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Aims: The optimal interlesion distance (ILD) for 90 and 50 W radiofrequency applications with low ablation index (AI) values in the atria has not been established. Excessive ILDs can predispose to interlesion gaps, whereas restrictive ILDs can predispose to procedural complications. The present study sought, therefore, to experimentally determine the optimal ILD for 90 W-4 s and 50 W applications with low AI values to optimize catheter ablation outcomes in humans., Methods and Results: Posterior intercaval lines were created in eight adult sheep using CARTO and the QDOT-MICRO catheter in a temperature-controlled mode. In four animals, the lines were created with 50 W applications, a target AI value ≥350, and ILDs of 6, 5, 4, and 3 mm, respectively. In the other four animals, the lines were created with 90 W-4 s applications and ILDs of 6, 5, 4, and 3 mm, respectively. Activation maps were created immediately after ablation and at 21 days to assess linear block prior to gross and histological analyses. All eight lines appeared transmural and continuous on histology. However, for 50 W-only applications with an ILD of 3 mm resulted in durable linear electrical block, whereas for 90 W applications, only the lines with ILDs of 4 and 3 mm were blocked. No complications were detected during ablation procedures, but all power and ILD combinations except 50 W-6 mm resulted in asymptomatic shallow lung lesions., Conclusion: In the intercaval region in sheep, for 50 W applications with an AI value of ∼370, the optimal ILD is 3 mm, whereas for 90 W-4 s applications, the optimal ILD is 3-4 mm., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: To describe the clinical, radiologic, and pathologic findings in cases where smoking-related interstitial fibrosis (SRIF) was diagnosed in surgical lung biopsy specimens from patients with clinical and imaging features of diffuse parenchymal lung disease (DPLD)., Methods: Cases were included in this study if patients had clinical and imaging evidence of DPLD and surgical lung biopsy specimens revealed SRIF. A dedicated multidisciplinary conference was held to correlate clinical, radiologic, and pathologic findings., Results: Six cases met inclusion criteria; all six (five women/one man, aged 42-57 years, mean age 47 years) were either current smokers (five of six) or ex-smokers (one of six) and were evaluated for respiratory symptoms and abnormal pulmonary function tests, most commonly reduced forced vital capacity (n = 3) and diffusing capacity for carbon monoxide (n = 6). The most common imaging abnormalities were bilateral ground-glass opacities, which correlated with histopathologic SRIF. Follow-up of up to 10 years showed stable or improved clinical symptoms, pulmonary function tests, and radiologic findings with smoking cessation (three patients) or a decrease in smoking (three patients). No specific treatments were given, and those treated with empiric corticosteroid tapers did not show discernible responses., Conclusions: SRIF can present as clinically meaningful diffuse parenchymal lung disease in relatively young heavy smokers, characterized by bilateral ground-glass opacities and a stable clinical course., (© American Society for Clinical Pathology, 2022.)

Objectives: To develop a risk model for predicting postoperative mortality and morbidity in patients with interstitial lung disease undergoing surgical lung biopsy., Methods: From 2004 to 2019, patients who underwent surgical lung biopsy for interstitial lung disease were included in this study. Based on the findings of the multivariable analysis using preoperative clinical variables, a risk model for predicting postoperative mortality and morbidity was developed., Results: During the study period, 1177 patients were enrolled. Among them, morbidity and mortality occurred in 45 (3.8%) and 29 (2.5%) patients, respectively, which gradually declined over time from 8.9% in 2004-2005 to 0% in 2018-2019. In the final multivariable analysis, the dyspnoea grade, a forced vital capacity of ≤60%, preoperative oxygen therapy and preoperative intensive care unit stay were found to be the independent factors associated with both morbidity and mortality; smoking >40 pack-years was additionally identified as a factor related to mortality. Diffusing capacity of carbon monoxide ≤50%, which was a significant factor in the univariable analysis, became insignificant after adjustment for the forced vital capacity in the multivariable analysis. The risk scoring system based on this model showed a good discriminant ability for both morbidity [area under the receiver operating characteristic curve (95% confidence interval): 0.830 (0.726-0.932)] and mortality [0.887 (0.804-0.975)]., Conclusions: We developed a scoring system for predicting the risk of morbidity and mortality, which could help determine surgical candidates for lung biopsy among patients with interstitial lung disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The role of heparin-binding protein (HBP) as an acute inflammatory marker in acute exacerbations of interstitial lung disease (AE-ILD) and some stable ILD patients is not well-established. The significance of increasing HBP during an AE-ILD is examined and the first attempt to incorporate HBP into the ILD evaluation system is made. Then, the benefit of HBP in AE-ILD was investigated. ILD patients (n = 108) were divided into subgroups based on the phase and severity of the disease. Linear trends of HBP across subgroups were observed, and correlations with common inflammatory markers were examined. Further, the HBP detection was adopted between serum and bronchoalveolar lavage fluid (BALF). Imaging and pathology changes were evaluated using various scoring criteria and compared to HBP. The relationship between HBP with ventilation, fibrosis progression, and changes in arterial oxygen levels and inflammatory markers were investigated to understand the mechanistic pathways. HBP was significantly higher in patients with AE-ILD at the early stage, compared to patients with ILD at the stable phase and its increase was both found in the serum and BALF. With the remission of the disease, there was a linear trend of progressive decline. HBP identified ILD patients who had co-infections. HBP levels increased earlier than CRP, PCT, and SAA. HBP was associated with pulmonary levels of ventilation and lesions by radiology examination, and its levels were significantly worse in AE-ILD patients. However, HBP did not show a correlation to the pathology quantitative evaluation. In conclusion, HBP could potentially evaluate the progression and prognosis of AE-ILD. Because ILD patients are susceptible to infection, and since HBP can identify co-infection, this marker would be of great clinical importance. HBP is possibly predictive of acute exacerbation., (©2022 Society for Leukocyte Biology.)

Objectives: Changes in postoperative pulmonary function vary among patients after lobectomy. We aimed to define preoperative factors that negatively influence postoperative % vital capacity (%VC) in patients treated by lobectomy., Methods: We included 276 patients who had been treated by lobectomy at our institution between 2007 and 2018 and their preoperative and postoperative pulmonary function data were complete. We assigned them to groups based on postoperative pulmonary function defined as better (good) or worse (poor) than predicted %VC, then compared clinicopathological findings between them. Poor postoperative pulmonary function was also assessed using logistic regression analysis., Results: Interstitial pneumonia (IP) was diagnosed in 37 (13.4%) patients. The preoperative and postoperative %VC values were, respectively, 101.1% (interquartile range, 90.5-110%) and 87.6% (interquartile range, 73.8-99.1%). Logistic regression analysis revealed that IP, advanced age (≥75 years), and induction therapy were independent risk factors for reduced postoperative pulmonary function [odds ratios 3.01 (1.41-6.41), 2.49 (1.35-4.60), and 9.03 (2.43-33.5), P = 0.0044, 0.0035, and 0.001, respectively]. Postoperative %VC worsened with increasing IP severity and advanced age. Six (75%) of 8 patients aged ≥80 years with usual IP or suspected usual IP on preoperative computed tomography images had poor postoperative %VC., Conclusions: Surgical indications for lobectomy based on predicted postoperative %VC require careful consideration for elderly patients with IP, particularly those aged ≥80 years., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objectives: Microscopic polyangiitis (MPA) is often complicated by interstitial lung disease (ILD); however, biomarkers that can be used to diagnose and predict the progression of MPA-ILD have not been identified. In this study, we evaluated various serum biomarkers in MPA-ILD to assess their diagnostic and predictive performance., Methods: We enrolled 49 patients with anti-neutrophil cytoplasmic antibody (ANCA)+ MPA and 10 healthy controls, with 32 of the MPA patients also presenting ILD. The presence of ILD was assessed by high-resolution CT and evaluated by ground-glass opacity and fibrosis score. We compared 16 biomarker profiles among MPA-ILD patients, those without ILD, and healthy controls and extracted biomarkers with higher levels in MPA-ILD groups to determine correlations with disease activity and other biomarkers. Three lung biopsies were examined by haematoxylin-eosin staining and immunostaining., Results: Initial serum C-C motif chemokine ligand 2 (CCL2) levels were significantly higher in the MPA-ILD group than those of the MPA group, and were significantly higher in MPA-ILD patients 1 year after immunosuppressive therapy than those before treatment. Initial serum CCL2 levels positively correlated with an increased fibrosis score during the year after treatment and with initial serum platelet-derived growth factor levels. Immunohistochemical staining showed intense CCL2 signals in CD68+/CD163+ macrophages and metaplastic epithelial cells in MPA-ILD lungs., Conclusion: CCL2 is associated with MPA-ILD pathogenesis and suggested its potential efficacy as a useful marker for diagnosing and predicting MPA-ILD progression. Therefore, targeting CCL2 in alveolar CD68+/CD163+ macrophages might represent a therapeutic intervention in ANCA+ MPA-ILD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The prognostic role of interstitial pneumonia with emphysema in lung cancer is not fully understood. This study aimed to examine the prognostic role of the presence of emphysema in patients with clinical stage I lung cancer and interstitial pneumonia., Methods: The presence of interstitial pneumonia and emphysema was evaluated on preoperative high-resolution computed tomography. In total, 836 consecutive patients with clinical stage I lung cancer who underwent complete resection between April 2007 and March 2016 were retrospectively analyzed using the log-rank test and Cox proportional hazard model to examine survival differences., Results: There was a significant difference in 5-year overall survival between patients with interstitial pneumonia and emphysema (n = 65) and those without (n = 771) (62.6% vs. 86.5%; P < 0.001). However, in patients with interstitial pneumonia on high-resolution computed tomography, there was no significant difference in 5-year overall survival between patients with emphysema (n = 65) and those without emphysema (n = 50) (62.6% vs. 59.4%, P = 0.84). Multivariable backward stepwise Cox proportional hazard analysis in patients with interstitial pneumonia showed that histology, %diffusing capacity of the lungs for carbon monoxide, radiologic interstitial pneumonia pattern and surgical procedure were independent prognostic factors for overall survival, but the presence of emphysema was not., Conclusions: The presence of emphysema was not an independent prognostic factor for overall survival in patients with clinical stage I lung cancer with interstitial pneumonia. Poor survival of patients with IP and emphysema may be due to the presence of interstitial pneumonia., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objectives: RA-associated interstitial lung disease (RA-ILD) is commonly associated with acute exacerbations (ILD-AE). This study examined the clinical characteristics and risk factors of ILD-AE and mortality of RA-ILD., Methods: We retrospectively collected data on 165 RA-ILD patients who visited or were admitted to our hospital between January 2007 and December 2019. We compared the clinical characteristics of patients who did and did not develop ILD-AE and identified variables significantly associated with ILD-AE. We also compared the admission characteristics of those who survived and those who died after admission for ILD-AE. ILD-AE was defined using previously proposed criteria, modified slightly for application to RA-ILD., Results: The mean patient age was 73.6 years (s.d. 9.7) and 97 (71.9%) patients were female. Thirty (22.2%) patients developed ILD-AE, 13 (43.3%) of whom died. In univariate analyses, neither the usual interstitial pneumonia (UIP) pattern nor MTX was associated with ILD-AE. In multivariate analyses, the UIP pattern was significantly associated with ILD-AE [odds ratio (OR) 2.55 (95% CI 1.05, 6.20), P = 0.038]. In the Cox proportional hazards model, the UIP pattern [hazard ratio (HR) 4.67 (95% CI 1.02, 21.45), P = 0.048] was significantly associated with death, while MTX use [HR 0.16 (95% CI 0.04, 0.72), P = 0.016] was significantly associated with survival., Conclusion: Our data suggest that the UIP pattern is related to ILD-AE. Furthermore, both the UIP pattern and non-use of MTX might be related to death from ILD-AE in RA-ILD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Many interstitial lung diseases (ILDs) are characterized by chronic progressive fibrosis. The antifibrotic agents may prevent disease progression of these diseases. Nintedanib is a triple tyrosine kinase inhibitor and has an antifibrotic effect. The proven beneficial effects of nintedanib in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc)-associated ILD, nintedanib was intended for use in many other fibrotic lung diseases consistent with the concept described below. With this trial, the concept and definition of progressive fibrosing ILD (PF-ILD) were created, a type of fibrosing diseases that progresses with fibrosis measured in forced vital capacity and high-resolution CT findings and worsening of respiratory symptoms at a certain rate or faster. PF-ILDs are composed of idiopathic interstial pneumonias such as non-specific interstitial pneumonia and unclassifiable interstitial pneumonia and inhalation lung diseases such as chronic hypersensitivity pneumonia and connective tissue disease-associated ILD such as rheumatoid arthritis-related ILD and SSc-related ILD and sarcoidosis and so on. Nintedanib significantly reduced the annual rate of decline in forced vital capacity over 52 weeks compared with placebo. Nintedanib received marketing approval in the United States and Japan for the treatment of PF-ILDs. This review summarizes the new concept of PF-ILDs and effectiveness of nintedanib to PF-ILDs and discussion points to be solved in the future when using nintedanib for PF-ILDs.

Using a reliable primate model is critical for developing therapeutic advances to treat humans infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we exposed macaques to high titers of SARS-CoV-2 via combined transmission routes. We observed acute interstitial pneumonia with endotheliitis in the lungs of all infected macaques. All macaques had a significant loss of total lymphocytes during infection, which were restored over time. These data show that SARS-CoV-2 causes a coronavirus disease 2019 (COVID-19)-like disease in macaques. This new model could investigate the interaction between SARS-CoV-2 and the immune system to test therapeutic strategies., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objectives: Interstitial lung disease (ILD) is a life-threatening extra-articular manifestation of rheumatoid arthritis (RA). We aimed to clarify the relationship between chronic ILD with a pattern of usual interstitial pneumonia (UIP) or non-UIP and mortality in RA patients. Methods: We retrospectively surveyed information of consecutive RA patients who visited our hospital from 2009 to 2014. The relationship between their mortality and chronic ILD (UIP or non-UIP) detected by high-resolution computed tomography was examined. Results: Of 2702 patients enrolled, 261 (9.7%) had chronic ILD and among these 120 had a UIP pattern. At the onset of RA, the prevalence of chronic ILD was 6%. Patients with chronic ILD had a higher mortality than those without. The most frequent cause of death was pneumonia including acute exacerbation (AE) of chronic ILD. Lung cancer death was frequently identified in deceased patients with chronic ILD with a UIP pattern compared with the other decedents ( p =.062). The estimated mortality of lung cancer in patients with chronic ILD with a UIP pattern was five times higher than the general population. Conclusion: RA patients with ILD with a UIP pattern have a high mortality rate and are prone to die of AE or lung cancer.

Introduction: Acute exacerbation of interstitial pneumonia (AE-IP) is a lethal complication after lung surgery. We conducted a prospective, multi-institutional phase II trial to assess the efficacy and safety of prophylactic measures., Method: Patients with lung cancer with dorsal subpleural fibrotic changes occupying three or more segments of both lower lobes and planned anatomical lung resection were enrolled. Prior to surgery, patients received a 125-mg bolus injection of methylprednisolone and continuous intravenous infusion of sivelestat sodium hydrate (sivelestat) for 2 days., Results: Sixty-nine patients were analysed. Preoperative high-resolution computed tomography (HRCT) showed 37 (53.6%) cases presented with usual interstitial pneumonia (UIP) and possible UIP pattern. There were 60 lobectomies and 9 segmentectomies. Thirty-eight cases were in clinical stage I. No adverse events associated with prophylaxis were observed. There were four cases of AE-IP (5.8%), higher than the expected 2.0%. Three of the four cases showed inconsistencies with the UIP pattern in preoperative HRCT and were pathologically diagnosed as UIP. All patients died of respiratory failure. Overall, 89.9% were diagnosed as idiopathic interstitial pneumonias; UIP was found in 48 patients (69.6%). Severe post-operative complications occurred in 11.6% of the cases. There were 35 deaths, 17 cases of lung cancer and 11 cases related to interstitial pneumonias. The overall survival rate at 3 years was 41.8% of the total and 47.2% of cases with clinical stage I., Conclusions: Perioperative use of sivelestat and low-dose methylprednisolone in patients with anatomical lung resection was safe but did not prove to be a prophylactic effect for AE-IP., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Various reports of disease-related lung pathologies in common variable immunodeficiency disorder (CVID) patients have been published, with differing histological and high-resolution computed tomography (HRCT) findings. Data were extracted from the validated Oxford Primary Immune Deficiencies  Database (PID) database (1986-2016) on adult, sporadic CVID patients with suspected interstitial lung disease (ILD). Histology of lung biopsies was studied in relation to length of follow-up, clinical outcomes, HRCT findings and chest symptoms, to look for evidence for different pathological processes. Twenty-nine CVID patients with lung histology and/or radiological evidence of ILD were followed. After exclusions, lung biopsies from 16 patients were reanalysed for ILD. There were no well-formed granulomata, even though 10 patients had systemic, biopsy-proven granulomata in other organs. Lymphocytic infiltration without recognizable histological pattern was the most common finding, usually with another feature. On immunochemistry (n = 5), lymphocytic infiltration was due to T cells (CD4 or CD8). Only one patient showed B cell follicles with germinal centres. Interstitial inflammation was common; only four of 11 such biopsies also showed interstitial fibrosis. Outcomes were variable and not related to histology, suggesting possible different pathologies. The frequent nodules on HRCT were not correlated with histology, as there were no well-formed granulomata. Five patients were asymptomatic, so it is essential for all patients to undergo HRCT, and to biopsy if abnormal HRCT findings are seen. Internationally standardized pathology and immunochemical data are needed for longitudinal studies to determine the precise pathologies and prognoses in this severe complication of CVIDs, so that appropriate therapies may be found., (© 2019 Crown copyright. Clinical and Experimental Immunology © 2019 British Society for Immunology.)

Background: Nanoparticle albumin-bound paclitaxel is indicated for the treatment of patients with lung cancer. It can induce interstitial lung disease, but the incidence of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease in clinical practice has not been determined. We investigated the incidence of interstitial lung disease in patients with lung cancer who had received nanoparticle albumin-bound paclitaxel therapy at our institution., Methods: We reviewed clinical data for patients with advanced lung cancer who received nanoparticle albumin-bound paclitaxel with or without carboplatin or bevacizumab therapy at the Nippon Medical School Main Hospital between April 2013 and September 2017. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and exclusion of other diseases., Results: A total of 110 advanced lung cancer patients received nanoparticle albumin-bound paclitaxel, and nine of them (8.2%) developed interstitial lung disease. Of those who developed interstitial lung disease, eight were treated with corticosteroids and three received cyclophosphamide pulse therapy. High-resolution computed tomography images demonstrated diffuse alveolar damage pattern pneumonitis in seven patients and organized pneumonia pattern pneumonitis in two patients. Six of the patients with diffuse alveolar damage pattern pneumonitis died from respiratory failure. The two patients with organized pneumonia pattern pneumonitis recovered. The incidence of interstitial lung disease was 19.0% (8/42) among patients with preexisting interstitial pneumonia and 1.5% (1/68) among those without preexisting interstitial pneumonia. Six patients with preexisting interstitial pneumonia met the criteria for acute exacerbation of interstitial pneumonia (14.3%)., Conclusion: Nanoparticle albumin-bound paclitaxel-associated interstitial lung disease was a severe and potentially fatal adverse event. We found it demonstrated diffuse alveolar damage or organized pneumonia pattern pneumonitis, and preexisting interstitial pneumonia was associated with higher rate of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease.

Objective: We aimed to determine the outcome of combination therapy with tofacitinib (TOF) in a case series of refractory rapidly progressive interstitial lung disease (ILD) associated with anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive (Ab+) DM. Patients who had poor prognostic factors and failed to respond to immunosuppressive therapy were selected for TOF treatment., Methods: Five patients with anti-MDA5 Ab+ DM-ILD who failed to respond to triple therapy with high dose glucocorticoids, CSA and CYC were given additional TOF (10 mg/day). To identify the poor prognostic factors, data from 15 consecutive patients (seven survived and eight died) with anti-MDA5 Ab+ DM-ILD before induction of TOF were analysed., Results: Three poor prognostic factors were identified: serum ferritin level >1000 ng/ml before therapy; ground-glass opacities in all six lung fields before therapy; and worsening of pulmonary infiltrates during therapy. All six patients who had all of the three factors and received triple therapy died before TOF therapy. There were five patients who had all of the three prognostic factors and failed to respond to triple therapy, but were able to receive the combination therapy with TOF; among them, three survived and two died. The survival rate of patients who received TOF was significantly better than that of the historical controls with immunosuppressive therapy before TOF. The patients who received TOF experienced complicated adverse events, particularly viral infection., Conclusion: Combination therapy with TOF might have the potential to control refractory anti-MDA5 Ab+ DM-ILD.

Elotuzumab, a humanized immunoglobulin G1 monoclonal antibody targeted against signaling lymphocytic activation molecule F7 (SLAMF7), has recently been used in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma. The clinical characteristics of drug-induced interstitial lung disease (ILD) due to elotuzumab have not been clarified. In this report, we describe a patient with refractory multiple myeloma who received elotuzumab in combination with lenalidomide and dexamethasone in whom fatigue, fever and diffuse pulmonary infiltration developed. The patient had a history of long-term therapy with lenalidomide without pulmonary toxicity. Bronchoscopy with bronchoalveolar lavage was negative for infection, and transbronchial lung biopsies showed active alveolitis with lymphocytic infiltration and myxomatous change of the thick alveolar wall. After the discontinuation of elotuzumab and lenalidomide, the patient's clinical symptoms gradually improved, and spontaneous remission of the pulmonary infiltration was observed. Based on the chest CT and lung pathology findings, the exclusion of infection and pulmonary edema, and according to the clinical course, we established a diagnosis of drug-induced ILD due to elotuzumab. Clinicians should bear in mind the potential for pulmonary toxicity in patients receiving elotuzumab-containing therapy.

Objective: To evaluate the effect of rituximab (RTX) in patients with RA-related interstitial lung disease (RA-ILD) and identify factors associated with outcome after treatment., Methods: An observational study of patients with RA-ILD was conducted from a cohort of RTX-treated RA patients in a single centre for >10 years. Progression was defined by any of the following: a decrease of pre-RTX forced vital capacity (FVC) >10% or diffusion capacity of carbon monoxide (DLCO) >15% predicted, worsening of the ILD score or death from progressive ILD., Results: Of 700 RA patients treated with RTX, 56 had RA-ILD (prevalence = 8%). After RTX, new ILD was diagnosed in 3/700 patients (incidence = 0.4%). Data for lung assessment were available for 44/56 patients. The median relative change pre- and post-RTX for FVC were -2.4% and +1.2% ( P = 0.025) and for DLCO were -4.4% and -1.3% ( P = 0.045). Post-RTX, 23/44 (52%) were stable and 7/44 (16%) had improved. Of the 14 (32%) with ILD that progressed, 9/56 (16%) were deaths due to progressive ILD. Factors associated with ILD progression were radiologic pattern of usual interstitial pneumonia, a previous history of lung progression and pre-RTX DLCO <46% predicted. Of those whose ILD progressed, 11/14 (79%) had severe ILD before RTX [median DLCO 42% predicted (interquartile range 41-49)]., Conclusion: In this cohort of patients where RTX was given for arthritis, most patients with ILD pre-RTX remained stable/improved after treatment over a prolonged follow-up period. Patients who deteriorated/died had the most severe ILD pre-RTX, suggesting the drug was not contributory. RTX appears to be an acceptable therapeutic choice for patients with RA-ILD and further studies are warranted., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

It is difficult to differentiate Pneumocystis pneumonia (PCP) from rituximab-induced interstitial lung disease (RILD) in lymphoma patients with diffuse pulmonary infiltrates who are receiving rituximab-containing chemotherapy. Using a clinical scoring system, we aim to differentiate PCP from RILD who are receiving rituximab-containing chemotherapy. We reviewed the medical records of lymphoma patients who had received rituximab-containing chemotherapy between 2012 and 2015 in a tertiary hospital. Among 613 lymphoma patients receiving rituximab-containing chemotherapy, 97 (16%) had diffuse pulmonary infiltrates. Of these, 16 (16%) with an alternative diagnosis and 22 (23%) with an indeterminate diagnosis were excluded. Finally, 21 (22%) patients were classified as having PCP and the remaining 38 (39%) as having RILD. Fever, short duration of symptoms (≤5 days), systemic inflammatory response syndrome (SIRS), and severe extent of disease on CT scan (>75%) were more common in patients with PCP than in those with RILD. Clinical scores were determined using the following system: SIRS = score 1, symptom duration ≤5 days = score 1, extent of disease on CT >75% = score 4. A score of ≥2 differentiated PCP from RILD with 91% sensitivity (95% CI, 70-99) and 71% specificity (95% CI, 54-84). A clinical scoring system based on presence of SIRS, short duration of symptoms, and severe extent of disease on CT scan appears to be useful in differentiation of PCP from RILD., (© The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Interstitial lung disease (ILD) is important drug related toxicity because it commonly forced to discontinue the treatment., Methods: To characterize the prevalence and patterns of pemetrexed induced ILD, an independent ILD advisory board composed of external experts performed reassessment of ILD in two post marketing surveillance (PMS) studies for malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC)., Results: ILD incidences were originally 1.6% and 2.6% in 903 MPM and 683 NSCLC patients in safety analyses, respectively. Based on the reassessment by the board, the incidence was 1.1% MPM and 1.8% NSCLC. Common possible risk factors of ILD in MPM and NSCLC patients were male gender, 60 years or older age, and pre-existing ILD. Asbestosis in MPM, and smoking history in NSCLC are also considered as risk, respectively. In terms of computed tomography (CT) pattern, 7 of 10 cases in MPM patients had acute interstitial pneumonia pattern, which four were fatal. Eight of the 12 NSCLC patients had diffuse grand glass opacity, which all had recovered. Onset of ILD in MPM varied between the first and the fifth courses of pemetrexed treatment, and the latest onset was 48 days after the last administration. For NSCLC, it was between the second and the ninth course, 7 and 56 days after the last administration., Conclusions: The risk of pemetrexed-related ILD is similar level as other anti-cancer drugs under clinical settings. Careful observations continuously during and at least for 2 months after the last administration of pemetrexed are advised., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Interstitial lung disease (ILD) is sometimes seen in patients with primary lung cancer. Therapeutic interventions for lung cancer patients with ILD sometimes provoke acute exacerbation (AE) of pre-existing lung disease. Although postoperative AE after lung resection is a potentially fatal complication, prophylactic treatments have yet to be established. Prophylaxis for postoperative AE is imperative for thoracic surgeons. However, no animal models for preclinical research into postoperative management and prophylactic interventions for AE of ILD have been developed. The objective of this study was to establish a new mouse model of AE of ILD, for further investigation of prophylactic interventions., Methods: C57BL/6 mice were intratracheally administered bleomycin (BLM, 1 mg/kg) or saline on Day 0 to induce pulmonary fibrosis, and lipopolysaccharide (LPS, 0.5 mg/kg) or saline to induce inflammatory stimulation on Day 7. Mice were divided into four groups: control group; LPS group; BLM group and BLM + LPS group. Histological changes and computed tomography (CT) images of the lung, lung water content, oxygen partial pressure (pO2) of arterial blood and cell counts and inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) were assessed on Day 8. Survival rates were also determined., Results: In the BLM + LPS group, chest CT showed diffuse ground-glass opacities, and pO2 was significantly decreased. The most severe inflammatory reaction was evident in the BLM + LPS group, with increased infiltrating cells on histopathology and increased lung water content. Total cell and neutrophil counts and levels of cytokines such as monocyte chemoattractant protein-1, interleukin-6 and keratinocyte chemoattractant in the BALF were significantly elevated in the BLM + LPS group. These findings mimic human AE of ILD. Furthermore, survival curves demonstrated that the BLM + LPS group had the lowest survival rate among all groups., Conclusions: A new mouse model of AE of ILD was developed. This model represents an attractive experimental method for preclinical research of postoperative management and prophylactic interventions for AE of ILD in lung cancer patients., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: An aggregate risk score (range 0-6 points) for predicting mortality after surgical biopsy for interstitial lung disease (ILD) was recently developed from four independent variables: intensive care unit treatment (2 points), age >67 years (1.5 points), immunosuppression (1.5 points), open biopsy (1 point). In the development cohort, patients were grouped in four classes of aggregate score (A, B, C, D) showing incremental risk of death within 90 days from biopsy. We tested this mortality risk model in an independent cohort., Methods: The aggregate risk score and the corresponding class of 90-day mortality risk was retrospectively determined in 151 consecutive patients undergoing biopsy for uncertain ILD at the Center for Thoracic Surgery, University of Insubria (Varese, Italy) in 1997-2012. We evaluated, by Spearman's ρ test, the correlation between aggregate risk score and mortality rate in the development cohort and in our cohort. Fisher's exact test was used for comparison of overall mortality rate between the two cohorts., Results: The mortality rate correlation with risk score differed in our cohort (ρ = 0.127; P = 0.06) compared with the development cohort (ρ = 0.352; P < 0.0001). In our dataset mortality polarized: it was minimal in Classes A and B (2% and 0%, respectively), 33% in Classes C and D. This skewed mortality distribution was possibly contributed by significantly lower overall mortality rate in our cohort than in the development cohort (2.6% vs 10.6%; P = 0.0017). Despite the difference in mortality distribution, in our dataset, we confirmed that ILD patients with aggregate score >2 (Classes C and D) were at exceedingly high risk of postoperative mortality., Conclusions: The aggregate score is a simple and useful risk score for ILD. Our dataset confirms that lung biopsy is reasonably safe in Class A and B patients while, in Class C and D patients, it is indicated only if histology would substantially change management and prognosis., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

We recently reported that increasing blood monocyte turnover that was associated with tissue macrophage death better predicts terminal disease progression in adult SIV-infected macaques than does declining CD4(+) T cell levels. To understand better mechanisms of pathogenesis, this study relates severity of lung-tissue damage to the ratio, distribution, and inflammatory responses of lung macrophage subsets during SIV infection in rhesus macaques exhibiting varying rates of monocyte turnover. In vivo BrdU incorporation was used to evaluate kinetics of monocyte/tissue macrophage turnover. Tissue damage was scored microscopically from H&E-stained lung-tissue sections, and cytokine expression was examined via immunohistochemistry and confocal microscopy. Increased monocyte turnover in SIV-infected rhesus macaques significantly correlated with severity of lung-tissue damage, as exhibited by perivasculitis, vasculitis, interstitial pneumonia, alveolar histiocytosis, foamy macrophages, multinucleated giant cells, fibrin, and edema in the alveoli. In addition, the higher monocyte turnover correlated with declining AI ratio, increased accumulation of IM in the perivascular region of the lung, and higher expression of IL-6 in the IM of the lung tissue exposed to a LPS, calcium ionophore, and tumor promoter combination stimulation ex vivo. Accumulation of IM associated with increasing monocyte turnover during SIV infection appears to contribute to chronic pulmonary inflammation and tissue damage during disease progression to AIDS., (© Society for Leukocyte Biology.)

Objectives: Although some interstitial pneumonia (IP) cases are not detected on computed tomography (CT) before surgery, they are confirmed by pathological diagnosis after pulmonary resection. In the present study, we aimed to investigate patients who underwent pulmonary resection for non-small-cell lung cancer (NSCLC) and subsequently showed pathological findings of IP but no apparent interstitial changes on CT., Methods: We retrospectively analysed 1688 patients with NSCLC who underwent pulmonary resection and presented with a radiological or pathological diagnosis of IP in 64 institutions between January 2000 and December 2009. We compared 135 patients without radiological findings but with pathological findings of IP (Group A) with 1553 patients with radiological findings of IP (Group B)., Results: The percent vital capacity and predicted diffusing capacity for carbon monoxide were higher in Group A than in Group B. Although there was no significant difference in the occurrence of acute exacerbation (AE) between both groups, the mortality after AE in Group A was significantly lower than that in Group B. The overall survival rates of patients in Groups A and B at 5 years were 59.1 and 40.9%, respectively (P = 0.0031)., Conclusions: The mortality after AE in patients with only pathological findings of IP was significantly lower than in those with radiological findings of IP. Moreover, the patients with only pathological findings of IP had a better prognosis than those with radiological findings of IP. Thus, our findings suggest that patients with pathological findings of IP and without radiological abnormality had early-stage IP., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Since the first reports in early 2013, >440 human cases of infection with avian influenza A(H7N9) have been reported including 122 fatalities. After the isolation of the first A(H7N9) viruses, the nucleotide sequences became publically available. Based on the coding sequence of the influenza virus A/Shanghai/2/2013 hemagglutinin gene, a codon-optimized gene was synthesized and cloned into a recombinant modified vaccinia virus Ankara (MVA). This MVA-H7-Sh2 viral vector was used to immunize ferrets and proved to be immunogenic, even after a single immunization. Subsequently, ferrets were challenged with influenza virus A/Anhui/1/2013 via the intratracheal route. Unprotected animals that were mock vaccinated or received empty vector developed interstitial pneumonia characterized by a marked alveolitis, accompanied by loss of appetite, weight loss, and heavy breathing. In contrast, animals vaccinated with MVA-H7-Sh2 were protected from severe disease., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We report the case of catastrophic antiphospholipid syndrome (CAPS) complicated with mixed connective tissue disease (MCTD). A female patient was diagnosed with acute interstitial pneumonia (AIP) with MCTD by chest CT scan. Corticosteroid therapy was refractory for lung involvement, and she died due to acute respiratory failure. The autopsy revealed that AIP was compatible with lung involvement of CAPS. We therefore suggest that chest CT might reveal AIP-like findings in CAPS patients whose condition is complicated with pulmonary manifestations.

Objectives: Interstitial lung disease (ILD) includes a wide spectrum of pulmonary pathologies. The role of surgical lung biopsy (SLB) in the diagnosis of ILD is still controversial. The purpose of this study was to ascertain whether SLB is worthwhile in the management of ILD., Methods: One hundred and three patients underwent SLB for ILD from April 2008 to March 2010 at a single institution. Outcomes included patient demographics, preoperative investigations, preoperative diagnosis and treatment, surgical approach, number and site of biopsies, complications, length of postoperative stay and postoperative pathological diagnosis and treatment., Results: Fifty-one (49.6%) patients were male and 52 (50.4%) were female. The median age was 58 (range 26-78). Major complications were seen in 7 patients (6.8%). Five patients (4.9%) died within 30 days following surgery. Definitive pathological diagnosis (DPD) was reached in 72 (69.9%) patients, whereas no DPD was achieved in 31 (30.1%). Within the group of patients who received DPD, this differed from the clinical diagnosis in 53 patients (51.5%), and was concordant in 19 (18.4%). The DPD was helpful in guiding the management of 47 patients (45.6%), who had a change in their treatment following the procedure. The median hospital stay was 4 days (range 2-42 days)., Conclusions: SLB is a well-recognized procedure. Although it provides a diagnosis for the majority of patients, in our series SLB was inconclusive in a considerable number of cases and did not lead to a therapeutic change for more than half of all patients. Furthermore, SLB is not without risk and can be associated with a prolonged hospital stay. We believe that SLB should be performed in a select group of patients with ILD after discussion by a multidisciplinary panel.

In order to develop a practical risk score for 90-day mortality following surgical lung biopsy (SLB) for interstitial lung disease (ILD) we reviewed 311 consecutive patients undergoing SLB for ILD between 2002 and 2009. Postoperative complication, 30-day and 90-day mortality rates were 11.5%, 9% and 10.6% respectively. Univariable and multivariable analyses, validated by bootstrap statistics, were used to identify factors associated with 90-day mortality. A scoring system was developed by proportionally weighting the regression coefficients of the significant predictors of 90-day mortality: age >67 (P < 0.0001, weighted score 1.5), preoperative intensive care unit (ICU) admission (P = 0.006, weighted score 2), immunosuppressive treatment (P = 0.004, weighted score 1.5) and open surgery (P = 0.03, weighted score 1). Patients were grouped in four classes showing incremental risk of death at 90 days: class A, score 0 (2%); class B, score 1-2 (12%); class C, score 2.5-3 (40%); class D, score >3 (86%); P <0.0001). SLB entails a considerable surgical risk with an overall 90-day mortality around 10%. We were able to develop a practical risk score which, if validated by other independent studies, can be easily used to stratify the risk of SLB candidates and assess the cost-effectiveness of this procedure.

Anti-clinically amyopathic dermatomyositis (CADM)-140/MDA5 autoantibodies are specifically detected in patients with dermatomyositis and are known to have a strong association with rapidly progressive interstitial lung disease (RP-ILD). Here we report an amyopathic dermatomyositis (ADM) patient who developed RP-ILD characterized by elevated anti-CADM-140/MDA5 titer. Respiratory symptoms gradually improved, and anti-CADM-140/MDA5 titer decreased in parallel to below the cutoff level. It may be useful to quantify CADM-140-specific autoantibodies for monitoring disease activity in patients with ADM and RP-ILD.

Objective: To elucidate the patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma, we reviewed seven cases of everolimus-induced interstitial lung disease., Methods: Seven patients with metastatic renal cell carcinoma, which continued to progress despite treatment with sunitinib or sorafenib, developed interstitial lung disease after treatment with everolimus., Results: Chest X-ray demonstrated diffuse infiltrates in lung fields, and chest computed tomography showed bilateral reticular and ground-glass opacities. Serum levels of lactate dehydrogenase (7/7), C-reactive protein (6/7), pulmonary surfactant associated protein D (1/7) and Krebs von den Lungen 6 (5/7) were elevated. The bronchoalveolar lavage fluid obtained from four patients with Grade 3 interstitial lung disease showed lymphocytosis. The transbronchial lung biopsy specimens showed interstitial lymphocytic infiltration and septal thickening of alveolar walls. In two cases with mild interstitial lung disease, the everolimus therapy was successfully continued. In four cases with Grade 3 interstitial lung disease, the drug was discontinued and steroid therapy was initiated. Pulmonary symptoms and radiological abnormalities resolved within 2 months., Conclusions: Serum Krebs von den Lungen 6 was elevated compared with baseline in all cases with interstitial lung disease. Some patients who developed mild interstitial lung disease during everolimus treatment could continue to receive the treatment. Even when severe interstitial lung disease developed, withdrawal of the drug and short-term use of high-dose steroids resulted in rapid recovery. Prompt recognition of interstitial lung disease exacerbation as well as exclusion of progressive disease or infection is of primary importance.

The clinical course of diffuse alveolar damage (DAD) was studied in six consecutive cases of dermatomyositis (DM) based on our hospital records over 8 years. Three patients had severe myopathy at presentation, and the other three patients showed clinically amyopathic DM (CADM). Interstitial pneumonia in all patients developed shortly after they manifested DM. DAD in five deceased patients, which was proven pathologically, did not respond to steroid therapy combined with cyclosporine or tacrolimus. Of these, two patients began receiving combination therapy before suffering respiratory symptoms, and one of them had elevated serum Krebs von der Lungen-6 (KL-6) levels before visible abnormalities appeared on a plain chest X-ray. Only one patient with CADM survived; this patient received intravenously administered pulse cyclophosphamide (IVCY) therapy intravenously for DAD from the early stage. Delayed adjunctive IVCY was ineffective for progressed DAD in the remaining five patients. Elevated serum ferritin levels were observed in all four patients examined and might have predicted the lethal DAD, as in a previous report. In conclusion, promptly beginning IVCY therapy may be beneficial for patients with DM and interstitial pneumonia who show elevated serum levels of ferritin or KL-6 with minimal pulmonary abnormalities.

A 6-year-old girl, who had received corticosteroid and cyclosporine on the diagnosis of interstitial pneumonitis related to juvenile dermatomyositis, developed severe thrombocytopenia. Her thrombocytopenia was resistant to repeated intravenous immunoglobulin administration and methylprednisolone pulse therapy. After additional treatment with mycophenolate mofetil (MMF), instead of cyclosporine, the thrombocytopenia improved, facilitating a reduction in the dose of corticosteroid without exacerbation of the interstitial pneumonitis. We propose MMF as effective option in the treatment of immune thrombocytopenic purpura with autoimmune disease.

Bronchoalveolar lavage (BAL) is widely accepted as a key diagnostic procedure in interstitial lung diseases (ILD). We performed a study to obtain reference intervals of differential cell patterns in BAL fluid with special attention to the origin of lavage fluid, e.g. bronchial/alveolar, to atopy and smoking status and to age of the healthy people. We performed bronchoalveolar lavage in 55 healthy subjects with known atopy status (age: 18-64 years, non-smokers/smokers: 34/21) and determined differential cell counts and lymphocyte subsets in BAL fluid and blood. Moreover, in a subgroup of non-smoking healthy individuals we measured the expression of the regulatory T cell marker forkhead box protein 3 (FoxP3) on blood and BAL fluid lymphocytes in addition to a comprehensive set of activation markers. Differential cell counts from the alveolar lavage fraction differed significantly from calculated pooled fractions (n = 11). In contrast, marginal differences were found between atopic and non-atopic subjects. Interestingly, the BAL fluid CD4(+) /CD8(+) ratio correlated strongly with age (r(2) = 0·50, P < 0·0001). We consider the bronchial and alveolar fraction to be lavage fluid from fundamentally different compartments and recommend analysis of the alveolar fraction in diagnostic work-up of ILD. In addition, our data suggest that age corrected BAL fluid CD4(+) /CD8(+) ratios should be used in the clinical evaluation of patients with interstitial lung diseases., (© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.)

Objectives: In efforts to obtain complete results, current practice in surgical lung biopsy (LB) for interstitial lung disease (ILD) recommends sending lung tissue samples for bacterial, mycobacterial, fungal, and viral cultures. This study assesses the value of this practice by evaluating the microbiology findings obtained from LB for ILD and their associated costs., Methods: A total of 296 consecutive patients (140 women, 156 men, median age=61 years) underwent LB for ILD from 2002 to 2009. All had lung tissue sent for microbiology examination. Microbiology results and resultant changes in patient management were analyzed retrospectively. A cost analysis was performed based upon nominal hospital charges adjusted on current inflation rates. Cost data included cultures, stains, smears, direct fluorescent antibody studies, and microbiologist consulting fees., Results: As many as 25 patients (8.4%) underwent open LB and 271 (91.6%) underwent thoracoscopic LB. A total of 592 specimens were assessed (range 1-4 per patient). The most common pathologic diagnoses were idiopathic pulmonary fibrosis in 122 (41.2%), cryptogenic organizing pneumonia in 31 (10.5%), and respiratory bronchiolitis ILD in 16 (5.4%). Microbiology testing was negative in 174 patients (58.8%). A total of 118 of 122 (96.7%) positive results were clinically considered to be contaminants and resulted in no change in clinical management. The most common contaminants were Propionibacterium acnes (38 patients; 31%) and Penicillium fungus (16 patients; 13%). In only four patients (1.4%), the organism cultured (Nocardia one, Histoplasma one, and Aspergillus fumigatus two) resulted in a change in clinical management. The cost of microbiology studies per specimen was $984 (€709), with a total cost for the study cohort being $582,000 (€420,000)., Conclusions: The yield and impact on clinical management of microbiology specimens from LB for ILD is very low. Its routine use in LB is questionable. We suggest it should be limited to those cases of ILD with a high suspicion of infection. Substantial cost savings are possible with this change in clinical practice.

Objectives: Consensus is lacking on the immunological tests to perform for diagnosis of interstitial lung diseases (ILDs). In particular, the value of detecting anti-SSA antibody in this context is unknown. We aimed to determine whether the detection of anti-SSA antibody in patients with ILD can identify a subgroup of patients with CTD., Methods: We compared the characteristics of patients with newly diagnosed apparently idiopathic ILD with anti-SSA antibody [anti-SSA(+) group] and without anti-SSA antibody (control group). RESULTS; Anti-SSA(+) patients (n = 15) more often had extra-respiratory signs (xerostomia and ocular dryness), auto-immune features, a CT scan pattern of non-specific interstitial pneumonia and more severe lung function alteration than controls (n = 30). Of patients who were anti-SSA(+), 2 met the criteria for SS and 13 (86%) of 15 met the criteria for the diagnosis of undifferentiated CTD., Conclusions: Our results suggest that identification of anti-SSA antibody in patients with early ILD can reveal a specific subgroup of patients with more ground glass opacity and more severe lung function impairment than those without anti-SSA antibody.

Common variable immunodeficiency (CVID) is a common primary immune deficiency, caused by undefined defects in lymphocyte function, and is treated routinely by immunoglobulin substitution. CVID complications include airway disease (AD) and interstitial lung disease (ILD). It was not known if AD and ILD in CVID have a common immunological aetiology and should be considered separate features of the same disease, or as distinct syndromes that require specialized monitoring and treatment. We used high-resolution computed tomography (CT) to diagnose AD or ILD in paediatric CVID patients. Spirometry and body plethysmography did not differentiate between ILD and AD. Patients with AD (n = 11, 20%) developed more pneumonias while children with ILD (n = 8, 15%) showed immune dysregulation characterized by autoimmune complications, more severe memory B cell reduction and expansion of non-naive cytotoxic T cells. In conclusion, ILD and AD in CVID have dissimilar clinical and immunological characteristics, suggesting distinct aetiology requiring tailored monitoring and treatment of these patient subgroups., (© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.)

Objective: Post-surgical interstitial pneumonia (IP) is a part of postoperative acute respiratory distress syndrome (ARDS). Some cases of ARDS may be an acute exacerbation of idiopathic pulmonary fibrosis (IPF) that is generally not recognised as IPF prior to surgery. In this study, we evaluated IP on preoperative computed tomography (CT) and histopathological findings in patients who underwent thoracic surgery, and attempted to identify high-risk patients who might develop postoperative ARDS., Methods: A retrospective review of preoperative CT and histopathological examination was performed in 487 patients who underwent lobectomy for primary lung cancer at our institute., Results: The incidence of ARDS was 2.05%, and histopathological finding of IP was the only predictor of ARDS (P = 0.038, odds ratio (OR) = 6.89). The incidence of IP on histopathological examination was 9.7% for all cases of lung cancer; and the incidence of ARDS in the IP-positive group (31.8%) was significantly different from that in the IP-negative group (1.5%) (P<0.05). However, in 85.7% of patients with ARDS, who were histologically IP-positive, IP was masked by emphysematous findings and thus not detected on preoperative CT., Conclusions: In this study, histopathological finding of IP was the only predictor of ARDS; however, it was difficult to identify preoperatively because emphysematous change was also present in the majority of cases, which masks the findings of IP on CT. If identification of the high-risk case of ARDS is insisted upon, screening the presence or absence of IP (e.g., just in the patients with emphysema or IP finding on CT) by histopathological examination, as the need arises, after surgery using resected lung might be one of the additional methods of identifying those at high risk of ARDS., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Bleomycin (BLM)-induced lung injury has become a model for studies of interstitial pneumonitis and pulmonary fibrosis. BLM induces lung injury in two phases: early inflammation characterized by infiltration of inflammatory cells into the lungs, followed by a late phase of fibrosis characterized by deposition of collagen. In this study, we examined the role of mizoribine (MZB) in the regulation of inflammatory tissue injury caused by BLM. We examined the role of MZB using a mouse model of BLM-induced lung injury. We demonstrated that mice subjected to instillation of BLM into the lungs had a significantly increased number of macrophages and lymphocytes in bronchoalveolar lavage fluid (BALF), but that those treated with MZB in the early phase showed a significant reduction in the total number of BALF macrophages and lymphocytes. However, MZB was unable to inhibit fibrosis in the late phase of BLM injury. Our findings suggest that MZB inhibits the proliferation of both lymphocytes and macrophages in the early phase of the BLM-induced acute inflammatory response, as well as its development and amplification, but does not inhibit fibrotic change in the late phase.

The aim of the present study was to evaluate whether the interferon-induced helicase (IFIH1) Ala946Thr (rs1990760 A>G) polymorphism is associated with susceptibility to systemic lupus erythematosus (SLE) and dermatomyositis (DM) or polymyositis (PM) in the Japanese population. The study population consisted of 243 SLE patients, 125 DM/PM patients, and 268 healthy controls from Japan. A Taqman single nucleotide polymorphism genotyping assay was designed for rs1990760 by Applied Biosystems. There were no significant differences between SLE and DM/PM patients and healthy controls regarding the frequency of each genotype and allele. However, the frequency of the AA genotype and the A allele tended to be higher in PM patients with interstitial lung disease (ILD). Additionally, when comparing the AA and AG + GG genotypes at rs1990760, the AA genotype was significantly more frequent in PM patients with ILD than in healthy controls [odds ratio, 3.23 (95% confidence interval, 1.06-9.81); P = 0.04] or in PM patients without ILD [odds ratio, 5.40 (95% confidence interval, 1.37-21.26); P = 0.027]. Our observations suggest that the G allele protects against the onset of ILD and that the AA genotype is a risk factor for lung injury in PM patients.

Inflammatory bowel disease (IBD) is associated with a number of extraintestinal manifestations that may involve most organ systems. Extraintestinal manifestations are more common in Crohn disease (CD) and may include rheumatologic, ocular, dermatologic, biliary and pulmonary manifestations. The most common pulmonary manifestations of IBD are drug-induced lung disease. Other manifestations include parenchymal disease, pleuritis and overlap syndromes. We present a case series of 7 patients with non-infectious pulmonary manifestations of IBD, which included cryptogenic organizing pneumonia, usual interstitial pneumonitis (UIP), Langerhan's granulomatosis, and eosinophilic pneumonia. Concurrent extraintestinal manifestations present in these patients included arthralgia, iritis, and pyoderma gangrenosum. In most patients the development of pulmonary disease parallels that of the intestinal disease activity, extraintestinal manifestations and concurrent use of 5-ASA medications., (Copyright © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Objectives: Myositis-specific autoantibodies are useful for diagnosing PM/DM. Recently, two new myositis-specific autoantibodies against melanoma differentiation-associated gene 5 (MDA5) and transcriptional intermediary factor 1-gamma (TIF1-gamma) were identified in DM. Here, we detected these autoantibodies in patient sera using new assays with recombinant MDA5 and TIF1-gamma, and associated clinical features with the presence of anti-MDA5 or anti-TIF1-gamma antibodies., Methods: We screened 135 Japanese patients with various CTDs, including 82 with DM. DM patients were classified as clinically amyopathic DM (CADM), cancer-associated DM or classical DM without cancer. Anti-MDA5 and anti-TIF1-gamma antibodies were detected by their ability to immunoprecipitate biotinylated recombinant proteins., Results: Sera from 21 (26%) of 82 DM patients immunoprecipitated MDA5, and every anti-MDA5-positive patient had DM (except one patient with SSc). Sera from 20 (65%) of 31 CADM patients reacted with MDA5. Notably, anti-MDA5-positive DM patients had significantly more interstitial lung disease than anti-MDA5-negative DM patients (95 vs 32%, P < 0.001). Sera from 12 (15%) of 82 DM patients immunoprecipitated TIF1-gamma, and anti-TIF1-gamma antibodies were only detected in DM patients. Strikingly, 7 (58%) of 12 patients with cancer-associated DM had sera that reacted with TIF1-gamma. Anti-TIF1-gamma-positive DM patients had significantly more internal malignancies than anti-TIF1-gamma-negative DM patients (58 vs 9%, P < 0.001)., Conclusions: Anti-MDA5 and anti-TIF1-gamma antibodies were confirmed to be serological DM subset markers. Anti-MDA5 and anti-TIF1-gamma antibodies were detected based on their ability to immunoprecipitate biotinylated recombinant MDA5 and TIF1-gamma, and were closely associated with life-threatening complications in DM.

Interstitial lung disease (ILD) is an intractable disease induced by various factors in humans. However, there is no universally effective treatment for ILD. In this study, we investigated the role of transforming growth factor (TGF)-beta signalling in the pathogenesis of ILD by using model mice. Injection of interleukin (IL)-18 plus IL-2 in C57BL6 (B6) mice resulted in acute ILD by infiltration of natural killer (NK) cells and a significant increase of TGF-beta mRNA in the lung. To examine the pathogenetic role of TGF-beta in ILD mice, we used SB-431542 (4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]-benzamide), which is a potent and selective inhibitor of TGF-beta receptor I (TbetaRI), also known as activin receptor-like kinase 5 (ALK5). Treatment of B6-ILD mice with SB-431542 resulted in improvement of ILD, delay in mortality, reduction of the expression of interferon (IFN)-gamma and IL-6 in the lungs. The same treatment also decreased significantly the percentage of natural killer (NK) cells in the lungs (P < 0.05) and mRNA expression levels of certain chemokines such as CCL2, CCL3, CCL4, CCL5 and CXCL10 in B6-ILD. These findings were confirmed by IL-18 plus IL-2 treatment of Smad3-deficient (Smad3(-/-)) mice (P < 0.05). Our results showed that inhibition of TGF-beta signalling reduced the percentage of NK cells and the expression of certain chemokines in the lungs, resulting in improvement of ILD. The findings suggest that TGF-beta signalling may play an important role in the pathogenesis of IL-18 plus IL-2-induced ILD in mice.

Lymphocytes play a crucial role in lung inflammation. Different interstitial lung diseases may show distinct lymphocyte activation profiles. The aim of this study was to examine the expression of a variety of activation markers on T lymphocyte subsets from blood and bronchoalveolar lavage fluid (BALF) of patients with different granulomatous interstitial lung diseases and healthy controls. Bronchoalveolar lavage cells and blood cells from 23 sarcoidosis patients, seven patients with hypersensitivity pneumonitis and 24 healthy controls were analysed. Lymphocyte activation status was determined by flow cytometry. Lymphocytes were stained with antibodies against CD3, CD4, CD8, CD25, CD28, CD69, very late antigen-1 (VLA)-1, VLA-4 and human leucocyte antigen D-related (HLA-DR). In general, CD28, CD69 and VLA-1 expression on BALF CD4+ lymphocytes and HLA-DR expression on BALF CD8+ lymphocytes was different in patients with hypersensitivity pneumonitis and sarcoidosis patients with parenchymal involvement. This BALF lymphocyte phenotype correlated with carbon monoxide diffusing lung capacity (Dlco) values across interstitial lung diseases (ILD) (r2 = 0.48, P = 0.0002). In sarcoidosis patients, CD8+CD28(null) blood lymphocytes correlated with lower Dlco values (r = -0.66, P = 0.004), chronic BALF lymphocyte activation phenotype (r2 = 0.65, P < 0.0001), radiographic staging (stage I versus stage II and higher, P = 0.006) and with the need for corticosteroid treatment (P = 0.001). Higher expression of CD69, VLA-1 and HLA-DR and lower expression of CD28 on BALF lymphocytes suggests prolonged stimulation and chronic lymphocyte activation in patients with ILD. In sarcoidosis, blood CD8+CD28(null) cells might be a new biomarker for disease severity but needs further investigation.