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Background and Purpose: Interstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway., Methods: We established an arthritis model by combining chicken type II collagen and complete Freund's adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-β1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1β in combination with TGF-β1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD., Results: Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-β1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD., Conclusion: In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD., (© 2024. The Author(s).)

Rationale and Objectives: Bleeding is a major complication of transbronchial lung cryobiopsy (TBLC), and pre-placing a bronchial balloon is one of the clinical practices used to prevent it, but with very weak evidence, which should be confirmed. This study aimed to conduct whether pre-placing a bronchial balloon in TBLC for diagnosing interstitial lung disease (ILD) is more safety., Materials and Methods: In this prospective, single-center, randomized controlled trial, patients with suspected ILD were enrolled and randomly assigned to pre-placed balloon and none-pre-placed balloon groups. The primary outcome was incidence of moderate bleeding in each group. The secondary endpoints were the incidence of severe bleeding, pneumothorax, and other procedural complications., Results: Exactly 250 patients were enrolled between August 2019 and March 2022, with 125 in each group. There were no significant differences in severe bleeding between the none-pre-placed balloon group and pre-placed balloon group (1.6% vs. 0.8%; adjusted p = 0.520), while more moderate bleeding occurred in the none-pre-placed balloon group (26.4% vs. 6.4%, adjusted p = 0.001), as well as more use of hemostatic drug (28.0% vs. 6.4%, adjusted p = 0.001). Three patients in the none-pre-placed balloon group used the bronchial balloon. More samples could be acquired in the pre-placed balloon group than in the none-pre-placed balloon group (3.8 ± 0.9 vs. 3.1 ± 0.9, p < 0.001). There were no significant differences in multidisciplinary discussion (MDD) between the two groups (89.6% vs. 91.2%, adjusted p = 0.182)., Conclusion: A pre-placed bronchial balloon can reduce the incidence of moderate bleeding and increase the confidence of the bronchoscopists. However, it had no effect on increasing the diagnostic rate of MDD and reducing severe bleeding., Registration Number: NCT04047667 ( www., Clinicaltrials: gov identifier)., (© 2024. The Author(s).)

Background: Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFβ1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients., Methods: Fourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients' informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFβ1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFβ1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test., Results: Cultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFβ1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFβ1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFβ1 after 24 h of treatment (p < 0.05 vs. untreated cells)., Conclusions: In cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFβ1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis., (© 2024. The Author(s).)

Background: The prognosis of patients with lung cancer accompanied by interstitial pneumonia is poorer than that of patients with lung cancer but without interstitial pneumonia. Moreover, the available therapeutic interventions for lung cancer patients with interstitial pneumonia are limited. Therefore, a new treatment strategy for these patients is required. The aim of the present study was to investigate the pathophysiological relationship between interstitial pneumonia and lung cancer and explore potential therapeutic agents., Methods: A novel hybrid murine model of lung cancer with interstitial pneumonia was established via bleomycin-induced pulmonary fibrosis followed by orthotopic lung cancer cell transplantation into the lungs. Changes in tumor progression, lung fibrosis, RNA expression, cytokine levels, and tumor microenvironment in the lung cancer with interstitial pneumonia model were investigated, and therapeutic agents were examined. Additionally, clinical data and samples from patients with lung cancer accompanied by interstitial pneumonia were analyzed to explore the potential clinical significance of the findings., Results: In the lung cancer with interstitial pneumonia model, accelerated tumor growth was observed based on an altered tumor microenvironment. RNA sequencing analysis revealed upregulation of the hypoxia-inducible factor 1 signaling pathway. These findings were consistent with those obtained for human samples. Moreover, we explored whether ascorbic acid could be an alternative treatment for lung cancer with interstitial pneumonia to avoid the disadvantages of hypoxia-inducible factor 1 inhibitors. Ascorbic acid successfully downregulated the hypoxia-inducible factor 1 signaling pathway and inhibited tumor progression and lung fibrosis., Conclusions: The hypoxia-inducible factor 1 pathway is critical in lung cancer with interstitial pneumonia and could be a therapeutic target for mitigating interstitial pneumonia-mediated lung cancer progression., (© 2023. The Author(s).)

Risk factors of severe coronavirus disease 2019 (COVID-19) have been previously reported; however, histological risk factors have not been defined thus far. The aim of this study was to clarify subclinical hidden interstitial lung disease (ILD) as a risk factor of severe pneumonia associated with COVID-19. We carefully examined autopsied lungs and chest computed tomography scanning (CT) images from patients with COVID-19 for interstitial lesions and then analyzed their relationship with disease severity. Among the autopsy series, subclinical ILD was found in 13/27 cases (48%) in the COVID-19 group, and in contrast, 8/65 (12%) in the control autopsy group (p = 0.0006; Fisher's exact test). We reviewed CT images from the COVID-19 autopsy cases and verified that subclinical ILD was histologically detectable in the CT images. Then, we retrospectively examined CT images from another series of COVID-19 cases in the Yokohama, Japan area between February-August 2020 for interstitial lesions and analyzed the relationship to the severity of COVID-19 pneumonia. Interstitial lesion was more frequently found in the group with the moderate II/severe disease than in the moderate I/mild disease (severity was evaluated according to the COVID-19 severity classification system of the Ministry of Health, Labor, and Welfare [Japan]) (moderate II/severe, 11/15, 73.3% versus moderate I/mild, 108/245, 44.1%; Fisher exact test, p = 0.0333). In conclusion, it was suggested that subclinical ILD could be an important risk factor for severe COVID-19 pneumonia. A benefit of these findings could be the development of a risk assessment system using high resolution CT images for fatal COVID-19 pneumonia., (© 2023. The Author(s).)

Introduction: Antigen identification impacts diagnosis as well as prognosis in patients with hypersensitivity pneumonitis. An antigen may also be present in other etiologies of interstitial lung disease, however it is unknown whether identification impacts survival., Methods: We evaluated a retrospective cohort in order to determine if antigen identification affects transplant free survival in patients with hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, connective tissue disease interstitial lung disease, and interstitial pneumonia with autoimmune features. Only patients with definite or high probability of hypersensitivity pneumonitis by American Thoracic Society guidelines were included in the analysis., Results: Transplant free survival was improved with antigen identification in patients with hypersensitivity pneumonitis but not in patients with idiopathic pulmonary fibrosis, connective tissue disease interstitial lung disease, and interstitial pneumonia with autoimmune features., Conclusion: Our study suggests that removal of identified antigen in interstitial lung diseases other than hypersensitivity pneumonitis may not be impactful. Additionally, it further suggests that definitive diagnosis of hypersensitivity pneumonitis with bronchoalveolar lavage and transbronchial biopsy may be beneficial prior to recommending antigen removal., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The diagnostic accuracy and safety of transbronchial lung cryobiopsy (TBLC) via a flexible bronchoscope under sedation compared with that of surgical lung biopsy (SLB) in the same patients is unknown., Methods: Retrospectively the data of fifty-two patients with interstitial lung diseases (median age: 63.5 years; 21 auto-antibody positive) who underwent TBLC followed by SLB (median time from TBLC to SLB: 57 days) was collected. The samples from TBLC and SLB were randomly labelled to mask the relationship between the two samples. Diagnosis was made independently by pathologists, radiologists, and pulmonary physicians in a stepwise manner, and a final diagnosis was made at multidisciplinary discussion (MDD). In each diagnostic step the specific diagnosis, the diagnostic confidence level, idiopathic pulmonary fibrosis (IPF) diagnostic guideline criteria, and treatment strategy were recorded., Results: Without clinical and radiological information, the agreement between the histological diagnoses by TBLC and SLB was 42.3% (kappa [κ] = 0.23, 95% confidence interval [CI]: 0.08-0.39). However, the agreement between the TBLC-MDD and SLB-MDD diagnoses and IPF/non-IPF diagnosis using the two biopsy methods was 65.4% (κ = 0.57, 95% CI: 0.42-0.73) and 90.4% (47/52), respectively. Out of 38 (73.1%) cases diagnosed with high or definite confidence at TBLC-MDD, 29 had concordant SLB-MDD diagnoses (agreement: 76.3%, κ = 0.71, 95% CI: 0.55-0.87), and the agreement for IPF/non-IPF diagnoses was 97.4% (37/38). By adding the pathological diagnosis, the inter-observer agreement of clinical diagnosis improved from κ = 0.22 to κ = 0.42 for TBLC and from κ = 0.27 to κ = 0.38 for SLB, and the prevalence of high or definite diagnostic confidence improved from 23.0% to 73.0% and from 17.3% to 73.0%, respectively. Of all 383 TBLC performed during the same period, pneumothorax occurred in 5.0% of cases, and no severe bleeding, acute exacerbation of interstitial lung disease, or fatal event was observed., Conclusions: TBLC via a flexible bronchoscope under deep sedation is safely performed, and the TBLC-MDD diagnosis with a high or definite confidence level is concordant with the SLB-MDD diagnosis in the same patients., (© 2023. The Author(s).)

Background: Interstitial lung diseases (ILD), such as idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP), and chronic obstructive pulmonary disease (COPD) are severe, progressive pulmonary disorders with a poor prognosis. Prompt and accurate diagnosis is important to enable patients to receive appropriate care at the earliest possible stage to delay disease progression and prolong survival. Artificial intelligence-assisted lung auscultation and ultrasound (LUS) could constitute an alternative to conventional, subjective, operator-related methods for the accurate and earlier diagnosis of these diseases. This protocol describes the standardised collection of digitally-acquired lung sounds and LUS images of adult outpatients with IPF, NSIP or COPD and a deep learning diagnostic and severity-stratification approach., Methods: A total of 120 consecutive patients (≥ 18 years) meeting international criteria for IPF, NSIP or COPD and 40 age-matched controls will be recruited in a Swiss pulmonology outpatient clinic, starting from August 2022. At inclusion, demographic and clinical data will be collected. Lung auscultation will be recorded with a digital stethoscope at 10 thoracic sites in each patient and LUS images using a standard point-of-care device will be acquired at the same sites. A deep learning algorithm (DeepBreath) using convolutional neural networks, long short-term memory models, and transformer architectures will be trained on these audio recordings and LUS images to derive an automated diagnostic tool. The primary outcome is the diagnosis of ILD versus control subjects or COPD. Secondary outcomes are the clinical, functional and radiological characteristics of IPF, NSIP and COPD diagnosis. Quality of life will be measured with dedicated questionnaires. Based on previous work to distinguish normal and pathological lung sounds, we estimate to achieve convergence with an area under the receiver operating characteristic curve of > 80% using 40 patients in each category, yielding a sample size calculation of 80 ILD (40 IPF, 40 NSIP), 40 COPD, and 40 controls., Discussion: This approach has a broad potential to better guide care management by exploring the synergistic value of several point-of-care-tests for the automated detection and differential diagnosis of ILD and COPD and to estimate severity. Trial registration Registration: August 8, 2022., Clinicaltrials: gov Identifier: NCT05318599., (© 2023. The Author(s).)

Background: Indium lung is characterized by interstitial pneumonia and/or emphysema which occurs in indium-tin oxide (ITO) workers. Indium lung is now known to progress after stopping exposure to ITO, but the long-term influences of ITO remain unclear., Case Presentation: Forty seven years old, a never-smoker, who had been engaged in an ITO manufacturing process for 8 years. Emphysema was indicated by the medical check-up for ex-ITO workers, and he was diagnosed with indium lung. He underwent partial lung resections for pneumothorax two times, and obstructive pulmonary dysfunction had progressed through the years. He underwent right single lung transplant 20 years after ITO exposure. Pathologically, his lung showed severe distal acinar emphysema and honeycomb change. Fibrosis and destruction of the lung tissue significantly progressed compared to the previous partial resections. Scanning electron microscopy combined with energy dispersive spectroscopy revealed that the deposited particles contained indium and tin. After the transplantation, his respiratory function was improved., Conclusions: In this case, ITO resided in the lung tissue for 20 years, and lung tissue destruction kept progressing. Careful medical follow-up is recommended for ITO-workers even if they are asymptomatic., (© 2023. The Author(s).)

Background: The difference in diagnostic yield between surgical lung biopsy and transbronchial lung cryobiopsy (TBLC) in diffuse parenchymal lung diseases (DPLD) has been reported to be due to differences in the rate of interpathologist agreement, specimen size, and specimen adequacy. In TBLC, the specimens containing large airway components are generally believed as inadequate specimens for histological evaluation, but the detailed characteristics of TBLC specimens including the large airway and the impact on histological diagnostic rates of DPLD have not been investigated., Methods: We retrospectively reviewed the specimen characteristics of patients with DPLD who underwent TBLC., Results: Between February 2018 and January 2020, 74 patients and 177 specimens were included. There were 85 (48.0%) large airway specimens (LAS) that contained bronchial gland or bronchial cartilage. The ideal specimen ratio was significantly lower in the LAS-positive group than that in the LAS-negative group (5.8% vs. 45.6%), and the proportion of bronchioles, alveoli, and perilobular area were similarly lower in the LAS-positive group. The presence of traction bronchiectasis and diaphragm overlap sign on high-resolution computed tomography (HRCT) were also significantly higher in the LAS-positive group than those in the LAS-negative group. We observed a statistically significant trend in histological diagnostic yield (40.7% in LAS positive group; 60.8% in LAS positive and negative group; 91.6% in LAS negative group) (Cochran-Armitage trend test)., Conclusion: LAS is a specimen often collected in TBLC and contains a low percentage of bronchioles, alveoli, and perilobular area. Since the histological diagnostic yield tends to be higher in cases that do not contain LAS, it may be important to determine the biopsy site that reduces the frequency of LAS collection by referring to the HRCT findings in TBLC., (© 2022. The Author(s).)

Background: Lymphoid interstitial pneumonia (LIP) is a very rare disease and its malignant transformation is even more rare. LIP is easily misdiagnosed by clinicians and radiologists., Case Presentation: The medical record of a 64-year-old female with Sjogren's syndrome was reviewed. The clinical and pathological data along with chest CT images were obtained. The literature related to the transformation was reviewed. There were no specific clinical manifestations of LIP and its transformation into malignant lymphoma in the patient. The chest CT mainly displayed multiple cystic foci, with multiple nodules and ground-glass shadows in both lungs., Conclusions: Malignant transformation to lymphoma is suspected with findings of large nodules (> 11 mm) or their sizes doubly increased, pleural effusion and alveolar consolidation., (© 2022. The Author(s).)

Background: The etiology of interstitial lung diseases (ILDs) is varied. Early diagnosis and a specific pathological type could significantly improve the prognosis. Mostly, it is difficult to make the etiology diagnosis of ILD through traditional biopsy methods. It will be of great significance to explore an effective biopsy method., Methods: The prospective study was designed to evaluate the diagnostic value of transbronchial lung cryobiopsy (TBCB) combined with rapid on-site evaluation (ROSE), compared with conventional transbronchial lung biopsy (TBLB), in a large sample of ILD patients. All patients enrolled will undergo both TBLB and TBCB procedures. The study will observe the differences in the diagnostic efficiency of pathological typing and incidence of operation-related complications between TBCB and TBLB. Besides, it will analyze the relationship between the time of biopsy and the incidence of complications, the relationship between freezing time, size of specimen, and complications. And it will evaluate the consistency of pathological, clinical, and radiology., Discussion: It may be the first time that ROSE technique will be used in the diagnosis of ILD. The results of this study will clarify the value of TBCB in the diagnosis of ILD and confirm its safety and effectiveness, which is expected to significantly improve the efficiency of diagnosis in ILD patients., Trail Registration: The trial was registered on the Chinese Clinical Trial Registry website ( http://www.chictr.org.cn/showproj.aspx?proj=57834 ) (Registration number: ChiCTR2000035492)., (© 2022. The Author(s).)

Background: Bronchoalveolar lavage (BAL) is a major diagnostic tool in interstitial lung disease (ILD). Its use remains largely quantitative, usually focused on cell differential ratio. However, cellular morphological features provide additional valuable information. The significance of the "immune alveolitis" cytological profile, characterized by lymphocytic alveolitis with activated lymphocytes and macrophages in epithelioid transformation or foamy macrophages desquamating in cohesive clusters with lymphocytes, remains unknown in ILD. Our objective was to describe patients' characteristics and diagnoses associated with an immune alveolitis profile in undiagnosed ILD., Methods: We performed a monocentric retrospective observational study. Eligible patients were adults undergoing diagnostic exploration for ILD and whose BAL fluid displayed an immune alveolitis profile. For each patient, we collected clinical, radiological and biological findings as well as the final etiology of ILD., Results: Between January 2012 and December 2018, 249 patients were included. Mean age was 57 ± 16 years, 140 patients (56%) were men, and 65% of patients were immunocompromised. The main etiological diagnosis was Pneumocystis pneumonia (PCP) (24%), followed by drug-induced lung disease (DILD) (20%), viral pneumonia (14%) and hypersensitivity pneumonitis (HP) (10%). All PCP were diagnosed in immunocompromised patients while HP was found in only 8% of this subgroup. DILD and viral pneumonia were also commonly diagnosed in immunocompromised patients (94% and 80%, respectively)., Conclusion: Our study highlights the additional value of BAL qualitative description in ILD. We suggest incorporating the immune alveolitis profile for the diagnosis and management of ILD, especially in immunocompromised patients, since it guides towards specific diagnoses., (© 2022. The Author(s).)

Background: Interstitial lung disease (ILD) may cause life-threatening complications of primary Sjogren's syndrome (pSS), and has a poor prognosis in terms of survival and quality of life. To date, few studies have investigated the risk factors for ILD detected by high-resolution computed tomography (HRCT) in pSS patients with or without respiratory symptoms., Methods: Data of 333 patients with newly diagnosed pSS were retrospectively analysed. Interstitial lung disease involvement was defined as typical abnormalities on HRCT and/or pulmonary function tests. Multivariate regression model was used to evaluate the association between interstitial lung disease and pSS characteristics., Results: Sixty-six patients (19.82%) were diagnosed with pSS-ILD. Ground glass opacities (87.88%) and septal/sub pleural lines (81.82%) were most frequent. Based on pulmonary high-resolution computed tomography, patients were divided into nonspecific (n = 42), usual (n = 20), lymphocytic interstitial pneumonia (n = 3) and cryptogenic organising pneumonia (n = 1) groups. There was a strong association between erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) and the HRCT-score. Pulmonary function tests revealed impaired diffusion capacity for carbon monoxide and total lung capacity, and coexistence of small airway lesions in pSS-interstitial lung disease. On logistic regression analysis, age, Raynaud's phenomenon, lymphopenia, cough, dyspnoea and rampant dental caries were risk factors associated with pSS-interstitial lung disease., Conclusions: Interstitial lung disease involvement in pSS is a common clinical occurrence. The clinical manifestation is nonspecific and variable; Raynaud's phenomenon and lymphopenia may predict its onset. pSS patients with advanced age, dry cough and dyspnoea should be systematically evaluated for ILD involvement and managed according to their symptoms., (© 2022. The Author(s).)

Background: The usefulness and safety of transbronchial lung cryobiopsy (TBLC) for reassessment of diffuse parenchymal lung disease (DPLD) with progression is still unknown. Our purpose was to clarify the usefulness and safety of TBLC for reassessment of DPLD with progression., Methods: This retrospective study included 31 patients with DPLD diagnosed by surgical lung biopsy who progressed in the clinical course and underwent TBLC for reassessment between January 2017 and September 2019 at Kanagawa Cardiovascular & Respiratory Center. Two pulmonologists independently selected the clinical diagnosis, treatment strategy, and confidence level of the treatment strategy based on clinical and radiological information with and without pathological information from TBLC. A consensus was reached among the pulmonologists regarding the clinical diagnosis, treatment strategy, and confidence level of the treatment strategy. Complications of TBLC were also examined., Results: Seven (22.6%), 5 (16.1%), and 6 (19.4%) of clinical diagnosis was changed after TBLC for Pulmonologist A, for Pulmonologist B, and for consensus, respectively. The treatment strategy was changed in 7 (22.6%), 8 (25.9%), and 6 (19.4%) cases after TBLC for Pulmonologist A, for Pulmonologist B and for consensus, respectively. The definite or high confidence level of the consensus treatment strategy was 54.8% (17/31) without TBLC and 83.9% (26/31) with TBLC. There were 6 cases of moderate bleeding, but no other complications were noted., Conclusions: Pathological information from TBLC may contribute to decision-making in treatment strategies for the progression of DPLD, and it may be safely performed., (© 2022. The Author(s).)

Background: A balloon occlusion technique is suggested for use in cryobiopsy for interstitial lung diseases because of the bleeding risk. However, it may interfere with selection of the involved bronchus for peripheral pulmonary lesions (PPLs). A two-scope technique, in which two scopes are prepared and hemostasis is started using the second scope immediately after cryobiopsy, has also been reported. This study aimed to evaluate the safety and diagnostic utility of transbronchial cryobiopsy using the two-scope technique for PPLs., Methods: Data of patients who underwent conventional biopsy followed by cryobiopsy using the two-scope technique for PPLs from November 2019 to March 2021 were collected. The incidence of complications and risk factors for clinically significant bleeding (moderate to life-threatening) were investigated. Diagnostic yields were also compared among conventional biopsy, cryobiopsy, and the combination of them., Results: A total of 139 patients were analyzed. Moderate bleeding occurred in 25 (18.0%) patients without severe/life-threatening bleeding. Although five cases required transbronchial instillation of thrombin, all bleeding was completely controlled using the two-scope technique. Other complications included two pneumothoraces and one asthmatic attack. On multivariable analysis, only ground-glass features (P < 0.001, odds ratio: 9.30) were associated with clinically significant bleeding. The diagnostic yields of conventional biopsy and cryobiopsy were 76.3% and 81.3%, respectively (P = 0.28). The total diagnostic yield was 89.9%, significantly higher than conventional biopsy alone (P < 0.001)., Conclusions: The two-scope technique provides useful hemostasis for safe cryobiopsy for PPLs, with a careful decision needed for ground-glass lesions., (© 2021. The Author(s).)

Background: Accelerated nodulosis (ARN) is a rare variant of rheumatoid nodules (RNs) that is characterized by a rapid onset or the worsening of RNs. It generally develops at the fingers in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX). Few case reports have described ARN at an extracutaneous location., Case Presentation: An elderly patient with long-standing RA was admitted to our hospital with acute respiratory failure. Computed tomography upon admission showed diffuse ground-glass opacities superimposed with subpleural reticular shadowing and honeycombing and multiple nodules in the lungs and liver. Despite the discontinuation of MTX and introduction of an immunosuppressive regimen with pulse methylprednisolone followed by a tapering dose of prednisolone and intravenous cyclophosphamide, the patient died due to the acute exacerbation (AE) of RA-related interstitial lung disease (ILD) following the parallel waxing and waning of a diffuse interstitial shadow and pulmonary and liver nodules. At autopsy, RNs were scattered throughout both lung fields in addition to extensive interstitial changes. RNs were also detected in the liver and kidneys. The foci of cryptococcosis were mainly identified in alveolar spaces. Based on the clinical and pathological findings, these nodules were most consistent with ARN because of acute increases in the size and number of previously detected pulmonary nodules., Conclusion: The present case is noteworthy because ARN was concurrently detected in multiple internal organs and may be associated with the AE of RA-related ILD., (© 2021. The Author(s).)

Background: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is often positive in patients with interstitial lung disease (ILD), which is also often present in patients with microscopic polyangiitis (MPA). A possible association between MPO-ANCA, MPA, and idiopathic ILD remains unclear. The objective of this study was to determine whether high-resolution computed tomography (HRCT) classification based on recent idiopathic pulmonary fibrosis guideline and specific CT findings can obtain new knowledge of prognostic factors in all MPO-ANCA-positive patients with ILD including both idiopathic ILD and MPA-ILD., Methods: We analyzed 101 consecutive MPO-ANCA-positive patients with respiratory disease. We assessed the diagnostic accuracy of CT findings, HRCT pattern, and specific radiological signs. Prognostic predictors were determined using Cox regression models., Results: Subjects with chronic ILD included 22 patients with MPA-ILD and 39 patients with ILD but without MPA. A quarter of the patients were radiological indeterminate for usual interstitial pneumonia (UIP) pattern, which resulted in a better prognosis than that for UIP pattern. "Increased attenuation around honeycomb and traction bronchiectasis" and "anterior upper lobe honeycomb-like lesion" were found to be highly frequent radiological findings (39% and 30%, respectively). In addition, the latter finding was a significant negative prognostic factor., Conclusions: Radiological indeterminate for UIP was a useful HRCT classification in MPO-ANCA-positive patients with ILD. In addition, anterior upper lobe honeycomb-like lesion was found to be specific radiological finding that was a significant prognostic factor. The present results might aid in the assessment of appropriate strategies of diagnosis in these patients., (© 2021. The Author(s).)

Background: Transbronchial lung cryobiopsy is a safe technique increasingly used in the study of lung diseases. Until now, only a case of pneumatocele was described but this interesting condition is probably underestimated because CT scan is routinely not performed after transbronchial lung cryobiopsies., Case Presentation: We report a case of a woman presenting two pneumatoceles after lung cryobiopsies performed for the study of an interstitial lung disease. The finding was obtained with a CT scan performed because of the appearance of hemoptysis, four days after the biopsies., Conclusions: Small cavitations could develop after cryobiopsies in the absence of an active infection. Studies that prospectively perform CT scan of the chest in patients who have undergone these samplings could be useful to know the incidence of iatrogenic lesions., (© 2021. The Author(s).)

Background: To assess mortality rate (MR) and standardized mortality rate (SMR) of rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients and to evaluate the role of radiographic patterns in mortality., Methods: A longitudinal multicentric study was conducted in RA-ILD patients from 2005 to 2015 and followed-up until October 2018 in Madrid. Patients were included in the Neumologia-Reumatología y Enfermedades Autoinmunes Registry, from diagnosis of ILD. The main outcome was all-cause mortality. The radiographic pattern at baseline [usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), or others] was the independent variable. Covariables included sociodemographic and clinical data. Survival techniques were used to estimate MR, expressed per 1000 persons-year with their 95% confidence intervals [CI]. Cox multiple regression model was run to examine the influence of radiographic patterns on survival. SMR [CI] was calculated comparing MR obtained with MR expected in the general population of Madrid by indirect age-gender standardization., Results: 47 patients were included with a follow-up 242 patients-year. There were 16 (34%) deaths, and most frequent causes were acute ILD exacerbation and pneumonia. MR was 64.3 [39.4-104.9], and 50% of the patients died at 8.3 years from ILD diagnosis. After adjusting for confounders, (UIP compared to NSIP was associated with higher mortality risk. The overall SMR was 2.57 [1.4-4.17]. Women of 60-75 years of age were the group with the highest SMR., Conclusions: RA-ILD is associated with an excess of mortality compared to general population. Our results support that UIP increases the risk of mortality in RA-ILD, regardless other factors.

Background: Current interstitial lung disease (ILD) diagnostic guidelines assess criteria across clinical, radiologic and pathologic domains. Significant interobserver variation in histopathologic evaluation has previously been shown but the specific source of these discrepancies is poorly documented. We sought to document specific areas of difficulty and develop improved criteria that would reduce overall interobserver variation., Methods: Using an internet-based approach, we reviewed selected images of specific diagnostic features of ILD histopathology and whole slide images of fibrotic ILD. After an initial round of review, we confirmed the presence of interobserver variation among our group. We then developed refined criteria and reviewed a second set of cases., Results: The initial round reproduced the existing literature on interobserver variation in diagnosis of ILD. Cases which were pre-selected as inconsistent with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) were confirmed as such by multi-observer review. Cases which were thought to be in the spectrum of chronic fibrotic ILD for which UIP/IPF were in the differential showed marked variation in nearly all aspects of ILD evaluation including extent of inflammation and extent and pattern of fibrosis. A proposed set of more explicit criteria had only modest effects on this outcome. While we were only modestly successful in reducing interobserver variation, we did identify specific reasons that current histopathologic criteria of fibrotic ILD are not well defined in practice., Conclusions: Any additional classification scheme must address interobserver variation in histopathologic diagnosis of fibrotic ILD order to remain clinically relevant. Improvements to tissue-based diagnostics may require substantial resources such as larger datasets or novel technologies to improve reproducibility. Benchmarks should be established for expected outcomes among clinically defined subgroups as a quality metric.

Background: The surgical lung biopsy (SLB) is the recommended sampling technique when the pathological analysis of the lung is required in the work-up of an interstitial lung disease (ILD) but trans-bronchial lung cryobiopsy (TBLC) is increasingly recognized as an alternative approach. As TBLCs have lower mortality and morbidity risks than SLB, this study aimed to investigate the safety of TBLCs in patients at higher risk of complications and for whom SLB was not considered as an alternative., Method: This prospective study was conducted in two hospitals in which TBLCs were performed in patients with body mass index (BMI) > 35, and/or older than 75 years, and/or with severely impaired lung function (FVC < 50% or DLCO < 30%), and/or systolic pulmonary artery pressure > 45 mmHg, and/or a clinically significant cardiac disease. Patients with any of these risk factors constituted the high-risk group. Clinical outcomes were compared with those obtained in patients without these risk factors (low-risk group)., Results: Ninety-six patients were included between April 2015 and April 2020, respectively 38 and 58 in the high-risk or the low-risk group. No statistically significant difference was observed between both groups in terms of severity and rate of bleeding, pneumothorax, or duration of hospital stay (p value ranging from 0.419 to 0.914)., Conclusion: This preliminary study on a limited number of patients suggests that TBLC appears safe in those in whom lung biopsy is at high-risk of complications according to their age, BMI, lung impairment, and cardiac comorbidities.

Background: Patients with lung cancer and interstitial lung disease treated with radiotherapy are at risk of developing radiation pneumonitis. However, the association between interstitial lung abnormalities (ILAs) and radiation pneumonitis in patients with limited-stage small-cell lung cancer (LS-SCLC) remains unclear. Furthermore, the prognosis is uncertain for patients with SCLC and ILAs treated with chemoradiotherapy. We investigated the impact of ILAs on radiation pneumonitis and assessed the prognosis of patients with LS-SCLC and ILAs treated with chemoradiotherapy., Methods: We retrospectively reviewed the medical records of 149 patients with LS-SCLC who received first-line treatment between January 2009 and December 2016., Results: In the univariate analysis, the patients with ILAs showed a higher incidence rate of radiation pneumonitis compared with those without ILAs (64% vs. 10%, P < 0.001). Multivariate analysis confirmed that ILAs were significantly associated with the incidence of radiation pneumonitis. In the univariate analysis, patients with ILAs showed poorer overall survival than those without ILAs (median, 18.9 vs. 67.9 months, P = 0.0338). Multivariate analysis showed that ILAs were a significant independent negative prognostic factor. However, the 2-year and 5-year survival rates for the patients with ILAs treated with chemoradiotherapy were 36% and 26%, respectively, and 8% and 0%, respectively, for those treated with chemotherapy alone., Conclusions: ILAs were found to be a predictive factor for radiation pneumonitis in patients with LS-SCLC treated with chemoradiotherapy. Patients with LS-SCLC and ILAs who were treated with chemoradiotherapy had both the possibility of long-term survival and risk of radiation pneumonitis.

Background: Non-small-cell lung cancer (NSCLC) has been reported to develop in patients with interstitial pneumonia (IP); however, clinical, radiological, and pathological features remain to be elucidated., Methods: We retrieved the records of 120 consecutive NSCLC patients associated with IP who underwent surgery at Toranomon Hospital between June 2011 and May 2017. We classified the patients into three groups according to NSCLC location using high-resolution computed tomography: group A, within a fibrotic shadow and/or at the interface of a fibrotic shadow and normal lung; group B, within emphysematous tissue and/or at the interface of emphysematous tissue and normal lung; and group C, within normal lung. In 64 patients, programmed death ligand-1 (PD-L1) status was assessed with immunohistostaining., Results: Most of the patients (89; 70%) were classified as group A. This group tended to have squamous cell carcinoma with the usual interstitial pneumonia (UIP). These cancers were located mainly in the lower lobes and seven of the eight postoperative acute exacerbations (pAE) of IP developed in this group. NSCLC in the group B were mainly squamous cell carcinomas located in the upper lobes. No patient with PD-L1 negative was classified into group B. None of the patients in group C showed UIP. and most of the cancers were adenocarcinoma. The frequency of epidermal growth factor receptor mutation-positive NSCLC was the highest in this group., Conclusions: The three groups each showed characteristic features in terms of tumor location, histopathology, PD-L1 expression, and frequency of pAEof IP.

Background: Usual interstitial pneumonia can present with a probable pattern on high-resolution computed tomography (HRCT), but the probability of identifying usual interstitial pneumonia by surgical lung biopsy in such cases remains controversial. We aimed to determine the final clinical diagnosis in patients with a probable usual interstitial pneumonia pattern on HRCT who were subjected to surgical lung biopsy., Methods: HRCT images were assessed and categorized by three radiologists, and tissue slides were evaluated by two pathologists, all of whom were blinded to the clinical findings. The final clinical diagnosis was accomplished via a multidisciplinary discussion. Patients with a single layer of honeycombing located outside of the lower lobes on HRCT were not excluded., Results: A total of 50 patients were evaluated. The most common final clinical diagnosis was fibrotic hypersensitivity pneumonitis (38.0%) followed by idiopathic pulmonary fibrosis (24.0%), interstitial lung disease ascribed to gastroesophageal reflux disease (12.0%) and familial interstitial lung disease (10.0%). In the group without environmental exposure (n = 22), 10 patients had a final clinical diagnosis of idiopathic pulmonary fibrosis (45.5%). Irrespective of the final clinical diagnosis, by multivariate Cox analysis, patients with honeycombing, dyspnoea and fibroblastic foci on surgical lung biopsy had a high risk of death., Conclusions: The most common disease associated with a probable usual interstitial pneumonia pattern on HRCT is fibrotic hypersensitivity pneumonitis followed by idiopathic pulmonary fibrosis and interstitial lung disease ascribed to gastroesophageal reflux disease. In patients without environmental exposure, the frequencies of usual interstitial pneumonia and a final clinical diagnosis of idiopathic pulmonary fibrosis are not sufficiently high to obviate the indications for surgical lung biopsy.

Background: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited., Case Presentation: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264&#95;269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells., Conclusions: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

Background: Stereotactic ablative radiotherapy (SABR) has become an established treatment option for medically-inoperable early-stage (Stage I-IIA) non-small cell lung cancer (ES-NSCLC). SABR is able to obtain high rates of local control with low rates of symptomatic toxicity in this patient population. However, in a subset of patients with fibrotic interstitial lung disease (ILD), elevated rates of SABR-related toxicity and mortality have been described. The Assessment of Precision Irradiation in Early Non-Small Cell Lung Cancer and Interstitial Lung Disease (ASPIRE-ILD) study will conduct a thorough prospective evaluation of the clinical outcomes, toxicity, changes in diagnostic test parameters and patient-related outcomes following SABR for ES-NSCLC for patients with fibrotic ILD., Methods: ASPIRE-ILD is a single-arm Phase II prospective study. The accrual target is 39 adult patients with T1-2N0M0 non-small cell lung cancer with co-existing ILD who are not candidates for surgical excision. Pathological confirmation of diagnosis is strongly recommended but not strictly required. Enrolled patients will be stratified by ILD-related mortality risk. The starting SABR dose will be 50 Gy in 5 fractions every other day (biologically effective dose: 100 Gy 10 or 217 Gy 3 ), but the radiation dose can be de-escalated up to two times to 50 Gy in 10 fractions daily (75 Gy 10 or 133 Gy 3 ) and 45 Gy in 15 fractions daily (58 Gy 10 or 90 Gy 3 ). Dose de-escalation will occur if 2 or more of the first 7 patients in a cohort experiences grade 5 toxicity within 6 months of treatment. Similarly, dose de-escalation can also occur if 2 or more of the first 7 patients with a specific subtype of ILD experiences grade 5 toxicity within 6 months of treatment. The primary endpoint is overall survival. Secondary endpoints include toxicity (CTC-AE 4.0), progression-free survival, local control, patient-reported outcomes (cough severity and quality of life), rates of ILD exacerbation and changes in pulmonary function tests/high-resolution computed tomography findings post-SABR., Discussion: ASPIRE-ILD will be the first prospective study specifically designed to comprehensively evaluate the effectiveness and safety of SABR for ES-NSCLC in patients with co-existing ILD., Trial Registration: Clinicaltrials.gov identifier: NCT03485378. Date of registration: April 2, 2018.

Background: Increasing evidence indicates the utility of transbronchial lung cryobiopsy (TBLC) for the diagnosis of interstitial lung disease (ILD). However, only one study has compared TBLC and surgical lung biopsy (SLB) performed on the same patients., Methods: We identified seven patients with ILD with TBLC and SLB. We evaluated the clinical characteristics and made a pathological diagnosis based on the official ATS/ERS/JRS/ALAT clinical practice guideline of idiopathic pulmonary fibrosis with both TBLC and SLB., Results: Six cases were diagnosed as Usual interstitial pneumonia (UIP) in both TBLC and SLB. One case was diagnosed as indeterminate for UIP with TBLC and probable UIP with SLB. Etiological diagnosis with TBLC and SLB were concordant in 2 cases of idiopathic pulmonary fibrosis (IPF) but discordant for other diagnoses. Major histological findings of UIP including dense fibrosis, peripheral distribution, and fibroblastic foci showed high concordance between TBLC and SLB, which implies that TBLC can reliably detect these features. In contrast, loose fibrosis, cellular infiltration, and airway disease showed poor concordance between the two methods., Conclusion: Our study showed that TBLC is useful for UIP diagnosis but not for other ILD. With a multidisciplinary approach, diagnosis of IPF may be determined by TBLC, whereas ILD other than IPF may require SLB.

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a sometimes life-threatening complication in RA patients. SKG mice develop not only arthritis but also an ILD resembling RA-ILD. We previously reported that tofacitinib, a JAK inhibitor, facilitates the expansion of myeloid-derived suppressor cells (MDSCs) and ameliorates arthritis in SKG mice. The aim of this study was to elucidate the effect of tofacitinib on the ILD in SKG mice., Methods: We assessed the effect of tofacitinib on the zymosan (Zym)-induced ILD in SKG mice histologically and examined the cells infiltrating the lung by flow cytometry. The effects of lung MDSCs on T cell proliferation and Th17 cell differentiation were assessed in vitro. We also evaluated the effects of tofacitinib on MDSCs and dendritic cells in vitro., Results: Tofacitinib significantly suppressed the progression of ILD compared to the control SKG mice. The MDSCs were increased, while Th17 cells, group 1 innate lymphoid cells (ILC1s), and GM-CSF+ILCs were decreased in the lungs of tofacitinib-treated mice. MDSCs isolated from the inflamed lungs suppressed T cell proliferation and Th17 cell differentiation in vitro. Tofacitinib promoted MDSC expansion and suppressed bone marrow-derived dendritic cell (BMDC) differentiation in vitro., Conclusion: Tofacitinib facilitates the expansion of MDSCs in the lung and ameliorates ILD in SKG mice.

Background: Biomarkers have been actively investigated to supplement functional and imaging modalities to predict the severity, therapeutic responsiveness, and progression of connective tissue disease-associated interstitial lung disease (CTD-ILD). This study aimed to evaluate Krebs von den Lungen 6 (KL-6) as a potential biomarker reflecting the severity of CTD-ILD as assessed through computed tomography (CT) and pulmonary function test (PFT) parameters., Methods: This retrospective study included 549 Korean patients with rheumatoid arthritis, systemic sclerosis, inflammatory myositis, and other CTDs with or without concurrent ILD. Serum KL-6 concentration (U/mL) was measured using the latex-enhanced immunoturbidimetric assay method. CT and PFT results were collected within 1 year of serum collection. A semiquantitative grade of ILD extent was evaluated through CT scan (grade 1, 0-25%; grade 2, 26-50%; grade 3, 51-75%; grade 4, 76-100%)., Results: CTD-ILD patients (n = 165) had elevated serum KL-6 levels compared to CTD patients without ILD (n = 384) (p < 0.001), and those findings were preserved after adjusting for age, sex, and CTD type. The semiquantitative grade of ILD on CT scan was significantly proportional to the KL-6 level, and the optimal cut-off KL-6 value effectively differentiated each ILD grade. The percent diffusing capacity of the lung for carbon monoxide (DLCO) (p < 0.001) and forced vital capacity (FVC) (p < 0.001) parameters had a moderate, negative correlation with the KL-6 level., Conclusion: Serum KL-6 levels were increased in CTD-ILD patients and had a positive correlation with CT grade and a negative correlation with FVC and DLCO. Serum KL-6 levels may reflect CTD-ILD severity.

Background: By comparing diagnoses made by pre-transplant surgical lung biopsy (SLB) and the final pathologic diagnosis of the explanted pathology (EP), we aimed to study the factors that could impact pathologic diagnoses in patients with interstitial lung disease (ILD)., Methods: We retrospectively reviewed the lung transplant database at Cleveland Clinic [01/01/2006-12/31/2013] to include all lung transplant recipients with a prior diagnosis of ILD. Two pulmonary pathologists independently reviewed each SLB and lung explant. The diagnoses were labeled as concordant (same diagnosis on SLB and explant) or discordant (diagnosis on SLB and explant were different) by consensus., Results: Of 389 patients transplanted for ILD, 217 had an SLB before transplant. Pathological diagnoses were concordant in 190 patients (87.6%) [165 UIP (86.8%), 13 NSIP (6.8%), 8 CHP (4.2%) and 4 other diagnoses (2.1%). In 27 cases (12.4%), the diagnosis on SLB differed from EP. 8/27 were diagnosed with UIP on SLB and of these, 5 were re-classified as NSIP. 14/19 (73.7%) patients with a SLB diagnosis "other than UIP" were re-categorized as UIP based on explant. Discordant cases had a greater time between SLB and EP than concordant cases (1553 days vs 1248 days)., Conclusions: The pathologic diagnosis of ILD by SLB prior to lung transplant is accurate in most patients, but may be misleading in a small subset of patients. The majority of discordant cases that were reclassified as UIP could be due to a sampling error, or perhaps, an increased time from the date of the SLB to transplant. Future studies examining how multidisciplinary consensus diagnosis affects this discordance are necessary.

Background: Standardization of trans-bronchial lung cryobiopsy in diffuse parenchymal lung diseases is imminent; however, the majority of published series on cryobiopsy include a limited number of patients and are characterized by several differences in procedural technical details., Methods: This is an observational, retrospective cohort study. Aim of the study was to suggest some sampling strategies related to transbronchial cryobiopsy in the diagnostic work-up of patients with diffuse parenchymal lung diseases., Results: Six hundred ninety-nine patients with suspected diffuse parenchymal lung disease were recruited. A specific pathological diagnosis was achieved in 614/699 cases (87.8%) and a multidisciplinary diagnosis was obtained in 630/699 cases (90.1%). Diagnostic yield was significantly influenced by the number of samples taken (1 vs ≥ 2 biopsies, p < 0.005). In 60.4% of patients, biopsies were taken from one site and in 39.6% from different sites (in the same lobe or in two different lobes), with a significant increase in diagnostic yield, specifically in patients with fibrotic lung diseases (65.5% vs 93.4%, p < 0.0001). The 2.4 mm or 1.9 mm probes were used, with no differences in terms of diagnostic yield. Regarding safety, pneumothorax occurred in 19.2% and was influenced by baseline lung function; in all patients Fogarty balloon has been used and severe haemorrhage occurred in 0.7% of cases. Three patients (0.4% of cases) died within 30 days after the procedure., Conclusions: We propose some sampling strategies of cryobiopsy which seem to be associated with a higher diagnostic yield and a favorable risk/benefit ratio: sampling at least two samples in different sites, using either the 2.4 mm or the 1.9 mm probe, intubating the patients and using bronchial blockers/catheters.

Background: We aimed to investigate the efficacy of abatacept in preclinical mouse models of digestive involvement, pulmonary fibrosis, and related pulmonary hypertension (PH), mimicking internal organ involvement in systemic sclerosis (SSc)., Methods: Abatacept has been evaluated in the chronic graft-versus-host disease (cGvHD) mouse model (abatacept 1 mg/mL for 6 weeks), characterized by liver and intestinal fibrosis and in the Fra-2 mouse model (1 mg/mL or 10 mg/mL for 4 weeks), characterized by interstitial lung disease (ILD) and pulmonary vascular remodeling leading to PH., Results: In the cGvHD model, abatacept significantly decreased liver transaminase levels and markedly improved colon inflammation. In the Fra-2 model, abatacept alleviated ILD, with a significant reduction in lung density on chest microcomputed tomography (CT), fibrosis histological score, and lung biochemical markers. Moreover, abatacept reversed PH in Fra-2 mice by improving vessel remodeling and related cardiac hemodynamic impairment. Abatacept significantly reduced fibrogenic marker levels, T-cell proliferation, and M1/M2 macrophage infiltration in lesional lungs of Fra-2 mice., Conclusion: Abatacept improves digestive involvement, prevents lung fibrosis, and attenuates PH. These findings suggest that abatacept might be an appealing therapeutic approach beyond skin fibrosis for organ involvement in SSc.

Background: Pulmonary emphysema combined with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) occurs more often in smokers but also in never-smokers. This study aimed to describe a new finding characterized by peculiar emphysematous change with SSc-associated ILD (SSc-ILD)., Methods: We conducted a retrospective review of 21 consecutive patients with SSc-ILD diagnosed by surgical lung biopsy and focused on the radio-pathological correlation of the emphysematous change., Results: Pathological pulmonary emphysema (p-PE) with SSc-ILD was the predominant complication in 16 patients (76.2%) with/without a smoking history, of whom 62.5% were never-smokers. A low attenuation area (LAA) within interstitial abnormality on high-resolution computed tomography (HRCT) was present in 31.3%. Diffusing capacity of the lung for carbon monoxide (D LCO ) was lower, disease extent on HRCT higher, and intimal/medial thickening in muscular pulmonary arteries more common in the patients with p-PE with SSc-ILD. However, forced vital capacity (FVC) was well preserved regardless of whether p-PE was observed. Most SSc-ILD patients had pulmonary microvasculature changes in arterioles (90.5%), venules (85.7%), and interlobular veins (81.0%)., Conclusions: Pulmonary emphysematous changes (LAA within interstitial abnormalities on HRCT and destruction of fibrously thickened alveolar walls) are specific and novel radio-pathological features of SSc-ILD. Peripheral vasculopathy may help to destroy the fibrously thickened alveolar walls, resulting in emphysematous change in SSc-ILD.

Background: Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease., Results: To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function., Conclusions: Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating spatial proximity analyses into other pathogenicity prediction tools may improve accuracy for other genes and genetic diseases.

Background: Clinically amyopathic dermatomyositis with anti-Melanoma Differentiation-Associated gene 5 (MDA5) antibody often presents with severe interstitial lung disease. Although serum ferritin level is known to reflect interstitial lung disease activity, there are few case reports describing this association., Case Presentation: A 58-year-old man was referred to our outpatient clinic with a 3-week history of cough and respiratory distress. He had erythema over the V area of the neck and a Gottron's sign. Chest computed tomography revealed diffuse ground-glass opacities and reticular shadows in both lungs. Test for anti-MDA5 antibody was positive. After admission, he received triple combination therapy (methylprednisolone pulse therapy, tacrolimus, and cyclophosphamide). However, his respiratory condition worsened as the serum ferritin level increased. Despite no apparent deterioration on chest radiography, he ultimately died due to respiratory failure., Conclusions: In this case, triple combination therapy was not effective for the patient's respiratory condition. The serum ferritin level was correlated with disease activity and was more useful than chest radiography for monitoring clinical status.

Background: Clinical guidelines specify that diagnosis of interstitial pulmonary fibrosis (IPF) requires identification of usual interstitial pneumonia (UIP) pattern. While UIP can be identified by high resolution CT of the chest, the results are often inconclusive, making surgical lung biopsy necessary to reach a definitive diagnosis (Raghu et al., Am J Respir Crit Care Med 183(6):788-824, 2011). The Envisia genomic classifier differentiates UIP from non-UIP pathology in transbronchial biopsies (TBB), potentially allowing patients to avoid an invasive procedure (Brown et al., Am J Respir Crit Care Med 195:A6792, 2017). To ensure patient safety and efficacy, a laboratory developed test (LDT) must meet strict regulatory requirements for accuracy, reproducibility and robustness. The analytical characteristics of the Envisia test are assessed and reported here., Methods: The Envisia test utilizes total RNA extracted from TBB samples to perform Next Generation RNA Sequencing. The gene count data from 190 genes are then input to the Envisia genomic classifier, a machine learning algorithm, to output either a UIP or non-UIP classification result. We characterized the stability of RNA in TBBs during collection and shipment, and evaluated input RNA mass and proportions on the limit of detection of UIP. We evaluated potentially interfering substances such as blood and genomic DNA. Intra-run, inter-run, and inter-laboratory reproducibility of test results were also characterized., Results: RNA content within TBBs preserved in RNAprotect is stable for up to 14 days with no detectable change in RNA quality. The Envisia test is tolerant to variation in RNA input (5 to 30 ng), with no impact on classifier results. The Envisia test can tolerate dilution of non-UIP and UIP classification signals at the RNA level by up to 60% and 20%, respectively. Analytical specificity studies utilizing UIP and non-UIP samples mixed with genomic DNA (up to 30% relative input) demonstrated no impact to classifier results. The Envisia test tolerates up to 22% of blood contamination, well beyond the level observed in TBBs. The test is reproducible from RNA extraction through to Envisia test result (standard deviation of 0.20 for Envisia classification scores on > 7-unit scale)., Conclusions: The Envisia test demonstrates the robust analytical performance required of an LDT. Envisia can be used to inform the diagnoses of patients with suspected IPF.

Interstitial lung disease (ILD) is a major pulmonary manifestation of connective tissue disease (CTD), leading to significant morbidity and mortality. Chest high-resolution computed tomography (HRCT) is presently considered the diagnostic gold standard for pulmonary fibrosis diagnosis and quantification in the clinical arena. However, not negligible doses of ionizing radiation limit the use of HRCT, especially for serial follow-up in younger female patients. In the past decade, lung ultrasound (LUS) has been proposed to assess ILD by detecting and quantifying sonographic B-lines. Previous studies demonstrate that B-lines have a good diagnostic accuracy, especially high sensitivity, and correlate well with HRCT findings, suggesting LUS as a novel, non-invasive, and non-ionizing imaging method to be used in patients with CTD-ILD. Although preliminary data are promising, challenges and controversies still remain. For example, the mechanisms of B-line generation are not fully understood; the diagnostic accuracy and performance characteristics of LUS partially depend on the scanning scheme and scoring system used; and up-to-date B-lines cannot discriminate the early cellular inflammation from the chronic fibrotic phase in CTD-ILD. Therefore it is important for clinicians to understand the strengths and limitations of LUS in CTD-ILD patients, to maximize its value.

Background: Goodpasture's syndrome is a rare disease that is characterized by rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage., Case Presentation: A 71-year-old Japanese man who had chronic interstitial pneumonia was diagnosed as having Goodpasture's syndrome. Both anti-glomerular basement membrane antibody and myeloperoxidase anti-neutrophil cytoplasmic antibody were increased. Despite intensive treatments, including mechanical ventilation, he died from respiratory failure. Pathological findings at autopsy showed rapidly progressive glomerulonephritis in his kidneys, diffuse alveolar hemorrhage, hyaline membranes, and fibroblastic foci in his lungs. The cause of death was diagnosed as respiratory failure as a result of diffuse alveolar damage induced by a combination of diffuse alveolar hemorrhage and exacerbation of interstitial pneumonia., Conclusions: We report a case of Goodpasture's syndrome complicated with pre-existing chronic interstitial pneumonia and positive myeloperoxidase anti-neutrophil cytoplasmic antibody. We reviewed six similar cases reported in the literature and concluded that Goodpasture's syndrome with pre-existing interstitial pneumonia and myeloperoxidase anti-neutrophil cytoplasmic antibody is related to a poor prognosis.

Background: Micronodular lesions are common findings in lung imaging. As an important differential diagnosis, we describe a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia; it is notable that the diagnosis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is often delayed. This case provides supporting evidence to establish lung biopsy by cryotechnique as the option of first choice when considering a diagnostic strategy for micronodular lung lesions., Case Presentation: We report a case of a 65-year-old white woman who presented with obstructive symptoms of chronic coughing and dyspnea confirmed by conventional lung function tests. A computed tomography scan presented disseminated micronodules in all the lobes of her lungs. With the help of bronchoscopic cryobiopsy it was possible to obtain a high yield sample of lung parenchyma. On histologic examination, the micronodules correlated with a diffuse neuroendocrine cell hyperplasia. In the context of clinical symptoms, radiological aspects, and histomorphological aspects we made the diagnosis of a diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Obstructive symptoms were treated with inhaled steroids and beta-2-mimetics continuously. A comparison between current computed tomography scans of our patient and scans of 2014 revealed no significant changes. Last ambulatory checks occurred in January and May of 2016. The course of disease and the extent of limitation of lung function have remained stable., Conclusions: The diagnosis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is best made in a multidisciplinary review including clinical presentation, lung imaging, and histomorphological aspects. This report and current literature indicate that transbronchial lung cryobiopsy can be used as a safe and practicable tool to obtain high quality biopsies of lung parenchyma in order to diagnose micronodular lesions of the lung.

Background: Anti-glycyl-tRNA synthetase (anti-EJ) antibody is occasionally positive in patients with interstitial lung disease (ILD). We aimed to define the clinical, radiological and pathological features of patients with anti-EJ antibody-positive ILD (EJ-ILD)., Methods: We retrospectively analyzed the medical records of 12 consecutive patients with EJ-ILD who underwent surgical lung biopsy., Results: The median follow-up time was 74 months (range, 17-115 months). The median age was 62 years (range, 47-75 years). Seven of 12 patients were female. Eight patients presented with acute onset. Six patients eventually developed polymyositis/dermatomyositis. On high-resolution computed tomography, consolidation and volume loss were predominantly observed in the middle or lower lung zone. Nine patients presented pathologically nonspecific interstitial pneumonia with organizing pneumonia, alveolar epithelial injury and prominent interstitial cellular infiltrations whereas the other three patients were diagnosed with unclassifiable interstitial pneumonia. Although all patients but one improved with the initial immunosuppressive therapy, five patients relapsed. When ILD relapsed, four of the five patients were treated with corticosteroid monotherapy. Four of the six patients without relapse have been continuously treated with combination therapy of corticosteroid and immunosuppressant., Conclusions: Patients with EJ-ILD often had acute onset of ILD with lower lung-predominant shadows and pathologically nonspecific interstitial pneumonia or unclassifiable interstitial pneumonia with acute inflammatory findings. Although the disease responded well to the initial treatment, relapse was frequent. Because of the diversity of the clinical courses, combination therapy of corticosteroid and immunosuppressant should be on the list of options to prevent relapse of EJ-ILD.

Background: Integrin α3 (ITGA3) gene mutations are associated with Interstitial Lung disease, Nephrotic syndrome and Epidermolysis bullosa (ILNEB syndrome). To date only six patients are reported: all carried homozygous ITGA3 mutations and presented a dramatically severe phenotype leading to death before age 2 years, from multi-organ failure due to interstitial lung disease and congenital nephrotic syndrome. The involvement of skin and cutaneous adnexa was variable with sparse hair and nail dysplasia combined or not to skin lesions ranging from skin fragility to epidermolysis bullosa-like blistering., Results: We report on two siblings of 13 and 9 years born to non-consanguineous healthy parents, who display growth delay, severe pulmonary fibrosis with fatigue, dyspnea on exertion and wheezing, atrophic skin with erythematosus lesions, rare eyelashes/eyebrows and pachyonychia. By exome sequencing, we identified two unreported ITGA3 missense mutations, c.373G>A (p.(G125R)) in exon 3 and c.821G>A (p.(R274Q)) in exon 6, affecting highly conserved residues in the integrin α3 extracellular N-terminal β-propeller domain. Homology modelling of α3β1 heterodimer fragment, encompassing the mutation sites, showed that G125 plays a pivotal structural role in the β-propeller, while R274 might prevent the interaction between integrin and urokinase complex., Conclusion: We report a variant of ILNEB syndrome in two siblings differing from the previously reported patients in the lack of nephrotic impairment and survival beyond childhood. Our siblings are the first reported compound heterozygous for ITGA3 mutations; this state as well as the hypomorphic nature of their p.(R274Q) mutation likely account for their survival.

Background: Childhood interstitial lung disease (chILD) is a heterogeneous group of rare disorders characterized by abnormal imaging findings, impaired gas exchange; and is associated with substantial morbidity and mortality. Neuroendocrine cell hyperplasia (NEHI) is a unique sub-group, which is more prevalent in infants and children younger than 2 years of age, and typically manifests with chronic tachypnea, retractions, hypoxemia and failure to thrive. NEHI insidiously appears in the first year of life, subtly masquerading as one of the more common lung diseases of childhood. Therefore, the diagnosis of NEHI is challenging and requires a systematic approach., Case Presentation: We report a case of an infant, with a history of recurrent respiratory infections and wheezing, who presented with persistent hypoxemia (PaO2 88 mmHg) and chronic respiratory symptoms, that prompted an extensive diagnostic work up for chILD; eventually a diagnosis of NEHI was made., Conclusion: NEHI is a rare chILD disorder presenting in the first 2 years of life with common but challenging key clinical features. Increased awareness among pediatricians and prompt recognition of the clinical presentation may enable timely diagnosis and improve disease management and prognosis.

Background: MicroRNA (miRNA) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from patients with SSc-ILD. A chronic lung fibrotic murine model was used., Methods: RNA was isolated from lung tissue of 12 patients with SSc-ILD and 5 controls. High-resolution computed tomography (HRCT) was performed at baseline and 2-3 years after treatment. Lung fibroblasts and peripheral blood mononuclear cells (PBMC) were isolated from healthy controls and patients with SSc-ILD. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DNA Intelligent Analysis (DIANA)-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin., Results: Lung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q < 0.25). DIANA-miRPath revealed 57 Kyoto Encyclopedia of Genes and Genomes pathways related to the most dysregulated miRNA. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts only mildly expressed miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and weaker lung induction of several genes after bleomycin exposure compared to wild-type mice., Conclusions: miRNA are dysregulated in the lungs and PBMC of patients with SSc-ILD. Based on mRNA-miRNA interaction analysis and pathway tools, miRNA may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD.

Background: The extent of lung involvement visualized by high-resolution computed tomography (HRCT) is a predictor of decline in forced vital capacity (FVC) in scleroderma-interstitial lung disease. Our objective was to evaluate the performance of three different HRCT-defined staging systems in the Scleroderma Lung Study I (SLS I) over a 1-year period., Methods: We assessed two visual semiquantitative scores: the maximum fibrosis score (MaxFib, the fibrosis score in the zone of maximal lung involvement) and visual assessment of total lung involvement (TLI) as proposed by Goh and Wells. In addition, we evaluated the computer-aided diagnosis and calculated the quantitative percentage with fibrosis (QLF) and TLI., Results: The mean duration of the disease was 3.2 years, and the mean FVC was 67.7 %. Regardless of the staging system used, a greater degree of fibrosis/TLI on HRCT scans was associated with a greater decline in FVC in the placebo group. Using the MaxFib and QLF, the mean absolute changes in FVC from baseline were 0.1% and -1.4%, respectively, in <25% lung involvement vs. a change of -6.2% and -6.9%, respectively, with >25% involvement (negative score denotes worsening in FVC). Conversely, cyclophosphamide was able to stabilize decline in FVC in subjects with greater degree of involvement detected by HRCT. Using the visual MaxFib and QLF, the mean absolute improvements in FVC were 1.2 and 1.1, respectively, with >25% involvement., Conclusions: HRCT-defined lung involvement was a predictor of decline in FVC in SLS I. The choice of staging system for cohort enrichment in a clinical trial depends on feasibility., Trial Registration: ClinicalTrials.gov identifier: NCT00004563 (Scleroderma Lung Study I) ISRCTN15982171. Registered 19 Aug 2015.

Background: Nonspecific interstitial pneumonia (NSIP) is characterized by interstitial infiltration of T lymphocytes, and subpopulations of these cells may be associated with the progression of fibrosis. However, few studies evaluate the correlation of prognosis with this characteristic. Therefore, we performed morphological and quantitative analyses of T lymphocytes in patients with NSIP and evaluated the relationship between T lymphocytes and prognosis., Methods: Immunohistochemistry was used to detect the presence of CD4+ and CD8+ T lymphocytes in 55 biopsies of patients with NSIP to determine the numbers of these T cell subpopulations in lymphoid follicles as well as in perivascular, interstitial, and peribronchial anatomical compartments. The relationship between CD4+ and CD8+ T lymphocyte populations and prognosis was analyzed., Results: The mean age of 55 patients was 48.9 ± 10.5 years, and 36 (65 %) of patients were women. All patients were followed for a mean duration of 46 ± 25 months. Thirteen (23.6 %) patients died during follow-up. Perivascular CD4+ lymphocyte infiltration (HR, 0.939; 95 % CI, 0.883-0.999; p = 0.048) was an independent risk factor for survival. Perivascular infiltrates of CD4+ T lymphocytes correlated with survival time (r = 0.270, p = 0.046). Patients with improved forced vital capacity survived longer and had higher numbers of CD4+ T lymphocytes that infiltrated perivascular tissue. The densities of CD4+ and CD8+ T lymphocytes infiltrating other tissues were not significantly associated with survival time., Conclusions: Perivascular infiltration of CD4+ T lymphocytes in patients with NSIP correlated with prognosis. The underlying mechanisms are unknown and require further studies.

Background: Fibroblastic foci profusion on histopathology and severity of traction bronchiectasis on highresolution computed tomography (HRCT) have been shown to be predictors of mortality in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the relationship between fibroblastic foci (FF) profusion and HRCT patterns in patients with a histopathologic diagnosis of usual interstitial pneumonia (UIP), fibrotic non-specific interstitial pneumonia (NSIP) and chronic hypersensitivity pneumonitis (CHP)., Methods: The HRCT scans of 162 patients with a histopathologic diagnosis of UIP or fibrotic NSIP (n = 162) were scored on extent of groundglass opacification, reticulation, honeycombing, emphysema and severity of traction bronchiectasis. For each patient, a fibroblastic foci profusion score based on histopathologic appearances was assigned. Relationships between extent of fibroblastic foci and individual HRCT patterns were investigated using univariate correlation analysis and multivariate linear regression., Results: Increasing extent of reticulation (P < 0.0001) and increasing severity of traction bronchiectasis (P < 0.0001) were independently associated with increasing FF score within the entire cohort. Within individual multidisciplinary team diagnosis subgroups, the only significant independent association with FF score was severity of traction bronchiectasis in patients with idiopathic pulmonary fibrosis (IPF)/UIP (n = 66, r(2) = 0.19, P < 0.0001) and patients with chronic hypersensitivity pneumonitis (CHP) (n = 49, r(2) = 0.45, P < 0.0001). Furthermore, FF score had the strongest association with severity of traction bronchiectasis in patients with IPF (r(2) = 0.34, P < 0.0001) and CHP (r(2) = 0.35, P < 0.0001). There was no correlation between FF score and severity of traction bronchiectasis in patients with fibrotic NSIP. Global disease extent had the strongest association with severity of traction bronchiectasis in patients with fibrotic NSIP (r(2) = 0.58, P < 0.0001)., Conclusion: In patients with fibrotic lung disease, profusion of fibroblastic foci is strikingly related to the severity of traction bronchiectasis, particularly in IPF and CHP. This may explain the growing evidence that traction bronchiectasis is a predictor of mortality in several fibrotic lung diseases.

Background: The pathological appearance of idiopathic pleuroparenchymal fibroelastosis (IPPFE) with hematoxylin-eosin staining is similar to that of usual interstitial pneumonia (UIP) in patients with idiopathic pulmonary fibrosis (IPF). The amount of elastic fibers (EF) and detailed differences between IPPFE and IPF have not been fully elucidated. The aim of this study was to quantify the EF and identify the differences between IPPFE and IPF., Methods: We evaluated six patients with IPPFE and 28 patients with IPF who underwent surgical lung biopsy or autopsy. The patients' clinical history, physical findings, chest high-resolution computed tomography (HRCT) findings, and pathological features of lung specimens were retrospectively evaluated. The amounts of EF in lung specimens were quantified with Weigert's staining using a camera with a charge-coupled device and analytic software in both groups., Results: Fewer patients with IPPFE than IPF had fine crackles (50.0% vs. 96.4%, p = 0.012). Patients with IPPFE had a lower forced vital capacity (62.7 ± 10.9% vs. 88.6 ± 21.9% predicted, p = 0.009), higher consolidation scores on HRCT (1.7 ± 0.8 vs. 0.3 ± 0.5, p < 0.0001), lower body mass indices (17.9 ± 0.9 vs. 24.3 ± 2.8, p < 0.0001), and more pneumothoraces than did patients with IPF (66.7 vs. 3.6%, p = 0.002). Lung specimens from patients with IPPFE had more than twice the amount of EF than did those from patients with IPF (28.5 ± 3.3% vs. 12.1 ± 4.4%, p < 0.0001). The amount of EF in the lower lobes was significantly lower than that in the upper lobes, even in the same patient with IPPFE (23.6 ± 2.4% vs. 32.4 ± 5.5%, p = 0.048). However, the amount of EF in the lower lobes of patients with IPPFE was still higher than that of patients with IPF (23.6 ± 2.4% vs. 12.2 ± 4.4%, p < 0.0001)., Conclusion: More than twice the amount of EF was found in patients with IPPFE than in those with IPF. Even in the lower lobes, the amount of EF was higher in patients with IPPFE than in those with IPF, although the distribution of lung EF was heterogeneous in IPPFE specimens.

Background: Acute interstitial pneumonia is a rare interstitial lung disease that rapidly progresses to respiratory failure or death. Several studies showed that myofibroblast plays an important role in the evolution of diffuse alveolar damage, which is the typical feature of acute interstitial pneumonia. However, no evidence exists whether alveolar epithelial cells are an additional source of myofibroblasts via epithelial-mesenchymal transition in acute interstitial pneumonia., Case Presentation: In this report, we present a case of acute interstitial pneumonia in a previously healthy 28-year-old non-smoking woman. Chest high-resolution computed tomography scan showed bilateral and diffusely ground-glass opacification. The biopsy was performed on the fifth day of her hospitalization, and results showed manifestation of acute exudative phase of diffuse alveolar damage characterized by hyaline membrane formation. On the basis of the preliminary diagnosis of acute interstitial pneumonia, high-dose glucocorticoid was used. However, this drug showed poor clinical response and could improve the patient's symptoms only during the early phase. The patient eventually died of respiratory dysfunction. Histological findings in autopsy were consistent with the late form of acute interstitial pneumonia., Conclusions: The results in this study revealed that alveolar epithelial cells underwent epithelial-mesenchymal transition and may be an important origin of myofibroblasts in the progression of acute interstitial pneumonia. Conducting research on the transformation of alveolar epithelial cells into myofibroblasts in the lung tissue of patients with acute interstitial pneumonia may be beneficial for the treatment of this disease. However, to our knowledge, no research has been conducted on this topic.

Background: Diagnosing a specific type of Interstitial Lung Disease (ILD) is a challenging process and often necessitates that a Video-assisted Thoracoscopic Surgery (VATS) Lung Biopsy be performed. By analysing the proportion of patients who have their treatment changed after undergoing a VATS lung biopsy, this study aimed to determine the utility of performing this procedure in patients with ILD., Methods: The clinical data from sixty-six patients with suspected ILD, who underwent VATS lung biopsies at the New Royal Infirmary of Edinburgh (NRIE) in the period of 16th May 2011 - 11th February 2013, were analysed retrospectively. The main outcome measures considered in this study were: CT scan differential diagnoses, VATS lung biopsy histological differential diagnoses, post-VATS lung biopsy consensus diagnoses, 30-day mortality, surgical complications (minor and major), resultant changes in treatment and responses to these changes in treatment., Results: Following VATS biopsy a definite pathological diagnosis was made in 74.2% of cases. A change in treatment was initiated in 47.2% of patients, including in 80% of patients diagnosed with Hypersensitivity Pneumonitis and 60% of patients diagnosed with sarcoidosis. A positive response to treatment was experienced in 58% of patients whom underwent a change in treatment. Only 54% of patients who received a consensus diagnosis of UIP after VATS lung biopsy, had been given a differential diagnosis of "probable UIP" at CT scan. 15% of patients who received a differential diagnosis of "probable UIP" at CT scan, had their diagnosis changed to Hypersensitivity Pneumonitis after lung biopsy. There was one mortality (1.5%) in this series of patients and no other major complications. Minor complications to surgery were experienced in 28.8% of patients., Conclusions: This study highlights the effectiveness of performing VATS lung biopsies in patients with suspected ILD. The procedure leads to a change in treatment in almost half of all patients, including in the vast majority of cases of Hypersensitivity Pneumonitis. It also prevents what would be the inappropriate over-treatment of UIP. It has been shown to be a relatively safe procedure and thus, should be performed in all patients with suspected ILD, indeterminate in type from prior CT imaging.