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Multifaceted analysis is recommended for the diagnosis of primary ciliary dyskinesia (PCD). A 31-year-old woman had situs inversus, bronchiectasis, family history of PCD, and compound heterozygous mutations in DNAH5. Her cilia were immotile. Defects in the outer dynein arms were revealed by transmission electron microscopy and loss of DNAH5 proteins in the entire length of axonemes using immunofluorescence (IF). A 17-year-old boy had bronchiectasis and heterozygous mutations in DNAH11. His cilia were motile with normal ultrastructure. The loss of DNAH11 proteins at the proximal region of cilia was revealed by IF. IF could be useful to support PCD diagnosis.

Hospital-acquired severe acute respiratory virus coronavirus 2 (SARS-CoV-2) infection is a healthcare challenge. We hypothesized that polymerase chain reaction testing of symptomatic triaged outpatients and all inpatients before hospitalization in Shinjuku, a coronavirus disease 2019 (COVID-19) epicenter in Tokyo, using the Tokyo Women's Medical University (TMWU) model would be feasible and efficient at preventing COVID-19. This retrospective study enrolled 2981 patients from March to May 2020. The prevalence of SARS-CoV-2 infection was 1.81% (95% credible interval [CI]: 0.95–3.47%) in triaged symptomatic outpatients, 0.04% (95% CI: 0.0002–0.2%) in scheduled asymptomatic inpatients, 3.78% (95% CI: 1.82–7.26%) in emergency inpatients, and 2.4% (95% CI: 1.49–3.82%) in symptomatic patients. There were no cases of hospital-acquired SARS-CoV-2 infection. This shows that the TWMU model could prevent hospital-acquired SARS-CoV-2 infection and is feasible and effective in reducing the impact of SARS-CoV-2 infection in the hospitals.

Primary ciliary dyskinesia (PCD) is diagnosed through multiple methods, including transmission electron microscopy (TEM), a high-speed video microscopy analysis (HSVA), immunofluorescence (IF), and genetic testing. A primary cell culture has been recommended to avoid the misdiagnosis of secondary ciliary dyskinesia derived from infection or inflammation and improve diagnostic accuracy. However, primary cells fail to differentiate into ciliated cells through repeated passages. The conditional reprogramming culture (CRC) method, a combination of a Rho-kinase inhibitor and fibroblast feeder cells, has been applied to cystic fibrosis. The goal of this study was to evaluate the value of CRC in diagnosing PCD in Japanese patients.Eleven patients clinically suspected of having PCD were included. Airway epithelial cells were obtained from an endobronchial forceps biopsy and cultured at the air-liquid interface (ALI) combined with CRC. Ciliary movement, ultrastructure, and mutated ciliary protein evaluation were performed using HSVA, TEM, and IF, respectively. Genetic testing was performed on some patients.CRC yielded dense and well-differentiated ciliated cells with a high success rate (∼90%). In patients with PCD, the ciliary ultrastructure phenotype (outer dynein arm defects or normal ultrastructure) and IF findings (absence of the mutated ciliary protein) were confirmed after CRC. In DNAH11-mutant cases with normal ultrastructure by TEM, the HSVA revealed stiff and hyperfrequent ciliary beating with low bending capacity in CRC-expanded cells, thereby supporting the diagnosis.CRC could be a potential tool for improving diagnostic accuracy and contributing to future clinical and basic research in PCD.

A 33-year-old woman presented with a productive cough from childhood. She had suffered from repeated bacterial pneumonia. Her clinical and imaging findings revealed chronic sinusitis, bronchiectasis and situs inversus. We suspected primary ciliary dyskinesia (PCD) and performed a bronchial mucosal biopsy. The ciliary beat pattern according to high-speed video microscopy was complete loss. Electron microscopic findings of cilia showed defect of outer dynein arm (ODA). A genetic examination detected compound heterozygous mutations of DNAH5 that encode ODA components. There are few reports of genetic mutation analyses in Japanese PCD patients. We herein report a PCD patient with DNAH5 mutations and review the related literature.

Introduction: Eosinophilic pneumonia (EP) is characterized by a marked accumulation of eosinophils in the lungs and blood. Eosinophils and mast cells play an important role in the pathogenesis of EP via release of biomarkers such as tryptase and interleukin (IL)-33. However, the potential role of these biomarkers is not fully understood. Objectives: We aimed to evaluate the differences among the levels of tryptase and IL-33 in bronchoalveolar lavage fluid (BALF) from several types of EP. We evaluated the differences between the levels of these biomarkers in the recurrent and nonrecurrent cases. Method: We prospectively collected the clinical data of patients with EP, diagnosed between 2006 and 2015 in our institution. Bronchoscopy was performed before steroid treatment; BALF was collected. The clinical characteristics of EP patients and the levels of tryptase and IL-33 in BALF were evaluated. Results: We enrolled 15 patients with chronic EP (CEP), 5 with acute EP (AEP), 10 with drug-induced EP, and 6 with angiitis-related EP. Tryptase levels in the CEP group were significantly higher than that in the drug-induced EP group (p = 0.048), while the AEP group had the highest IL-33 levels. Recurrence of EP was noted in 67% of patients with CEP. The levels of tryptase and IL-33 were notably higher in the recurrent cases than that in the nonrecurrent CEP group (p = 0.004, p = 0.04, respectively). Furthermore, there was a positive correlation between the levels of tryptase and IL-33 in the BALF of patients with CEP (ρ = 0.69, p = 0.004). Conclusions: Tryptase and IL-33 in BALF are useful biomarkers for the assessment of EP types. These biomarkers could be used to predict disease recurrence.

Objective Primary ciliary dyskinesia (PCD) is a rare hereditary disease. Most reports of PCD in Japan are case reports, and clinical analysis has not been performed. Differences in the causative genes might affect the clinical features in different ethnic groups. The purpose of this study was to clarify the clinical features of Japanese patients with PCD. Methods We performed a retrospective chart review of PCD patients seen at Mie University Hospital and patients whose blood samples were sent to us for genetic analysis from 2011 to 2020. Data on the following items were collected and analyzed: age at first visit to the hospital, age at diagnosis of PCD, process of referral to our facility, chief complaint, situs status, PrImary CiliARy DyskinesiA Rule (PICADAR) score, nasal nitric oxide concentration, otoscopic findings, rhinoscopic findings, and paranasal computed tomography scan findings. Results Sixty-seven patients (24 male, 43 female) were diagnosed with PCD during the study period. Age at diagnosis ranged from 2 months to 69 years (median, 17 years). Respiratory symptoms (77%) were the most common complaint, followed by nasal (15%) and aural (8%) symptoms. Situs inversus was present in 17 (25%) cases. Only 2 cases had congenital cardiac anomalies. The mean PICADAR score was 7.3 (range, 3-14) points. Approximately 50% of tympanic membranes showed retraction, suggesting otitis media with effusion. The mean Lund-Mackay score was 12.8 (range, 7-17) points, suggesting that the radiographic findings were not always severe. There was no significant difference in the total Lund-Mackay score between patients with and without situs inversus (12.7 vs. 12.6, respectively). Conclusion Situs inversus was present in 25% of Japanese PCD patients, which is much lower than observed in other countries. This is a result of differences in the major disease-causing genes. The general rule that "situs inversus is observed in approximately 50% of PCD patients" cannot be applied, at least, in Japanese PCD patients.

BACKGROUND Asthma control has been shown to improve after clinical use of molecular-targeted biologic drugs. Although most patients have shown favorable responses to biologic drugs, some individuals need to switch to another biologic drug. To date, limited data are available regarding patients who received multiple biologic drugs. OBJECTIVE We aimed to evaluate the characteristics and outcomes of patients treated with multiple biologic drugs. METHODS We reviewed severe asthma patients who received biologic drugs between May 2009 and September 2019. Clinical characteristics of patients and changes in annualized asthma exacerbation rates, asthma control test (ACT), and oral corticosteroid (OCS) dose, before and after the use of the final biologic drug, were evaluated. RESULTS Of the 105 patients who received biologic drugs, 20 patients received multiple biologic drugs. Twelve patients received two biologic drugs, six received three, and two received four. Patients who received multiple biologic drugs tended to have a significantly higher number of allergic or eosinophilic airway comorbidities (allergic rhinitis: p = 0.02, chronic rhinosinusitis with nasal polyps: p < 0.001). Approximately half of the patients changed to different treatments due to uncontrolled comorbidities. Annualized exacerbation rates, ACT, and OCS dose significantly improved after the latest biologic drug use (p = 0.035, p < 0.001, and p = 0.038, respectively). CONCLUSIONS The results of this study indicated that allergic and eosinophilic airway comorbidities should be considered during the selection of biologic drugs. Furthermore, most patients who received multiple biologic drugs achieved disease control after switching to the optimal biologic drug.

Background Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33. Methods In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay. Results Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro. Conclusions Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.

Introduction: Omalizumab has been widely used in Japan. Although some cases cannot achieve good control, the reason for treatment failure with omalizumab has not been fully elucidated. Therefore, in this study, we aimed to evaluate the characteristics of patients who had failed to achieve disease control by omalizumab treatment in a real world setting. Method: We retrospectively reviewed medical record between March 2009 and May 2016 (only omalizumab available in this period in Japan). We evaluated the patient characteristics including age, sex, treatment duration, complication, smoking status, eosinophil counts, total IgE, BMI, FeNO, and OCS use. Treatment failure was judged by physician’s decision based on the exacerbation rate, ER visit, and symptoms. We also evaluated alternative treatment after discontinuation of omalizumab. Results: Total 65 patients were included in this study. Compared to the omalizumab-effective group, the omalizumab-ineffective group contained significantly higher number of patients who had eosinophilic complication (otitis media and sinusitis) and OCS use. Multivariate analysis showed that eosinophilic otitis media was associated with treatment failure with omalizumab (odds ratio 17.35, 95%CI (1.535-196.3), p=0.021). Most of the omalizumab-ineffective group with eosinophilic complication received mepolizumab or benralizumab as an alternative therapy. Conclusion: Eosinophilic complication may affect treatment failure with omalizumab. Anti-IL-5 or anti-IL-5Rα antibodies rather than anti-IgE antibody, omalizumab, should be considered as an additional therapy for severe asthma patients who have eosinophilic complication.

The efficacy of transbronchial needle aspiration (TBNA) with endobronchial ultrasonography using a guide sheath (EBUS-GS) for cases of peripheral pulmonary lesions (PPLs) has not been well established. The purpose of this study was to evaluate the efficacy of TBNA with EBUS-GS for PPLs.We evaluated 130 patients suspected to have lung cancer who underwent transbronchial brushing (brushing), transbronchial biopsy (TBB), and TBNA with EBUS-GS. The pathological diagnostic yields of TBNA were compared to that of TBB and brushing. The histological diagnosis of TBNA was compared to that of surgical specimens. The results of epidermal growth factor receptor (EGFR) gene mutation in TBNA samples were compared to that in TBB or surgical specimens.The diagnostic yields of this study were 62.9% for brushing, 80.0% for TBB, and 77.1% for TBNA. Histological diagnosis was 84.8% for TBB and/or TBNA and pathological diagnosis was 86.7% for all the procedures. TBB and TBNA had significance higher than brushing (p0.05). TBB and TBNA had a tendency of higher diagnostic yields than brushing if EBUS probe was adjacent to PPLs (p = 0.058). Histological evaluations were obtained from TBNA specimens from 50 of 105 patients (47.6%) and these were identical to those of surgical specimens from 29 of 32 patients (90.6%). The results of EGFR gene mutation in TBNA specimens were identical to the same tissue obtained by surgery or TBB.TBNA with EBUS-GS for PPLs was a useful tool for accurate diagnosis and EGFR gene mutation analysis. This method may improve diagnostic accuracy and be useful for molecular testing. This study was approved by the institutional review board (Date of approval: May 27, 2013, approval number: 2816) of Tokyo Women's Medical University Hospital.

Background Sarcoidosis is a systemic granulomatous disease caused by CD4+ cell-dominant inflammation. Meanwhile, diffuse panbronchiolitis is a chronic inflammatory respiratory disease predominantly caused by CD8+ lymphocytes and neutrophils. Herein, we report a rare case of sarcoidosis in which the clinical presentation had become evident as diffuse panbronchiolitis after splenectomy for sarcoidosis. Case presentation A 23-year-old Japanese woman was referred to our hospital due to splenomegaly of unknown etiology. Upon admission, chest computed tomography scan revealed centrilobular and randomly distributed small nodules in both lungs. Bronchoalveolar lavage revealed a high proportion of lymphocytes and a decreased CD4/CD8 ratio. However, the biopsy specimens obtained from both the liver and lungs revealed noncaseating epithelioid granulomas, which confirmed the diagnosis of sarcoidosis. The patient underwent splenectomy due to progressive cytopenia and high risk of splenic rupture. After the surgery, the condition of the patient was consistently good for 3 months. Then, she gradually developed productive cough and dyspnea. Both sinus and chest computed tomography scan revealed chronic paranasal sinusitis and deterioration of centrilobular nodules in both lung fields, respectively. The second bronchoalveolar lavage revealed a high proportion of neutrophils, and the bronchoalveolar lavage fluid tested positive for Hemophilus influenzae. The titer of cold agglutinin was elevated, thereby confirming the diagnosis of diffuse panbronchiolitis. On the basis of the clinical and radiological findings, the condition of the patient improved with low-dose macrolide therapy for 3 months. Conclusions The coexistence of sarcoidosis and diffuse panbronchiolitis has not been previously reported, and the hidden profiles of diffuse panbronchiolitis may have been revealed by splenectomy.

Introduction: Chronic eosinophilic pneumonia (CEP) is easy to relapse, sometimes requiring long-term steroid treatment. Mast cell tryptase is known to be involved in fibrosis and remodeling, but the relevance to eosinophilic pneumonia has not been elucidated. In this study, clinical significance of tryptase in BALF in patients with eosinophilic pneumonia was examined. Method: In the BALF from 16 cases of CEP, 5 cases of acute eosinophilic pneumonia (AEP), 9 cases of drug induced eosinophilic pneumonia (Drug), and 5 cases of angitiis (Angiitis), tryptase concentration was measured by UniCAP method and was compared with clinical characteristics. Results: Nine cases of CEP (56%), 1 case of AEP (20%), and 1 case of Drug (11%) were BALF tryptase-positive. Tryptase levels in CEP were significantly higher than those in the other groups (p Conclusion: Current study showed tryptase levels in recurrent CEP patients were higher than the other groups, associated with high prevalence of asthma. Mast cell tryptase in BALF may be an indicator of chronicity and refractory of CEP.

Background: Pulmonary eosinophilia (PE) occurs due to various causes, such as infections, drugs, autoimmune processes, and obstructive lung diseases. Infiltration of eosinophils is found in the airways, interstitium and alveoli, resulting inflammation and tissue injury. The airway secreted mucins MUC5AC and MUC5B may be associated with the pathogenesis of PE; MUC5AC production can be increased by eosinophils, and MUC5B plays a role in an ameliorating pathway for eosinophilia. However, the composition of the airway secreted mucins in PE has not been evaluated yet. Aims: To determine the concentrations of the airway secreted mucins MUC5AC and MUC5B in patients with pulmonary eosinophilia. Methods: Diagnostic BAL was performed via fiberoptic bronchoscopy according to established guidelines. After the BAL, patients who met criteria for PE (elevated BAL eosinophil count greater than 25%, chronic eosinophilic pneumonia with asthma n=5, drug-induced pneumonia n=2, acute eosinophilic pneumonia n=1) and patients who showed no apparent lung disease (control, n=8) were enrolled to this study. The absolute concentrations of MUC5AC and MUC5B in BAL fluids were measured by ELISA. Results: The mean percentage of eosinophils in BAL fluids in PE was 63±24%. The concentrations of mucins in PE with chronic eosinophilic pneumonia were significantly higher with MUC5AC, and significantly lower with MUC5B, respectively, as compared with controls (p Conclusions: The composition of the airway secreted mucins MUC5AC and MUC5B in PE patients was altered, which may be involved in the pathogenesis of eosinophilic airway inflammation, especially with asthma.

Background Omalizumab , an anti-IgE antibody , has been widely used in many countries, including Japan. However, some patients do not respond to omalizumab, and the cause of treatment failure has not been fully elucidated. Objective This study aimed to evaluate the characteristics of adult asthma patients who failed to achieve disease control with omalizumab in a real-world setting. Methods We retrospectively reviewed the medical records of patients in Tokyo Women's Medical University Hospital between March 2009 and May 2016. The patient characteristics and factors for treatment failure with omalizumab were evaluated, as were treatment alternatives after discontinuation of omalizumab. Results In total, 59 patients were included in this study. The omalizumab-ineffective group had a significantly higher number of patients with eosinophilic sinusitis (P = 0.001) and eosinophilic otitis media (P = 0.023) than the omalizumab-effective group. A multivariate analysis revealed that both eosinophilic chronic rhinosinusitis (odds ratio: 23.4; P = 0.011) and eosinophilic otitis media (odds ratio: 6.71; P = 0.039) were associated with treatment failure with omalizumab. Most patients with eosinophilic comorbidities of the ear, nose, and throat (ENT) in the omalizumab-ineffective group received mepolizumab or benralizumab as alternative therapy, following which disease control was achieved. Conclusion Eosinophilic comorbidities of the ENT may affect treatment failure with omalizumab in patients with severe asthma. Anti-interleukin-5 antibody or anti-interleukin-5Rα antibody rather than anti-IgE antibody should be considered as an additional therapy for patients with severe asthma who have eosinophilic comorbidities of the ENT.

Background Increased sputum production is an important feature of COPD, in which a large amount of secretions stagnated in the respiratory lumen may aggravate airflow limitation, impair airway mucociliary transport, and cause recurrent respiratory infection and, hence, acute exacerbations of the diseases. There is evidence that airway mucus hypersecretion is associated with the severity and prognosis of COPD, but the symptoms are generally difficult to treat. Methods In an open, non-controlled study, we examined the effect of the anticholinergic agent tiotropium on airway mucus hypersecretion in 22 COPD patients. After a 4-week run-in period, the patients received 18 μg of tiotropium once daily delivered through the handihaler for 8 weeks, while symptoms and their impact associated with sputum were scored according to cough and sputum assessment questionnaire (CASA-Q). At week 0 and week 8, spirometry was performed before and 30 min after the administration of albuterol . To test the effect of tiotropium on airway mucociliary transport, nasal clearance time was measured. To evaluate airway mucus production, solid composition of the sputum (dry/wet weight ratio) was measured. Results Treatment with tiotropium increased both prebronchodilator FEV1 and postbronchodilator FEV1 . Tiotropium decreased cough symptom scores and provided with favorable influences on sputum-related symptoms, and none of the patients complained of worsening of the symptoms judging from the CASA-Q score. Both solid composition of the sputum and mucin contents decreased and nasal clearance time was shortened from 29.4 ± 5.1 to 20.6 ± 4.1min (p Conclusions Tiotropium decreases symptoms associated with sputum in COPD patients, an effect that may be related to the inhibition of airway mucus hypersecretion and improvement of airway mucociliary clearance .

Background The purpose of this study was to evaluate the diagnostic accuracy of Cryo with endobronchial ultrasonography using a guide sheath (EBUS-GS) for peripheral pulmonary lesions (PPLs) to assess the volume of specimen, determine DNA sequencing analysis, and evaluate the utility of rapid on-site evaluation (ROSE). Methods Out of 30 patients assessed for eligibility, 23 were enrolled in this prospective study. The histological diagnostic yield of Cryo was evaluated and the volume was compared to that of trans-bronchial biopsy (TBB). DNA analysis of Cryo was performed using next generation sequencing (NGS). ROSE was compared with the final diagnosis. Results The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy rate was 85%, 100%, 100%, 50%, 87% for Cryo and 80%, 100%, 100%, 42.9%, 82.6% for TBB, respectively. The mean volume was 0.078 cm3 for Cryo and 0.003 cm3 for TBB (p Conclusions Cryo with EBUS-GS for PPLs is a safe and potentially useful diagnostic strategy. It has a high diagnostic yield, and provides significantly larger specimens than TBB. It also provides high quantity and quality of DNA for NGS and high concordance rate between ROSE and the final diagnosis.

Background Transmembrane protein 16A (TMEM16A) is associated with mucus secretion and ion transport in asthma. Clarithromycin (CAM) is reported to inhibit IL-13-induced goblet cell metaplasia. However, the effect of CAM on TMEM16A function and expression remains unclear. Methods Tracheal epithelial cells from guinea pigs were cultured for ~14 days at an air-liquid interface in medium containing IL-13 (10 ng/ml) in the absence or presence of CAM (20 µg/ml) or a TMEM16A inhibitor, T16Ainh-A01 (10 µg/ml). Electrophysiological studies were performed by Ussing׳s short-circuit technique. The cells were used for immunofluorescence staining with antibodies against TMEM16A, MUC5AC, and α-tubulin. The cells were also examined by transmission electron microscopy. TMEM16A protein levels in the cell lysates were determined by ELISA. For the in vivo study, guinea pigs were treated intratracheally with IL-13 in the absence or presence of CAM or T16Ainh-A01. Results CAM decreased the MUC5AC-positive cells and reduced TMEM16A expression in them and increased the α-tubulin-positive cells. CAM inhibited TMEM16A protein levels in a dose-dependent manner, and decreased UTP-induced Cl ion transport. In cells treated with IL-13 for 24 h, TMEM16A appeared prior to MUC5AC protein expression, and was inhibited by CAM. In the in vivo study, CAM inhibited IL-13-induced goblet cell metaplasia and TMEM16A expression. The inhibitory effects of CAM were similar to those of T16Ainh-A01. Conclusions CAM inhibited IL-13-induced TMEM16A expression, Cl ion transport and goblet cell metaplasia both in vitro and in vivo. CAM may thus improve airway mucociliary differentiation by attenuating TMEM16A expression in IL-13-related asthma.

A 38-year-old woman with sustained right chest pain was referred to our hospital. She showed pleural effusion and peripheral blood eosinophilia. Thoracentesis revealed eosinophilic pleural effusion in which the smear, culture and cytological examinations were all negative. Although she had no notable dietary history, chest CT revealed linear opacities, which suggested the migration tracks of paragonimiasis. The diagnosis was confirmed using enzyme-linked immunosorbent assays, which showed elevated Paragonimus westermani and Paragonimus miyazakii antibody levels. After the initiation of praziquantel therapy, all clinical findings were promptly improved. The detection of a migration track may therefore be useful in the diagnosis of paragonimiasis.

Asthma and COPD overlap (ACO) is an important clinical phenotype, due to the low-health-related quality of life (QOL), rapid decline in lung function, frequent exacerbation, and high economic burden. However, no large-scaled therapeutic trials of ACO have been conducted. At present, ACO is treated according to asthma/COPD guidelines. The goals of ACO treatment are to relieve symptoms and improve QOL and lung functions. Treatment must also prevent disease progression, airway remodeling, exacerbation, complications, and comorbidities. To achieve these goals, ACO needs first to be assessed based on pathophysiological findings. Comprehensive long-term management includes medication, reduction of risk factors, environmental improvement, patient education, rehabilitation, and vaccination. Drug treatment for ACO employs a combination of inhaled corticosteroids (ICSs) and long-acting bronchodilators; long-acting muscarinic antagonists and/or long-acting β2-agonists. The dose of ICS is determined according to ACO severity. Leukotriene receptor antagonists and theophylline are used as add-on drugs. Macrolides and expectorants are recommended for reduction of mucus hypersecretion. Anti-IgE and anti–IL-5 antibodies, oral corticosteroids, and oxygen therapy are additional treatments for the most severe ACO. The therapeutic effects are evaluated using lung function tests, eosinophil counts in sputum and blood, FeNO, and symptom questionnaires. ACO exacerbation is treated by inhalation of short-acting β2-agonist and systemic corticosteroids. The doses of corticosteroids are determined based on the asthma/COPD component of the exacerbation. Administration of antibiotics is recommended if sputum is purulent. Referral to specialists is necessary in cases of inability to control symptoms by medication, uncertain diagnosis with atypical features, or severe complications and comorbidities. Keywords: Inhaled corticosteroids, Long-acting bronchodilators, Long-term management of ACO, Severity of ACO, Treatment of ACO exacerbation

Rationale: Cottin first described CPFE and there is accumulating evidence that respiratory dysfunction is more severe and the prevalence of pulmonary arterial hypertension (PAH) is higher in patients with CPFE than in patients with COPD alone. It has recently been reported that relative pulmonary artery (PA) enlargement, defined as a PA to ascending aorta (A) diameter ratio greater than one (PA:A>1) is associated with severe exacerbations in COPD patients, but there is little information about clinical features of CPFE. Therefore, in the present study, we compared clinical characteristics between patients of CPFE and COPD, including the evaluation of PA/A ratio and the cardiovascular disease. Methods: We conducted a retrospective observational study of patients with COPD (n=41) and CPFE (n=24) in our outpatient clinic. We compared the two groups in terms of age, sex, smoking history, severity, comorbidity, and pulmonary function. We also evaluated a ratio of PA/A in predicting PAH, according to the measurement by CT. Results: There were no differences between the two groups in terms of age, sex, and smoking history. FEV 1 /FVC ratio in the CPFE group was significantly higher than that in the COPD group (72.6% vs. 53.1%, p Conclusions: These results suggest that, in patients with CPFE, coronary artery diseases which require PCI are often comorbid, but influences of this comorbidity in the development of CPFE remain to be elucidated.

A 25‐year‐old Japanese woman suffered from repeated respiratory tract infections. Because of her characteristic medical history and imaging findings, we suspected primary ciliary dyskinesia (PCD) and performed a transbronchial biopsy. The biopsy revealed complex abnormalities of the ciliary structure including cleavage of the B‐subfibers observed by transmission electron microscopy analysis and the complete loss of ciliary motion by video analysis. Genetic examinations to diagnose PCD have progressed in recent years. However, in this case, the well‐known genetic mutations in causal genes of PCD were not detected via whole‐exome sequencing of the blood. Cleavage of the B‐subfibers in patients with PCD has never been reported. This case appears to be the first report of this PCD subtype in humans.

Background Emphysema and chronic obstructive pulmonary disease (COPD) are well known independent risk factors for lung cancer. However, the developmental mechanisms between emphysema/COPD and lung cancer remain unknown. The purpose of this study was to evaluate PD-L1, FGFR1, PIK3CA, PTEN, and p16 expression in squamous cell carcinoma (SCC) associated with emphysema/COPD. Methods A total of 59 patients with squamous cell lung carcinoma (SCC) resected between 2008 and 2012 were retrospectively reviewed. Emphysema was assessed according to the Goddard score. Total severity was divided into none-mild (0–7), moderate (8–15), and severe (≥ 16). Local severity around the existing tumor was divided into no emphysema (0) and presence of emphysema (1–4). COPD severity was based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. PD-L1, FGFR1, PIK3CA, PTEN, and p16 expression were evaluated by immunohistochemistry (IHC). Expression level was classified as tumor cells (TC) 3 (≥ 50%), TC2 (5–49%), TC1 (1–4%), or TC0 (

Cough variant asthma (CVA) is a common cause of chronic persistent cough, in which allergic airway inflammation may play a role. Although current guidelines recommend bronchodilators and anti-inflammatory drugs for the treatment, comparison of the efficacy of these medications has not been investigated. This study was designed to evaluate the effectiveness of pranlukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta₂-adrenergic agonist, in the treatment of CVA. The study was a randomized, controlled, parallel-group, multicenter trial. After a 4-week run-in period, 49 patients with newly diagnosed CVA were assigned to receive oral pranlukast (225 mg, b.i.d.) or inhaled salmeterol (100 μg, b.i.d.) for 4 weeks. Primary outcome measure was cough symptom and secondary outcome measures were pulmonary function and eosinophilic airway inflammation. Treatment with pranlukast and salmeterol each decreased cough symptom scores, where the changes from baseline values were significantly greater in the pranlukast group than in the salmeterol group. Forced expiratory volume in 1 second and peak expiratory flow (PEF) increased in the two treatment groups with the same magnitudes, but significant decreases in diurnal variation of PEF and eosinophil counts and eosinophil cationic protein contents in the peripheral blood and induced sputum were observed only in the pranlukast group. In view of antitussive and anti-inflammatory actions, the leukotriene receptor antagonist pranlukast seems to be more effective than the long-acting beta₂-adrenergic agonist salmeterol in the treatment of CVA.