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Background: Idiopathic pulmonary fibrosis (IPF) predominantly affects individuals aged > 60 years who have several comorbidities. Nintedanib is an approved treatment for IPF, which reduces the rate of decline in forced vital capacity (FVC). We assessed the efficacy and safety of nintedanib in patients with IPF who were elderly and who had multiple comorbidities., Methods: Data were pooled from five clinical trials in which patients were randomised to receive nintedanib 150 mg twice daily or placebo. We assessed outcomes in subgroups by age < 75 versus ≥ 75 years, by < 5 and ≥ 5 comorbidities, and by Charlson Comorbidity Index (CCI) ≤ 3 and > 3 at baseline., Results: The data set comprised 1690 patients. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks versus placebo in patients aged ≥ 75 years (difference: 105.3 [95% CI 39.3, 171.2]) (n = 326) and < 75 years (difference 125.2 [90.1, 160.4]) (n = 1364) (p = 0.60 for treatment-by-time-by-subgroup interaction), in patients with < 5 comorbidities (difference: 107.9 [95% CI 65.0, 150.9]) (n = 843) and ≥ 5 comorbidities (difference 139.3 [93.8, 184.8]) (n = 847) (p = 0.41 for treatment-by-time-by-subgroup interaction) and in patients with CCI score ≤ 3 (difference: 106.4 [95% CI 70.4, 142.4]) (n = 1330) and CCI score > 3 (difference: 129.5 [57.6, 201.4]) (n = 360) (p = 0.57 for treatment-by-time-by-subgroup interaction). The adverse event profile of nintedanib was generally similar across subgroups. The proportion of patients with adverse events leading to treatment discontinuation was greater in patients aged ≥ 75 years than < 75 years in both the nintedanib (26.4% versus 16.0%) and placebo (12.2% versus 10.8%) groups. Similarly the proportion of patients with adverse events leading to treatment discontinuation was greater in patients with ≥ 5 than < 5 comorbidities (nintedanib: 20.5% versus 15.7%; placebo: 12.1% versus 10.0%)., Conclusions: Our findings suggest that the effect of nintedanib on reducing the rate of FVC decline is consistent across subgroups based on age and comorbidity burden. Proactive management of adverse events is important to reduce the impact of adverse events and help patients remain on therapy., Trial Registration: ClinicalTrials.gov NCT00514683, NCT01335464, NCT01335477, NCT02788474, NCT01979952.

Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease (CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different-yet largely unknown-mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population., Competing Interests: Competing interests: PS reports grants, personal fees, non-financial support and other from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Roche and PPM Services; and personal fees from Red X Pharma, Galapagos and Chiesi outside the submitted work. His wife is an employee of Novartis. OD reports personal fees from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi; personal fees and non-financial support from Pfizer; and personal fees from Abbvie, Acceleron Pharma, Anamar, Amgen, Catenion, CSL Behring, ChemomAb, Ergonex, GSK, Inventiva, Italfarmaco, iQone, iQvia, Medac, Medscape, Menarini, Mepha, MSD, Lilly, Novartis, Roche, Sanofi, Target BioScience, UCB, Baecon Discovery, Blade Therapeutics, Curzion Pharmaceuticals and Glenmark Pharmaceuticals, outside the submitted work. In addition, OD has a patent US8247389, EP2331143 issued. CJR reports grants and personal fees from Boehringer Ingelheim and Hoffmann-La Roche, outside the submitted work. AT reports grants, personal fees, non-financial support and other from BI Hellas, during the conduct of the study; and other from Roche, outside the submitted work. In addition, AT has a patent for inhaled or aerosolised delivery of thyroid hormone to the lung as a novel therapeutic agent in fibrotic lung diseases issued. JSL reports grants from NIH and Boehringer Ingelheim, and personal fees from Boehringer Ingelheim, Galapagos, Celgene and Genentech, outside the submitted work. FB reports grants, personal fees and non-financial support from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Boehringer Ingelheim; personal fees and non-financial support from Savara, Bristol Myers Squibb and Roche; and personal fees from Galapagos, outside the submitted work. DB reports grants, personal fees, non-financial support and other from BI Hellas and other from Roche, outside the submitted work. A-MH-V reports personal fees, grants, non-financial support and other from Boehringer Ingelheim, personal fees and non-financial support from Actelion, personal fees from Bayer and Roche, outside the submitted work. BC reports personal fees and non-financial support from AstraZeneca, Sanofi and BMS; grants, personal fees and non-financial support from Boehringer Ingelheim and Roche; and personal fees from Genzyme, outside the submitted work. ELM reports personal fees from Boehringer Ingelheim, outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease. Diagnosis of IPF requires considerable expertise and experience. Since the publication of the international IPF guideline in the year 2011 and the update 2018 several studies and technical advances have occurred, which made a new assessment of the diagnostic process mandatory. The goal of this guideline is to foster early, confident, and effective diagnosis of IPF. The guideline focusses on the typical clinical context of an IPF patient and provides tools to exclude known causes of interstitial lung disease including standardized questionnaires, serologic testing, and cellular analysis of bronchoalveolar lavage. High-resolution computed tomography remains crucial in the diagnostic workup. If it is necessary to obtain specimens for histology, transbronchial lung cryobiopsy is the primary approach, while surgical lung biopsy is reserved for patients who are fit for it and in whom a bronchoscopic diagnosis did not provide the information needed. After all, IPF is a diagnosis of exclusion and multidisciplinary discussion remains the golden standard of diagnosis., (© 2021 S. Karger AG, Basel.)

Aim: Interstitial lung diseases (ILD) are a group of lung disorders characterized by interstitial lung thickening. Krebs von den Lungen-6 (KL-6) is a molecule that is predominantly expressed by damaged alveolar type II cells and it has been proposed as a potential biomarker of different ILD. Materials & methods: A growing literature about KL-6 has been reviewed and selected to evaluate its role in the clinical management of ILD to predict disease diagnosis, activity, prognosis and treatment response. Results: KL-6 concentrations have been evaluated in fibrotic and granulomatous lung diseases and it was demonstrated to be a biomarker of disease severity useful for clinical follow-up of ILD patients. KL-6 levels differentiated between fibrotic ILD, such as idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis, and nonfibrotic lung disorders, including sarcoidosis and pulmonary alveolar proteinosis. Conclusion: KL-6 is predictive biomarker useful in the clinical management of ILD patients, in particular in patients with severe fibrotic lung disorders.

Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease. Diagnosis of IPF requires considerable expertise and experience. Since publication of the international IPF guideline in the year 2011 and Update 2018 several studies and technical advances occurred, which made a new assessment of the diagnostic process mandatory. In view of the antifibrotic drugs which have been approved for the treatment of IPF patients, the goal of this guideline is to foster early, confident and effective diagnosis of IPF. The guideline focusses on the typical clinical setting of an IPF patient and provides tools to exclude known causes of interstitial lung disease including standardised questionnaires, serologic testing and cellular analysis of bronchoalveolar lavage. High resolution computed tomography remains crucial in the diagnostic work-up. If it is necessary to obtain specimen for histology transbronchial lung cryobiopsy is the primary approach, while surgical lung biopsy is reserved for patients who are fit for it and in whom bronchoscopic diagnosis did not provide the information needed. Despite considerable progress, IPF remains a diagnosis of exclusion and multidisciplinary discussion remains the golden standard of diagnosis., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-016., (© Georg Thieme Verlag KG Stuttgart · New York.)

Increased procoagulant activity in the alveolar compartment and uncontrolled inflammation are hallmarks of the acute respiratory distress syndrome (ARDS). Here, we investigated whether the contact phase system of coagulation is activated and may regulate inflammatory responses in human lungs. Components of the contact phase system were characterized in bronchoalveolar lavage fluids (BALF) from 54 ARDS patients and 43 controls, and their impact on cytokine/chemokine expression in human precision cut lung slices (PCLS) was assessed by a PCR array. Activation of the contact system, associated with high levels of coagulation factor XIIa (Hageman factor, FXIIa), plasma kallikrein and bradykinin, occurred rapidly in ARDS lungs after the onset of the disease and virtually normalized within one week from time of diagnosis. FXII levels in BALF were higher in ARDS non-survivors than survivors and were positively correlated with tumor necrosis factor (TNF)-α concentration. FXII induced the production and release of interleukin (IL)-8, IL-1β, IL-6, leukemia inhibitory factor (LIF), CXCL5 and TNF-α in human PCLS in a kallikrein-kinin-independent manner. In conclusion, accumulation of FXII in ARDS lungs may contribute to the release of pro-inflammatory mediators and is associated with clinical outcome. FXII inhibition may thus offer a novel and promising therapeutic approach to antagonize overwhelming inflammatory responses in ARDS lungs without interfering with vital haemostasis.

Granulomatous lung diseases are a heterogeneous group of disorders that have a wide spectrum of pathologies with variable clinical manifestations and outcomes. Precise clinical evaluation, laboratory testing, pulmonary function testing, radiological imaging including high-resolution computed tomography and often histopathological assessment contribute to make a confident diagnosis of granulomatous lung diseases. Differential diagnosis is challenging, and includes both infectious (mycobacteria and fungi) and noninfectious lung diseases (sarcoidosis, necrotising sarcoid granulomatosis, hypersensitivity pneumonitis, hot tub lung, berylliosis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, rheumatoid nodules, talc granulomatosis, Langerhans cell histiocytosis and bronchocentric granulomatosis). Bronchoalveolar lavage, endobronchial ultrasound-guided transbronchial needle aspiration, transbronchial cryobiopsy, positron emission tomography and genetic evaluation are potential candidates to improve the diagnostic accuracy for granulomatous lung diseases. As granuloma alone is a nonspecific histopathological finding, the multidisciplinary approach is important for a confident diagnosis., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at err.ersjournals.com, (Copyright ©ERS 2017.)

Background: The galaxy sign is an irregularly marginated pulmonary nodule formed by a confluence of multiple small nodules, and it is a diagnostic radiological finding for pulmonary sarcoidosis. However, the clinical significance of the galaxy sign for sarcoidosis has been poorly investigated., Objective: This study aimed to investigate the clinical significance and detailed radiological features of the galaxy sign in patients with pulmonary sarcoidosis., Methods: We retrospectively reviewed 87 patients with biopsy-proven sarcoidosis and 108 patients with pulmonary tuberculosis. Galaxy sign incidence was assessed on thoracic high-resolution computed tomography (HRCT) images from each group. Correlations of galaxy sign with clinical characteristics and disease outcomes were evaluated for patients with sarcoidosis., Results: HRCT findings were available for 65 of 87 patients with pulmonary sarcoidosis and all 108 patients with pulmonary tuberculosis. Galaxy sign incidence was significantly higher in patients with pulmonary sarcoidosis (n=15, 23.1%) than in those with pulmonary tuberculosis (n=2, 1.9%, p<0.001). Among the 65 patients with pulmonary sarcoidosis, those with galaxy signs (n=15) were significantly younger (median: 32 years, interquartile range [IQR] 28-38 years) than those without (n=50) (median: 62 years, IQR 37.7-73 years). The CD4/CD8 ratio in bronchoalveolar lavage fluid (BALF) was also significantly lower in the former group (median: 2.6, IQR 2.0-3.9 vs. median 5.8, IQR 3.7-8.6, p<0.001)., Conclusion: Galaxy signs are associated with younger age and low BALF CD4/CD8 ratio but not disease severity.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterised by dyspnea and loss of lung function., Methods: Using pooled data from the replicate, randomized, 52-week, placebo-controlled INPULSIS(®) trials, we characterized the safety and tolerability of nintedanib 150 mg twice daily in patients with IPF and described how adverse events were managed during these trials., Results: One thousand and sixty- one patients were treated (nintedanib 638; placebo 423). Higher proportions of patients in the nintedanib group than the placebo group had ≥ 1 dose reduction to 100 mg bid (27.9% versus 3.8%) or treatment interruption (23.7% versus 9.9%). Adverse events led to permanent treatment discontinuation in 19.3% and 13.0% of patients in the nintedanib and placebo groups, respectively. Diarrhea was the most frequent adverse event, reported in 62.4% of patients in the nintedanib group versus 18.4% in the placebo group; however, only 4.4% of nintedanib-treated patients discontinued trial medication prematurely due to diarrhea. Monitoring of liver enzymes before and periodically during nintedanib treatment was recommended so that liver enzyme elevations could be managed through dose reduction or treatment interruption., Conclusion: Nintedanib had a manageable safety and tolerability profile in patients with IPF. Recommendations for adverse event management minimized permanent treatment discontinuations in the INPULSIS(®) trials., Trial Registration: clinicaltrials.gov NCT01335464 and NCT01335477.

Interstitial lung diseases (ILDs) are a heterogeneous group of >100 pulmonary disorders. ILDs are characterized by an irreversible architectural distortion and impaired gas exchange; however, there is great variability in the clinical course. ILD diagnosis requires a combination of clinical data, radiological imaging and histological findings (when a lung biopsy is required). At the same time, successful management of ILD patients strictly depends on an accurate and confident diagnosis. In this context, the detection of reliable biomarkers able to identify ILD subtypes, avoiding lung biopsy, as well as the capacity to stratify patients and predict over time the disease course, has become a primary aim for all research studies in this field.

Background: Interstitial pneumonias (IP) cover a broad spectrum of diseases. Open lung biopsies reveal histological patterns and suggest possible diagnoses. Complete clinical records are necessary for final diagnoses. Especially idiopathic interstitial pneumonias (IIP) according to the ATS/ERS classification can only be diagnosed under these predictions. The aim of this study was to compare the results of histological evaluations with the final diagnosis after interdisciplinary case evaluation., Patients and Methods: 88 patients with interstitial pneumonia that underwent open lung biopsies were investigated. Histology and clinical records were available for review. Diagnosis was made in three steps: first on the sole basis of histology, second with clinical information given initially and third, on the basis of an interdisciplinary case evaluation., Results: 63 patients (72%) were diagnosed as idiopathic interstitial pneumonias according to ATS/ERS criteria. Further 10 (11%) cases of hypersensitivity pneumonitis, 7 (8%) Langerhans cell histiocytosis and 8 (9%) interstitial pneumonias of other known causes or associations were detected. Histological patterns alone agreed with the final diagnosis in 67%. In 82% histology and clinical information given to the pathologist could provide correct diagnosis. In the rest of cases, especially in non idiopathic interstitial pneumonias, an interdisciplinary case evaluation was needed., Conclusions: Diagnosis of interstitial pneumonias by open lung biopsies needs sufficient clinical information. Because of the overlap of histological patterns, an interdisciplinary case evaluation that includes at least one clinical expert and one pathologist with excellent expertise and the follow-up of the patients is necessary to find correct diagnosis in all cases., Virtual Slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5031706258025129.

Hypersensitivity pneumonitis (HP) is a complex syndrome caused by the inhalation of environmental antigens. Chronic HP may mimic other fibrotic lung diseases, such as idiopathic pulmonary fibrosis. Recognition of the antigen is important for diagnosis; avoidance of further exposure is critical for treatment. Fibrosis on biopsy or high-resolution computed tomography is a predictor of increased mortality. Additional research is needed to understand why the disease develops only in a minority of exposed individuals and why cases of chronic HP may progress without further antigen exposure., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A 51-year-old active smoker with primary acquired pulmonary alveolar proteinosis (PAP) diagnosed by biopsy and anti-GM-CSF antibodies was treated safely with whole-lung lavage (WLL). This resulted in a rapid improvement of symptoms and arterial blood oxygenation, but not of standard lung function parameters. However, we also performed the multiple-breath nitrogen washout (MBW) test to determine the lung clearance index (LCI) as well as indices of acinar ventilation heterogeneity (S(acin)) and conductive ventilation heterogeneity (S(cond)). At baseline, a distinct abnormality was seen for S(acin) and LCI, while S(cond) was at the upper limit of normal for this subject. S(acin), in particular, was in excess of the S(acin) abnormality corresponding to a 20-pack-year smoking history. Immediately after WLL, S(acin) and S(cond) both fell to within a normal range while LCI also decreased but remained abnormal. The S(acin) decrease was much greater than the S(cond) decrease, which was to be expected after 1 week of smoking cessation at the hospital (smoking was resumed after release from hospital). A follow-up visit 7 weeks after WLL revealed a spectacular improvement on CT scan and improvements in standard lung function. Another follow-up visit 14 weeks after WLL showed further improvements in standard lung function, and both S(acin) and S(cond) remained well within the normal range, and LCI was above the upper limit of normal. We conclude that in this patient, removal of excess surfactant by WLL resulted in a restored ventilation distribution in most of the distal air spaces., (Copyright © 2012 S. Karger AG, Basel.)

Objective: The aim of this study was to investigate the relationship between SP-D and KL-6 serum concentrations and the extent of interstitial lung involvement, as measured by a quantitative HRCT score and the functional impairment, in patients with systemic sclerosis (SSc). Moreover we analysed the association between these lung-specific biomarkers and skin involvement, anti-Scl-70 antibody titres and an index of disease activity., Methods: Serum SP-D, KL-6 and anti-Scl-70 concentrations were determined by ELISA in 25 SSc patients. Disease activity and lung function parameters were assessed, and the extent of ILD was measured by a HRCT score., Results: SP-D and KL-6 concentrations were higher in patients with SSc and lung fibrosis than in healthy controls. KL-6 correlated positively with the HRCT-fibrosis score (r=0.68, p<0.001), SP-D showed a weaker correlation (r=0.44, p=0.025). Increased KL-6 concentrations were associated with decreased DLCO and decreased FVC in SSc patients, SP-D showed no association. Furthermore KL-6, but not SP-D, showed a strong association with skin involvement as expressed by the modified Rodnan skin score (r=0.71, p<0.0001) and a disease activity index (r=0.73, p<0.0001)., Conclusion: KL-6 is more strongly associated than SP-D with the HRCT-fibrosis score, and, different from SP-D, it correlates with skin involvement and disease activity. We suggest that KL-6 may be a useful biomarker in the assessment of scleroderma patients.

Background: Cystic fibrosis (CF) is a chronic progressive disease leading to obstructive pulmonary impairment, fibrosis and shortened life expectancy. Serum levels of KL-6, high molecular weight human MUC1 mucin, are increased in the majority of patients with various interstitial lung disorders. Whether they are also elevated in CF has not been investigated before., Objective: To evaluate whether serum KL-6 levels are elevated and correlate with pulmonary function variables in CF., Design: Serum KL-6, lactate dehydrogenase (LDH) and C-reactive protein (CRP) levels were measured in 72 consecutive CF and 80 age- and sex-matched healthy control subjects. The relationship between serum KL-6 levels and pulmonary function variables was analyzed., Results: Serum KL-6 levels in CF patients were significantly increased compared to healthy subjects. Receiver operating characteristic curve analysis revealed that the diagnostic accuracy of KL-6 was better than that of LDH and CRP. Serum KL-6 levels showed an inverse relationship with vital capacity (VC) % predicted and forced expiratory volume in one second (FEV1) % predicted., Conclusions: Serum KL-6 levels are elevated and appear to be correlated with pulmonary function variables in CF. These results suggest that KL-6 may be a useful noninvasive marker to monitor disease severity.