Accumulation of evidence suggest that it is essentially important to achieve remission or at least low disease activity of arthritis to prevent new emergence, progression, or acute exacerbation of RA-ILD. RA-ILD patients frequently show high titers of autoantibodies including rheumatoid factor and anti-CCP antibody, and the excessive formation of tertiary lymphoid organs is found in the local affected lungs, indicating the adaptive immune response as a key pathogenic inducer. In this regard, non-TNF inhibitors targeting adaptive immune responses such as abatacept and rituximab were reported to be promising for the stabilization and improvement of RA-ILD. Nintedanib, an anti-fibrotic agent, was shown to be effective for reducing the decline of forced vital capacity in RA-ILD. In this review, we summarized the current evidence in the pathogenesis, clinical features, and treatments for RA-ILD and provide future prospects.

Objective: Although interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc), its prognostication remains challenging. Given that CT represents the gold standard imaging technique in ILD assessment, a systematic review on chest CT findings as predictors of mortality or ILD progression in SSc-ILD was performed.

Materials and methods: Three databases (Medline, Embase, and Web of Science) were searched to identify all studies analyzing CT mortality or ILD progression predictors in SSc-ILD, from inception to December 2020. ILD progression was defined by worsening of forced vital capacity and/or CT ILD findings. Manuscripts not written in English, with not available full-text, not focusing on SSc-ILD or with SSc-ILD not extrapolated, otherwise with overlap syndromes, pediatric patients, <10 cases or predictors other than CT features were excluded.

Results: Out of 3,513 citations, 15 full-texts (2,332 patients with SSc-ILD) met the inclusion criteria. ILD extent and extensive ILD, ILD densitometric analysis parameters, fibrotic extent and reticulation extent resulted as independent mortality predictors. Extensive ILD is also an independent predictor of death, need for supplemental oxygen or lung transplantation. Honeycombing extent is an independent risk factor for respiratory mortality. Independent predictors of ILD progression were not identified.

Conclusions: ILD extent and extensive ILD independently predict mortality in SSc-ILD on CT, as well as ILD densitometric analysis, fibrotic extent and reticulation extent. Extensive ILD is also a predictor of death, need for supplemental oxygen, or lung transplantation. Honeycombing extent predicts respiratory mortality. CT predictors of ILD progression need to be further investigated.

Objective: Although interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc), its prognostication remains challenging. Given that CT represents the gold standard imaging technique in ILD assessment, a systematic review on chest CT findings as predictors of mortality or ILD progression in SSc-ILD was performed.

Materials and methods: Three databases (Medline, Embase, and Web of Science) were searched to identify all studies analyzing CT mortality or ILD progression predictors in SSc-ILD, from inception to December 2020. ILD progression was defined by worsening of forced vital capacity and/or CT ILD findings. Manuscripts not written in English, with not available full-text, not focusing on SSc-ILD or with SSc-ILD not extrapolated, otherwise with overlap syndromes, pediatric patients, <10 cases or predictors other than CT features were excluded.

Results: Out of 3,513 citations, 15 full-texts (2,332 patients with SSc-ILD) met the inclusion criteria. ILD extent and extensive ILD, ILD densitometric analysis parameters, fibrotic extent and reticulation extent resulted as independent mortality predictors. Extensive ILD is also an independent predictor of death, need for supplemental oxygen or lung transplantation. Honeycombing extent is an independent risk factor for respiratory mortality. Independent predictors of ILD progression were not identified.

Conclusions: ILD extent and extensive ILD independently predict mortality in SSc-ILD on CT, as well as ILD densitometric analysis, fibrotic extent and reticulation extent. Extensive ILD is also a predictor of death, need for supplemental oxygen, or lung transplantation. Honeycombing extent predicts respiratory mortality. CT predictors of ILD progression need to be further investigated.

The role of heparin-binding protein (HBP) as an acute inflammatory marker in acute exacerbations of interstitial lung disease (AE-ILD) and some stable ILD patients is not well-established. The significance of increasing HBP during an AE-ILD is examined and the first attempt to incorporate HBP into the ILD evaluation system is made. Then, the benefit of HBP in AE-ILD was investigated. ILD patients (n = 108) were divided into subgroups based on the phase and severity of the disease. Linear trends of HBP across subgroups were observed, and correlations with common inflammatory markers were examined. Further, the HBP detection was adopted between serum and bronchoalveolar lavage fluid (BALF). Imaging and pathology changes were evaluated using various scoring criteria and compared to HBP. The relationship between HBP with ventilation, fibrosis progression, and changes in arterial oxygen levels and inflammatory markers were investigated to understand the mechanistic pathways. HBP was significantly higher in patients with AE-ILD at the early stage, compared to patients with ILD at the stable phase and its increase was both found in the serum and BALF. With the remission of the disease, there was a linear trend of progressive decline. HBP identified ILD patients who had co-infections. HBP levels increased earlier than CRP, PCT, and SAA. HBP was associated with pulmonary levels of ventilation and lesions by radiology examination, and its levels were significantly worse in AE-ILD patients. However, HBP did not show a correlation to the pathology quantitative evaluation. In conclusion, HBP could potentially evaluate the progression and prognosis of AE-ILD. Because ILD patients are susceptible to infection, and since HBP can identify co-infection, this marker would be of great clinical importance. HBP is possibly predictive of acute exacerbation.

Background: To investigate the role of cell senescence in systemic sclerosis (SSc), we analyzed telomere shortening (TS) in SSc patients and the effect of targeting DNA damage in the bleomycin model of skin fibrosis.

Results: Telomere length (TL) in blood leukocytes of 174 SSc patients and 68 healthy controls was measured by Southern blot, and we found shorter age-standardized TL in SSc patients compared to healthy controls. TL was shorter in SSc patients with ILD compared to those without ILD and in anti-topoisomerase I positive compared to anti-centromere positive patients. To analyze the potential role of DNA damage in skin fibrosis, we evaluated the effects of the DNA protective GSE4 peptide in the bleomycin mouse model of scleroderma and the fibrotic response of cultured human dermal fibroblasts. Administration of GSE4-nanoparticles attenuated bleomycin-induced skin fibrosis as measured by Masson's staining of collagen and reduced Acta2 and Ctgf mRNA expression, whereas transduction of dermal fibroblasts with a lentiviral GSE4 expression vector reduced COL1A1, ACTA2 and CTGF gene expression after stimulation with bleomycin or TGF-β, in parallel to a reduction of the phospho-histone H2A.X marker of DNA damage.

Conclusions: SSc is associated with TS, particularly in patients with lung disease or anti-topoisomerase I antibodies. Administration of GSE4 peptide attenuated experimental skin fibrosis and reduced fibroblast expression of profibrotic factors, supporting a role for oxidative DNA damage in scleroderma.

Background: Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD), and is associated with worse outcomes and increased mortality. Evaluation of PH is recommended in lung transplant candidates but there are currently no standardized screening approaches. Recent trials have identified therapies that are effective in this setting, providing another rationale to routinely screen ILD patients for PH.

Research question: What screening strategies for identifying PH in patients with ILD are supported by expert consensus?

Study design and methods: The study convened a panel of 16 pulmonologists with expertise in PH and ILD and utilized a modified Delphi consensus process with 3 surveys to identify PH screening strategies. Survey 1 consisted primarily of open-ended questions. Surveys 2 and 3 were developed from responses to Survey 1 and contained statements about PH screening that panelists rated from -5 (strongly disagree) to +5 (strongly agree).

Results: Panelists reached consensus on several triggers for suspicion of PH including: symptoms, clinical signs, findings on chest computed tomography or other imaging, abnormalities in pulse oximetry, elevations in brain natriuretic peptide (BNP) or N-terminal propeptide (NT-proBNP), and unexplained worsening in pulmonary function tests or 6-minute walk distance. Echocardiography and BNP/NT-proBNP were identified as screening tools for PH. Right heart catheterization was deemed essential for confirming PH.

Interpretation: Many patients with ILD may benefit from early evaluation of PH now that an approved therapy is available. Protocols to evaluate patients with ILD often overlap with evaluations for PH-ILD and can be used to assess the risk of PH. Since standardized approaches are lacking, this consensus statement is intended to aid clinicians in the identification of patients with ILD and possible PH, and provide guidance for timely right heart catheterization.

Introduction: The aim of the study was to know the management of patients with diffuse interstitial lung disease (ILD) associated with a systemic autoimmune diseases (SAD) in pulmonology outpatient clinics in Spain. Methodology: The ILD work area of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) designed a self-completed questionnaire of 25 questions, on aspects related to the diagnosis and treatment of ILD-SAD. This was distributed among the attendees of the winter meeting of the ILD Area and later via e-mail to all the members of the ILD area of SEPAR. Participation was anonymous, voluntary and without consideration.

Result(s): 74 pulmonologists from 58 hospitals participated. 77% had a specialized ILD consultation. All Units with SEPAR accreditation had a committee made up of pulmonologists and radiologists and a majority participation of pathologists and rheumatologists. In 75% of the centers there was a close collaboration with Rheumatology for the management of ILD-SAD. 85% considered that the frequency of ILD-SAD consults is increasing, the most frequent being ILD associated with rheumatoid arthritis. The treatment of ILD-SAD is decided by consensus between pulmonologist and rheumatologist in 91.3% of the cases. 67% of pulmonologists consider that immunosuppressants and biological therapies can slow down the progression of ILD-SAD. 51% use antifibrotics therapies in these pathologies.

Conclusions: Almost all of the accredited Spanish ILD Units by SEPAR have established collaborations with Rheumatology for the adequate management of patients with ILD-SAD, this practice having been extended to units not yet accredited.