Publications by authors named "Hideaki Yamakawa"

69 Publications

Decision-Making Strategy for the Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD).

J Clin Med 2021 Aug 25;10(17). Epub 2021 Aug 25.

Department of Internal Medicine, Division of Respiratory Diseases, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.

Rheumatoid arthritis (RA) is a common type of autoimmune arthritis. Patient clinical outcomes might be influenced by numerous respiratory diseases, but interstitial lung disease (ILD) is the most important comorbidity. RA-associated ILD (RA-ILD) is divided into acute/subacute and chronic forms. In the acute/subacute course, if the disease is severe as indicated by a diffuse alveolar damage pattern, high-dose corticosteroids combined with antimicrobial agents should be promptly initiated while considering the differential diagnoses, primarily acute exacerbation (AE) of RA-ILD, drug-induced pneumonitis, and Pneumocystis pneumonia. As initial therapeutic management in the chronic course, the RA itself should be stabilized without delay; thereafter, the activity of ILD itself can be stabilized, considering the safety of each anti-rheumatic drug. The formation of the usual interstitial pneumonia (UIP) pattern is the most important determinant because lung function can worsen more quickly with this pattern. However, because clinicians can fail to identify specific radiological patterns, it is important to determine whether each patient with RA-ILD has UIP-like lesions such as subpleural reticulation, traction bronchiectasis, and honeycombing especially progressively enlarged cysts. In patients with progressive RA-ILD and high risk for infection or AE of ILD in whom fibrosis is dominant, clinicians should consider starting an anti-fibrotic agent.
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http://dx.doi.org/10.3390/jcm10173806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432201PMC
August 2021

Anti-PL-7 antibody-positive dermatomyositis with progressive interstitial pneumonia complicated with tracheal ulcer.

Respir Med Case Rep 2021 2;33:101449. Epub 2021 Jun 2.

Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.

Tracheobronchial lesions are rare extramuscular complications for idiopathic inflammatory myopathies including dermatomyositis. We herein report a 65-year-old woman with tracheal ulcer during the progression of dermatomyositis-associated interstitial lung disease. Treatment with corticosteroids combined with immunosuppressive agents resulted in improvement of the tracheal ulcer and pulmonary involvement. We believe that the tracheal ulceration might reflect the disease behaviour of dermatomyositis and dermatomyositis-associated interstitial pneumonia.
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http://dx.doi.org/10.1016/j.rmcr.2021.101449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349009PMC
June 2021

A patient with hepatocellular carcinoma who developed invasive pulmonary aspergillosis after corticosteroid treatment.

Clin Case Rep 2021 Aug 10;9(8):e04628. Epub 2021 Aug 10.

Department of Respiratory Medicine Saitama Red Cross Hospital Saitama Japan.

Lung or head and neck cancer have been indicated as solid cancers associated with invasive pulmonary aspergillosis (IPA), but the relationship with hepatocellular carcinoma (HCC) is unknown. We report a case of HCC in which the presence of cirrhosis and corticosteroid administration may have caused the development of IPA.
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http://dx.doi.org/10.1002/ccr3.4628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353416PMC
August 2021

Predictive factors for the long-term use of pirfenidone in patients with fibrosing interstitial lung disease.

Respir Investig 2021 Jul 19;59(4):414-420. Epub 2021 Feb 19.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan. Electronic address:

Background: Pirfenidone is an anti-fibrotic agent approved for idiopathic pulmonary fibrosis (IPF), and long-term treatment data and the effect of continuation after disease progression have been reported. The efficacy and safety of pirfenidone in fibrosing interstitial lung disease (ILD) patients without IPF have been recently reported in clinical trials; therefore, the benefits of long-term treatment are also expected. This study aims to analyze the long-term treatment data of pirfenidone and clarify the predictive factors for long-term use of pirfenidone in non-IPF patients.

Methods: We retrospectively reviewed the records of consecutive fibrosing ILD patients who started using pirfenidone between 2008 and 2014.

Results: Of the 266 fibrosing ILD patients, 167 patients had IPF, and 99 had non-IPF. Despite the non-significant differences in body size and pulmonary function between IPF and non-IPF patients, the non-IPF patients had better overall survival than the IPF patients (median 4.06 years vs. 2.09 years, p < 0.0001). In addition, the non-IPF patients had a significantly longer time to treatment discontinuation than the IPF patients (median 2.20 years vs. 1.20 years, p = 0.002). Multivariate logistic regression analysis for ≥2 years of use of pirfenidone showed that the percent predicted forced vital capacity (%FVC) and age were predictive factors common to both IPF and non-IPF patients.

Conclusions: Our results indicate that non-IPF patients can continue using pirfenidone for longer durations than IPF patients. Initiation of pirfenidone for fibrosing ILD patients with higher %FVC and younger age would lead to long-term use of pirfenidone.
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http://dx.doi.org/10.1016/j.resinv.2021.01.002DOI Listing
July 2021

Hairspray Inhalation-induced Interstitial Pneumonitis Evaluated by a Transbronchial Lung Cryobiopsy.

Intern Med 2021 Jul 22;60(14):2285-2289. Epub 2021 Feb 22.

Department of Respiratory Medicine, Saitama Red Cross Hospital, Japan.

A 60-year-old Japanese woman was admitted to our hospital with a fever and shortness of breath occurring immediately after using hairspray. Chest high-resolution computed tomography (HRCT) showed ground-glass opacities (GGOs) predominantly distributed around the bronchovascular bundles, and a pathological evaluation by a transbronchial lung cryobiopsy (TBLC) revealed fibrotic non-specific interstitial pneumonia (f-NSIP). Her symptoms disappeared without the use of corticosteroids, and GGOs on HRCT improved markedly over time. This case suggests that a pathological evaluation by a TBLC for lung injury due to inhalation pathogen exposure may provide a more accurate diagnosis and a better understanding of the pathology from bronchial to interstitial lesions than transbronchial lung biopsy.
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http://dx.doi.org/10.2169/internalmedicine.5674-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355392PMC
July 2021

Utility of radial endobronchial ultrasonography combined with transbronchial lung cryobiopsy in patients with diffuse parenchymal lung diseases: a multicentre prospective study.

BMJ Open Respir Res 2021 01;8(1)

Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.

Background: Radial endobronchial ultrasonography (R-EBUS) has been used in conjunction with transbronchial lung cryobiopsy (TBLC) to diagnose diffuse parenchymal lung disease (DPLD) and to decrease the risk of bleeding complications. The diagnostic utility of different R-EBUS signs, however, remains unknown.

Objectives: This study aimed to determine whether different R-EBUS signs could be used to more accurately diagnose DPLD and whether bronchial bleeding could be prevented with use of R-EBUS during TBLC.

Method: Eighty-seven patients with DPLD were included in this multicentre prospective study, with 49 patients undergoing R-EBUS. R-EBUS signals were characterised as displaying either dense or blizzard signs. Pathological confidence of specimens obtained from TBLC was compared between patients with dense versus blizzard signs, and severity of bronchial bleeding was determined based on whether R-EBUS was performed or not.

Results: All patients with dense signs on R-EBUS showed consolidation on high-resolution CT (HRCT) imaging. Pathological confidence of lung specimens was significantly higher in patients with dense signs versus those with blizzard signs (p<0.01) and versus those who did not undergo R-EBUS (p<0.05). Patients who underwent TBLC with R-EBUS were more likely to experience no or mild bronchial bleeding than patients who did not undergo R-EBUS (p<0.01), with shorter procedure times (p<0.01).

Conclusions: The dense R-EBUS sign corresponded with consolidation on HRCT. High-quality lung specimens may be obtainable when the dense sign is observed on R-EBUS, and R-EBUS combined with TBLC may reduce risk of bronchial bleeding and shorten procedure times.
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http://dx.doi.org/10.1136/bmjresp-2020-000826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812092PMC
January 2021

The Usefulness of a Transbronchial Lung Cryobiopsy for Diffuse Bronchiolitis.

Intern Med 2021 May 7;60(9):1457-1462. Epub 2020 Dec 7.

Department of Respiratory Medicine, Saitama Red Cross Hospital, Japan.

We herein report four cases of diffuse bronchiolitis proven by a transbronchial lung cryobiopsy (TBLC). Based on various aspects, including the pathological findings, we definitively diagnosed two patients with diffuse panbronchiolitis (DPB) and the other two with primary ciliary dyskinesia (PCD). One of the DPB patients had more severe peribronchiolar fibrosis than the other, and the disease course was refractory to macrolide therapy. One of the PCD patients was additionally diagnosed with combined constrictive bronchiolitis. This report highlights the importance of a TBLC in the differentiation of bronchiolitis, suggesting its utility for helping pulmonologists formulate a treatment strategy.
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http://dx.doi.org/10.2169/internalmedicine.6028-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170248PMC
May 2021

Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity.

Respir Investig 2021 Mar 12;59(2):247-251. Epub 2020 Nov 12.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Japan.

Background: Interstitial lung disease (ILD) patients commonly become obese or overweight due to deteriorated daily living activities and the adverse effects of prednisolone. This study aimed to clarify the effect of weight loss on pulmonary function test (PFT) in ILD patients with obesity.

Methods: Among all consecutive ILD patients with a body mass index (BMI) ≥ 27 kg/m who received nutrition education for improving obesity between June 2014 and December 2018, we retrospectively included patients who successfully decreased their body weight by over 2 kg and underwent follow-up PFT within 6 months. The results of PFT at baseline and follow-up and the level of Krebs von den Lungen-6 (KL-6) were compared.

Results: Eleven patients (5 men and 6 women; median BMI of 34.1 kg/m), were enrolled. For PFT at baseline, the percentages of forced vital capacity (%FVC), functional residual capacity (%FRC), and diffusing capacity of the lung for carbon monoxide (%DLCO) were 69.3%, 59.9%, and 54%, respectively. The median KL-6 was 1035 U/mL. The median interval from baseline to the follow-up PFTs was 41 days. Compared to the baseline results of PFT, %FVC, %FRC, and %DLCO significantly increased (p = 0.018, 0.0006, and 0.024, respectively), and the changes in body weight and FVC were strongly correlated (p = 0.0004). In addition, the median serum level of KL-6 at follow-up tended to decrease by 206.5 U/mL (p = 0.083).

Conclusion: In ILD patients with obesity, weight loss is important and potentially improves their disease course.
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http://dx.doi.org/10.1016/j.resinv.2020.10.002DOI Listing
March 2021

Levetiracetam-induced interstitial lung disease in a patient with advanced lung cancer.

Respir Med Case Rep 2020 28;31:101241. Epub 2020 Sep 28.

Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.

An 85-year-old woman with antibiotics-resistant pneumonia after surgery for metastatic brain tumor from lung cancer was consulted to our department. Chest CT showed diffuse GGO bilaterally. BALF showed elevated ratios of lymphocytes and CD4/CD8. Tests for bacteria, mycobacteria, and fungi were negative. She improved following levetiracetam discontinuance and systemic corticosteroid administration, and we diagnosed levetiracetam-induced lung injury. Although levetiracetam is widely used, few reports of levetiracetam-induced pneumonia exist. Changes in chest images may occur after levetiracetam administration if patients have multiple risk factors for development of drug-induced interstitial lung disease. Bronchoscopy is useful for differential diagnosis if new lung lesions appear after starting levetiracetam.
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http://dx.doi.org/10.1016/j.rmcr.2020.101241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528199PMC
September 2020

The potential utility of anterior upper lobe honeycomb-like lesion in interstitial lung disease associated with connective tissue disease.

Respir Med 2020 10 21;172:106125. Epub 2020 Aug 21.

Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chuo-ku, Saitama, 330-8553, Japan. Electronic address:

Background: Interstitial lung disease (ILD) is associated with high morbidity and mortality in patients with connective tissue disease (CTD). Because some patients with CTD overlap present with ILD first, with CTD diagnosed later, specific radiologic signs are needed to help differentiate each CTD or CTD-ILD from idiopathic ILD.

Objectives: To determine whether specific CT findings can help differentiate CTD as rheumatoid arthritis (RA), systemic sclerosis (SSc), or polymyositis/dermatomyositis (PM/DM).

Methods: We analyzed 143 consecutive ILD patients with RA, SSc, or PM/DM. We assessed diagnostic accuracy of CT findings of CTD-ILD, CT pattern, and signs including "anterior upper lobe honeycomb-like lesion" and "low attenuation area (LAA) within an interstitial abnormality" for each CTD-ILD. Prognostic predictors were determined using Cox regression models.

Results: Subjects were 78 patients with RA-ILD, 38 with SSc-ILD, 24 with PM/DM-ILD, and 3 with overlapping CTD-ILD. High frequency of anterior upper lobe honeycomb-like lesion suggests that CTD-ILD is due to RA-ILD (22%) rather than SSc-ILD (8%) or PM/DM-ILD (8%), whereas LAA within an interstitial abnormality suggests that CTD-ILD is due to SSc-ILD (26%) rather than RA-ILD (4%) or PM/DM-ILD (0%). Multivariate analysis showed that while not associated with survival, current or ex-smoker, honeycombing, and acute exacerbation were negative prognostic factors of mortality.

Conclusions: The tendency is high for RA-ILD, in which anterior upper lobe honeycomb-like lesion is a specific feature, to show UIP or NSIP/UIP pattern, combined emphysema, and honeycombing; SSc-ILD to show NSIP pattern and LAA within an interstitial abnormality; and PM/DM-ILD to show NSIP pattern and non-honeycombing.
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http://dx.doi.org/10.1016/j.rmed.2020.106125DOI Listing
October 2020

Amyloidosis of the respiratory system: 16 patients with amyloidosis initially diagnosed by pulmonologists.

ERJ Open Res 2020 Jul 27;6(3). Epub 2020 Jul 27.

Dept of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.

Background: diagnosis of amyloidosis of the respiratory system is rare. Few data are available regarding clinical presentation, precursor proteins, diagnostic procedures, comorbidities, complications, and outcome. We assessed clinical features of a series of patients with amyloidosis of the respiratory system in two Japanese centres.

Methods: Medical records of 16 patients with amyloidosis of the respiratory system were retrospectively analysed. Amyloid was diagnosed by polarisation microscopy using Congo red-stained tissue specimens and classified immunohistochemically.

Results: Median patient age was 71 years, and median follow-up period was 5 years. Immunoglobulin light-chain (AL)-λ amyloidosis was found in eight and AL-κ in five patients. Two patients harboured wild-type transthyretin and one harboured serum amyloid A-derived amyloid. Five different forms of amyloidosis of the respiratory system were observed: nodular pulmonary amyloidosis (seven patients), diffuse alveolar-septal amyloidosis (five), mediastinal lymph node amyloidosis (three), tracheobronchial amyloidosis (one), and pleural amyloidosis (one). One patient had diffuse alveolar-septal amyloidosis and mediastinal lymph node amyloidosis. Three of five patients with diffuse alveolar-septal amyloidosis were diagnosed by transbronchial lung biopsy as having concurrent diffuse alveolar haemorrhage or pneumocystis pneumonia. Two of three patients with mediastinal lymph node amyloidosis were diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration.

Conclusions: Not only nodular pulmonary amyloidosis, diffuse alveolar-septal amyloidosis, and tracheobronchial amyloidosis but also mediastinal lymph node amyloidosis and pleural amyloidosis should be considered in the differential diagnosis of amyloidosis of the respiratory system. Useful diagnostic methods include transbronchial lung biopsy for diffuse alveolar-septal amyloidosis and endobronchial ultrasound-guided transbronchial needle aspiration for mediastinal lymph node amyloidosis.
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http://dx.doi.org/10.1183/23120541.00313-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383056PMC
July 2020

Enlarged Bronchial Diverticula with Lung Fibrosis Progression.

Intern Med 2020 Nov 28;59(22):2967-2968. Epub 2020 Jul 28.

Department of Respiratory Medicine, Saitama Red Cross Hospital, Japan.

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http://dx.doi.org/10.2169/internalmedicine.5194-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725622PMC
November 2020

Unilateral upper lung-field pulmonary fibrosis radiologically consistent with pleuroparenchymal fibroelastosis after thoracic surgery: Clinical and radiological courses with autopsy findings.

Respir Investig 2020 Jul 10. Epub 2020 Jul 10.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.

Background: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia characterized by pleural and parenchymal involvements predominantly in the upper lobes. Unilateral upper-lung field pulmonary fibrosis (upper-PF) radiologically consistent with PPFE was recently reported in patients with a history of open thoracotomy and presented with impaired thoracic movements in the operated side with unknown mechanisms. This retrospective study aimed to elucidate the clinical and radiological courses and pathological findings of unilateral upper-PF.

Methods: All the consecutive patients diagnosed as having unilateral upper-PF between March 2012 and April 2018 were included. Radiological images and clinical courses before and after the diagnosis were thoroughly reviewed.

Results: Fourteen patients were included. Unilateral upper-PF was diagnosed after a median of 4.8 years from the open thoracotomy or video-assisted thoracic surgery for treating lung or esophageal cancer, or bronchiectasis. Before or at diagnosis, 12 (85.7%) of 14 patients developed aberrant intrathoracic/extrathoracic air suggestive of pleural fistula, although the degree was slight. Of note, the upper-PF lesion apparently deteriorated once aberrant air emerged in all the patients. After diagnosis, the upper-PF lesion transformed into cystic lesion in 9 patients, 4 of whom eventually developed pulmonary aspergillosis. The prognosis was poor, with a median overall survival of 49.3 months. The autopsy in one patient demonstrated findings consistent with PPFE and chronic pleuritis.

Conclusions: Unilateral upper-PF developed after thoracic surgeries and had many clinical, radiological, and pathological characteristics in common with idiopathic PPFE. Our results indicate that the commonly observed aberrant air may be correlated with disease development and progression.
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http://dx.doi.org/10.1016/j.resinv.2020.05.001DOI Listing
July 2020

Prospective multicentre study on the safety and utility of transbronchial lung cryobiopsy with endobronchial balloon.

ERJ Open Res 2020 Apr 22;6(2). Epub 2020 Jun 22.

Dept of Respiratory Medicine, Japanese Red Cross Medical Center, Shibuya, Japan.

Transbronchial lung cryobiopsy (TBLC) has been increasingly utilised to diagnose diffuse parenchymal lung diseases (DPLDs) and lung cancers; however, TBLC protocols have not yet been standardised and the rate of complications associated with this procedure vary widely. Therefore, this prospective multicentre observational study investigated the safety and utility of the TBLC technique in patients with diffuse and localised respiratory diseases. This study was conducted at multiple medical centres in Japan between July 2018 and April 2019. The study's primary end-point was the rate of severe or serious adverse events associated with TBLC. Adverse events included bronchial bleeding, pneumothorax, pneumonia, respiratory failure, and an acute exacerbation of interstitial pneumonia. Adverse events were graded according to severity. During the TBLC procedure, an endobronchial balloon catheter for bronchial blockade was used in all patients. Pathological confidence and quality of specimens were categorised into three groups. A total of 112 patients were included. Neither severe nor serious adverse events were identified; therefore, the primary end-point was met. Nineteen patients (17%) experienced no bronchial bleeding. Mild or moderate bronchial bleeding was identified in 67% and 16% of patients, respectively. Mild pneumothoraces were identified in four patients (3.6%). The safety profile in patients aged ≥75 years was not significantly different from younger patients. Definite or probable pathological diagnoses were made in 84.9% of patients. This TBLC protocol with routine use of an endobronchial balloon had an acceptable safety profile and diagnostic yield in patients, including elderly ones, with diffuse and localised respiratory diseases.
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http://dx.doi.org/10.1183/23120541.00008-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306501PMC
April 2020

Nivolumab-induced contact dermatitis in a patient with advanced lung cancer.

Respir Med Case Rep 2020 15;30:101134. Epub 2020 Jun 15.

Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.

An 85-year-old man was being treated for advanced squamous cell lung carcinoma with nivolumab as a second-line treatment. From the beginning of the third course, erythema appeared on his trunk and gradually progressed. Around the start of the fifth course, erythema spread to the proximal part of all limbs in addition to the trunk and was accompanied by a strong itching sensation. He was diagnosed as having contact dermatitis by a dermatologist because his rash was observed only where the moisture-absorbing fiber material of his underwear made contact with the skin surface. After suspending treatment of nivolumab, changing his underwear to a cotton material, and using moisturizers and steroid ointments, his rash disappeared in about a month and the size of his lung tumors remained reduced. The patient developed contact dermatitis despite the use of similar underwear without any skin problems for several years. We speculated that nivolumab-induced T-cell activation may have occurred in his skin, making him more likely to develop contact dermatitis, whose onset is thought to involve T-cell activation. No cases of contact dermatitis have been reported previously although the frequency of eruption as an immune-related adverse event is relatively high. When using immune checkpoint inhibitors including nivolumab, clinicians need to pay attention to the occurrence of skin disorders related to T-cell activation.
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http://dx.doi.org/10.1016/j.rmcr.2020.101134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303977PMC
June 2020

IgG4-related Bronchial Gland Inflammation Proved by Transbronchial Cryobiopsy.

Am J Respir Crit Care Med 2020 06;201(12):1554-1556

Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.

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http://dx.doi.org/10.1164/rccm.201910-2016IMDOI Listing
June 2020

Clinical, radiological, and pathological features of anti-asparaginyl tRNA synthetase antibody-related interstitial lung disease.

Respir Investig 2020 May 22;58(3):196-203. Epub 2020 Feb 22.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6-16-1 Tomiokahigashi, Kanazawa-ku, Yokohama 236-0051, Japan.

Background: Myositis and interstitial lung disease (ILD) frequently occur in patients with anti-aminoacyl-tRNA synthetase (ARS) antibodies. Nearly half of ARS-ILD patients have the acute or subacute form of the disease, and one-third of these patients show a deterioration in pulmonary function over the long-term course because of frequent recurrences and refractoriness to therapy. Several reports recently described different characteristics depending on the individual anti-ARS antibodies, and the anti-asparaginyl tRNA synthetase (KS) antibody was strongly linked to ILD rather than to myositis. We therefore hypothesized that KS-ILD may have clinical characteristics that differ from those of other ARS-ILDs. The aim of this study was to clarify the clinical, radiological, and pathological features of KS antibody-positive ILD.

Methods: We retrospectively analyzed 19 consecutive patients with KS-ILD who underwent initial clinical measurements and high-resolution computed tomography and pathological assessments. We also analyzed disease behavior based on pulmonary function test results during the follow-up period.

Results: Our KS-ILD cohort included patients with dermatomyositis (10.5%), primary Sjögren syndrome (5.3%), and idiopathic ILD (84.2%). Most patients presented with chronic onset (89.5%) and a nonspecific pattern of interstitial pneumonia at each radiological and pathological assessment (89.4% and 85.7%, respectively). The pulmonary function test results showed that the mean changes from the initial %forced vital capacity and %diffusing capacity of the lung for carbon monoxide at 3 years were 3.7% ± 2.9% and 9.35% ± 3.0%, respectively.

Conclusions: Most KS-ILD patients showed a tendency for chronic disease onset and long-term stabilization of pulmonary function.
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http://dx.doi.org/10.1016/j.resinv.2019.12.003DOI Listing
May 2020

Predictive factors of mortality in rheumatoid arthritis-associated interstitial lung disease analysed by modified HRCT classification of idiopathic pulmonary fibrosis according to the 2018 ATS/ERS/JRS/ALAT criteria.

J Thorac Dis 2019 Dec;11(12):5247-5257

Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.

Background: Interstitial lung disease (ILD) is associated with high morbidity and mortality in rheumatoid arthritis (RA). Although usual interstitial pneumonia (UIP) pattern was reported as a poor prognostic factor, in clinical practice, we often cannot classify high-resolution computed tomography (HRCT) patterns specifically as UIP or nonspecific interstitial pneumonia (NSIP). This study of RA-ILD aimed to elucidate prognosis by using our modified HRCT pattern classification according to the latest guideline on idiopathic pulmonary fibrosis (IPF).

Methods: We analysed the medical records of 96 consecutive patients diagnosed as having RA-ILD. The modified HRCT classifications were defined as definite UIP, probable UIP, indeterminate for UIP (i.e., early UIP or NSIP/UIP), NSIP, organizing pneumonia (OP), NSIP+OP, and unclassifiable. Predictors of prognosis were determined using Cox regression models.

Results: Our RA-ILD cohort included definite UIP (21%), probable UIP (20%), indeterminate for UIP (30%) including NSIP/UIP (27%), alternative diagnosis (29%) including NSIP (14%), and other patterns. Interrater agreement for HRCT pattern was good (κ=0.75). Multivariate analysis showed that older age, history of acute exacerbation, and radiological honeycombing were negative prognostic factors of mortality.

Conclusions: NSIP/UIP pattern of indeterminate for UIP was the major pattern in RA-ILD. Although classifications of HRCT patterns were not related to survival, the presence of radiological honeycombing could be a useful predictor of poor prognosis, and acute exacerbation of ILD can seriously impact patient survival regardless of the presence of a UIP or indeterminate for UIP pattern. Our modified HRCT classification based on the latest IPF guideline might be useful to assess appropriate strategies of diagnosis in future RA-ILD studies, and radiological honeycombing could better predict poor prognosis rather than HRCT pattern.
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http://dx.doi.org/10.21037/jtd.2019.11.73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987998PMC
December 2019

Impact of radiological honeycombing in rheumatoid arthritis-associated interstitial lung disease.

BMC Pulm Med 2020 Jan 30;20(1):25. Epub 2020 Jan 30.

Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.

Background: Interstitial lung disease (ILD) is the most common and important pulmonary manifestation of rheumatoid arthritis (RA). A radiological honeycomb pattern has been described in diverse forms of ILD that can impact survival. However, the clinical course and sequential radiological changes in the formation of the honeycomb pattern in patients with RA-ILD is not fully understood.

Methods: We evaluated the sequential changes in computed tomography findings in 40 patients with chronic forms of RA-ILD without the honeycomb pattern at initial diagnosis. We classified the patients into the Non-honeycomb group and Honeycomb group, and then analyzed the characteristics and prognosis of the two groups. The term "honeycomb formation" indicated a positive finding of honeycombing on any available follow-up CT.

Results: Our RA-ILD cohort included patients with probable usual interstitial pneumonia (UIP) (35%), nonspecific interstitial pneumonia (NSIP) (20%), and mixed NSIP/UIP (45%). Among all RA-ILD patients, 16 (40%) showed honeycomb formation on follow-up CT (median time between initial and last follow-up CT was 4.7 years). Patient characteristics and prognosis were not significantly different between the Non-honeycomb and Honeycomb groups. However, Kaplan-Meier survival curve for the time from the date of honeycomb formation to death showed a poor median survival time of 3.2 years.

Conclusions: A certain number of patients with RA-ILD developed a honeycomb pattern during long-term follow-up, regardless of whether they had UIP or NSIP. Prognosis in the patients with characteristics of both progressive ILD and honeycomb formation could be poor. Although radiological findings over the disease course and clinical disease behavior in RA-ILD are heterogenous, clinicians should be alert to the possibility of progressive disease and poor prognosis in patients with RA-ILD who form a honeycomb pattern during follow-up observation.
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http://dx.doi.org/10.1186/s12890-020-1061-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993451PMC
January 2020

A case of pulmonary tumor thrombotic microangiopathy associated with lung cancer diagnosed by cell-block immunohistochemistry of pulmonary microvascular cytology.

Respir Med Case Rep 2019 23;28:100956. Epub 2019 Oct 23.

Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.

Pulmonary tumor thrombotic microangiopathy (PTTM) is rare but should be considered as a possible diagnosis in patients with cancer. In this case, PTTM induced by lung cancer was more accurately diagnosed using cell block immunohistochemistry of pulmonary microvascular cytology (PMC) because we could confirm that lung adenocarcinoma was the origin of PTTM by the positive result of TTF-1 for atypical cells in PMC. The PMC procedure was minimally invasive and safer than lung biopsy. We believe that the cell block technique of PMC should be considered as one diagnostic option in PTTM.
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http://dx.doi.org/10.1016/j.rmcr.2019.100956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838463PMC
October 2019

Nintedanib allows retreatment with atezolizumab of combined non-small cell lung cancer/idiopathic pulmonary fibrosis after atezolizumab-induced pneumonitis: a case report.

BMC Pulm Med 2019 Aug 22;19(1):156. Epub 2019 Aug 22.

Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chuo-ku, Saitama, Saitama, 330-8553, Japan.

Background: Nintedanib is a tyrosine kinase inhibitor that efficiently slows the progression of idiopathic pulmonary fibrosis (IPF) and has an acceptable tolerability profile. In contrast, immune checkpoint inhibitors (ICIs) such as programmed death 1 and programmed death ligand 1 inhibitors have shown clinical activity and marked efficacy in the treatment of non-small cell lung cancer. However, it is unclear whether nintedanib reduces the risk of ICI-induced pneumonitis in IPF.

Case Presentation: A 78-year-old man with squamous cell lung carcinoma in IPF underwent second-line treatment with pembrolizumab. He was diagnosed as having pembrolizumab-induced pneumonitis after two cycles. He was administered prednisolone (PSL) and then improved immediately. Thereafter, his lung cancer lesion enlarged despite treatment with TS-1. Atezolizumab was then administered as 4th-line chemotherapy, but he immediately developed atezolizumab-induced pneumonitis after 1 cycle. The re-escalated dosage of PSL improved the pneumonitis, and then nintedanib was started as additional therapy. Under careful observation with nintedanib, atezolizumab was re-administered on day 1 of an every-21-day cycle. After three cycles, it remained stable without exacerbation of drug-induced pneumonitis.

Conclusion: This case indicates the possibility that the addition of nintedanib to ICI therapy might prevent drug-induced pneumonitis or acute exacerbation of IPF. However, whether anti-fibrotic agents such as nintedanib are actually effective in preventing ICI-induced pneumonitis in ILD remains unknown and additional research is greatly needed to identify effective therapies for ILD combined with lung cancer.
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http://dx.doi.org/10.1186/s12890-019-0920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704625PMC
August 2019

A Large Pulmonary Arteriovenous Malformation.

Intern Med 2019 11 22;58(22):3345-3346. Epub 2019 Jul 22.

Department of Respiratory Medicine, Saitama Red Cross Hospital, Japan.

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http://dx.doi.org/10.2169/internalmedicine.3014-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911750PMC
November 2019

Evaluation of changes in the serum levels of Krebs von den Lungen-6 and surfactant protein-D over time as important biomarkers in idiopathic fibrotic nonspecific interstitial pneumonia.

Respir Investig 2019 Sep 16;57(5):422-429. Epub 2019 Apr 16.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6-16-1 Tomioka-higashi, Kanazawa-ku, Yokohama 236-0051, Japan. Electronic address:

Background: Some cases of idiopathic fibrotic nonspecific interstitial pneumonia (f-NSIP) show a progressive course that is similar to that of idiopathic pulmonary fibrosis. However, it is difficult to predict poor patient outcomes. This study aimed to evaluate whether serial changes in serum levels of Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) can predict disease progression.

Methods: We retrospectively analyzed the medical records of 75 patients with idiopathic f-NSIP. Disease behavior was categorized into two groups depending on long-term change of pulmonary function: progressive type (≥5%/year relative decline in the slope of forced vital capacity [FVC] and/or ≥7.5%/year relative decline in the slope of %diffusing capacity of the lung for carbon monoxide [%D]) and stable type. Levels of KL-6 and SP-D and results of pulmonary function tests, which were performed parallelly, were reviewed and analyzed using a linear mixed-effects model.

Results: The study subjects comprised 62 patients with stable type and 13 patients with progressive type disease behavior. Among these subjects, 50 patients fulfilled the diagnostic criteria of interstitial pneumonia with autoimmune features (IPAF). Serum levels of both KL-6 and SP-D at baseline showed a negative correlation with %D, but not with FVC, and these biomarkers were not related to disease progression. Persistently high levels of KL-6 and SP-D correlated with progressive type disease behavior in idiopathic (non-IPAF) f-NSIP.

Conclusions: Changes in serum KL-6 and SP-D levels over time may provide useful predictive information on disease behavior during treatment in patients with idiopathic f-NSIP and especially in those with non-IPAF f-NSIP.
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http://dx.doi.org/10.1016/j.resinv.2019.03.006DOI Listing
September 2019

Tracheal Ulcers Associated with Anti-synthetase Syndrome.

Intern Med 2019 08 17;58(16):2411-2412. Epub 2019 Apr 17.

Department of Respiratory Medicine, Saitama Red Cross Hospital, Japan.

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http://dx.doi.org/10.2169/internalmedicine.2730-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746650PMC
August 2019

Negative impact of anorexia and weight loss during prior pirfenidone administration on subsequent nintedanib treatment in patients with idiopathic pulmonary fibrosis.

BMC Pulm Med 2019 Apr 11;19(1):78. Epub 2019 Apr 11.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Tomioka-Higashi 6-16-1, Kanazawa-ku, Yokohama, 236-0051, Japan.

Background: Current clinical practice guidelines for idiopathic pulmonary fibrosis (IPF) conditionally recommend use of pirfenidone and nintedanib. However, an optimal treatment sequence has not been established, and the data of treatment sequence from pirfenidone to nintedanib are limited. This study aimed to evaluate safety, tolerability and efficacy of nintedanib switched from pirfenidone in patients with IPF.

Methods: Thirty consecutive IPF cases, which discontinued pirfenidone because of a decline in forced vital capacity (FVC) or intolerable adverse event (AE), and newly started nintedanib (150 mg twice daily) from September 2015 to August 2017 (switch-group) were retrospectively reviewed. Subsequently, we compared the characteristics, treatment status, and AEs between the switch-group and other 64 IPF patients newly started nintedanib during the same period without any prior anti-fibrotic treatment (pirfenidone-naïve group).

Results: In the switch group, median age, body weight, body mass index (BMI), and %FVC were 72 years old, 54.9 kg, 21.0 kg/m, and 52.9%, respectively. Most common AE of nintedanib was aspartate aminotransferase/alanine aminotransferase elevation (71.9%), followed by anorexia (46.7%) and diarrhea (46.7%); whereas, anorexia (63.3%) and ≥ 5% weight loss from baseline (56.7%) were common during pirfenidone administration. Sixteen patients (53.3%) discontinued nintedanib within 6 months (early termination). Multivariate logistic regression analysis revealed a significant association between low BMI and early nintedanib termination in the switch-group (p = 0.0239). Nintedanib suppressed FVC decline as compared with that during administration period of pirfenidone in 70% of the patients who could undergo lung function before and after switching to nintedanib. The incidence of early termination of nintedanib was higher in the switch-group than in the pirfenidone-naïve group, whereas body-weight, BMI, absolute FVC values, and %FVC were significantly lower in the switch-group (just before nintedanib initiation) than in the pirfenidone-naïve group. Nintedanib-induced anorexia was more frequent and severer in the switch-group than in the pirfenidone-naïve group, but no significant differences were observed in terms of other AEs.

Conclusions: A high incidence of early termination of nintedanib was noted when patients were switched from pirfenidone. Anorexia and weight loss during prior pirfenidone administration may increase the rate of the early termination of subsequent nintedanib treatment.
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http://dx.doi.org/10.1186/s12890-019-0841-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458823PMC
April 2019

Low starting-dosage of nintedanib for the reduction of early termination.

Respir Investig 2019 May 13;57(3):282-285. Epub 2019 Feb 13.

Kanagawa Cardiovascular and Respiratory Center, Department of Respiratory Medicine, Tomioka-Higashi 6-16-1, Kanazawa-ku, Yokohama 236-0051, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.resinv.2018.12.010DOI Listing
May 2019

Anti-Ku antibody-positive desquamative interstitial pneumonia.

Respir Med Case Rep 2019 16;26:115-117. Epub 2018 Dec 16.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.

A 66-year-old man, an ex-smoker, was referred to our hospital for slightly progressive respiratory symptoms of cough and dyspnea on exertion and chest abnormal shadow. Chest high-resolution computed tomography showed wide-ranging ground-glass attenuation and reticulation with lower lobe predominance. Bronchoalveolar lavage (BAL) fluid revealed a marked increase in lymphocytes (53.0%), and a surgical lung biopsy revealed a pattern of desquamative interstitial pneumonia (DIP) with hyperplasia of the lymphoid follicles. His serum was positive for anti-Ku and anti-SS-A antibodies, and he had signs (such as Raynaud's phenomenon, joint pain, and mechanic's hand) suspicious of connective tissue disease (CTD) although a definitive diagnosis of CTD had not been established. On the basis of the findings in our patient obtained from the serologic domain, BAL, and pathological examination, clinicians should consider the important correlation of DIP with CTD as well as with smoking.
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http://dx.doi.org/10.1016/j.rmcr.2018.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302154PMC
December 2018

Interstitial lung disease associated with anti-citrullinated peptide/protein antibody-positive anti-synthetase syndrome.

J Thorac Dis 2018 Oct;10(10):5924-5931

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanazawa-ku, Yokohama 236-0051, Japan.

Little has been reported on the characteristics of interstitial lung disease (ILD) associated with anti-citrullinated peptide/protein antibody (ACPA)-positive anti-synthetase syndrome (ASS). We sought to investigate the clinical, radiologic, and pathologic features of patients with ILD associated with ACPA-positive ASS. Medical records of seven ILD patients with positive results of both ACPA and anti-aminoacyl-tRNA synthetase antibody were retrospectively reviewed. Five patients had clinical symptoms associated with ASS other than ILD. On high-resolution computed tomography (HRCT) analysis, a nonspecific interstitial pneumonia (NSIP) pattern was shown in 3 patients and NSIP with organizing pneumonia (OP) overlap in 2 patients. Coronal slices of these 5 patients showed lower lung disease predominance with traction caudally on major fissures due to lower lobe volume loss. These were features that could commonly be observed in ASS-associated ILD. Pathological findings available for 3 patients showed NSIP. The characteristics of ILD associated with ACPA-positive ASS appear to be similar to those of ILD associated with ASS, but not to rheumatoid arthritis (RA) or ACPA, especially in terms of the radiological findings.
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http://dx.doi.org/10.21037/jtd.2018.09.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236144PMC
October 2018

Clinical characteristics and early outcomes of patients newly diagnosed with pulmonary Mycobacterium avium complex disease.

Respir Investig 2019 Jan 24;57(1):54-59. Epub 2018 Oct 24.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6-16-1 Tomioka-higashi, Kanazawa-ku, Yokohama, 236-0051, Japan.

Background: The incidence of asymptomatic pulmonary Mycobacterium avium complex (MAC) disease appears to be increasing. This study aimed to determine the clinical characteristics and examine early outcomes of patients newly diagnosed with MAC disease.

Methods: We retrospectively reviewed the medical records of all 184 patients newly diagnosed with MAC disease between April 2013 and March 2015 at our hospital. Culture conversion, defined as at least two consecutive negative cultures, was used as the early outcome measure.

Results: Of 184 patients, 45 were male and 139 were female, with a mean age of 70 years. Abnormal chest shadow found during an annual health check-up (58 patients) or incidentally during visits for other diseases (72 patients), was the major reason for referral to hospital, typically with no symptoms. Anti-MAC IgA antibody was positive in 64.5% of patients, and the positive rate was associated with the extent of lesions. Clarithromycin-based multi-drug chemotherapy was initiated in 111 patients. Culture conversion was achieved in 61 of 82 (74.4%) patients who were able to continue multi-drug chemotherapy. Patients who achieved culture conversion were more likely to be younger, female, and have a lower smear grade and nodular-bronchiectatic type. Multivariate logistic regression analysis identified patient age and smear grade as predictive variables.

Conclusions: Abnormal chest shadow found during health check-up was the major reason for hospital visits, and most were asymptomatic. Culture conversion was achieved in three-fourths of patients treated, and was associated with age and smear grade, supporting early intervention at a younger age.
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http://dx.doi.org/10.1016/j.resinv.2018.08.006DOI Listing
January 2019

Emphysema formation in a never-smoker with scleroderma-related interstitial pneumonia.

Respir Med Case Rep 2018 13;25:211-212. Epub 2018 Sep 13.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.

We report a case of pathological emphysema formation in a never-smoker with scleroderma-related interstitial pneumonia. We realized the importance of pulmonary vasculopathy causing the coexistence of emphysema and fibrosis in scleroderma. Our discovery provides novel information that emphysema can occur in patients with scleroderma-related interstitial pneumonia who have never smoked.
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http://dx.doi.org/10.1016/j.rmcr.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143697PMC
September 2018
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