Showing papers by "Yoshikazu Inoue published in 2020"

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

Abstract: Background: This guideline addresses the diagnosis of hypersensitivity pneumonitis (HP). It represents a collaborative effort among the American Thoracic Society, Japanese Respiratory Society, and Asociacion Latinoamericana del Torax.Methods: 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.Results: 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.Conclusions: The guideline committee developed a systematic approach to the diagnosis of HP. The approach should be reevaluated as new evidence accumulates.

Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis

Abstract: Background Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte–...

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

Abstract: Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombom...

MAPK mutations and cigarette smoke promote the pathogenesis of pulmonary Langerhans cell histiocytosis.

Abstract: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare smoking-related lung disease characterized by dendritic cell (DC) accumulation, bronchiolocentric nodule formation, and cystic lung remodeling. Approximately 50% of patients with PLCH harbor somatic BRAF-V600E mutations in cells of the myeloid/monocyte lineage. However, the rarity of the disease and lack of animal models have impeded the study of PLCH pathogenesis. Here, we establish a cigarette smoke-exposed (CS-exposed) BRAF-V600E-mutant mouse model that recapitulates many hallmark characteristics of PLCH. We show that CD11c-targeted expression of BRAF-V600E increases DC responsiveness to stimuli, including the chemokine CCL20, and that mutant cell accumulation in the lungs of CS-exposed mice is due to both increased cellular viability and enhanced recruitment. Moreover, we report that the chemokine CCL7 is secreted from DCs and human peripheral blood monocytes in a BRAF-V600E-dependent manner, suggesting a possible mechanism for recruitment of cells known to dominate PLCH lesions. Inflammatory lesions and airspace dilation in BRAF-V600E mice in response to CS are attenuated by transitioning animals to filtered air and treatment with a BRAF-V600E inhibitor, PLX4720. Collectively, this model provides mechanistic insights into the role of myelomonocytic cells and the BRAF-V600E mutation and CS exposure in PLCH pathogenesis and provides a platform to develop biomarkers and therapeutic targets.

Long‐term treatment with nintedanib in Asian patients with idiopathic pulmonary fibrosis: Results from INPULSIS®‐ON

Abstract: Background and objective The efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) were investigated in the placebo-controlled INPULSIS® trials. All patients who completed an INPULSIS® trial could receive open-label nintedanib in the extension trial INPULSIS®-ON. Methods We assessed the long-term efficacy and safety of nintedanib in patients of Asian race who were treated in INPULSIS®-ON. Analyses were descriptive. Results A total of 215 Asian patients were treated in INPULSIS®-ON, of whom 121 continued nintedanib in INPULSIS®-ON and 94 initiated nintedanib in INPULSIS®-ON having received placebo in an INPULSIS® trial. At baseline of INPULSIS®-ON, the mean (SD) age of Asian patients was 66.3 (7.5) years, 80.5% were males and mean (SD) forced vital capacity (FVC) was 78.9 (19.3) % predicted. Median total exposure to nintedanib in both INPULSIS® and INPULSIS®-ON was 42.2 months; maximum exposure was 64.1 months. In INPULSIS®, the annual rate (SE) of decline in FVC over 52 weeks in Asian patients was -124 (20) mL/year in the nintedanib group and -218 (24) mL/year in the placebo group. In INPULSIS®-ON, the annual rate (SE) of decline in FVC over 192 weeks in Asian patients was -127 (11) mL/year. Diarrhoea was reported in Asian patients at event rates of 58.8 and 82.5 events per 100 patient exposure-years in patients who continued and initiated nintedanib in INPULSIS®-ON, respectively. Conclusion The effect of nintedanib on slowing disease progression in Asian patients with IPF is sustained over the long term. Long-term treatment with nintedanib has an acceptable safety and tolerability profile.

Acute exacerbation of idiopathic interstitial pneumonias related to chemotherapy for lung cancer: nationwide surveillance in Japan.

Abstract: Background Chemotherapy-induced acute exacerbation (AEx) of idiopathic interstitial pneumonias (IIPs) seriously compromises the success of treatment of Japanese lung cancer patients. Here, we conducted a nationwide surveillance to clarify the risk of AEx and compare it with the survival benefit of chemotherapy for this population. Methods Advanced nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC) patients with IIPs were retrospectively analysed. For the surveillance of first-line chemotherapy in 2009, we gathered clinical data from 396 patients who received chemotherapy at 19 institutions between January 1990 and July 2009. In a consecutive retrospective study in 2012, we analysed data from 278 patients from 17 institutions who received second-line chemotherapy between April 2002 and March 2012. Results Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively. Conclusion Combination chemotherapies consisting of CP or CE are candidates for standard first-line treatments for patients with advanced lung cancer accompanied by IIP. Second-line chemotherapy should be considered for patients remaining fit enough to receive it.

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

Abstract: 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.

High-resolution CT features distinguishing usual interstitial pneumonia pattern in chronic hypersensitivity pneumonitis from those with idiopathic pulmonary fibrosis.

Abstract: Radiologic diagnosis of chronic hypersensitivity pneumonitis (CHP) presenting a usual interstitial pneumonia (UIP) pattern is challenging. The aim of this study was to identify the high-resolution CT (HRCT) findings which are useful to discriminate CHP–UIP from idiopathic pulmonary fibrosis (IPF). This study included 49 patients with well-established bird-related CHP–UIP, histologically confirmed, and 49 patients with IPF. Two groups of observers independently assessed HRCT, evaluated the extent of each abnormal HRCT finding. When their radiological diagnosis was CHP–UIP, they noted the HRCT findings inconsistent with IPF. Correct CT diagnoses were made in 79% of CHP–UIP and 53% of IPF. Although no apparent difference was seen in the extent of each HRCT finding, upper or mid-lung predominance, extensive ground-glass abnormality, and profuse micronodules were more frequently pointed out as inconsistent findings in CHP–UIP than IPF (p = 0.007, 0.010, 0.001, respectively). On regression analysis, profuse micronodules [OR 13.34 (2.85–62.37); p = 0.001] and upper or mid-lung predominance of findings [OR 2.86 (1.16–7.01); p = 0.022] remained as variables in the equation. In this cohort, some IPF cases were misdiagnosed as CHP–UIP. Profuse micronodules and upper or mid-lung predominance are important clues for the differentiation of CHP–UIP from IPF.

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

Abstract: 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. 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. 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.

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

Abstract: 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.

Validation of a new serum granulocyte-macrophage colony-stimulating factor autoantibody testing kit.

Abstract: Very recently, a modest but significant efficacy of granulocyte–macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL−1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

Twenty-five years of Respirology: Advances in idiopathic pulmonary fibrosis

Abstract: Being a dreadful and devastating disease with poor prognosis, idiopathic pulmonary fibrosis (IPF) is still a major challenge for clinicians. Nonetheless, pulmonary fibrosis is probably the field of respiratory medicine in which the most outstanding achievements have been gained in the last decades. The pathogenic perception of an inflammatory response to a given stimulus followed by fibrotic deposition has shifted towards a much more complex theory. Currently, IPF is thought to be a disease in which a genetically predisposed epithelium is prone to premature senescence with subsequent activation of aberrant developmental pathways and anomalous signalling which leads to recruitment and activation of myofibroblasts and excessive fibrotic deposition. The role of immune cells in IPF is still unclear and controversial. Several risk factors have been associated to IPF: tobacco smoke, male gender, advanced age, environmental exposures among them. Evidence accumulated in the last 25 years has shown that genetic susceptibility plays a role in IPF development. Rare and common genetic variants, involved in key cellular function as host defence, telomere length maintenance and intercellular communication, have been linked to IPF. The second great achievement in IPF was the refining of is definition, diagnosis and management over the years. The advent of high-resolution computed tomography (HRCT), with improved imaging quality and definition, dramatically changed the diagnostic process in IPF. From the first descriptions in the last years of the 19th century to the initial original experiences with HRCT, interstitial lung diseases (ILD) have long been a complex of disorders chiefly defined and classified by pathologists. In 2000, an international consensus statement described the clinical picture of IPF. IPF was defined as a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with the histological pattern of usual interstitial pneumonia (UIP) on surgical lung biopsy (SLB) samples. Accordingly, pathological confirmation of the disease was deemed an essential part of the diagnostic process. SLB was recommended in patients with suspected IPF and without contraindications to surgery. Exclusion of secondary causes for ILD, as significant domestic and occupational exposures, collagen vascular disease, sarcoidosis and drug toxicity through clinical examination and history elicitation, was considered necessary. Abnormal lung function, with evidence of restriction, impaired gas exchange and reduction of diffusing capacity of the lung for CO, was also required. In the absence of histology, major and minor criteria required for diagnosis were stated, with the inclusion of transbronchial lung biopsy or bronchoalveolar lavage (BAL). Nevertheless, it was recognized the high diagnostic accuracy of HRCT, and it was asserted that the utility of SLB was of particular importance in patients with atypical radiological and/or clinical presentation. These guidelines, even if inherently biased by the methodology used to draw them, provided clinicians and patients with a better understanding of the clinical course of the disease, conceived precise diagnostic criteria and raised the awareness of the disease worldwide. Following this statement, in 2005, the National Heart, Lung, and Blood Institute created the IPF Clinical Research Network (IPFnet), a network of highly selected specialized centres of excellence, with the specific aim of improving the therapeutic portfolio of IPF through well-designed clinical research. The first evidence-based guidelines on IPF were published in 2011. This document, that was produced using a more robust methodological approach, introduced new important concepts. First, the guidelines clearly defined the HRCT features of UIP, possible UIP and inconsistent with UIP patterns, as well as the features of histological patterns of UIP, probable UIP, possible UIP and inconsistent with UIP found on SLB. Second, it was recognized that the presence of a radiological UIP was highly predictive of a UIP pattern on SLB. Accordingly, in the right clinical context, the need for an SLB was no more deemed necessary. Given the possible complications associated with SLB, the procedure was therefore discouraged in this setting of patients. For patients without a UIP pattern on HRCT, specific combinations of HRCT and SLB patterns were given to increase the likelihood of an accurate diagnosis of IPF. Third, the major and minor criteria previously stated disappeared. Respiratory functional impairment and bronchoscopy with ancillary procedures (BAL and/or transbronchial biopsy) were no longer required for the diagnosis of IPF. In particular, BAL and/or transbronchial biopsy were considered appropriate only in a minority of patients. Fourth, the use of a multidisciplinary discussion between expert pulmonologists, radiologists and pathologists was strongly recommended in the evaluation of IPF, for the reason that multidisciplinary discussion improves interobserver agreement and the accuracy of diagnosis. In 2017, an expert consensus statement released by the Fleischner Society further refined the diagnostic approach to IPF. Among the major goals of this paper was the definition of a new radiological pattern, namely probable UIP, which incorporated traction bronchiectasis in its definition for the first time. According to this document, an SLB should be only necessary in patients with a clinical

Serum immunoglobulin a antibodies to glycopeptidolipid core antigen for Mycobacteroides abscessus complex lung disease

Abstract: Background: Mycobacteroides abscessus complex (MABC) exhibits smooth morphotypes, expressing glycopeptidolipid (GPL), and rough morphotypes, expressing diminished GPL, on the MABC cell wall. Few reports have focused on the relationship between anti-GPL-core immunoglobulin A (IgA) antibody and colony morphology in MABC lung disease. Methods: This study aimed to test GPL core antigen in patients with MABC lung disease to investigate the relationship between coinfection/contamination in other nontuberculous mycobacteria species and colony morphology variant in MABC isolates. Patients with MABC lung disease and contamination diagnosed between 2012 and 2017 at our hospital were enrolled retrospectively. Results: Of the assessed patients, 43 patients with MABC lung disease and 13 with MABC contamination were included. There was a significant difference in anti-GPL-core IgA antibody levels between them (P = 0.02). Forty-three patients with MABC lung disease were divided into two groups as positive and negative antibodies groups. A significant increase in the positive anti-GPL-core IgA antibody was observed in coexistence with both Mycobacterium avium complex (MAC) (P = 0.02) and the isolate of the smooth variant (P = 0.03) in MABC.Conclusions: Anti-GPL-core IgA antibodies in patients with MABC are greatly influenced by MAC coexistence, and colony morphology variant of the MABC isolate.

Bacterial population kinetics in heteroresistant Mycobacterium tuberculosis harbouring rare resistance-conferring mutations in gyrA and rpoB imply an epistatic interaction of mutations in a pre-XDR-TB patient.

Abstract: OBJECTIVES Bacterial population kinetics of strains harbouring drug resistance-conferring mutations within a patient often show cryptic resistance in clinical practice. We report a case that showed emergence and dominance of Mycobacterium tuberculosis with uncommon rpoB and gyrA mutations, followed by an rpoC compensatory mutation, during treatment. METHODS A pre-XDR-TB patient showed heteroresistance to rifampicin and levofloxacin during treatment as a result of intermittent self-cessation. WGS was applied to investigate intra-host strain composition using five pairs of isolates from sputum samples. RESULTS The subclone in this study possessed rare mutations conferring resistance to rifampicin (rpoB V170F) and levofloxacin (gyrA S91P) and it rapidly outcompeted other subclones during treatment that included levofloxacin but not rifampicin (<7 days). The high-probability compensatory mutation rpoC V483A also emerged and became dominant subsequent to the rpoB V170F mutation. CONCLUSIONS To the best of our knowledge, this is the first case showing the emergence of such a rare variant that dominated the population within a patient during treatment of TB.

Is corticosteroid use truly not associated with improved outcomes in AE-IPF?

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

Abstract: 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.

Severe clopidogrel-induced DRESS with eosinophilic pneumonia associated with Epstein-Barr virus reactivation.

Abstract: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a type of hypersensitivity drug reaction. Here, we report the case of a 78-year-old man who presented with a rash, fever, dry cough, and swollen parotid glands who had been prescribed clopidogrel for one year. Computed tomography showed consolidation and interlobular septal thickening with enlarged mediastinal lymph nodes. As oxygen therapy was ineffective, the patient was intubated and bronchoalveolar lavage cellular analysis showed an increase in eosinophils. Clopidogrel was discontinued and the parotid biopsy revealed periductal lymphocytic infiltration. High doses of corticosteroids were administered, and his symptoms improved. However, his symptoms recurred when clopidogrel was restarted. Skin biopsy showed mild lymphocytic infiltration in the upper dermis with vasculitis, and Epstein-Barr virus (EBV) DNA was detected in his blood and lymph node tissue. On the basis of the pathology and disease manifestations, the patient was diagnosed with DRESS. Once clopidogrel treatment ceased, his symptoms never recurred.

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

Abstract: 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 MYD88 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.

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

Abstract: 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.

Efficacy of recombinant thrombomodulin for poor prognostic cases of acute exacerbation in idiopathic interstitial pneumonia: secondary analysis of the SETUP trial

Abstract: Background Acute exacerbation (AE) in idiopathic pulmonary fibrosis and other idiopathic interstitial pneumonias (IIPs) are poor prognostic events although they are usually treated with conventional therapy with corticosteroids and immunosuppressants. Previously, we demonstrated the safety and efficacy of recombinant human soluble thrombomodulin (rhTM) for AE-IIP in the SETUP trial. Here, we aimed to clarify the efficacy of rhTM for poor-prognosis cases of AE-IIP. Methods In this study, we included 85 patients, in whom fibrin degradation product (FDP)/d-dimer was evaluated at AE, from the 100 patients in the SETUP trial. The AE-IIP patients in the rhTM arm (n=39) were diagnosed using the Japanese criteria from 2014 to 2016 and treated with intravenous rhTM for 6 days in addition to the conventional therapy. The AE-IIP patients in the control arm (n=46) were treated with the conventional therapy without rhTM between 2011 and 2013. The subjects were classified into higher and lower FDP/d-dimer groups based on the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation scoring system. A multivariate Cox proportional hazard regression analysis with stepwise selection was performed to reveal the prognostic factors of AE-IIP. Results We developed a prognostic scoring system using two significant prognostic factors, higher FDP/d-dimer at AE and prednisolone therapy before AE, with 3 and 2 points assigned for each parameter, respectively. The prognostic scores ranged from 0 to 5. Survival of AE-IIP patients with a prognostic score=0 was significantly better than that of patients with score ≥2. Survival was improved with the rhTM therapy (p Conclusions Treatment with rhTM might improve survival in AE-IIP cases with poor prognoses. Trial registration number UMIN000014969, date: 28 August 2014.

Effects of nintedanib on progression of ILD in patients with fibrosing ILDs and a progressive phenotype: further analyses of the INBUILD trial

Abstract: Introduction: In the INBUILD trial in subjects with fibrosing ILDs and a progressive phenotype despite management deemed appropriate in clinical practice, nintedanib slowed the rate of decline in FVC (mL/year) over 52 weeks versus placebo. Subjects continued blinded randomised treatment until the end of the trial. The treatment period was variable and dependent on the date of enrollment. Aim: To assess the effects of nintedanib on progression of ILD over the whole INBUILD trial. Methods: Time to i) death, ii) first acute exacerbation of ILD or death, and iii) disease progression (absolute decline in FVC ≥10% predicted) or death were assessed over the whole trial. Results: Mean (SD) exposure to trial medication was 15.6 (7.2) and 16.8 (5.8) months in the nintedanib (n=332) and placebo (n=331) groups, respectively. In the nintedanib and placebo groups, respectively, 10.8% and 13.6% of subjects died (HR 0.78 [95% CI: 0.50, 1.21]), 13.9% and 19.6% of subjects had an acute exacerbation of ILD or died (HR 0.67 [95% CI: 0.46, 0.98]), and 40.4% and 54.7% of subjects had disease progression or died (HR 0.66 [95% CI: 0.53, 0.83]). Diarrhoea was the most common adverse event, with incidence rates of 136.4 and 23.0 events per 100 patient–years in the nintedanib and placebo groups, respectively. Adverse events led to treatment discontinuation in 22.0% and 14.5% of subjects in the nintedanib and placebo groups, respectively. Conclusions: In the INBUILD trial, nintedanib slowed the progression of ILD in patients with fibrosing ILD and a progressive phenotype.

Airway-centered Fibroelastosis Accompanied by Subpleural Lesions of Unknown Cause in a Young Man Who Later Developed Pulmonary Hypertension.

Abstract: A 26-year-old man with a history of bronchial asthma was found to have high-density shadows along the bronchovascular bundle and in the subpleural area on computed tomography of the chest. Surgical lung biopsy specimens from the right S5 showed fibroelastosis in the subpleural and central airway area with alveolar destruction. He was diagnosed with airway-centered fibroelastosis of unknown cause after multidisciplinary discussions. The patient developed pulmonary hypertension and died 6 years later. The patient was younger in comparison to patients in earlier reports and had more obvious subpleural fibroelastic lesions in the upper lobes than in previously described cases.

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

Abstract: 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

Characteristics and prognosis of interstitial pneumonias complicated with pneumomediastinum.

Abstract: Background The clinical characteristics and prognostic impact of complication with pneumomediastinum in patients with interstitial pneumonias (IPs) are not well studied due to the relatively limited nature of available reports. The purpose of this study was to clarify the characteristics and prognostic factors of IPs complicated with pneumomediastinum. Methods Consecutive patients with IPs complicated with pneumomediastinum detected by computed tomography (CT) between July 1, 2011, and April 30, 2014 were retrospectively reviewed. Clinical data including symptoms associated with pneumomediastinum, laboratory data, lung function tests, treatments, and mortality were collected from medical records. Results Forty-five patients (25 males, 20 females), including 32 with idiopathic IP (IIPs) and 13 connective tissue disease-associated interstitial lung diseases (CTD-ILDs) were identified. The median age of onset of pneumomediastinum was 72 years (interquartile range [IQR] 68–79 years). The most common symptom associated with occurrence of pneumomediastinum was appearance or worsening of dyspnoea. No specific treatment was performed for most (84%) of the cases. The median period between occurrence and improvement of pneumomediastinum was 29 days (IQR 5–69 days). Multivariate analysis revealed that IIPs and no improvement of pneumomediastinum were associated with poor prognosis. Conclusions Patients with IIPs complicated with pneumomediastinum and those without improvement of pneumomediastinum had poor prognosis.