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Sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy, was recently approved for pharmaceutical use in Japan and shows promise as a treatment for autoimmune pulmonary alveolar proteinosis (APAP). For APAP patients with severe respiratory failure due to advanced lung fibrosis, lung transplantation is also a treatment option; however, APAP may recur after the procedure. Here, we report a case of successful sargramostim inhalation therapy for post-transplant APAP relapse in a patient who underwent living lung transplantation owing to severe fibrosis. Inhaled GM-CSF may be a useful treatment option for APAP recurrence in patients who have undergone lung transplantation. CLINICAL TRIAL REGISTRATION: Pulmonary Alveolar Proteinosis GM-CSF Inhalation Efficacy Trial II registered to Japan Registry of Clinical Trials (jRCTs031220127)., Competing Interests: Declaration of competing interest K.N has received funding from Nobelpharma, and consulting fees from Nobelpharma unrelated to the present manuscript. The other authors have no conflicts of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Background: No previous studies have compared respiratory clinics and respiratory specialized facilities regarding causative diseases for bloody sputum and hemoptysis in Japan., Methods: We retrospectively compared causative diseases for bloody sputum and hemoptysis between 3 respiratory clinics (clinic group) and 7 departments of respiratory medicine at hospitals (hospital group) in Japan., Results: We collected data from 231 patients (median age, 51 years; age range, 24-96 years; 109 men (47.2%)) in the clinic group and 556 patients (median age, 73 years; age range, 21-98 years; 302 men (54.3%)) in the hospital group. In the former group, the main causative disease was acute bronchitis (91 patients, 39.4%), acute upper respiratory tract infection (34 patients, 14.7%), and bronchiectasis (BE) (29 patients, 12.6%). In the latter group, the main causative diseases were BE (102 patients, 18.3%), lung cancer (97 patients, 17.4%), and non-tuberculous mycobacterial disease (NTM) (89 patients, 16%). In particular, in patients ≥60 years old, BE was an important causative disease for bloody sputum and hemoptysis in both groups., Conclusions: The present study is the first to compare respiratory clinics and respiratory specialized facilities. Depending on the facility in which the patient is examined, lung cancer, BE, and NTM were identified as diseases requiring special attention as causes of bloody sputum and hemoptysis., Competing Interests: Conflict of interest KT received a Grant-in-Aid for Scientific Research from Ministry of Health, Labour and Welfare (No. 20K08545). The other authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Long-term macrolide therapy for non-cystic fibrosis bronchiectasis (NCFB) can play a significant role. However, such data are insufficient regarding the efficacy against severe exacerbation and adverse effects, including the emergence of macrolide-resistant pathogens and prolonged macrolide use beyond 1 year., Methods: Randomized controlled trials (RCTs) and prospective observational studies comparing the efficacy and safety of macrolides and placebo in adult patients with NCFB were screened on April 10, 2024. The primary outcome was severe exacerbation frequency., Results: Ten RCTs ≤1 year study durations were included. Most studies mainly included patients with a history of >2 exacerbations. Macrolides had a tendency to reduce the frequency of severe exacerbations compared with placebo (odds ratio = 0.54, 95% confidence interval (CI) = 0.25-1.18). Macrolides significantly reduced the frequency of exacerbations (rate ratio = 0.58, 95% CI = 0.48-0.69), prolonged the time to first exacerbation (rate ratio = 0.41, 95% CI = 0.30-0.55), improved the changes in SGRQ scores [mean difference (MD) = -3.99, 95% CI = -4.63-3.44] and percent predicted forced expiratory volume in 1 s (MD = -2.30, 95% CI = 0.26-4.33), and reduced sputum volume (gram) (MD = -7.44, 95% CI = -9.15-5.74). Additionally, macrolides did not increase drug-related adverse events leading to discontinuation. Qualitative SR of pathogens indicated macrolides might increase the number of macrolide-resistant oropharyngeal and sputum pathogens and the emergence of Pseudomonas aeruginosa., Conclusions: Our results support macrolide therapy for patients with NCFB. Studies with an observation period of >1 year or those focusing on patients with/without a minimal exacerbation history are required to determine the long-term effects on patients with NCFB., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Cryobiopsy use is anticipated to become more common in diagnosing lung diseases. In Japan, inserting a Fogarty catheter through a suction channel above the endotracheal tube's cuff for hemostasis is common practice. However, the rigid nature of the endotracheal tube poses challenges to tracheal intubation using a bronchoscope. The endotracheal tube cuff must be removed to prevent interference during Fogarty catheter insertion. To simplify the procedure and enhance safety, we devised and implemented a method of inserting a hemostatic Fogarty catheter with a suction tube externally attached to a softer endotracheal tube. This study aimed to evaluate the sustainability of this Fogarty catheter insertion method using suction tubes., Methods: The hemostatic Fogarty catheter insertion method was retrospectively validated. We compared outcomes between 60 patients who underwent the conventional method with a suction channel above the cuff and 50 patients who underwent the novel approach with an externally attached suction tube., Results: The physicians performing bronchoscopy and inserting the Fogarty catheter in the group in which the suction tube was externally attached for Fogarty catheter insertion had little experience. However, the overall bronchoscopy time was shorter; the two groups showed no significant differences in complications., Conclusion: Regarding cryobiopsy procedures, using an externally attached suction tube for Fogarty catheter insertion was practical and comparable to the conventional method of using a suction channel above the cuff. This method made the procedure more simple and safe., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)

Background: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT., Methods: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateⅠ, moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated., Results: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity., Conclusion: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan., Competing Interests: Declaration of Competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Evidence regarding the association of the usage of biologic agents (Etanercept, Tocilizumab, adalimumab and so on), such as anti-tumor necrosis factor α, with the incidence and risk factors of non-tuberculous Mycobacteria (NTM) infection is limited. Therefore, this study aimed to investigate the incidence and risk factors of NTM and their associations with biologic agents' usage, and also investigated the potential of Mycobacterium avium complex (MAC) antibodies as a predictor of NTM infection development., Methods: This retrospective study included 672 patients with autoimmune diseases from four hospitals in Nagasaki, Japan, from January 1, 2011, to June 30, 2019, who fulfilled the inclusion criteria., Results: Of the 672 patients, 9 (1.3%) developed complicated NTM infection, including two with disseminated infection, after the introduction of biologic agents. Of the nine patients, two died due to NTM infection but none tested positive for MAC antibodies prior to initiation of biologic agents. The mortality rate was higher in patients complicated with NTM than without NTM (22.2% vs 2.6%, P = 0.024). The corticosteroids dosage at the time of initiating the biologic agents was significantly higher in the NTM group than in the non-NTM group (median, 17 mg vs 3 mg, P = 0.0038)., Conclusion: In the patients undergoing therapy with biologic agents, although NTM complication was rare, it could be fatal. In particular, for patients on a relatively high dose corticosteroids, careful observation is essential for identifying NTM complication, even if the MAC antibody test is negative., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: The Guidelines for the Management of Cough and Sputum (2019) of the Japanese Respiratory Society (JRS) were the first internationally published guidelines for the management of sputum. However, the data used to determine the causative diseases of bloody sputum and hemoptysis in these guidelines were not obtained in Japan., Methods: A retrospective analysis was performed using the clinical information of patients with bloody sputum or hemoptysis who visited the department of respiratory medicine at a university or core hospital in Japan., Results: Included in the study were 556 patients (median age, 73 years; age range, 21-98 years; 302 males (54.3%)). The main causative diseases were bronchiectasis (102 patients (18.3%)), lung cancer (97 patients (17.4%)), and non-tuberculous mycobacterial disease (89 patients (16%)). Sex and age differences were observed in the frequency of causative diseases of bloody sputum and hemoptysis. The most common cause was lung cancer in males (26%), bronchiectasis in females (29%), lung cancer in patients aged <65 years (19%), and bronchiectasis in those aged >65 years (20%)., Conclusions: The present study is the first to investigate the causative diseases of bloody sputum and hemoptysis using data obtained in Japan. When investigating the causative diseases of bloody sputum and hemoptysis, it is important to take the sex and age of the patients into account., Competing Interests: Declaration of competing interest KT received Grants-in-Aid for Scientific Research from Ministry of Health, Labour and Welfare (Nos. 20K08545). The other authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The evidence for macrolide therapy in adult asthma is not properly established and remains controversial. We conducted a systematic review and meta-analysis to examine the efficacy and safety of macrolide therapy for adult asthma., Methods: We searched randomized controlled trials from MEDLINE via the PubMed, CENTRAL, and Ichushi Web databases. The primary outcome was asthma exacerbation. The secondary outcomes were serious adverse events (including mortality), asthma-related quality of life (symptom scales, Asthma Control Questionnaire, and Asthma Quality of Life Questionnaire), rescue medication (puffs/day), respiratory function (morning peak expiratory flow, evening peak flow, and forced expiratory volume in 1 s), bronchial hyperresponsiveness, and minimum oral corticosteroid dose. Of the 805 studies, we selected seven studies for the meta-analysis, which was conducted using a random-effects model., Systematic Review Registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN000050824)., Results: No significant difference between macrolide and placebo for asthma exacerbations was observed (risk ratio 0.71, 95 % confidence interval [CI] 0.46-1.09; p = 0.12). Macrolide therapy for adult asthma showed a significant improvement in rescue medication with short-acting beta-agonists (mean difference -0.41, 95 % CI -0.78 to -0.04; p = 0.03). Macrolide therapy did not show more serious adverse events (odd ratio 0.61, 95 % CI 0.34-1.10; p = 0.10) than those with placebo. The other secondary outcomes were not significantly different between the macrolide and placebo groups., Conclusions: Macrolide therapy for adult asthma may be more effective than placebo and could be a treatment option., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

This retrospective observational study aimed to assess the clinical characteristics of platypnea-orthodeoxia syndrome in patients with coronavirus disease 2019 (COVID-19) treated using mechanical ventilation or high-flow nasal canula. We analyzed 42 consecutive patients with COVID-19 from January 2020 to March 2022. The primary outcomes were the incidence of platypnea-orthodeoxia syndrome, the time with required long-term oxygen therapy, and short-term prognosis. Additionally, we examined the relationships between platypnea-orthodeoxia syndrome and COVID-19 severity, the time with long-term oxygen therapy, and short-term prognosis. Of the 42 included patients, 15 (35.7 %) had platypnea-orthodeoxia syndrome. Although mortality was not significantly different between both groups, the oxygen withdrawal rate in the platypnea-orthodeoxia syndrome group was significantly lower than that in the group without this syndrome. Clinical staff should be aware of the possibility of platypnea-orthodeoxia syndrome during positional changes in patients with COVID-19. Recognizing POS can improve early detection, countermeasures, and safety during physiotherapy., Competing Interests: Declaration of competing interest Tetsuya Hara reports lecture fees from Ono Pharmaceutical Co., Ltd., and grants from Ono Pharmaceutical Co., Ltd., Edwards Lifesciences Co., Ltd., and Asahi Kasei Pharma Co., Ltd., outside of the submitted work. Masatoshi Hanada, Yuji Ishimatsu, Noriho Sakamoto, Nobuyuki Ashizawa, Hirotomo Yamanashi, Motohiro Sekino, Koichi Izumikawa, Hiroshi Mukae, Koya Ariyoshi, Takahiro Maeda, Shuntaro Sato, and Ryo Kozu have no conflict of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Aspiration pneumonia is an important condition in elderly patients and detecting dysphagia early can help clinicians identify patients with a high risk of aspiration pneumonia. We previously reported the usefulness of the Assessment of Swallowing Ability for Pneumonia (ASAP) in predicting the occurrence of and mortality from pneumonia in patients in acute care hospitals; however, there are very few reports on the utility of this screening test for patients in stable condition., Methods: Elderly patients in stable condition (n = 133) without pneumonia were prospectively enrolled. Associations between ASAP, Functional Independence Measure (FIM), Controlling Nutrition Status (CONUT), and Charlson Co-morbidity Index (CCI) scores and occurrence of/mortality from pneumonia during hospitalization were evaluated., Results: The occurrence of pneumonia was observed in 27 (20.3%) patients, and 18 (13.5%) died during hospitalization. Multivariate analysis showed that low ASAP score and low FIM motor were independent predictors for the occurrence of pneumonia, and low ASAP score was an independent predictor for mortality from pneumonia. Areas under the curve for ASAP, FIM motor, FIM cognition, and CONUT scores were 0.895 (95% confidence interval [CI], 0.829-0.960), 0.913 (95% CI, 0.860-0.968), 0.841 (95% CI, 0.761-0.921), and 0.753 (95% CI, 0.649-0.858), respectively, for occurrence, and 0.881 (95% CI, 0.807-0.955), 0.904 (95% CI, 0.860-0.949), 0.829 (95% CI, 0.727-0.931), 0.746 (95% CI, 0.617-0.874), respectively, for mortality., Conclusion: The ASAP and FIM motor are useful for predicting the occurrence of and mortality from pneumonia in elderly inpatients in long-term care hospitals., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

We describe a rare case of a 20-year-old Japanese man with idiopathic pulmonary hemosiderosis (IPH) recurrence in adults with childhood onset (racIPH). IPH commonly occurs in children, and data regarding racIPH are lacking. A review of the literature showed that only five cases of racIPH have been reported (including the present case) and that racIPH shows features that are intermediate between childhood- and adult-onset IPH with respect to age and a lower frequency of smoking history. We also found that the degree of anemia was usually not severe, and a favorable response to corticosteroid therapy is expected in racIPH., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

An internet questionnaire survey for investigating empirical antibiotic usage and bacterial superinfections in patients with coronavirus disease-2019 (COVID-19) in Japan was conducted among the chief physicians of respiratory disease departments of 715 Japanese Respiratory Society-certified hospitals using Google Forms between January 28, 2021 and February 28, 2021. Responses to the questionnaire survey were obtained from 198 of 715 hospitals (27.6%). The survey revealed that the complication incidences of community-acquired pneumonia; hospital-acquired pneumonia, including ventilator-associated pneumonia; and sepsis were 2.86, 5.59, and 0.99%, respectively, among patients with moderate/severe and critical COVID-19. Bacterial co-infection and secondary infection rarely affected patients with COVID-19 in Japan, and the isolated pathogens were not specific to these patients. Moreover, the anti-inflammatory effects of macrolides for COVID-19 were not observed in several studies. These results might be useful in clinical practice for COVID-19., Competing Interests: Conflict of Interest H·K received honoraria from MSD Co., Ltd., Astellas Pharma Inc., Pfizer Inc., Asahi Kasei Pharma Corporation, Shionogi Co., Ltd., and Sumitomo Dainippon Pharma Co., Ltd. The other authors have no conflict of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to clarify the involvement of anaerobes in aspiration pneumonia by measuring volatile sulfur compounds (VSCs), which are metabolites of anaerobic bacteria in the mouth., Methods: This study included 84 older adult patients (mean age, 82.5 ± 7.34 years) who had dementia and were hospitalized for more than 6 months. We measured the VSCs in the patient's mouth with Oral Chroma and obtained the data of pneumonia development in the past 6 months. We also evaluated the association or correlation of VSCs and some factors which might be the risk factors of aspiration pneumonia., Results: The development of pneumonia had no significant association with the VSCs in the patient's mouth., Conclusion: The present pilot study suggests that anaerobes might not be the main causative pathogens of aspiration pneumonia in older adult patients., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Recently, culture-independent molecular methods, such as DNA sequencing techniques targeting the 16S-ribosomal RNA (rRNA) gene and/or other housekeeping genes with Sanger method-based technologies, next generation sequencing (NGS), and metagenomic analysis, have been developed for detecting microorganisms in the human body; these can provide information on microbiomes of samples from individuals with or without infectious diseases. Determining the bacterial species is crucial in identifying causative bacteria of upper and lower respiratory tract infections, especially for Streptococcus species, but NGS analysis is often not precise enough to identify bacteria at the species level. This review briefly introduces previous observations of the microbiome of samples from various respiratory and other infections assessed using the clone library method with Sanger sequencing of the 16S-rRNA gene. On analysis of 16S-rRNA gene-sequence data of bronchoalveolar lavage fluid obtained from pneumonia lesions in patients with bacterial pneumonia and lung abscess, anaerobes are often detected in non-elderly patients with pneumonia, and the detection rate of Staphylococcus aureus in patients with hospital-acquired pneumonia is lower than that previously reported. Analysis of pleural effusion samples from patients with pleurisy indicated a more important role of anaerobes than previous believed. The other topics reviewed include microbiomes of nontuberculous mycobacteriosis and lower respiratory tract infections in children with permanent tracheostomy due to neuromuscular disorders, in nasal discharge, in bacterial vaginosis, in the intracystic fluid of postoperative maxillary cyst, and in bacterial conjunctivitis; urine microbiota in urethritis; fecal microbiota; and newly detected infectious organisms in the human respiratory tract., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Assessment of swallowing functions in elderly people with pneumonia is important. Videofluoroscopic and videoendoscopic examinations have been known as reliable assessments of swallowing functions. However, it is often difficult to use these tools in patients with pneumonia due to their poor condition and/or inadequate hospital facilities. We have previously constructed the Assessment of Swallowing Ability for Pneumonia (ASAP) as a straightforward evaluation for swallowing function. This study investigates the efficacy of the ASAP in predicting several outcomes in elderly patients with pneumonia., Methods: Elderly patients with pneumonia (n = 130) who were admitted to Tobata Kyoritsu Hospital from January to June 2016 were enrolled prospectively. Associations between their ASAP scores and in-hospital mortality, recurrence of pneumonia within 30 days, 6-month mortality, and detection of antibiotic-resistant bacteria were evaluated., Results: Lower ASAP scores were associated with higher rates of in-hospital mortality, recurrence of pneumonia, and 6-month mortality. The areas under the curve were 0.84 (95% confidence interval [CI], 0.72-0.96) for in-hospital mortality, 0.76 (95% CI, 0.67-0.85) for recurrence of pneumonia, 0.74 (95% CI, 0.64-0.84) for 6-month mortality, and 0.67 (95% CI, 0.52-0.82) for detection of antibiotic-resistant bacteria. Multivariate analysis showed that a lower ASAP score was an independent risk factor for in-hospital mortality, recurrence of pneumonia, and 6-month mortality., Conclusions: The ASAP was useful for predicting short- and long-term mortalities and recurrence of pneumonia., Competing Interests: Conflict of Interest The authors state that they have no conflict of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Phase IV clinical trials in Western countries have reported that combined therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) has a manageable safety profile. However, data on the long-term safety and tolerability of this combination treatment in the real-world setting in Japan are limited., Methods: The retrospective data of 46 patients with IPF who received combination therapy with pirfenidone and nintedanib were obtained from 16 institutes in Japan. Adverse events and adverse drug reactions (ADRs) were reported through a retrospective review of medical records., Results: Nintedanib and pirfenidone were added to preceding treatment with antifibrotic drugs in 32 (69.6%) and 13 (28.3%) patients, respectively. In one patient (2.1%), the two drugs were concurrently initiated. The mean duration of monotherapy before initiating the combination was 26.3 months. In 26 of 38 patients (68.4%), the Gender-Age-Physiology index stage was II or III. Thirty-three patients (71.7%) had some ADRs, and 14 patients (30.4%) permanently discontinued either drug or both drugs owing to the development of ADRs during the observation period (mean: 59 weeks). The percentage of grade III or IV IPF according to the Japanese Respiratory Society severity classification was higher in patients who permanently discontinued either drug or both drugs than in those who continued both drugs (90.9% [10/11; 3 undetermined grade] vs. 61.1% [11/18; 1 undetermined grade]). Decreased appetite (18/46, 39.1%) and diarrhea (16/46, 34.8%) were frequently observed ADRs. Two patients (4.3%) had serious ADRs (liver toxicity and pneumothorax)., Conclusions: Real-world data imply that combination therapy with pirfenidone and nintedanib for IPF has a manageable safety/tolerability profile., Competing Interests: Conflict of Interest Shu Hisata, Kensuke Kataoka, Yoshinobu Saito, and Motoyasu Kato received honoraria from Nippon Boehringer Ingelheim Co., Ltd.; Masashi Bando, Sakae Homma, and Takashi Ogura received honoraria from Nippon Boehringer Ingelheim Co., Ltd. and Shionogi & Co., Ltd.; Yasuhiko Nishioka received honoraria, donations, and research funding from Nippon Boehringer Ingelheim Co., Ltd.; Kazuhiro Yatera received honoraria from Nippon Boehringer Ingelheim Co., Ltd., and donations from Shionogi & Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd.; Hiroshi Mukae received honoraria, donations, and research funding from Nippon Boehringer Ingelheim Co., Ltd. and Shionogi & Co., Ltd.; Shinyu Izumi, Susumu Sakamoto, Kizuku Watanabe, Yasuo Shimizu, Hiromichi Hara, Yuko Waseda, Yoshinori Tanino, Seishu Hashimoto, and Naohiko Inase have no conflicts of interest to declare., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Co-infections of Streptococcus anginosus group (SAG) bacteria and obligate anaerobes are observed in patients with empyema; however, their epidemiology and pathology remain unknown. A retrospective study was performed with 44 patients who underwent pleural effusion microbiota evaluation between January 2006 and March 2018, using the clone library method for detecting empyema caused by SAG bacteria. Based on culture analysis of pleural effusion, 12 patients were diagnosed with empyema caused by SAG bacteria. Obligate anaerobe phylotypes were detected in eight patients (66.7%) using the clone library method, whereas anaerobic culture analysis detected anaerobes in only two patients (16.7%). No significant difference was observed between the clinical features of SAG-mediated empyema with and without anaerobes using the clone library method, except for chest computed tomographic data. Co-infection of SAG bacteria and obligate anaerobes may be underestimated if conventional culture methods are used. SAG-mediated empyema with and without anaerobes may present different radiological features; therefore, further studies are required., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Cough and sputum are common complaints at outpatient visits. In this digest version, we provide a general overview of these two symptoms and discuss the management of acute (up to three weeks) and prolonged/chronic cough (longer than three weeks). Flowcharts are provided, along with a step-by-step explanation of their diagnosis and management. Most cases of acute cough are due to an infection. In chronic respiratory illness, a cough could be a symptom of a respiratory infection such as pulmonary tuberculosis, malignancy such as a pulmonary tumor, asthma, chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis, drug-induced lung injury, heart failure, nasal sinus disease, sinobronchial syndrome, eosinophilic sinusitis, cough variant asthma (CVA), atopic cough, chronic laryngeal allergy, gastroesophageal reflux (GER), and post-infectious cough. Antibiotics should not be prescribed for over-peak cough but can be considered for atypical infections. The exploration of a single/major cause is recommended for persistent/chronic cough. When sputum is present, a sputum smear/culture (general bacteria, mycobacteria), cytology, cell differentiation, chest computed tomography (CT), and sinus X-ray or CT should be performed. There are two types of rhinosinusitis. Conventional sinusitis and eosinophilic rhinosinusitis present primarily with neutrophilic inflammation and eosinophilic inflammation, respectively. The most common causes of dry cough include CVA, atopic cough/laryngeal allergy (chronic), GER, and post-infectious cough. In the last chapter, future challenges and perspectives are discussed. We hope that the clarification of the pathology of cough hypersensitivity syndrome will lead to further development of "pathology-specific non-specific therapeutic drugs" and provide benefits to patients with chronic refractory cough., Competing Interests: Conflict of Interest Dr. Hiroshi Mukae received honoraria from Daiichi Sankyo Co., Ltd., Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., KYOLIN Pharmaceutical Co., Ltd., Pfizer Japan Inc., MSD K.K., Taisho Pharma Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Astellas Pharma Inc., and AstraZeneca K.K., a research grant from Nippon Boehringer Ingelheim Co., Ltd., and subsidies or donations from Fujifilm Toyama Chemical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Taisho Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., KYORIN Pharmaceutical Co., Ltd., and Shionogi & Co., Ltd.; Dr. Takeshi Kaneko received honoraria from Pfizer Japan Inc., KYORIN Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., AstraZeneca K.K., Novartis Pharma K.K., Nippon Boehringer Ingelheim Co., Ltd., and Meiji Seika Pharma Co., Ltd., and a research grant from Teijin Home Healthcare Ltd., Ono Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd.; Dr. Toshio Katsunuma received honoraria from KYORIN Pharmaceutical Co., Ltd., Maruho Co., Ltd. and Torii Pharmaceutical Co., Ltd.; Dr. Akio Niimi received honoraria from AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., MSD K.K., KYORIN Pharmaceutical Co., Ltd., GlaxoSmithKline K.K. and Novartis Pharma K.K., a research grant from Novartis Pharma K.K., Boston Scientific Corporation, MSD K.K., and Nippon Boehringer Ingelheim Co., Ltd., and subsidies or donations from Nippon Boehringer Ingelheim Co., Ltd., KYORIN Pharmaceutical Co., Ltd. and Ono Pharmaceutical Co., Ltd.; Dr. Hiroto Matsuse received honoraria from MSD K.K., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Pfizer Japan Inc., KYORIN Pharmaceutical Co., Ltd., and Astellas Pharma Inc.; Dr. Kazuhiro Yatera received honoraria from AstraZeneca K.K., Novartis Pharma K.K., Nippon Boehringer lngelheim Co., Ltd., Astellas Pharma Inc., GlaxoSmithKline K.K., and KYORIN Pharmaceutical Co., Ltd., and subsidies or donations from Kirigaoka Tsuda Hospital, Tochiku Hospital, Hagiwara Central Hospital, Kurate Hospital, Shionogi & Co., Ltd., Teijin Home Healthcare Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K., Novartis Pharma K.K., and Nippon Boehringer Ingelheim Co., Ltd.; Dr. Arata Azuma received honoraria from Nippon Boehringer Ingelheim Co., Ltd.; Dr. Hirokazu Arakawa received subsidies or donations from Novartis Pharma K.K.; Dr. Takashi Iwanaga received honoraria from KYORIN Pharmaceutical Co., Ltd., a research grant from KYORIN Pharmaceutical Co., Ltd., Pearl Therapeutics, Inc., and Meiji Seika Pharma Co., Ltd., and subsidies or donations from Nippon Boehringer Ingelheim Co., Ltd., Astellas Pharma Inc., Teijin Pharma Ltd., and KYORIN Pharmaceutical Co., Ltd.; Dr. Yasuhiro Gon received honoraria from Novartis Pharma K.K., AstraZeneca K.K., GlaxoSmithKline K.K., Nippon Boehringer Ingelheim Co., Ltd., and KYORIN Pharmaceutical Co., Ltd., and a research grant from Novartis Pharma K.K. and AstraZeneca K.K.; Dr. Hirokazu Sakamoto received a research grant from Sanofi K.K. and Novartis Pharma K.K.; Dr. Yoko Shibata received honoraria from AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., and GlaxoSmithKlein K.K.; Dr. Tsutomu Tamada serves as a consultant to Novartis Pharma K.K. and AstraZeneca K.K.; Dr. Yasuhiko Nishioka received honoraria from Nippon Boehringer lngelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., and MSD K.K., a research grant from Taiho Pharmaceutical Co., Ltd., Nippon Boehringer lngelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Bonac Corporation, and subsidies or donations from Ono Pharmaceutical Co., Ltd., Nippon Boehringer lngelheim Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Asahi Kasei Pharma Corporation, and Chugai Pharmaceutical Co., Ltd.; Dr. Shigeharu Fujieda received patent royalties and/or licensing fees from KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Taiho Pharmaceutical Co., Ltd., and a research grant from Mitsubishi Tanabe Pharma Corporation, Tsumura Co., Ltd., Maruho Co., Ltd., and Sanofi K.K.; Dr. Naoyuki Miyashita received honoraria from Daiichi Sankyo Co., Ltd., AstraZeneca K.K., Astellas Pharma Inc., Pfizer Japan Inc., and Taisho Toyama Pharmaceutical Co., Ltd.; Dr. Akihito Yokoyama received honoraria from AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., GlaxoSmithKlein K.K., and Sanofi K.K., and a research grant from Astellas Pharma Inc. and Ono Pharmaceutical Co., Ltd. Drs. Yasushi Obase, Masaharu Shinkai, Kiyoshi Takeyama, Jiro Terada, Yoshihiro Yamamoto, Haruhiko Ogawa, Kiyoyasu Kurahashi, Shusaku Haranaga, Hiroyuki Mochizuki, Shigemi Yoshihara, and Jun Tamaoki have no conflict of interest.Drs. Yasushi Obase, Masaharu Shinkai, Kiyoshi Takeyama, Jiro Terada, Yoshihiro Yamamoto, Haruhiko Ogawa, Kiyoyasu Kurahashi, Shusaku Haranaga, Hiroyuki Mochizuki, Shigemi Yoshihara, and Jun Tamaoki have no conflict of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Before advance care planning, it is essential to understand the differences in preferences for medical care of terminal-phase pneumonia in elderly patients among the patients, their families, and their doctors. This study aimed to clarify these differences and investigate the actual care provided to elderly patients with pneumonia in nursing hospitals., Methods: Multicenter questionnaire surveys of 179 patients admitted to nursing homes and long-term care beds in hospitals of three healthcare corporations, their families, and their physicians were conducted between January and August 2018. The questionnaires mainly assessed preferences for life-prolonging medical care procedures, including antibiotic treatments, in terminal-phase pneumonia. A follow-up survey regarding the prognosis and the actual care provided by the physicians was conducted 1 year after the first survey., Results: Only 16.2% of the patients had sufficient prior discussions with their families about their care. More families preferred cardiac massage, intubation, and tracheostomy, while fewer families preferred peripheral intravenous fluids or antibiotics than physicians. A total of 30 patients' families (16.7%) answered to withhold antibiotic treatment, while all physicians supported antibiotic administration. The only significant factor related to withholding antibiotics was high age (P = 0.0057). The follow-up survey administered to the doctors revealed that 49 patients (35.7%) had died within one year. Of the 137 patients, 54 patients (39.4%) had developed pneumonia during this observation period and all were treated with antibiotics., Conclusions: This study revealed large discrepancies between patients/families and physicians regarding preferences for care. Medical staff should make efforts to fill the gap by ensuring advance care planning., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Endobronchial volatile sulfur compounds in patients with lung abscess or lung cancer were measured using the Oral Chroma™ gas chromatograph. High levels of hydrogen sulfide and methyl mercaptan were observed in some patients with lung abscess but not in patients with lung cancer. Measuring endobronchial volatile sulfur compounds could be useful for the rapid diagnosis of lung abscess caused by obligate anaerobes., Competing Interests: Declarations of interest None., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Tobacco smoking causes a variety of smoking-related diseases, death, and economic damage. Despite targeted anti-smoking campaigns, tobacco-related deaths are expected to increase in Japan. We investigated the current state of non-cancerous lung diseases such as idiopathic interstitial pneumonias (IIPs), chronic obstructive pulmonary disease (COPD), and combined pulmonary fibrosis and emphysema (CPFE), which are known to be highly related to tobacco smoking., Methods: This prospective multi-institutional observational study involved 29 major hospitals within the Fukuoka Prefecture area (Fukuoka tobacco-related lung disease registry study group). Patients diagnosed with IIPs, including CPFE and COPD, registered from September 1, 2013 to April 30, 2016 were included. Clinical background information, laboratory and pulmonary function test results, findings of imaging tests, including chest radiography and chest computed tomography, and DNA isolated from peripheral blood were collected from each patient. Follow-up surveillance involved collection of data regarding the exacerbation of disease and death until 5 years of registration. In the present study, we report the baseline characteristics of the patients registered in this surveillance study., Results: Overall, 1016 patients (524 with IIPs, including 145 CPFE and 492 with COPD) were enrolled. Among the patients with COPD, 96.8% were current or former smokers. Among the patients with IIPs, 69.9% were current or former smokers., Conclusion: This study revealed the current status of lung diseases potentially related to tobacco smoking in Fukuoka Prefecture. Both COPD and CPFE were highly related to tobacco smoking, whereas 30% of patients with IIPs had never smoked., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: There have been no reports on the relationship between lung radiological patterns and rheumatoid arthritis (RA) disease activity or RA treatment response in patients with RA-associated lung disease (RA-LD)., Methods: Patients with RA-LD who underwent treatment for RA from April 2005 to March 2015 were retrospectively evaluated. RA-LD patients were divided into three groups based on high-resolution computed tomography (HRCT) patterns [usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and bronchiolitis]. The disease activity score of 28 joints-erythrocyte sedimentation rate (DAS28-ESR) and the response of RA to treatment, as measured by the European League Against Rheumatism (EULAR) response criteria, were investigated., Results: A total of 77 patients (21 with UIP, 23 with NSIP, and 33 with bronchiolitis) were enrolled. Median scores (interquartile range) on the DAS28-ESR at baseline were 5.27 (4.76-5.74), 5.48 (4.24-6.34), and 5.04 (3.90-5.66) for UIP, NSIP, and bronchiolitis, respectively; there were no statistical differences between the three groups (p = 0.412). One year after baseline, 19 (90%), 14 (61%), and 19 (58%) of patients in the UIP, NSIP, and bronchiolitis groups, respectively, were considered good or moderate responders, as evaluated using the EULAR response criteria; there was a significant difference between these three groups (p = 0.014). Multiple logistic regression analysis revealed that the UIP pattern was significantly associated with good or moderate response to RA treatment 1 year after baseline (p = 0.012)., Conclusions: These results suggest that NSIP and bronchiolitis HRCT patterns may be risk factors for resistance to RA therapy., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

With the advent of new technologies evaluating the microbiome in the sample such as next-generation sequencer (NGS), current increase of an interest in understanding of the lung microbiome and its roles in lung diseases are marked. Gathering the data of bacterial flora in the lung and their changes during disease courses is unraveling the pathogenesis and the mechanism of disease progression particularly in patients with bronchial asthma, chronic obstructive pulmonary disease and infectious lung diseases. To clarify the relationship between the lung microbiome and pulmonary diseases, new information may help us to create new treatment and prevention strategies of some pulmonary diseases by controlling the lung microbiome. Using bacterial 16S ribosomal RNA gene sequence, NGS can rapidly estimate large amount of bacterial sequences in the phylum and genus levels, and some of them in species levels in a very short period of time. In addition to new information of the microbiome using NGS in the respiratory tract, other techniques using basically Sanger method in combination with the clone library construction can also be useful to identify pathogenic bacterial species with their ratio in the respiratory samples such as bacterial pneumonia, lung abscess and nontuberculous mycobacteriosis. These modalities to identify and semi-quantify bacterial burden in the respiratory tract have revealed new bacterial information in each infectious lung disease. This review describes current understanding of the lung microbiome in several representative lung diseases., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Respiratory comorbidities are frequently associated with idiopathic pulmonary fibrosis (IPF). However, little is known about their prognostic impact in hospitalized patients with IPF. We examined the impact of respiratory comorbidities on the mortality rates of hospitalized patients with IPF using a Japanese nationwide database., Methods: We identified 5665 hospitalized patients diagnosed with IPF between April 2010 and March 2013. The primary outcome was defined as the in-hospital mortality at 30 days after admission. The impact of respiratory comorbidities was assessed using a Cox proportional hazards model that incorporated clinically relevant factors., Results: In hospitalized patients with IPF, the prevalence of bacterial pneumonia, pulmonary hypertension, and lung cancer were 9.5%, 4.6%, and 3.7%, respectively. Among patients with bacterial pneumonia, the four most common pathogens were Streptococcus pneumoniae (31.6%), methicillin-resistant Streptococcus aureus (18.4%), Klebsiella pneumoniae (9.2%), and Pseudomonas aeruginosa (9.2%). Lung cancer was more commonly found in the lower lobes (60.1%) than in other lobes. The survival at 30 days from admission was 78.4% in all patients and significantly lower in IPF patients with bacterial pneumonia (adjusted hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.04-1.63; p < 0.023) and patients with lung cancer (adjusted HR, 1.99; 95% CI, 1.47-2.69; p < 0.001) than in others. Pulmonary hypertension was not associated with mortality. IPF patients with one or more of these three respiratory comorbidities had a poorer survival than others (p < 0.05)., Conclusions: Respiratory comorbidities, especially bacterial pneumonia and lung cancer, influence mortality in hospitalized patients with IPF., (Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Chlamydophila pneumoniae is a causative pathogen of lower respiratory tract infection, which generally infects healthy, young people. However, it is often difficult to evaluate acute C. pneumoniae infection using upper respiratory tract specimens and/or sputum samples due to its persistent infection or colonization. The interpretation of frequency of detection of C. pneumoniae seems to be insufficient in community-onset pneumonia. The aim of this study was to evaluate the presence of C. pneumoniae using bronchoalveolar lavage fluid (BALF) samples., Methods: BALF samples from 147 patients with pneumonia were retrospectively evaluated using C. pneumoniae-specific polymerase chain reaction (PCR) primers., Results: None of the samples had positive PCR results for C. pneumoniae using two different sets of specific primers. Single and paired serological analyses were performed in 54 (36.7%) and 37 (25.2%) patients, respectively. These analyses revealed that 1 of 37 (2.7%) patients had a presumptive acute infection with C. pneumoniae, 8 of the 54 (14.8%) patients were suspected of having a C. pneumoniae infection, and 7 of the 37 (18.9%) patients were suspected of having past C. pneumoniae infection. In addition, cultivation and/or 16S rRNA gene sequencing detected Haemophilus influenzae in the presumptive case using the serological method., Conclusions: The results of the present study revealed that C. pneumoniae might be a minor causative agent of community-onset pneumonia according to an evaluation of specimens obtained from the lower respiratory tract., (Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: The prognostic significance of serial measurements of serum KL-6 levels in patients with idiopathic pulmonary fibrosis (IPF) is unclear; hence, it was assessed in this study., Methods: Medical records of 66 patients with IPF, who were not treated with pirfenidone prior to enrollment, were retrospectively reviewed for information on clinical progress, forced vital capacity (FVC), survival, and serum KL-6 levels. We assessed initial serum levels of KL-6, serial changes in serum KL-6 levels, yearly decline in FVC (ΔFVC), and the rate of decline (%ΔFVC)., Results: Patients with increased serum KL-6 levels during follow-up had a significantly steeper decline in ΔFVC than those with no KL-6 increase (-201 vs. -50.7ml/year; p=0.0001). Patients with both initial serum KL-6 ≥1000U/ml and serial increases in serum KL-6 had the steepest decline, while those with both initial serum KL-6 <1000ml and no serial increases in KL-6 had the least decline in ΔFVC and %ΔFVC. Relative to the non-increased KL-6 group, survival in the increased KL-6 group tended to be poorer (p=0.0530). Patients with both initial serum KL-6 values <1000U/ml and no serial increase in KL-6 had more favorable prognoses than those with serial increases in KL-6 or initial serum KL-6 values ≥1000U/ml (p<0.0044). Prognosis was significantly poorer in patients with serial KL-6 changes >51.8U/ml/year than in those with serial KL-6 changes <51.8U/ml/year (p=0.0009)., Conclusion: Thus, serial serum KL-6 measurements can be useful for assessing prognosis in patients with IPF., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Evaluating the ratio of CD4/CD8 T-lymphocytes in the bronchoalveolar lavage fluid (BALF) is important for understanding the clinical and pathological conditions of patients with sarcoidosis. However, few studies have thus far demonstrated the usefulness of evaluating the relationship between the ratios of CD4/CD8 T-lymphocytes in the mediastinal lymph nodes and BALF. This study aimed to investigate and identify the relationships between CD4/CD8 T-lymphocyte ratio in the mediastinal lymph nodes and BALF in patients with sarcoidosis., Methods: Thirty-three consecutive patients with sarcoidosis with enlarged mediastinal and/or hilar lymphadenopathy were enrolled in the study, and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and bronchoalveolar lavage (BAL) were simultaneously performed. The CD4/CD8 T-lymphocyte ratios in the mediastinal lymph nodes and BALF were evaluated using immunohistochemistry and flow cytometry, respectively., Results: The interobserver variability in the CD4/CD8 ratio in the mediastinal lymph nodes as determined by immunostaining was low, and the pathological and cytological profiles of T-lymphocytes in the mediastinal and/or hilar lymph nodes and BALF were correlated in patients with sarcoidosis. Additionally, the CD4/CD8 T-lymphocyte ratios in BALF were significantly higher than those in the mediastinal lymph nodes. Importantly, non-caseating granulomas were detected at a high rate by using EBUS-TBNA., Conclusions: Performing EBUS-TBNA in patients with sarcoidosis allows correct diagnosis as well as the estimation of the ratio of CD4/CD8 T-lymphocytes in BALF., (Copyright © 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

We report a case of adult T-cell leukemia/lymphoma (ATL) with rapidly progressive pulmonary areas of ground-glass attenuation (GGA) and nodules resulting from acute transformation of chronic ATL. A 48-year-old Japanese man was admitted for progressive dyspnea. Chest computed tomography showed rapidly progressive bilateral pulmonary areas of GGA and nodules. Flow cytometry of bronchoalveolar lavage fluid and immunohistochemical examination of lung biopsy specimens revealed invasion of ATL cells. Systemic chemotherapy improved the pulmonary findings. Rapidly expanding areas of GGA and nodules are a rare manifestation of pulmonary invasion of ATL that clinicians should nevertheless keep in mind., (Copyright © 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)