Intrinsic clarithromycin heteroresistance in Mycobacterium avium.

BACKGROUND: Mycobacterium avium is associated with pulmonary disease in otherwise healthy adults. Several clarithromycin-refractory cases have been reported, including some cases caused by clarithromycin-susceptible strains. OBJECTIVES: To characterize the reason for the discrepancy between clinical response and antibiotic susceptibility results. METHODS: We conducted population analysis of clarithromycin-tolerant and heteroresistant subpopulations of M. avium cultured in vitro and in homogenates of infected lungs of mice. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for 28 M. avium and two M. kansasii strains. Mice were intranasally infected with M. avium and treated with or without clarithromycin (100 mg/kg) thrice weekly. They were sacrificed on day 35 and the bacteria in lung homogenates were tested for clarithromycin resistance. Population analysis assays were performed based on colony growth on plates containing two-fold dilutions of clarithromycin. RESULTS: The MBC/MIC ratios were ≥8 in all 28 strains of M. avium tested. In the population analysis assay, several colonies were observed on the plates containing clarithromycin concentrations above the MIC (2-64 mg/L). No growth of M. kansasii colonies was observed on the plates containing clarithromycin concentrations ≥2 mg/L. M. avium in the homogenates of infected lungs showed clearer clarithromycin-resistant subpopulations than in vitro, regardless of clarithromycin exposure. CONCLUSION: M. avium shows intrinsic heterogeneous resistance (heteroresistance) to clarithromycin. This may explain the observed discrepancies between clarithromycin susceptibility testing results and clinical response to clarithromycin treatment. Further studies are needed to confirm a link between heteroresistance and clinical outcomes.

Impact of partial pressure of arterial oxygen and radiologic findings on postoperative acute exacerbation of idiopathic interstitial pneumonia in patients with lung cancer.

PURPOSE: To establish accurate diagnostic criteria and predictors of treatment response for postoperative acute exacerbation (AE) in patients with lung cancer and idiopathic interstitial pneumonia (IIP). METHODS: Among 93 patients with IIP who underwent surgery for lung cancer, suspected postoperative AE developed in 20 (21.5%). Patients were divided into a progressive AE group, comprising patients with bilateral alveolar opacities and decreasing PaO2 ≥ 10 mmHg (n = 5); an incipient AE group, comprising patients with unilateral alveolar opacities and decreasing PaO2 ≥ 10 mmHg (n = 10); and an indeterminate AE group, comprising patients with alveolar opacities but decreasing PaO2 < 10 mmHg (n = 5). RESULTS: The progressive AE group had significantly higher 90-day mortality (80%) than the incipient AE group (10%, P = 0.017) or the indeterminate AE group (0%, P = 0.048). Bilateral opacities may indicate advanced AE and poor prognosis, whereas unilateral opacities may indicate an early stage of AE and a good prognosis. PaO2 < 10 mmHg may indicate conditions other than AE. CONCLUSIONS: In patients with lung cancer and IIP, decreasing PaO2 and HRCT findings may allow for the initiation of rapid and accurate treatment strategies for postoperative AE.

Efficacy of three sputum specimens for the diagnosis of Mycobacterium avium complex pulmonary disease.

BACKGROUND: In Mycobacterium avium complex pulmonary disease (MAC-PD), diagnosis requires a positive culture from at least two separate expectorated sputum specimens. The optimal number of sputum examinations remains unclear. OBJECTIVE: This study sought to elucidate the diagnostic yield of acid-fast bacilli in MAC-PD using 3 sputum specimens and to clarify the clinical characteristics of patients with MAC-PD diagnosed using 3 sputum specimens. Furthermore, we investigated the correlation between increased number of sputum specimens and diagnostic yield. METHODS: We reviewed the medical records of 139 patients with MAC-PD diagnosed at Toho University Omori Medical Center for whom at least three sputum specimens were examined before treatment from November 2014 through June 2021. Patients were classified into the 3-sputum diagnosed and the non-3 sputum diagnosed groups based on diagnostic procedure; clinical and radiological characteristics were compared. We also assessed diagnostic yield with the increased number of sputum specimens. RESULTS: Diagnostic yield with 3 sputum specimens was 16.5% (23/139). The 3-sputum diagnosed group had a lower body mass index [18.6(17-19.5) vs. 19.5(18-21.5); p = 0.014], and higher chest CT score [9(6.5-13) vs. 6(4-9); p = 0.011] including cavitary lesions (39.1% vs. 19%; p = 0.037) compared with the non-3 sputum diagnosed group. When the number of sputum specimens was increased to 6, the diagnostic yield increased to 23.7% (33/139). CONCLUSION: Diagnostic yield with 3 sputum specimens was 16.5%. Patients diagnosed using 3 sputum specimens had more severe chest CT findings including cavitary lesions. Increasing the number of sputum specimens to 6 improved diagnostic yield by 7.2%.

Prospective nationwide multicentre cohort study of the clinical significance of autoimmune features in idiopathic interstitial pneumonias.

BACKGROUND: Some patients with idiopathic interstitial pneumonia (IIP) show autoimmune features. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept in these patients. However, retrospective studies reported conflicting results of its prognosis. Therefore, this study was conducted to prospectively evaluate the clinical significance of autoimmune features in patients with IIP. METHODS: This nationwide multicentre study prospectively enrolled consecutive patients with IIP. At the diagnosis, we systematically evaluated 63 features suggestive of connective tissue diseases using a checklist including symptoms/signs and autoantibodies, which contained most items of the IPAF criteria and followed up with the patients. Clinical phenotypes were included in a cluster analysis. RESULTS: In 376 patients with IIP enrolled, 70 patients (18.6%) met the IPAF criteria. The proportion of patients with IPAF was significantly lower in idiopathic pulmonary fibrosis (IPF) than in non-IPF (6.0% vs 24.3%, respectively). During a median observation period of 35 months, patients with IPAF more frequently developed systemic autoimmune diseases and had less frequent acute exacerbation of IIPs than patients with non-IPAF. IPAF diagnosis was significantly associated with better survival and was an independent positive prognostic factor in total and patients with non-IPF. Cluster analysis by similarity of clinical phenotypes identified a cluster in which there was a higher number of women, and patients had more autoimmune features and a better prognosis than other clusters. INTERPRETATION: These observations suggest that some patients with IIP show autoimmune features with distinct characteristics and favourable prognosis. However, we were not able to determine the appropriate therapies for these patients.

Prevalence of idiopathic pulmonary fibrosis in Japan based on a claims database analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a cryptogenic chronic interstitial pneumonia with progressive fibrosis and a poor prognosis. A substantial number of epidemiological studies have been conducted in Europe and the United States (US). In contrast, in Japan, only one study reported the prevalence of IPF (10.0 per 100,000 population) using clinical data (2003-2007) from one prefecture; thus, the nationwide prevalence of IPF remains unknown. This study aimed to estimate the nationwide prevalence of IPF in Japan using a nationwide claims database. METHODS: We extracted data from a Japanese claims database provided by Medical Data Vision (MDV database, April 2008-March 2019) containing data from approximately 28 million patients from 385 acute-care hospitals. Patients with IPF (those diagnosed with IPF at least once) from April 2017 to March 2018 were identified in the MDV database. The number of patients in the MDV database was extrapolated nationwide using the fourth NDB Open Data (April 2017-March 2018), and the prevalence was estimated using demographic data as denominators. The prevalence in the US, considering the same definition of IPF, was also calculated and compared with that in Japan. RESULT: The number of patients with IPF in the MDV database was 4278. The estimated nationwide number of patients in Japan was estimated to be 34,040 (mean age: 73 years, percentage of men: 73%), and the prevalence was 27 per 100,000 population. In comparison with that in the US, the prevalence was similar in men and relatively lower in women until the age of 75-79 years, and it was notably lower in both sexes aged ≥ 80 years. CONCLUSIONS: We report the nationwide IPF prevalence in Japan using data from claims databases for the first time. The prevalence estimated in this study was higher than that reported in a previous study. The difference might be due to differences in study settings and definitions of IPF. Further research should be performed to determine the prevalence more accurately and compare it with those in other countries.

Impact of chronic co-infection in pulmonary Mycobacterium avium complex disease after treatment initiation.

BACKGROUND: The impact of co-infection with other pathogenic microorganisms after initiation of treatment for Mycobacterium avium complex pulmonary disease (MAC-PD) has not been clearly described. This study sought to clarify the clinical outcomes of co-infection with MAC after antimycobacterial therapy for MAC. METHODS: Co-infection status was defined as the detection of pathogenic microorganisms other than MAC in at least two consecutive sputum cultures 6-24 months after initiation of treatment. Chest computed tomography (CT) findings and culture results were compared between co-infection and MAC alone groups. RESULTS: The co-infection and MAC alone groups comprised 12 and 36 patients, respectively. The proportion of patients with sputum culture positive for MAC after 24 months of therapy did not differ significantly between the two groups [25% (3/12) vs. 16.7% (6/36); p = 0.671]. The proportion of patients with improved chest CT score after 24 months of starting treatment compared to baseline was significantly lower for the co-infection group than for the MAC alone group [16.7% (2/12) vs. 79.4% (27/34); p < 0.001]. In the co-infection group, median CT score values at 12 and 24 months did not differ from baseline. However, the MAC alone group showed significant improvement at 12 and 24 months compared with baseline. CONCLUSIONS: In the patient group with co-infection of other pathogenic microorganisms after treatment initiation for MAC there was no impact on therapeutic efficacy compared to the MAC alone group. However, therapeutic intervention interfered with improvement in chest CT findings such as nodule formation, bronchiectasis, infiltration, and cavitary lesions.

Surgical treatment for patients with idiopathic pulmonary fibrosis and lung cancer: postoperative acute exacerbation of idiopathic pulmonary fibrosis and outcomes.

Postoperative exacerbation of interstitial pneumonia in patients with interstitial lung disease and lung cancer has emerged as a serious problem. Therefore, we need to determine the risk factors for the development of postoperative exacerbation of interstitial pneumonia in this population. There are several subtypes of interstitial lung disease, which may lead to confusion about the treatment of patients with interstitial lung disease and lung cancer. Among the idiopathic forms of interstitial lung disease, we focused on idiopathic pulmonary fibrosis (IPF) and reviewed the surgical treatments used for patients with IPF and lung cancer.

Nation-wide survey of the treatment trend of microscopic polyangiitis and granulomatosis with polyangiitis in Japan using the Japanese Ministry of Health, Labour and Welfare Database.

OBJECTIVES: In Japan, clinical records of patients with intractable diseases, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), are compiled into a database. This study aimed to understand the current treatment status and changes in treatment regimens from our previous survey. METHODS: Using data from 2012 and 2013, patients with new-onset MPA and GPA were extracted and analysed. RESULTS: We analysed 1278 MPA and 215 GPA patients. The average age was 71.7 and 62.7 years, respectively. Methylprednisolone pulse therapy was used in 51.2% of MPA patients and 40.5% of GPA patients; the initial prednisolone-equivalent glucocorticoid dose was 39.5 mg/day in MPA and 46.6 mg/day in GPA. Concomitant intravenous or oral cyclophosphamide (CY) was administered to 22.6% of MPA and 56.3% of GPA. Young age, bloody sputum, low serum creatinine, and high C-reactive protein levels were independently associated with CY use in MPA. Compliance with treatment protocol for Japanese patients with myeloperoxidase (MPO)-anti-neutrophilic cytoplasmic antibody-associated vasculitis study criteria or the 2011 clinical practice guidelines for rapidly progressive glomerulonephritis was 42.7% and 49.7%, respectively. CONCLUSIONS: MPA was more prevalent than GPA in the registry. Compared to patients with GPA, MPA patients were older and used CY less frequently. No apparent changes in treatment trends were observed from the previous survey.

Pirfenidone plus inhaled N-acetylcysteine for idiopathic pulmonary fibrosis: a randomised trial.

BACKGROUND: A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown. METHODS: This 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide (D LCO) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability. RESULTS: 81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300 mL and -123 mL, respectively (difference -178 mL, 95% CI -324--31 mL; p=0.018). Serial change in D LCO, 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups. CONCLUSIONS: Combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.

Antihistamines and azithromycin as a treatment for COVID-19 on primary health care - A retrospective observational study in elderly patients.

BACKGROUND: Between March and April 2020, 84 elderly patients with suspected COVID-19 living in two nursing homes of Yepes, Toledo (Spain) were treated early with antihistamines (dexchlorpheniramine, cetirizine or loratadine), adding azithromycin in the 25 symptomatic cases. The outcomes are retrospectively reported. The primary endpoint is the fatality rate of COVID-19. The secondary endpoints are the hospital and ICU admission rates. Endpoints were compared with the official Spanish rates for the elderly. The mean age of our population was 85 and 48% were over 80 years old. No hospital admissions, deaths, nor adverse drug effects were reported in our patient population. By the end of June, 100% of the residents had positive serology for COVID-19. Although clinical trials are needed to determine the efficacy of both drugs in the treatment of COVID-19, this analysis suggests that primary care diagnosis and treatment with antihistamines, plus azithromycin in selected cases, may treat COVID-19 and prevent progression to severe disease in elderly patients.

Bronchial Brushing and Diagnosis of Pulmonary Nontuberculous Mycobacteria Infection.

BACKGROUND: The optimal bronchoscopy procedure for diagnosis of pulmonary nontuberculous mycobacteria (NTM) infection is unclear. OBJECTIVE: This study investigated the usefulness of bronchial brushing in bronchoscopy for diagnosis of pulmonary NTM infection in patients with suspected NTM lung disease and nodular bronchiectasis on chest computed tomography (CT) images. METHODS: Bronchoscopy was prospectively performed for 69 patients with clinically suspected pulmonary NTM infection on chest CT from December 2017 through December 2019. Before and after bronchial brushing, bronchial washing was performed with 20 or 40 mL of normal sterile saline at the same segmental or subsegmental bronchi. Before and after bronchial brushing, samples of the washing fluid (pre- and postbrushing samples) and brush deposits (brush samples) were obtained and cultured separately. RESULTS: NTM was detected in 37 of the 69 (53.6%) patients (Mycobacterium avium in 27, Mycobacterium intracellulare in 7, M. abscessus in 2, and M. kansasii in 2). NTM was detected in 34 (49.3%) prebrushing samples, in 27 (39.1%) postbrushing samples, and in 20 (29.0%) brush samples from the 69 patients. In 2 (2.9%) patients, NTM was detected only in postbrushing samples; in 1 (1.4%) patient, NTM was detected only in a brush sample. As compared with bronchial washing only, additional bronchial brushing increased the NTM culture-positive rate by 4.3% (3/69). Bronchial brushing caused bleeding, requiring hemostasis in 5 (7.2%) patients. CONCLUSION: Additional bronchial brushing increased the NTM culture-positive rate by only 4.3% (3/69), as compared with bronchial washing alone. Thus, the usefulness of brushing appears to be limited.

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation.Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis.Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).

Efficacy of early antifibrotic treatment for idiopathic pulmonary fibrosis.

BACKGROUND: Although antifibrotic drugs, including nintedanib and pirfenidone, slow the progression of idiopathic pulmonary fibrosis (IPF), there is little data about the timing of start of antifibrotic treatment in real-world clinical practice. The present study aimed to clarify the efficacy of nintedanib and pirfenidone in patients with early-stage IPF. METHODS: We compared survival and disease progression between patients with IPF with Japanese Respiratory Society (JRS) disease severity system stage I with and without oxygen desaturation on the 6-min walk test (6MWT) and increased the gender-age-physiology (GAP) staging. We examined the efficacy of antifibrotic drugs in patients with early-stage IPF. RESULTS: The severity of stage I IPF (n = 179) according to the JRS criteria consisted of the following GAP staging criteria: stage I, 111 cases; stage II, 58 cases; stage III, 10 cases. The duration from the initial visit to disease progression and survival time was significantly shorter in JRS stage I patients with oxygen desaturation on the 6MWT or with increased GAP staging (unfavorable group) compared with patients without those factors. In the unfavorable group, the relative decline in percentage predicted forced vital capacity (%FVC) over 6 months was significantly lower in patients undergoing antifibrotic treatment compared with non-treated patients. CONCLUSION: Antifibrotic drugs have a beneficial effect on the decline in %FVC in Japanese patients with early-stage IPF who have oxygen desaturation on the 6MWT or increased GAP staging.

Appendicular Skeletal Muscle Mass Correlates with Patient-Reported Outcomes and Physical Performance in Patients with Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF), an incurable lung disease of unknown cause, often presents with losses of skeletal muscle mass. IPF requires comprehensive care, but it has not been investigated which skeletal muscle mass index reflects holistic management factors: pulmonary function, patient-reported outcomes (PROs), and physical performance. We compared three representative indices of skeletal muscle mass with holistic management factors in IPF patients. Twenty-seven mild to severe IPF patients (21 male) with the mean age of 76.1 ± 5.9 years were enrolled. The three indices were appendicular skeletal muscle mass index (ASMI), cross-sectional area of pectoralis major (PMCSA), and cross-sectional area of erector spinae muscles (ESMCSA). ASMI is considered as a gold standard for sarcopenia assessment, while PMCSA and ESMCSA are frequently used in IPF. As PROs, we assessed breathlessness with the modified Medical Research Council dyspnea scale (mMRC), symptoms with the chronic obstructive pulmonary disease assessment test (CAT), and health-related quality of life with St. George's Respiratory Questionnaire (SGRQ). For physical performance, peripheral muscle strength and 6-min walk distance (6MWD) were investigated. In this cross-sectional study, ASMI showed the greatest number of significantly correlated indices, such as pulmonary function, peripheral muscle strength, 6MWD, mMRC, and SGRQ. PMCSA showed the next greatest number of correlations, with peripheral muscle strength, 6MWD, and mMRC, whereas ESMCSA showed no significant correlations with any index. Thus, ASMI correlated with both PROs and physical performance, and PMCSA correlated mainly with physical performance. In conclusion, assessing ASMI is helpful for the comprehensive care of patients with IPF.

Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: A Japanese population analysis of the SENSCIS trial.

OBJECTIVE: We examined the efficacy and safety of nintedanib in Japanese patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the global Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial. METHODS: Randomised patients received oral nintedanib 150 mg (N = 34) twice daily or placebo (N = 36) until the last patient reached 52 weeks of treatment (up to 100 weeks). Data were analysed using a subgroup analysis model with Japanese and non-Japanese patients as subgroup variables. RESULTS: In Japanese patients, the adjusted annual rate of forced vital capacity (FVC) decline over 52 weeks was -86.2 mL/year (nintedanib) and -90.9 mL/year (placebo); treatment difference, 4.67 mL/year (95% confidence interval, -103.28, 112.63). Treatment effect heterogeneity between Japanese and non-Japanese patients was not detected (treatment-by-visit-by-subgroup interaction; p = .49). FVC decline was smaller for nintedanib versus placebo through 100 weeks in Japanese patients. The most commonly reported adverse events with nintedanib were gastrointestinal and liver disorder events; most were mild-to-moderate in severity. CONCLUSION: In both Japanese and non-Japanese patients with SSc-ILD, nintedanib slowed the progression of ILD, with no heterogeneity detected between the subgroups. The safety profile for nintedanib in Japanese patients was similar to that observed in patients with idiopathic pulmonary fibrosis (ClinicalTrials.gov: NCT02597933).

A murine model of acute lung injury identifies growth factors to promote tissue repair and their biomarkers.

Type II alveolar epithelial cells (AEC2s) play a crucial role in the regeneration of type I AECs after acute lung injury. The mechanisms underlying the regeneration of AEC2s are not fully understood. To address this issue, here, we investigated a murine model of acute lung injury using mice expressing human Diphtheria Toxin Receptor (DTR) under the control of Lysozyme M promoter (LysM-DTR). DT injection induced the depletion of AEC2s, alveolar macrophages, and bone marrow (BM)-derived myeloid cells in LysM-DTR mice, and the mice died within 6 days after DT injection. Apoptotic AEC2s and bronchiolar epithelial cells appeared at 24 hr, whereas Ki67-positive proliferating cells appeared in the alveoli and bronchioles in the lung of LysM-DTR mice at 72-96 hr after DT injection. Transfer of wild-type BM cells into LysM-DTR mice accelerated the regeneration of AEC2s along with the up-regulation of several growth factors. Moreover, several metabolites were significantly decreased in the sera of LysM-DTR mice compared with WT mice after DT injection, suggesting that these metabolites might be biomarkers to predict AEC2s injury. Together, LysM-DTR mice might be useful to identify growth factors to promote lung repair and the metabolites to predict the severity of lung injury.

The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Lung Fibrosis in Mice.

The signaling pathways of growth factors, including platelet-derived growth factor, can be considered specific targets for overcoming the poor prognosis of idiopathic pulmonary fibrosis. Nintedanib, the recently approved multiple kinase inhibitor, has shown promising antifibrotic effects in patients with idiopathic pulmonary fibrosis; however, its efficacy is still limited, and in some cases, treatment discontinuation is necessary owing to toxicities such as gastrointestinal disorders. Therefore, more effective agents with less toxicity are still needed. TAS-115 is a novel multiple tyrosine kinase inhibitor that preferably targets platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, and c-FMS in addition to other molecules. In this study, we evaluated the antifibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo. TAS-115 inhibited the phosphorylation of PDGFR on human lung fibroblast cell line MRC-5 cells and suppressed their platelet-derived growth factor-induced proliferation and migration. Furthermore, TAS-115 inhibited the phosphorylation of c-FMS, a receptor of macrophage colony-stimulating factor, in murine bone marrow-derived macrophages and decreased the production of CCL2, another key molecule for inducing pulmonary fibrosis, under the stimulation of macrophage colony-stimulating factor. Importantly, the inhibitory effects of TAS-115 on both PDGFR and c-FMS were 3- to 10-fold higher than those of nintedanib. In a mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 significantly inhibited the development of pulmonary fibrosis and the collagen deposition in bleomycin-treated lungs. These data suggest that strong inhibition of PDGFR and c-FMS by TAS-115 may be a promising strategy for overcoming the intractable pathogenesis of pulmonary fibrosis.

Nationwide cloud-based integrated database of idiopathic interstitial pneumonias for multidisciplinary discussion.

Multidisciplinary discussion (MDD) requiring close communication between specialists (clinicians, radiologists and pathologists) is the gold standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). However, MDD by specialists is not always feasible because they are often separated by time and location. An online database would facilitate data sharing and MDD. Our aims were to develop a nationwide cloud-based integrated database containing clinical, radiological and pathological data of patients with IIPs along with a web-based MDD system, and to validate the diagnostic utility of web-based MDD in IIPs.Clinical data, high-resolution computed tomography images and lung biopsy slides from patients with IIPs were digitised and uploaded to separate servers to develop a cloud-based integrated database. Web-based MDD was performed using the database and video-conferencing to reach a diagnosis.Clinical, radiological and pathological data of 524 patients in 39 institutions were collected, uploaded and incorporated into the cloud-based integrated database. Subsequently, web-based MDDs with a pulmonologist, radiologist and pathologist using the database and video-conferencing were successfully performed for the 465 cases with adequate data. Overall, the web-based MDD changed the institutional diagnosis in 219 cases (47%). Notably, the MDD diagnosis yielded better prognostic separation among the IIPs than did the institutional diagnosis.This is the first study of developing a nationwide cloud-based integrated database containing clinical, radiological and pathological data for web-based MDD in patients with IIPs. The database and the web-based MDD system that we built made MDD more feasible in practice, potentially increasing accurate diagnosis of IIPs.

Chest High-Resolution CT Findings of Microscopic Polyangiitis: A Japanese First Nationwide Prospective Cohort Study.

OBJECTIVE. The lung is one of the organs possibly involved in microscopic polyangiitis (MPA), and myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) is commonly found in patients with MPA. The aim of this study was to assess pulmonary lesions in Japanese patients with MPA. SUBJECTS AND METHODS. This prospective study was based on 144 patients with MPA who were enrolled in the Remission Induction Therapy in Japanese Patients With ANCA-Associated Vasculitis and Rapidly Progressive Glomerulonephritis Study and who underwent chest high-resolution CT (HRCT) imaging at the time of diagnosis during 2011-2014. We reviewed the electronic case report forms of patients with MPA who did and did not have interstitial pneumonia (IP), and the clinical features and laboratory findings of these groups were compared. RESULTS. Abnormal HRCT findings were noted in 134 of the 144 patients (93%). Chest HRCT findings included ground-glass opacity (n = 72; 50%), reticulation (n = 69; 48%), traction bronchiectasis (n = 57; 42%), honeycombing (n = 44; 31%), and emphysema (n = 32; 22%). IP was diagnosed radiologically in 74 patients (51%), 38% of whom had the usual IP (UIP) pattern. Ground-glass opacity, reticulation, traction bronchiectasis, honeycombing, and interlobular septal thickening were frequent in patients with IP (p < 0.05). Patients with MPA with the UIP or possible UIP pattern also had minor findings, such as bronchial wall thickening, consolidation, increased attenuation around honeycombing, and traction bronchiectasis. CONCLUSION. IP (51%) was most commonly observed in Japanese patients with MPA, and 38% of these patients exhibited a UIP pattern. Increased attenuation around honeycombing or traction bronchiectasis was also found.

Cutting Edge: Anti-TIM-3 Treatment Exacerbates Pulmonary Inflammation and Fibrosis in Mice.

Promising results of immune checkpoint inhibitors have indicated the use of immunotherapy against malignant tumors. However, they cause serious side effects, including autoimmune diseases and pneumonitis. T cell Ig and mucin domain (TIM)-3 is a new candidate immune checkpoint molecule; however, the potential toxicity associated with anti-TIM-3 treatment is unknown. In this study, we investigated the pathological contribution of anti-TIM-3 mAb in a bleomycin-induced lung inflammation and fibrosis model. Anti-TIM-3-treated mice showed more severe inflammation and peribronchiolar fibrosis compared with control IgG-treated mice. Anti-TIM-3 mAb was associated with increased numbers of myofibroblasts, collagen deposition, and TGF-ß1 production in lungs. TIM-3 expression was only detected on alveolar macrophages that protect against fibrosis by apoptotic cell clearance. Treatment with anti-TIM-3 mAb inhibited the phagocytic ability of alveolar macrophages in vivo, resulting in the defective clearance of apoptotic cells in lungs. In summary, anti-TIM-3 mAb treatment might cause pneumonitis and it should be used with caution in clinical settings.