The providing multidisciplinary ILD diagnoses (PROMISE) study - study design of the national registry of Japan facilitating interactive online multidisciplinary discussion diagnosis.

BACKGROUND: Multidisciplinary discussion (MDD), in which physicians, radiologists, and pathologists communicate and diagnose together, has been reported to improve diagnostic accuracy compared to diagnoses made solely by physicians. However, even among experts, diagnostic concordance of MDD is not always good, and some patients may not receive a specific diagnosis due to insufficient findings. A provisional diagnosis based on the ontology with a diagnostic confidence level has recently been proposed. Additionally, we developed an artificial intelligence model to differentiate idiopathic pulmonary fibrosis (IPF) from other chronic interstitial lung diseases (ILD)s, which needs validation in a broader population. METHODS: This prospective nationwide ILD registry has recruited patients with newly diagnosed ILD at the referral respiratory hospitals in Japan and provides rapid MDD diagnoses and treatment recommendations through a central online MDD platform with a 3-year follow-up period. A modified diagnostic ontology is used. If no diagnosis reaches more than 50% certainty, the diagnosis is unclassifiable ILD. If multiple diseases are expected, the diagnosis with a high probability takes precedence. If the confidence levels for the top two possible diagnoses are equal, the diagnosis can be unclassifiable. The registry uses tentative diagnostic criteria for nonspecific interstitial pneumonia with organising pneumonia and smoking-related ILD not otherwise specified as possible new entities. Central MDD diagnosticians review the clinical data, test results, radiology images, and pathological specimens on a dedicated website and conduct MDD diagnoses using online meetings with a cloud-based reporting system. This study aims to (1) provide MDD diagnoses with treatment recommendations; (2) determine the overall ILD rates in Japan; (3) clarify the reasons for unclassifiable ILDs; (4) evaluate possible new disease entities; (5) identify progressive phenotypes and create a clinical prediction model; (6) measure the agreement rate between institutional and central diagnoses in ILD referral and non-referral centres; (7) identify key factors for each specific ILD diagnosis; and (8) create a new disease classification system based on treatment strategies, including the use of antifibrotic drugs. DISCUSSION: This study will provide ILD frequencies, including new entities, using central MDD on dedicated online systems, and develop a machine learning model for ILD diagnosis and prognosis prediction. TRIAL REGISTRATION: UMIN-CTR Clinical Trial Registry (UMIN000040678).

Risk factors for relapse of immune-related pneumonitis after 6-week oral prednisolone therapy: a follow-up analysis of a phase II study.

BACKGROUND: Immune-related pneumonitis (irP) is one of the most important immune-related adverse events caused by immune checkpoint inhibitors (ICIs). After corticosteroid therapy irP frequently relapses, which can interfere with cancer therapy. However, risk factors for irP relapse are unknown. METHODS: This study was a follow-up analysis of a phase II study that evaluated 56 patients with grade ≥ 2 irP treated with oral prednisolone, 1 mg/kg/day, tapered over 6 weeks. Clinical factors including patient characteristics, blood test findings, and response to prednisolone therapy were assessed to identify risk factors for irP relapse using the Fine-Gray test. RESULTS: Among 56 patients with irP, 22 (39.3%) experienced irP relapse after 6 weeks of prednisolone therapy during the follow-up observation period. Radiographic organising pneumonia (OP) pattern and duration to irP onset ≥ 100 days from ICI initiation were determined to be significant risk factors for irP relapse in a multivariate Fine-Gray test (hazard ratio [HR] = 3.17, 95% CI 1.37-7.32, p = 0.007, and HR = 2.61, 95% CI 1.01-6.74, p = 0.048, respectively). Other patient characteristics, blood test findings, irP severity, and response to prednisolone therapy were not associated with irP relapse. CONCLUSIONS: In irP patients treated with 6-week prednisolone tapering therapy, OP pattern and duration to irP onset ≥ 100 days were associated with relapse risk. Assessment of the risk factors for irP relapse will be helpful for irP management.

Association of constipation with the survival of patients with idiopathic interstitial pneumonias.

BACKGROUND: Constipation is associated with the prognosis of several chronic diseases. However, the effect of constipation on the prognosis of idiopathic interstitial pneumonias (IIPs) remains unclear. This study aimed to investigate the association between constipation and the prognosis of patients with IIPs. METHODS: In this single-center, observational study, the association between constipation and survival of patients with IIPs was retrospectively investigated using a marginal structural model (MSM) analysis with weighting of age, sex, body mass index, treatment (corticosteroids, immunosuppressants, and antifibrotic agents), and pulmonary function (percent predicted forced vital capacity and diffusing capacity of the lungs for carbon monoxide). RESULTS: A total of 433 patients with IIPs (148 and 285 patients with idiopathic pulmonary fibrosis [IPF] and those without IPF) were included in the study. During the observation period, 238 patients developed constipation. The MSM analysis showed that constipation was significantly associated with shorter overall survival (hazard ratio [HR], 2.374; 95% confidence interval, 1.924-2.928, p < 0.001). When the use of antifibrotic agents was weighted separately as nintedanib or pirfenidone, constipation was significantly associated with shorter survival (HR, 2.427; 95% CI, 1.972-2.988, p < 0.001; and HR, 2.395; 95% CI, 1.940-2.957, p < 0.001, respectively). Furthermore, a subgroup analysis showed that constipation was associated with worse survival in patients with IPF and in those without IPF, regardless of the disease severity. CONCLUSIONS: This study shows that constipation is an independent prognostic factor for patients with IIPs, suggesting its potential clinical utility.

3D-CT-derived lung volumes and mortality risk in patients with fibrotic hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is a complex and heterogenous interstitial lung disease (ILD) that occurs in susceptible individuals due to certain inhaled antigens. Fibrotic-HP is a major underlying disease of progressive pulmonary fibrosis. Therefore, in addition to the radiological features of HP, quantitatively measuring fibrosis is important to evaluate disease severity and progression. The present study aimed to compare three-dimensional computed tomography (3D-CT)-derived lung volumes (LVs) of patients with HP and determine its association with mortality risk. METHODS: In this retrospective and multicenter cohort study, 126 patients diagnosed with HP (fibrotic, n = 72 and non-fibrotic, n = 54) with a confidence level higher than moderate were enrolled. Each lobe LV was measured using 3D-CT at the time of diagnosis and standardized using predicted forced vital capacity. The 3D-CT LV was compared with those of 42 controls and 140 patients with idiopathic pulmonary fibrosis (IPF). RESULTS: Compared to patients with fibrotic-HP, the standardized total LV was significantly higher in controls and patients with non-fibrotic-HP and was similar in patients with IPF. Longitudinal analyses demonstrated that approximately half of the patients with fibrotic-HP had an annual decrease in total LV. Decreased total and lower-lobe LVs were associated with shorter survival, and were independently associated with mortality together with ongoing exposure to inciting antigens. A composite model consisting of ongoing exposure to inciting antigens and total or lower-lobe LV successfully classified mortality risk into three groups. CONCLUSIONS: Quantitatively measuring standardized LV can help determine disease severity, progression, and mortality risk in patients with fibrotic-HP.

Case of familial interstitial lung disease attributed to ATP-binding cassette transporter 3 gene mutation in identical twins.

Mutations in ABCA3 can result in surfactant deficiency, leading to respiratory distress syndrome in term neonates, and interstitial lung disease (ILD) in children. Here, we report an extremely rare case of ILD in an identical twin with novel ABCA3 germline mutations. Interestingly, they showed mostly similar, but slightly different, clinical features. Our cases suggest that, in addition to genetic factors, non-genetic factors are involved in the severity of the disease and its clinical course. Studies of gene-environment interactions, especially with twins, are needed, as they may contribute to the understanding of the clinical heterogeneity of ILD and its  association with various underlying conditions as well as rare variant mutations.

CXCL10 predicts autoimmune features and a favorable clinical course in patients with IIP: post hoc analysis of a prospective and multicenter cohort study.

BACKGROUND: Interstitial pneumonia with autoimmune features (IPAF), which does not meet any of the criteria for connective tissue diseases (CTD), has been attracting an attention in patients with idiopathic interstitial pneumonia (IIP). However, the biomarkers that reflect the clinical course of these patients have not been fully elucidated. OBJECTIVE: To identify useful serum biomarkers reflecting CTD-related features and favorable prognoses in patients with IIP. METHODS: This was a post hoc analysis of a prospective and multicenter cohort study between 2015 and 2020. Newly diagnosed patients with IIP were consecutively enrolled, and 74 autoimmune features and autoantibodies were comprehensively checked during IIP diagnosis. Serum levels of CXCL10, CXCL1, CCL2, BAFF, angiopoietin-2, and leptin were evaluated at the time of IIP diagnosis. RESULTS: Two hundred twenty-two patients (159 men and 63 women) with IIP were enrolled. The median observation duration was 36 months. The median age was 71 years old, and median %forced vital capacity (FVC) was 84.1% at the time of IIP diagnosis. The proportion of patients who met the classification criteria for IPAF was 11.7%. In patients with high serum CXCL10, changes in both %FVC and %diffusion lung capacity for carbon monoxide at one year were significantly higher than those in patients with low CXCL10 (p = 0.014 and p = 0.009, respectively), whereas these changes were not significant for other chemokines and cytokines. High CXCL10 levels were associated with acute/subacute onset (p < 0.001) and the diagnosis of nonspecific interstitial pneumonia with organizing pneumonia overlap (p = 0.003). High CXCL10 levels were related to a higher classification of IPAF (relative risk for IPAF was 3.320, 95%CI: 1.571-7.019, p = 0.003) and lower classification of progressive pulmonary fibrosis (PPF; relative risk for PPF was 0.309, 95%CI: 0.100-0.953, p = 0.027) compared to those with low CXCL10. Finally, survival was higher in patients with IPF and high CXCL10 (p = 0.044), and high CXCL10 was a significant prognostic factor in multivariate Cox proportional hazards models (hazard ratio 0.368, p = 0.005). CONCLUSIONS: High serum levels of CXCL10 are associated with CTD-related features, the favorable clinical course, and survival in patients with IIP, especially IPF. CLINICAL TRIAL NUMBER: Not applicable.

Obesity impairs ciliary function and mucociliary clearance in the murine airway epithelium.

Obesity is a risk factor for increased morbidity and mortality in viral respiratory infection. Mucociliary clearance (MCC) in the airway is the primary host defense against viral infections. However, the impact of obesity on MCC is unclear, prompting this study. Using murine tracheal tissue culture and in vitro influenza A virus (IAV) infection models, we analyzed cilia-driven flow and ciliary beat frequency (CBF) in the airway epithelium to evaluate MCC. Short-term IAV infection increased cilia-driven flow and CBF in control mice, but not in high-fat diet-induced obese mice. Basal cilia-driven flow and CBF were also lower in obese mice than in control mice. Mechanistically, the increase of extracellular adenosine triphosphate (ATP) release during IAV infection, which was observed in the control mice, was abolished in the obese mice; however, the addition of ATP increased cilia-driven flow and CBF both in control and obese mice to a similar extent. In addition, RNA sequencing and reverse transcription-polymerase chain reaction revealed the downregulation of several cilia-related genes, including Dnah1, Dnal1, Armc4, and Ttc12 (the dynein-related genes); Ulk4 (the polychaete differentiation gene); Cep164 (the ciliogenesis and intraflagellar transport gene); Rsph4a, Cfap206, and Ppil6 (the radial spoke structure and assembly gene); and Drc3(the nexin-dynein regulatory complex genes) in obese murine tracheal tissues compared with their control levels. In conclusion, our studies demonstrate that obesity attenuates MCC under basal conditions and during IAV infection by downregulating the expression of cilia-related genes and suppressing the release of extracellular ATP, thereby increasing the susceptibility and severity of IAV infection.NEW & NOTEWORTHY Our study shows that obesity impairs airway mucociliary clearance (MCC), an essential physical innate defense mechanism for viral infection. Mechanically, this is likely due to the obesity-induced downregulation of cilia-related genes and attenuation of extracellular ATP release. This study provides novel insights into the mechanisms driving the higher susceptibility and severity of viral respiratory infections in individuals with obesity.

Variability of radiological and clinical features in cases with usual interstitial pneumonia without honeycombing.

BACKGROUND: Usual interstitial pneumonia (UIP) cases without honeycombing (possible UIP) included various CT features and was often difficult to diagnose. PURPOSE: This study aimed to classify the cases with possible UIP on CT features using cluster analysis and evaluate the features of subsets of participants and the correlation of prognosis. MATERIALS AND METHODS: The study included 85 patients with possible UIP in the 2011 idiopathic pulmonary fibrosis (IPF) guideline with radiological diagnosis. All cases underwent surgical biopsies and were diagnosed by multidisciplinary discussion (MDD) from the nationwide registry in Japan. The readers evaluated pulmonary opacity, nodules, cysts, and predominant distribution which were reclassified by IPF guidelines in 2018. Additionally, cases were classified into four groups by cluster analysis based on CT findings. The differences in survival among IPF classification and the clusters were evaluated. RESULTS: Cases were diagnosed as IPF (n = 55), NSIP (n = 4), unclassifiable (n = 23), and others (n = 3) by MDD. Cluster analysis revealed 4 clusters by CT features (n = 47, 16, 19 and 3, respectively). Cluster 1 had fewer lesions overall. Cluster 2 have many pure ground-glass opacities and ground-glass opacities with reticulation. Cluster 3 had many reticular opacities and nodules with few lower predominant distributions. Cluster 4 was characterized by peribronchovascular consolidation.The mean survival time of cluster 1 (4518 days) was significantly better than cluster 2, 3, and 4 (1843, 2196, and 1814 days, respectively) (p = 0.03). CONCLUSION: In conclusion, UIP without honeycombing included various CT patterns and MDD diagnoses. Significangly differences in prognosis were observed among clusters classified by CT findings.

Antifibrotics and mortality in idiopathic pulmonary fibrosis: external validity and avoidance of immortal time bias.

BACKGROUND AND OBJECTIVE: Pooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity. METHODS: We used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event. RESULTS: Of 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine-Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81-0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86-0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65-0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78-0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations. CONCLUSIONS: The results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations.

Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial.

PURPOSE: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. PATIENTS AND METHODS: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. RESULTS: In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. CONCLUSION: The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

Characterization of BRAFThr599dup Mutation as a Targetable Driver Mutation Identified in Lung Adenocarcinoma by Comprehensive Genomic Profiling.

PURPOSE: Understanding the function of BRAF mutants is crucial for determining the best treatment strategy. This study aimed to characterize a rare BRAF variant, BRAFThr599dup, which was identified in a patient with lung adenocarcinoma (LUAD) by comprehensive genomic profiling. MATERIALS AND METHODS: We report a case of LUAD with BRAFThr599dup treated with dabrafenib and trametinib. We conditionally expressed wild-type BRAF, BRAFV600E, or BRAFThr599dup in Ba/F3 cells and BEAS-2B cells. Ba/F3 cells carrying double-mutant BRAF (BRAFThr599dup/R509H, BRAFV600E/R509H, or BRAFK601E/R509H) that lacked the dimerizing ability were also established. Knockout of endogenous BRAF or CRAF in Ba/F3-BRAFThr599dup cells and Ba/F3-BRAFV600E cells was performed using the CRISPR/Cas9 system. Cell viability, mitogen-activated protein kinase (MAPK) signaling activity, and sensitivity to dabrafenib and trametinib were evaluated. RESULTS: The patient was revealed to have BRAFThr599dup-positive tumor cells as a predominant clone, and dabrafenib and trametinib treatment showed modest efficacy. In Ba/F3 cells, both BRAFThr599dup and BRAFV600E similarly caused interleukin-3-independent proliferation and activated the MAPK pathway. Moreover, BRAFThr599dup and BRAFV600E similarly caused a significant increase in the anchorage-independent growth ability of BEAS-2B cells. Along with Ba/F3-BRAFV600E cells, Ba/F3-BRAFThr599dup cells were highly sensitive to a monomer-specific BRAF inhibitor, dabrafenib, with a half-maximal inhibitory concentration value of 29.7 nM. In the absence of wild-type BRAF, wild-type CRAF, or an intact dimer interface, the ability to induce oncogenic addiction and MAPK pathway activation in Ba/F3-BRAFThr599dup cells was not affected, which was in contrast to the findings in the BRAFK601E/R509H double-mutant model. CONCLUSION: BRAFThr599dup is a potent driver oncogene that activates the MAPK pathway without the requirement for dimerization in vitro. Because BRAFThr599dup has been recurrently reported across various cancer types, our findings should be further investigated both mechanistically and clinically.

Neutrophil-lymphocyte ratio being associated with mortality risk in patients receiving antifibrotic therapy.

BACKGROUND: Antifibrotic therapy is widely used for patients with progressive fibrotic interstitial lung disease (ILD), regardless of etiology. There is an urgent need for a simple, inexpensive, and repeatable biomarker to evaluate disease severity and mortality risk. METHODS: This retrospective multicohort study assessed the neutrophil-lymphocyte ratios (NLRs) of 416 patients with ILD who received antifibrotic therapy (Hamamatsu cohort, n = 217; Seirei cohort, n = 199). The mortality risk vs. NLR relationship was evaluated at therapy initiation and 1 year. The optimal NLR cutoff of 2.7 was selected according to the mortality risk. RESULTS: Survival was shorter in patients with high NLR than with low NLR (median: 2.63 vs. 4.01 years). The NLR classification results (cutoff: 2.7) were longitudinally preserved in >70 % of the patients, and patients with consistently high NLR had a higher risk of mortality than others (median, 2.97 vs. 4.42 years). In multivariate analysis, high NLR was significantly associated with mortality independent of age, sex, forced vital capacity, lung diffusing capacity for carbon monoxide (DLCO), or the gender-age-physiology (GAP) index. A combined GAP index-NLR assessment classified mortality risk into four groups. Subset analyses revealed that NLR assessment was more applicable to patients without advanced disease, not taking steroids, and with idiopathic pulmonary fibrosis (IPF) than to patients with advanced disease, taking steroids, and patients with Non-IPF. CONCLUSION: High NLR was associated with an increased mortality risk in patients with ILDs receiving antifibrotic therapy. Assessment of NLR may help predict disease severity and mortality risk in antifibrotic therapy.

Radiological and histopathological features and treatment response by subtypes of interstitial pneumonia with autoimmune features: A prospective, multicentre cohort study.

BACKGROUND: Patients with idiopathic interstitial pneumonia (IIP) have a favourable prognosis when they have interstitial pneumonia with autoimmune features (IPAF). However, precise IPAF-related findings from high-resolution computed tomography (HRCT) and lung histopathological specimens and the treatment response have not been fully determined. Therefore, this study was conducted to evaluate the relationship between findings on HRCT or lung histopathological specimens and the progression of interstitial pneumonia in patients with IPAF. METHODS: This multicentre cohort study prospectively enrolled consecutive patients with IIP. At the diagnosis of IIP, we systematically evaluated 74 features suggestive of connective tissue diseases and followed them up. HRCT, lung specimens, serum antibodies, and the clinical course were also evaluated. RESULTS: Among 222 patients with IIP, 26 (11.7%) fulfilled the IPAF criteria. During a median observation period of 36 months, patients with IPAF showed better survival than those without IPAF (p = 0.034). While histopathological findings were not related to IPAF, nonspecific interstitial pneumonia (NSIP) with organizing pneumonia (OP) overlap was the most prevalent HRCT pattern (p < 0.001) and the consolidation opacity was the most common radiological finding in IPAF (p = 0.017). Furthermore, in patients with IPAF, the diagnosis of COP or NSIP with OP overlap was associated with a higher increase in %FVC in 1 year than in those with idiopathic pulmonary fibrosis, NSIP, or unclassifiable IIP (p = 0.002). CONCLUSIONS: This study shows the presence of consolidation opacity on HRCT and the diagnosis of COP or NSIP with OP overlap are associated with IPAF and its favourable treatment response in patients with IPAF.

Impact of preexisting interstitial lung disease on mortality in COVID-19 patients from the early pandemic to the delta variant epidemic: a nationwide population-based study.

BACKGROUND: COVID-19 patients with preexisting interstitial lung disease (ILD) were reported to have a high mortality rate; however, this was based on data from the early stages of the pandemic. It is uncertain how their mortality rates have changed with the emergence of new variants of concern as well as the development of COVID-19 vaccines and treatments. It is also unclear whether having ILD still poses a risk factor for mortality. As COVID-19 continues to be a major concern, further research on COVID-19 patients with preexisting ILD is necessary. METHODS: We extracted data on COVID-19 patients between January 2020-August 2021 from a Japanese nationwide insurance claims database and divided them into those with and without preexisting ILD. We investigated all-cause mortality of COVID-19 patients with preexisting ILD in wild-type-, alpha-, and delta-predominant waves, to determine whether preexisting ILD was associated with increased mortality. RESULTS: Of the 937,758 adult COVID-19 patients, 7,333 (0.8%) had preexisting ILD. The proportion of all COVID-19 patients who had preexisting ILD in the wild-type-, alpha-, and delta-predominant waves was 1.2%, 0.8%, and 0.3%, respectively, and their 60-day mortality was 16.0%, 14.6%, and 7.5%, respectively. The 60-day mortality significantly decreased from the alpha-predominant to delta-predominant waves (difference - 7.1%, 95% confidence intervals (CI) - 9.3% to - 4.9%). In multivariable analysis, preexisting ILD was independently associated with increased mortality in all waves with the wild-type-predominant, odds ratio (OR) 2.10, 95% CI 1.91-2.30, the alpha-predominant wave, OR 2.14, 95% CI 1.84-2.50, and the delta-predominant wave, OR 2.10, 95%CI 1.66-2.66. CONCLUSIONS: All-cause mortality rates for COVID-19 patients with preexisting ILD decreased from the wild-type- to the more recent delta-predominant waves. However, these patients were consistently at higher mortality risk than those without preexisting ILD. We emphasize that careful attention should be given to patients with preexisting ILD despite the change in the COVID-19 environment.

CD109 Attenuates Bleomycin-induced Pulmonary Fibrosis by Inhibiting TGF-ß Signaling.

Pulmonary fibrosis is a fatal condition characterized by fibroblast and myofibroblast proliferation and collagen deposition. TGF-ß plays a pivotal role in the development of pulmonary fibrosis. Therefore, modulation of TGF-ß signaling is a promising therapeutic strategy for treating pulmonary fibrosis. To date, however, interventions targeting TGF-ß have not shown consistent efficacy. CD109 is a GPI-anchored glycoprotein that binds to TGF-ß receptor I and negatively regulates TGF-ß signaling. However, no studies have examined the role and therapeutic potential of CD109 in pulmonary fibrosis. The purpose of this study was to determine the role and therapeutic value of CD109 in bleomycin-induced pulmonary fibrosis. CD109-transgenic mice overexpressing CD109 exhibited significantly attenuated pulmonary fibrosis, preserved lung function, and reduced lung fibroblasts and myofibroblasts compared with wild-type (WT) mice. CD109-/- mice exhibited pulmonary fibrosis comparable to WT mice. CD109 expression was induced in variety types of cells, including lung fibroblasts and macrophages, upon bleomycin exposure. Recombinant CD109 protein inhibited TGF-ß signaling and significantly decreased ACTA2 expression in human fetal lung fibroblast cells in vitro. Administration of recombinant CD109 protein markedly reduced pulmonary fibrosis in bleomycin-treated WT mice in vivo. Our results suggest that CD109 is not essential for the development of pulmonary fibrosis, but excess CD109 protein can inhibit pulmonary fibrosis development, possibly through suppression of TGF-ß signaling. CD109 is a novel therapeutic candidate for treating pulmonary fibrosis.

Pan-cancer assessment of antineoplastic therapy-induced interstitial lung disease in patients receiving subsequent therapy immediately following immune checkpoint blockade therapy.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a serious adverse event potentially induced by any antineoplastic agent. Whether cancer patients are predisposed to a higher risk of DIILD after receiving immune checkpoint inhibitors (ICIs) is unknown. METHODS: This study retrospectively assessed the cumulative incidence of DIILD in consecutive cancer patients who received post-ICI antineoplastic treatment within 6 months from the final dose of ICIs. There was also a separate control cohort of 55 ICI-naïve patients with non-small cell lung cancer (NSCLC) who received docetaxel. RESULTS: Of 552 patients who received ICIs, 186 met the inclusion criteria. The cohort predominantly comprised patients with cancer of the lung, kidney/urinary tract, or gastrointestinal tract. The cumulative incidence of DIILD in the entire cohort at 3 and 6 months was 4.9% (95% confidence interval [CI] 2.4%-8.7%) and 7.2% (95% CI 4.0%-11.5%), respectively. There were significant differences according to cancer type (Gray's test, P = .04), with the highest cumulative incidence of DIILD in patients with lung cancer being 9.8% (95% CI 4.3%-18.0%) at 3 months and 14.2% (95% CI 7.3%-23.3%) at 6 months. DIILD was caused by docetaxel in six of these 11 lung cancer patients (54.5%). After matching, the cumulative incidence of docetaxel-induced ILD in patients with NSCLC in the post-ICI setting was higher than that in the ICI-naïve setting: 13.0% (95% CI 3.3%-29.7%) vs 4.3% (95% CI 0.3%-18.2%) at 3 months; and 21.7% (95% CI 7.9%-39.9%) vs 4.3% (95% CI 0.3%-18.2%) at 6 months. However, these were not significant differences (hazard ratio, 5.37; 95% CI 0.64-45.33; Fine-Gray P = .12). CONCLUSIONS: Patients with lung cancer were at high risk of developing DIILD in subsequent regimens after ICI treatment. Whether NSCLC patients are predisposed to additional risk of docetaxel-induced ILD by prior ICIs warrants further study.

Standardized 3D-CT lung volumes for patients with acute exacerbation of rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Fibrotic interstitial lung disease (ILD) is a progressive lung disease characterized by loss of lung volume, resulting in a leading cause of death in patients with RA. Crucially, acute exacerbation (AE) of ILD shows higher morbidity and mortality with rapid deterioration of the lungs. However, a quantitative assessment for physiological changes at AE has yet to be performed. This study hypothesized that quantitative assessments of lung volume (LV) accurately indicate disease severity and mortality risk in patients with AE-RA-ILD. METHODS: This multicentre cohorts study quantitatively assessed physiological changes of RA-ILD at diagnosis (n = 54), at AE (discovery-cohorts; n = 20, and validation-cohort; n = 33), and controls (n = 35) using 3D CT (3D-CT) images. LV was quantitatively measured using 3D-CT and standardized by predicted forced vital capacity. RESULTS: Patients with RA-ILD at diagnosis showed decreased LV, predominantly in lower lobes, compared with controls. Further substantial volume loss was found in upper- and lower lobes at AE compared with those at diagnosis. During AE, decreased standardized 3D-CT LV was associated with a worse prognosis in both cohorts. Subsequently, standardized 3D-CT LV was identified as a significant prognostic factor independent of age, sex and the presence of UIP pattern on CT by multivariate analyses. Notably, a composite model of age and standardized 3D-CT LV successfully classified mortality risk in patients with AE-RA-ILD. CONCLUSION: Volume loss at AE in patients with RA-ILD was associated with increased mortality. Assessing physiological change using standardized 3D-CT might help evaluate disease severity and mortality risk in patients with AE-RA-ILD.

Association of the lung immune prognostic index with the survival of patients with idiopathic interstitial pneumonias.

BACKGROUND AND OBJECTIVE: The lung immune prognostic index (LIPI), a simple index calculated from the blood lactate dehydrogenase level and derived neutrophil-to-lymphocyte ratio, is thought to be associated with host immune status. However, the utility of LIPI in patients with idiopathic interstitial pneumonias (IIPs) is unknown. METHODS: In this multicentre, retrospective, observational study, an association between LIPI and the survival of patients with IIPs was evaluated. RESULTS: Exploratory and validation cohorts consisting of 460 and 414 patients with IIPs, respectively, were included (159 and 159 patients had idiopathic pulmonary fibrosis [IPF], and 301 and 255 had non-IPF, respectively). In the exploratory cohort, patients with IPF and a low LIPI had significantly better survival than those with a high LIPI (median of 5.6 years vs. 3.9 years, p = 0.016). The predictive ability of LIPI for the survival of patients with IPF was validated in the validation cohort (median of 8.5 years vs. 4.4 years, p = 0.003). In a multivariate Cox proportional hazard analysis, LIPI was selected as an independent predictive factor for the survival of IPF patients. There was no significant association between LIPI and survival of non-IPF patients in the exploratory and validation cohorts. CONCLUSION: The LIPI was a predictive factor for the survival of patients with IPF and could aid the management of IPF.