Publications by authors named "Yoshikazu Inoue"

207 Publications

Idiopathic pulmonary fibrosis: Physician and patient perspectives on the pathway to care from symptom recognition to diagnosis and disease burden.

Respirology 2021 Oct 5. Epub 2021 Oct 5.

Development, Medical Affairs, Galapagos NV, Mechelen, Belgium.

Background And Objective: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease that requires ongoing care and is associated with considerable socioeconomic burden. We evaluated the IPF care pathway from symptom recognition to treatment. We describe the impact of IPF on healthcare resource use (HCRU), quality of life (QoL) and work impairment, and report differences in patient and physician perspectives using real-world data from France, Germany, Japan and the United States.

Methods: Quantitative, point-in-time data were collected as part of the Adelphi IPF II Disease Specific Programme™. Physician-reported data (patient demographics, medical history, diagnoses, treatment) were matched to patient-reported data (HCRU, QoL, work impairment). HCRU was measured as physician visits and hospitalizations. QoL and work impairment were measured using the EuroQol-5 Dimensions (EQ-5D) and Work Productivity and Activity Impairment questionnaires.

Results: Overall, 244 physicians reported data on 1249 patients, 739 of whom self-reported data. Diagnostic delays of 0.8 (Germany) to 2.0 (Japan) years after symptom onset were reported; treatment initiation was further delayed. In all countries, patients more often reported symptoms in the survey than did their physicians. On average, patients underwent 7-10 clinical tests before diagnosis. Antifibrotic use increased from 57% (2016) to 69% (2019); only 50% of patients with moderate/severe IPF were satisfied with their treatment. The 12-month hospitalization rates were 24% (Japan) to 64% (United States). Patients reported low QoL (mean EQ-5D visual analogue scale: 61.7/100).

Conclusion: Patients with IPF experience considerable diagnostic and treatment delays. More effective therapies and management are needed to reduce the disease burden.
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http://dx.doi.org/10.1111/resp.14154DOI Listing
October 2021

2020 guide for the diagnosis and treatment of interstitial lung disease associated with connective tissue disease.

Respir Investig 2021 Sep 30. Epub 2021 Sep 30.

Department of Diagnostic Radiology, Saitama International Medical Center, Saitama Medical University, Hidaka, Saitama, Japan.

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.
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http://dx.doi.org/10.1016/j.resinv.2021.04.011DOI Listing
September 2021

Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: Subgroup analysis of the randomised, double-blind, placebo-controlled, phase 3 INBUILD trial.

Respir Med 2021 Aug 12;187:106574. Epub 2021 Aug 12.

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. Electronic address:

Background: The efficacy of nintedanib in progressive fibrosing interstitial lung diseases (ILDs) was demonstrated in the randomised, double-blind, placebo-controlled INBUILD trial. This subgroup analysis evaluated the efficacy and safety of nintedanib in the Japanese population.

Methods: Patients with progressive fibrosing ILDs (evaluated by physicians within 24 months of screening) were randomised (1:1) to twice-daily 150-mg nintedanib or placebo; treatment continued until the last patient completed 52 weeks. The primary endpoint was the annual rate of decline in forced vital capacity (FVC) over 52 weeks. Time-to-first acute ILD exacerbation or death and time-to-death up until the last patient had completed the week 52 visit were evaluated. This subgroup analysis included 108 Japanese patients.

Results: The adjusted annual rates of FVC decline (mL/year) over 52 weeks for Japanese patients were -148.31 (nintedanib) and -240.36 (placebo), adjusted difference: 92.05 (95% CI: -10.69-194.80) and for non-Japanese patients were -67.41 (nintedanib) and -177.65 (placebo), adjusted difference: 110.24 (95% CI: 64.97-155.52). No heterogeneity in treatment effect between Japanese and non-Japanese subgroups was observed (treatment-by-subgroup interaction, p = 0.75). The risks of "acute exacerbation or death" (hazard ratio, 0.30 [95% CI: 0.10-0.91]) and mortality (hazard ratio, 0.54 [95% CI: 0.14-2.11]) in Japanese patients were numerically lower for nintedanib than placebo. There were no new or unexpected safety findings.

Conclusions: In Japanese patients, nintedanib slowed ILD progression, evidenced by a reduction in the annual rate of decline in FVC vs placebo. The efficacy and safety of nintedanib in Japanese patients were consistent with the overall INBUILD population. CLINICALTRIALS.GOV: NCT02999178 (21-Dec-2016).
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http://dx.doi.org/10.1016/j.rmed.2021.106574DOI Listing
August 2021

Nintedanib in progressive interstitial lung diseases: data from the whole INBUILD trial.

Eur Respir J 2021 Sep 2. Epub 2021 Sep 2.

Department of Medicine, National Jewish Health, Denver, CO, USA

The primary analysis of the INBUILD trial showed that in subjects with progressive fibrosing interstitial lung diseases (ILDs), nintedanib slowed the decline in forced vital capacity (FVC) over 52 weeks. We report the effects of nintedanib on ILD progression over the whole trial.Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice, were randomised to receive nintedanib or placebo. Subjects continued on blinded randomised treatment until all subjects had completed the trial. Over the whole trial, mean (sd) exposure to trial medication was 15.6 (7.2) and 16.8 (5.8) months in the nintedanib and placebo groups, respectively.In the nintedanib (n=332) and placebo (n=331) groups, respectively, the proportions of subjects who had ILD progression (absolute decline in FVC ≥10% predicted) or died were 40.4% and 54.7% in the overall population (HR 0.66 [95% CI: 0.53, 0.83]; p=0.0003), and 43.7% and 55.8% among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT) (HR 0.69 [0.53, 0.91]; p=0.009). In the nintedanib and placebo groups, respectively, the proportions who had an acute exacerbation of ILD or died were 13.9% and 19.6% in the overall population (HR 0.67 [95% CI: 0.46, 0.98]; p=0.04), and 15.0% and 22.8% among subjects with a UIP-like fibrotic pattern on HRCT (HR 0.62 [0.39, 0.97]; p=0.03).Based on data from the whole INBUILD trial, nintedanib reduced the risk of events indicating ILD progression.
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http://dx.doi.org/10.1183/13993003.04538-2020DOI Listing
September 2021

Drug-related pneumonitis with radiographic hypersensitivity pneumonitis pattern: Three case series.

Respir Med Case Rep 2021 18;34:101498. Epub 2021 Aug 18.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-Cho, Kita-Ku, Sakai City, Osaka, 591-8555, Japan.

Novel therapies have recently emerged for various diseases, and the management of drug-related pneumonitis (DRP) has become increasingly important. In particular, the hypersensitivity pneumonitis (HP) pattern of DRP has been increasingly recognized due to development of new therapeutic strategies, such as immunotherapy. However, literature describing detailed clinical cases is still lacking. Herein, we report three cases of DRP with typical HP radiographic pattern. These patients were treated with different drugs, namely nano albumin-bound (nab)-paclitaxel, everolimus, or nivolumab, but had common clinical features, including a good prognosis.
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http://dx.doi.org/10.1016/j.rmcr.2021.101498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390688PMC
August 2021

Prognostic significance of serum cytokines during acute exacerbation of idiopathic interstitial pneumonias treated with thrombomodulin.

BMJ Open Respir Res 2021 07;8(1)

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai City, Japan

Background: Acute exacerbation (AE) has been reported to herald a poor prognosis in idiopathic pulmonary fibrosis and is now thought to do so in idiopathic interstitial pneumonias (IIPs). However, the pathophysiology of AE-IIPs is not sufficiently understood. In our previously reported SETUP trial, we found better survival in patients with AE-IIPs treated with corticosteroids and thrombomodulin than in those treated with corticosteroids alone. In that study, we collected serum samples to evaluate changes in cytokine levels and retrospectively examined the prognostic significance and pathophysiological role of serum cytokines in patients with AE-IIPs.

Methods: This study included 28 patients from the SETUP trial for whom serial serum samples had been prospectively obtained. AE-IIPs were diagnosed using the Japanese Respiratory Society criteria. All patients were treated with intravenous thrombomodulin and corticosteroids from 2014 to 2016. Serum levels of 27 cytokines were measured using Bio-Plex. The high-resolution CT pattern at the time of diagnosis of AE was classified as diffuse or non-diffuse.

Results: Univariate analysis revealed that higher serum levels of interleukin (IL)-2, IL-7, IL-9, IL-12, IL13, basic fibroblast growth factor, granulocyte-macrophage colony-stimulating factor, interferon-γ inducible protein-10, platelet-derived growth factor and regulated on activation, normal T cell expressed and secreted (RANTES) at AE were significant predictors of 90-day survival. The HRCT pattern was also a significant clinical predictor of 90-day survival. Multivariate analysis with stepwise selection identified a higher serum RANTES level at AE to be a significant predictor of 90-day survival, including after adjustment for HRCT pattern. Multivariate analysis with stepwise selection suggested that a marked increase in the serum IL-10 level on day 8 could predict 90-day mortality.

Conclusions: A higher serum RANTES level at AE the time of diagnosis predicted a good survival outcome, and an elevated serum IL-10 level on day 8 predicted a poor survival outcome.

Trial Registration Number: UMIN000014969.
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http://dx.doi.org/10.1136/bmjresp-2021-000889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323382PMC
July 2021

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

Thorax 2021 Jul 16. Epub 2021 Jul 16.

Respiratory Medicine, Shizuoka City Shimizu Hospital, Shizuoka, Japan.

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.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216263DOI Listing
July 2021

Molecular Epidemiology of Drug-Resistant Mycobacterium Tuberculosis in Japan.

mSphere 2021 08 7;6(4):e0097820. Epub 2021 Jul 7.

Department of Microbiology, Faculty of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan.

Clinical isolates of drug-resistant (isoniazid and/or rifampicin-resistant) Mycobacterium tuberculosis were obtained from 254 patients diagnosed with drug-resistant tuberculosis in Japan from April 2015 to March 2017 in National Hospital Organization hospitals. The 254 patients were approximately 32% of all 795 patients who were diagnosed with culture-confirmed drug-resistant tuberculosis from 2015 to 2016 nationwide in Japan. The whole-genome sequences of all the isolates from the 254 patients and the lineages of these isolates were determined, and phylogenetic trees were constructed based on single nucleotide polymorphism concatemers. Of these patients, 202 (79.5%) were born in Japan and 52 (20.5%) were born elsewhere. Of the 254 drug-resistant isolates, 54 (21.3%) were multidrug resistant, being resistant to both isoniazid and rifampicin. The percentages of multidrug-resistant isolates were significantly higher in foreign-born (38.5% [20/52]) than Japanese-born patients (16.8% [34/202]). Of the 54 multidrug-resistant isolates, nine were extensively drug resistant, which were all obtained from Japanese-born patients. Five extensively drug-resistant isolates were obtained from patients with incipient tuberculosis. A significant number of multidrug-resistant M. tuberculosis strains were isolated from foreign-born patients from Asian countries that have a high tuberculosis burden. Foreign-derived isolates affect the nationwide genetic diversity of drug-resistant M. tuberculosis in Japan. Extensively drug-resistant M. tuberculosis isolates were transmitted among the Japanese population. The incidence rate of tuberculosis (TB) in Japan was 11.5 per 100,000 of the population in 2019. Of TB patients in Japan, 61.1% were aged >70 years, and 10.7% were born outside Japan, mostly in Asian countries with a high burden of tuberculosis. Of the tuberculosis patients in the present study, 5.4% and 1.0% showed resistance to isoniazid and rifampicin, respectively, and 0.7% were multidrug resistant. The objective of this study was to clarify the molecular epidemiological properties of drug-resistant tuberculosis in Japan. Molecular epidemiology provides several clues to inform potential measures to control drug-resistant tuberculosis in Japan.
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http://dx.doi.org/10.1128/mSphere.00978-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386464PMC
August 2021

Predictors of Morphine Efficacy for Dyspnea in Inpatients with Chronic Obstructive Pulmonary Disease: A Secondary Analysis of JORTC-PAL 07.

Palliat Med Rep 2021 7;2(1):15-20. Epub 2021 Jan 7.

Department of Palliative Care, National Center for Geriatrics and Gerontology, Obu, Japan.

This study aimed to explore the predictors of morphine efficacy in the alleviation of dyspnea in COPD. Dyspnea is prevalent in patients with chronic obstructive pulmonary disease (COPD) and often persists despite conventional treatment. A secondary analysis of a multi-institutional prospective before-after study was conducted focusing on morphine use for alleviating dyspnea in COPD patients. Subjects included COPD patients with dyspnea at seven hospitals in Japan. Patients received 12 mg/day of oral morphine (or 8 mg/day if they had low body weight or renal impairment). Univariate and multivariate logistic regression analyses were performed with numerical rating scale (NRS) score of the current dyspnea intensity in the evening of day 0, Eastern Cooperative Oncology Group Performance Status (ECOG PS; ≤2 or ≥3), age, and partial arterial pressure of carbon dioxide (PaCO) as independent factors; an improvement of ≥1 in the evening NRS score of dyspnea from day 0 to 2 was the dependent factor. Thirty-five patients were enrolled in this study between October 2014 and January 2018. Excluding one patient who did not receive the treatment, data from 34 patients were analyzed. In the multivariate analysis, lower PaCO was significantly associated with morphine efficacy for alleviating dyspnea (odds ratio [OR] 0.862, 95% confidence interval [CI] 0.747-0.994), whereas the NRS of dyspnea intensity on day 0 (OR 1.426, 95% CI 0.836-2.433), ECOG PS (OR 4.561, 95% CI 0.477-43.565), and patients' age (OR 0.986, 95% CI 0.874-1.114) were not. Morphine can potentially alleviate dyspnea in COPD patients with lower PaCO. Trial registration: UMIN000015288 (http://www.umin.ac.jp/ctr/index.htm).
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http://dx.doi.org/10.1089/pmr.2020.0078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241369PMC
January 2021

Diagnostic yield and safety of bronchofiberscopy for pulmonary alveolar proteinosis.

Respir Investig 2021 May 6. Epub 2021 May 6.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai City, Osaka 591-8555, Japan. Electronic address:

Background: Pulmonary alveolar proteinosis (PAP) is a diffuse lung disease characterized by the abnormal accumulation of surfactant-like material within the alveolar spaces and distal bronchioles. If high-resolution computed tomography (HRCT) indicates the presence of PAP, a definitive diagnosis of PAP is established when consistent pathological findings are obtained. Herein, we retrospectively studied the yield and safety of bronchofiberscopy in the diagnosis of PAP.

Methods: One hundred and fifty consecutive patients with PAP were prospectively registered in the PAP cohort database of the National Hospital Organization Kinki-Chuo Chest Medical Center between January 1991 and December 2018. We examined 86 patients who underwent bronchofiberscopy with bronchoalveolar lavage (BAL) and transbronchial lung forceps biopsy (TBLB).

Results: The patients included 56 men and 30 women, with a median age of 57 years. All patients had autoimmune PAP, and the median level of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies was 42.8 μg/mL. The diagnostic yield was 90.7% (78/86) with BAL and 81.4% (70/86) with TBLB. The combination of BAL and TBLB increased the yield to 98.8%. Age, disease severity score, and frequency of traction bronchiectasis on HRCT were significantly different between the TBLB-positive and TBLB-negative groups. No patient developed serious complications due to bronchofiberscopy; TBLB-related complications included pneumothorax (3.5%) and minimal bleeding (7.0%).

Conclusions: Bronchofiberscopy, in combination with BAL and TBLB, is an effective and safe method for the diagnosis of PAP, with a yield of 98.8%.
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http://dx.doi.org/10.1016/j.resinv.2021.03.012DOI Listing
May 2021

B cell-activating factors in autoimmune pulmonary alveolar proteinosis.

Orphanet J Rare Dis 2021 03 2;16(1):115. Epub 2021 Mar 2.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-Cho, Kita-Ku, Sakai City, Osaka, 591-8555, Japan.

Background: Autoimmune pulmonary alveolar proteinosis (APAP) results from the suppression of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling by a neutralizing autoantibody against GM-CSF. B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are involved in immunoglobulin G production and are overproduced in various autoimmune disorders. We hypothesized that BAFF and/or APRIL levels would be elevated in serum and bronchoalveolar lavage fluid (BALF) and serum and BALF levels of BAFF and APRIL respond to the treatments (whole lung lavage (WLL) or inhalation of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF)) in patients with APAP.

Subjects And Methods: BAFF and APRIL levels in serum and BALF from 110 patients with APAP were measured at baseline and during and after treatment, using an enzyme-linked immunosorbent assay kit. We enrolled 34 healthy volunteers as serum cytokine controls, and 13 disease controls for BALF. Associations of BAFF and APRIL levels with clinical measures were assessed to clarify their clinical roles.

Results: In patients with APAP, serum BAFF and APRIL levels were significantly increased relative to healthy volunteers (p < 0.0001 and p < 0.05, respectively), and BALF BAFF and APRIL levels were significantly increased versus disease controls (p < 0.0001 and p < 0.01, respectively). Serum BAFF levels (but not APRIL levels) were significantly correlated with Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, SP-A, and lactate dehydrogenase (p < 0.0001). There was no significant correlation between serum BAFF or APRIL levels and anti-GM-CSF autoantibody. BAFF and APRIL were negatively correlated with single-breath diffusion capacity for carbon monoxide (DLco) (p = 0.004) and forced vital capacity (p = 0.04), respectively. BAFF (but not APRIL) in BALF was negatively correlated with vital capacity (p = 0.04) and DLco (p = 0.006). There were significant correlations between disease severity and BAFF levels in serum (p = 0.04) and BALF (p = 0.007). Serum levels of anti-GM-CSF autoantibody, BAFF, and APRIL were not significantly affected by WLL or inhalation of recombinant human GM-CSF.

Conclusions: BAFF and APRIL levels of sera and BALF in APAP were significantly increased compared with healthy volunteer and disease control, and the BAFF and APRIL pathway might have important specific roles in pathogenesis of APAP. Our data suggest a new perspective of future treatment for APAP.
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http://dx.doi.org/10.1186/s13023-021-01755-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923513PMC
March 2021

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Nat Commun 2021 02 15;12(1):1032. Epub 2021 Feb 15.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
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http://dx.doi.org/10.1038/s41467-021-21011-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884840PMC
February 2021

Comparison of drug-susceptibility patterns and gene sequences associated with clarithromycin and azithromycin resistance in complex isolates and evaluation of the accumulation of intrinsic macrolide resistance.

J Med Microbiol 2021 Mar 11;70(3). Epub 2021 Feb 11.

Internal Medicine, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai-shi, Osaka, Japan.

complex (MABC) is an infectious agent associated with macrolide resistance and treatment failure. Despite drug-susceptibility testing for MABC isolates including clarithromycin (CAM), long-term treatment with azithromycin (AZM) for MABC disease is recommended. We compared phenotypic and genotypic resistance to AZM and CAM in clinical isolates and evaluated the accumulation of intrinsic macrolide resistance (AIM) and morphological changes by macrolides exposure. Forty-nine isolates were characterized regarding (41) sequevars. Sequencing data were compared to the nucleotide sequence of and . The AIM MIC was performed in three reference strains and 15 isolates were randomized [each set of five isolates with subsp. (MAA) T28, MAA C28 and subsp. (MAM)]. The 49 isolates were distributed as 24 MAA T28, 5 MAA C28 and 20 MAM. The MIC values to CAM at day 3 in MAA T28, C28 and MAM were 1, 0.12 and 0.12 µg ml, while those at day 14 were 32, 0.5 and 0.12 µg ml, respectively. The AZM-MIC values at day 3 of the above isolates were 4, 0.25 and 0.5 µg ml, while those at day 14 were >64, 0.5 and 0.5 µg ml, respectively. Neither mutations in of MAA T28 with acquired resistance nor deletions in of MAA T28 without inducible resistance were observed . For AIM MIC, MAA T28 showed that the time-to-detection of AZM resistance was significantly faster over that of CAM (<0.05). Morphological changes were not determined in all isolates. Our findings did not support the suggestion for the preferential use of AZM for, at least, MAA T28 disease due to the high-level MIC value and the increased AIM. The long duration of AZM-based treatment eventually may favour the emergence of isolates with a high-level of intrinsic resistance.
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http://dx.doi.org/10.1099/jmm.0.001326DOI Listing
March 2021

Multi-Institutional Prospective Cohort Study of Patients With Pulmonary Hypertension Associated With Respiratory Diseases.

Circ J 2021 03 2;85(4):333-342. Epub 2021 Feb 2.

Department of Respirology, Graduate School of Medicine, Chiba University.

Background: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis.Methods and Results:Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI.

Conclusions: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.
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http://dx.doi.org/10.1253/circj.CJ-20-0939DOI Listing
March 2021

Histologically Proven Dendriform Pulmonary Ossification: A Five-case Series.

Intern Med 2021 Jul 1;60(14):2261-2268. Epub 2021 Feb 1.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Japan.

Dendriform pulmonary ossification (DPO) is a rare condition characterized by metaplastic bone formation in the lung parenchyma. It has been reported to be often associated with primary lung diseases, such as usual interstitial pneumonia (UIP) or chronic aspiration of gastric acid; however, its clinical features and pathophysiology remain unclear, especially in idiopathic cases. We herein report five DPO cases, including three with an idiopathic origin. In all cases of idiopathic DPO, the pathological and radiological examinations showed localized pulmonary lesions suggesting inflammation or hemorrhaging.
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http://dx.doi.org/10.2169/internalmedicine.5906-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355403PMC
July 2021

Chest CT Diagnosis and Clinical Management of Drug-Related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper From the Fleischner Society.

Chest 2021 03 12;159(3):1107-1125. Epub 2021 Jan 12.

Center for Pulmonary Functional Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others.
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http://dx.doi.org/10.1016/j.chest.2020.11.027DOI Listing
March 2021

Resumption/efficacy and safety of an azithromycin-containing regimen against Mycobacterium avium complex lung disease in patients who experienced adverse effects with a clarithromycin-containing regimen.

Respir Investig 2021 Mar 9;59(2):212-217. Epub 2021 Jan 9.

Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, Japan.

Background: Antibiotic therapy, including clarithromycin (CLR), has been widely used for the management of Mycobacterium avium complex (MAC) lung disease in clinical settings. When patients develop adverse events (AEs) during CLR-based treatment, the treatment regimen is modified or chemotherapy itself is discontinued. The need for alternative macrolide treatment strategies is emphasized due to the high rate of AEs possibly caused by CLR. Thus, the current study aimed to examine the efficacy and safety of azithromycin (AZM) in patients with MAC lung disease whose treatment was switched from CLR to AZM.

Methods: We performed a retrospective study of patients with MAC lung disease. The inclusion criteria were as follows: (1) patients who experienced AEs during treatment with antibiotics, including CLR, between December 2012 and November 2017, and (2) those who had antimicrobial therapy that was switched from CLR to AZM. The efficacy and safety of AZM during the clinical course of the disease after switching the regimen from CLR to AZM were investigated.

Results: Antibiotic therapy was switched in 31 patients who presented with AEs including drug-induced fever, rash, dysgeusia, liver dysfunction, and neutropenia during treatment with CLR-containing regimens. After switching to AZM, the median duration of treatment was 1286 (364-4615) days. During follow-up, 13 patients had a negative conversion of sputum culture.

Conclusions: AZM may be safe and effective for patients with MAC lung disease who have difficulty tolerating CLR. In patients who experienced AEs possibly caused by CLR, switching from CLR to AZM might be an appropriate strategy.
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http://dx.doi.org/10.1016/j.resinv.2020.09.010DOI Listing
March 2021

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper from the Fleischner Society.

Radiology 2021 03 12;298(3):550-566. Epub 2021 Jan 12.

From the Department of Radiology, Kansai Rosai Hospital, Amagasaki, Japan (T.J.); Department of Radiology, Samsung Medical Center (K.S.L., H.Y.L.) and Department of Health Sciences and Technology, SAIHST (H.Y.L.), Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea; Department of Imaging, Dana-Farber Cancer Institute, Boston, Mass (M.N.); Department of Radiology (M.N.) and Center for Pulmonary Functional Imaging (H.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY (W.D.T.); Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minn (J.H.R.); Department of Medicine, University of British Columbia and Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada (C.J.R.); Department of Radiology, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain (T.F.); Department of Radiology, University of Massachusetts Medical Center, Worcester, Mass (A.A.B.); Departments of Medicine (K.K.B.) and Radiology (D.A.L.), National Jewish Health, Denver, Colo; Department of Radiology, Seoul National University College of Medicine, Seoul, Korea (J.M.G.); Diagnostic and Interventional Radiology, University Hospital Heidelberg, Translational Lung Research Center Heidelberg, member of the German Center of Lung Research, Heidelberg, Germany (H.U.K.); Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, England (A.G.N.); Complex Operative Unit of Pneumology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy (L.R.); Department of Radiology, Meander Medical Center, Amersfoort, the Netherlands (C.M.S.P.); Department of Radiology, University Hospitals Leuven, Leuven, Belgium (J.V.); Division of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, Northwell Health System, New York, NY (S.R.); Department of Radiology, Duke University School of Medicine, Durham, NC (G.D.R.); Department of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY (C.P.); and Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Osaka, Japan (Y.I.).

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others. This article is a simultaneous joint publication in and . The articles are identical except for stylistic changes in keeping with each journal's style. Either version may be used in citing this article. Published under a CC BY 4.0 license.
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http://dx.doi.org/10.1148/radiol.2021203427DOI Listing
March 2021

Lymphoplasmacytic lymphoma involving the mediastinum and the lung, followed by amyloidosis: A surgically and genetically proven case.

Respir Med Case Rep 2020 1;31:101313. Epub 2020 Dec 1.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-Cho, Kita-Ku, Sakai City, Osaka, 591-8555, Japan.

A 60-year-old man was admitted for ground glass opacity in the lower lung field and mediastinal lymphadenopathy. Blood tests revealed elevated serum IgM levels, and the urine test detected Bence-Jones protein. Surgical biopsy from the mediastinal lymph node and lung showed small lymphocytes and plasma cells between follicles, and AL kappa amyloid deposition. Genetic examination detected L265P mutation. Our diagnosis was lymphoplasmacytic lymphoma (LPL), involving the mediastinum and the lung, followed by amyloidosis. Mutation analysis, in addition to conventional histological evaluation, was useful for a precise diagnosis.
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http://dx.doi.org/10.1016/j.rmcr.2020.101313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723813PMC
December 2020

Current monitoring and treatment of progressive fibrosing interstitial lung disease: a survey of physicians in Japan, the United States, and the European Union.

Curr Med Res Opin 2021 02 11;37(2):327-339. Epub 2021 Jan 11.

National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.

Objective: To understand assumptions about and approaches to interstitial lung disease (ILD), including those of the progressive phenotype (progressive fibrosing ILD), this multinational survey assessed physicians' attitudes toward, knowledge of, and management strategies for progressive fibrosing ILD.

Methods: This internet-based survey of physicians was conducted between November 2018 and February 2019. Practical management strategies for progressive fibrosing ILD, and current approaches to the assessment and treatment of ILD, were compared between countries/regions (Japan vs. United States and European Union) and specialties (pulmonologists vs. rheumatologists).

Results: The survey was completed by 574 respondents. Compared with Western countries, the progressive fibrosing phenotype concept was not widely understood by Japanese respondents, with no notable differences in the understanding of this phenotype between pulmonologists and rheumatologists. Across all regions, pulmonary function tests, diffusing capacity of the lungs for carbon monoxide assessments, and pulse oximeter measurements were commonly performed at intervals of ≤6 months. In general, physicians in the United States and European Union preferred physiologic approaches for follow-up, while those in Japan preferred imaging and blood monitoring. Compared with rheumatologists, pulmonologists performed more frequent monitoring of autoimmune ILDs, and the differences between specialties were most pronounced in Japan. Regional differences in treatment approaches were observed, probably reflecting the local availability of agents and healthcare environments.

Conclusions: Awareness and management of progressive fibrosing ILD varied between specialties and regions, highlighting an unmet need for standardized diagnosis, treatment guidelines, and specialist education in this area.
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http://dx.doi.org/10.1080/03007995.2020.1860920DOI Listing
February 2021

Two New Cases of Pulmonary Infection by Mycobacterium shigaense, Japan.

Emerg Infect Dis 2020 11;26(11):2728-2732

We report 2 case-patients in Japan with Mycobacterium shigaense pulmonary infections. One patient was given aggressive treatment and the other conservative treatment, according to distinctive radiologic evidence. A close phylogenetic relationship based on whole-genome sequencing was found between strain from the conservatively treated patient and a reference strain of cutaneous origin.
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http://dx.doi.org/10.3201/eid2611.200315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588508PMC
November 2020

Clinical significance of serum anti-granulocyte-macrophage colony-stimulating factor autoantibodies in patients with sarcoidosis and hypersensitivity pneumonitis.

Orphanet J Rare Dis 2020 09 29;15(1):272. Epub 2020 Sep 29.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai City, Osaka, Japan.

Background: Anti-granulocyte-macrophage colony-stimulating factor autoantibody (GMAb) has been recognized as a diagnostic biomarker for autoimmune pulmonary alveolar proteinosis (aPAP). The aims of this study were to know the incidence of increased level of serum GMAb in granulomatous lung diseases (sarcoidosis and hypersensitivity pneumonitis [HP]) and to clarify the role of GMAb. Consecutive individuals diagnosed with sarcoidosis (n = 92) and HP (n = 45) at National Hospital Organization Kinki-Chuo Chest Medical Center were retrospectively analyzed. We measured serum GMAb levels at the diagnosis. Cut-off values of GMAb discriminating aPAP (n = 110) from healthy controls (n = 31) were determined by receiver operating characteristic (ROC) curve analysis. We compared the clinical features of sarcoidosis and HP patients with GMAb levels above the cut-off value ("Elevated-GMAb") with those of patients whose GMAb levels below the cut-off value ("Low-GMAb"). Radiological and pathological findings in elevated-GMAb patients were re-evaluated to elucidate the role of GMAb in granulomatous lung diseases.

Results: Analysis of ROC indicated a sensitivity and specificity of 100% at GMAb level of 3.33 μg/mL for discriminating aPAP from healthy controls (area under curve = 1.000, p < 0.0001). The percentages of elevated-GMAb sarcoidosis and HP patients were 5.4% (n = 5) and 11.1% (n = 5), respectively. The number of comorbid sarcoidosis and HP patients with aPAP was two and one, respectively. Elevated-GMAb sarcoidosis patients presented with significantly higher serum levels of Krebs von den Lungen (KL)-6, surfactant protein-D (SP-D), lactate dehydrogenase, and the requirement of systemic corticosteroid therapy. Elevated-GMAb HP patients demonstrated older age, higher serum KL-6, SP-D, carcinoembryonic antigen, and cytokeratin fragment 21-1 levels, and a higher percentage of lymphocytes in bronchoalveolar lavage than low-GMAb patients. A subset of patients presented with radiological and pathological findings characteristic of aPAP.

Conclusions: We demonstrated the percentage of elevated-GMAb sarcoidosis and HP patients who presented with several features suggestive of aPAP. Elevated-GMAb sarcoidosis and HP patients without definitive aPAP diagnosis may have subclinical or early-stage aPAP and may not necessarily indicate false positives. Upon diagnosis of sarcoidosis or HP, measurement of GMAb may be useful in detecting possible comorbidity of subclinical or early-onset aPAP.
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http://dx.doi.org/10.1186/s13023-020-01546-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525969PMC
September 2020

Seroradiologic prognostic evaluation of acute exacerbation in patients with idiopathic interstitial pneumonia: a retrospective observational study.

J Thorac Dis 2020 Aug;12(8):4132-4147

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-Cho, Kita-Ku, Sakai City, Osaka, Japan.

Background: We previously reported that high-resolution computed tomography (HRCT) patterns and certain serum marker levels can predict survival in patients with acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) and in those with idiopathic interstitial pneumonias (IIPs). The utility of serum marker changes before and during AE has not been previously evaluated. This study aimed to clarify whether changes in serum marker levels could improve the prognostic significance of HRCT patterns in patients with AE-IIPs.

Methods: Seventy-seven patients (60 males, 17 females) with AE-IIP diagnosed between 2004 and 2016 and whose serum Krebs von den Lungen (KL)-6 and surfactant protein (SP)-D levels were measured before and at the onset of AE were enrolled in this study. The HRCT pattern of each patient was classified as diffuse, multifocal, or peripheral. We examined the prognostic significance of the HRCT pattern, increased serum marker levels, and a combination of these parameters using Cox proportional hazard regression analysis.

Results: Fifty-three patients had IPF and 24 had non-IPF IIP. A serum KL-6 level that was increased compared with the level in the stable state (ΔKL-6/ST-KL-6: ≤0.211) was a significantly poor prognostic factor in patients with a multifocal pattern. Multivariate Cox analysis identified long-term oxygen therapy, a partial oxygen tension/fraction of inspired oxygen ratio ≤200 Torr, and an elevated SP-D level during a stable state to be significantly poor prognostic factors in all patients. A diffuse HRCT pattern was not a significant prognostic factor in an AE-IIP in multivariate analysis after adjustment; however, a multifocal pattern accompanying a ΔKL-6/ST-KL-6 ≤0.211 or a diffuse pattern was a significantly poor prognostic factor than a peripheral pattern or a multifocal pattern with ΔKL-6/ST-KL-6 >0.211.

Conclusions: Combining the HRCT pattern and the ΔKL-6/ST-KL-6 value can improve our ability to predict the survival of AE-IIP patients.
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http://dx.doi.org/10.21037/jtd-20-911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475580PMC
August 2020

Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis.

N Engl J Med 2020 10 7;383(17):1635-1644. Epub 2020 Sep 7.

From the Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati (B.C.T.); National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka (Y.I.), Aichi Medical University Hospital, Nagakute, Aichi (E.Y.), and Kanagawa Cardiovascular and Respiratory Center, Yokohama (T.B.) - all in Japan; Outpatients Clinic for Interstitial and Rare Lung Disease, Ruhrlandklinik University Hospital, Essen (F.B.), and Center for Interstitial and Rare Lung Diseases, Pulmonology, Thoraxklinik, Heidelberg University Hospital, and German Center for Lung Research, Heidelberg (M.K.) - all in Germany; the Departments of Critical Care and Respiratory Medicine, Royal Brompton Hospital, London (C.M.); Respiratory Diseases Department, Pontchaillou Hospital, IRSET UMR 1085, Rennes 1 University, Rennes, France (S.J.); the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus (E.B.), and Savara, Horsholm (C.G., I.T.) - both in Denmark; the Pneumology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (I.C.); the 2nd Pulmonary Medicine Department, General University Hospital "Attikon," Medical School, National and Kapodistrian University of Athens, Athens (S.A.P.); University of Health Sciences Turkey, Yedikule Chest Diseases and Thoracic Surgery Education and Research Hospital, Istanbul (E.C.); Pulmonary Clinic of St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (M.M.I.); Institute of Pulmonary and Allergy Medicine, Rabin Medical Center, Petah Tikva, Israel (M.R.K.); ILD Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, the Netherlands (M.V.); the University of Western Australia, Royal Perth Hospital, Perth, Australia (G.W.); and Savara, Austin, TX (T.J.).

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.

Methods: In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo) at week 24.

Results: In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group.

Conclusions: In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).
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http://dx.doi.org/10.1056/NEJMoa1913590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083051PMC
October 2020

Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline.

Am J Respir Crit Care Med 2020 08;202(3):e36-e69

This guideline addresses the diagnosis of hypersensitivity pneumonitis (HP). It represents a collaborative effort among the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax. Systematic reviews were performed for six questions. The evidence was discussed, and then recommendations were formulated by a multidisciplinary committee of experts in the field of interstitial lung disease and HP using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. The guideline committee defined HP, and clinical, radiographic, and pathological features were described. HP was classified into nonfibrotic and fibrotic phenotypes. There was limited evidence that was directly applicable to all questions. The need for a thorough history and a validated questionnaire to identify potential exposures was agreed on. Serum IgG testing against potential antigens associated with HP was suggested to identify potential exposures. For patients with nonfibrotic HP, a recommendation was made in favor of obtaining bronchoalveolar lavage (BAL) fluid for lymphocyte cellular analysis, and suggestions for transbronchial lung biopsy and surgical lung biopsy were also made. For patients with fibrotic HP, suggestions were made in favor of obtaining BAL for lymphocyte cellular analysis, transbronchial lung cryobiopsy, and surgical lung biopsy. Diagnostic criteria were established, and a diagnostic algorithm was created by expert consensus. Knowledge gaps were identified as future research directions. The guideline committee developed a systematic approach to the diagnosis of HP. The approach should be reevaluated as new evidence accumulates.
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http://dx.doi.org/10.1164/rccm.202005-2032STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397797PMC
August 2020

Insights into pathogenesis and clinical implications in myositis-associated interstitial lung diseases.

Curr Opin Pulm Med 2020 09;26(5):507-517

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.

Purpose Of Review: Interstitial lung diseases (ILDs) have been reported to be associated with myositis (including polymyositis and dermatomyositis). These myositis-associated ILDs carry significant morbidity and mortality. This review summarizes recent findings on myositis-associated ILD with a focus on pathogenesis and emerging treatment.

Recent Findings: Recent advances in genetics have revealed 22 myositis-associated genome-wide loci, which were significantly enriched in regulatory regions in immune cells. An analysis of such disease-associated loci elucidated potential drug targets (e.g., TYK2 targeted by tofacitinib). In another study, an intronic variant in WDFY4 in association with clinically amyopathic dermatomyositis (CADM) had an effect for higher expression of a truncated WDFY4 isoform. Truncated WDFY4 markedly enhanced the MDA5-mediated NF-κB activation and cell apoptosis, indicating the dysregulated WDFY4-MDA5 pathway as a novel pathogenesis of CADM. As a novel strategy, tofacitinib treatment showed a promising improvement in survival and clinical features of CADM-associated ILD.

Summary: The genetic differences in the myositis-susceptible loci may explain the heterogeneous phenotypes and treatment responses in myositis-associated ILD. The understanding of pathogenesis with the genetic background as well as autoantibodies will enable the practice of personalized treatment in the management of the disease.
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http://dx.doi.org/10.1097/MCP.0000000000000698DOI Listing
September 2020

Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society.

Lancet Respir Med 2020 07;8(7):726-737

Department of Radiology, Denver, CO, USA.

The term interstitial lung abnormalities refers to specific CT findings that are potentially compatible with interstitial lung disease in patients without clinical suspicion of the disease. Interstitial lung abnormalities are increasingly recognised as a common feature on CT of the lung in older individuals, occurring in 4-9% of smokers and 2-7% of non-smokers. Identification of interstitial lung abnormalities will increase with implementation of lung cancer screening, along with increased use of CT for other diagnostic purposes. These abnormalities are associated with radiological progression, increased mortality, and the risk of complications from medical interventions, such as chemotherapy and surgery. Management requires distinguishing interstitial lung abnormalities that represent clinically significant interstitial lung disease from those that are subclinical. In particular, it is important to identify the subpleural fibrotic subtype, which is more likely to progress and to be associated with mortality. This multidisciplinary Position Paper by the Fleischner Society addresses important issues regarding interstitial lung abnormalities, including standardisation of the definition and terminology; predisposing risk factors; clinical outcomes; options for initial evaluation, monitoring, and management; the role of quantitative evaluation; and future research needs.
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http://dx.doi.org/10.1016/S2213-2600(20)30168-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970441PMC
July 2020

Autoimmune Pulmonary Alveolar Proteinosis Complicated with Sarcoidosis: the Clinical Course and Serum Levels of Anti-granulocyte-macrophage colony-stimulating Factor Autoantibody.

Intern Med 2020 Oct 30;59(20):2539-2546. Epub 2020 Jun 30.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Japan.

Autoimmune pulmonary alveolar proteinosis (APAP) is caused by macrophage dysfunction due to anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody. We experienced 2 cases of APAP complicated with sarcoidosis in a 42-year-old woman and a 51-year-old man (age at the sarcoidosis diagnosis). APAP preceded sarcoidosis in the woman, and both diseases were diagnosed simultaneously in the man. Sarcoidosis lesions were observed in the lung, skin, and eyes, and the pathological findings of APAP were not marked at the diagnosis of sarcoidosis in either case. Low-grade positive serum anti-GM-CSF autoantibody was suspected to be correlated with the occurrence of sarcoidosis and resolution of APAP.
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http://dx.doi.org/10.2169/internalmedicine.3853-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662056PMC
October 2020

Perioperative complications of abdominal surgery in smokers.

J Anesth 2020 10 23;34(5):712-718. Epub 2020 Jun 23.

Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamineminami, Higashi-ku, Kumamoto, 861-8528, Japan.

Purpose: This study examined the association between smoking and perioperative complications of laparoscopic abdominal surgery and whether these complications were reduced with ≥ 4 weeks of preoperative smoking cessation.

Methods: A total of 555 patients who underwent gastric and colorectal cancer surgeries under general anesthesia were divided into the following groups retrospectively: 290 individuals without smoking history (NS group), 144 previous smokers (stopped smoking more than 8 weeks before surgery, PS group), and 121 current smokers (CS group) divided to two groups according to preoperative smoking cessation for < 4 (CS1, n = 76) and 4-8 weeks (CS2, n = 45).

Results: When compared with the NS group, postoperative hospitalization duration was significantly longer in the CS1 group (p < 0.01), whereas differences between the CS2 or PS groups and NS group were not significant. The total number of postoperative complications was higher in all groups of smoking than in NS group, independent on preoperative smoking cessation; however, suture failure was significantly more frequent only in CS1 group. Although pack-years did not significantly affect complication rates in smokers, duration of smoking cessation time in PS group was a negative predictor of postoperative complications.

Conclusion: Providing more than 4 weeks of smoking cessation before gastrointestinal surgery can reduce the duration of hospitalization and rate of suture failure.
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http://dx.doi.org/10.1007/s00540-020-02815-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511283PMC
October 2020

Massive atelectasis by mucoid impaction in an asthma patient during treatment with anti-interleukin-5 receptor antibody.

Respirol Case Rep 2020 Aug 18;8(6):e00599. Epub 2020 Jun 18.

Clinical Research Center National Hospital Organization Kinki-Chuo Chest Medical Center Osaka Japan.

Benralizumab is an interleukin-5 (IL-5) receptor α-directed cytolytic monoclonal antibody that reduces rapid and nearly complete depletion of eosinophils by enhancing antibody-dependent cell-mediated cytotoxicity. The depletion of eosinophilic inflammation is expected to reduce mucus hypersecretion and mucoid impaction. A 75-year-old non-smoking female had been treated for uncontrolled bronchial asthma with multiple drugs. Treatment with benralizumab was initiated after the asthma attack; however, four months later, she developed massive atelectasis in the left lung leading to the tracheal deviation, to the extent that nasal high-flow therapy was required. The laboratory data showed elevated neutrophil count, whereas blood eosinophils were almost completely depleted. The thick mucus was removed by bronchofiberscopy and the atelectasis was completely resolved. No exacerbation has been observed for nine months after discontinuation of benralizumab and initiation of erythromycin. This is the first documented case that developed atelectasis by mucoid impaction during treatment with anti-IL-5 receptor antibody.
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http://dx.doi.org/10.1002/rcr2.599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300730PMC
August 2020
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