Nationwide survey in Japan of the causative diseases of bloody sputum and hemoptysis in departments of respiratory medicine at university hospitals and core hospitals.

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.

Serum anti-PCK1 antibody levels are a prognostic factor for patients with diabetes mellitus.

BACKGROUND: Autoantibodies develop in autoimmune diseases, cancer, diabetes mellitus (DM), and atherosclerosis-related diseases. However, autoantibody biomarkers have not been successfully examined for diagnosis and therapy. METHODS: Serological identification of antigens through recombinant cDNA expression cloning (SEREX) was used for primary screening of antigens. The cDNA product was expressed in bacteria and purified. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) was used to evaluate antibody levels in serum samples. RESULTS: Phosphoenolpyruvate carboxykinase 1 (PCK1) was recognized as an antigen by serum IgG antibodies in the sera of patients with atherosclerosis. AlphaLISA showed significantly higher serum antibody levels against recombinant PCK1 protein in patients with DM and cardiovascular disease than in healthy donors, but not in those with acute ischemic stroke, transient ischemic attack, or obstructive sleep apnea syndrome. The area under the receiver operating characteristic curve for anti-PCK1 antibodies was 0.7024 for DM. The serum anti-PCK1 antibody levels were associated with age, platelet count, and blood pressure. Anti-PCK1-antibody-positive patients showed significantly lower overall survival than the negative patients. CONCLUSIONS: Serum anti-PCK1 antibody levels were found to be associated with DM. The anti-PCK1 antibody marker is useful for predicting the overall survival of patients with DM.

Pulmonary tumor thrombotic microangiopathy during good response to immuno-chemotherapy for advanced non-small cell lung cancer: a case report.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy is a rapidly progressive and fatal disease in which tumor cells embolize to the pulmonary microvasculature. This condition is characterized by severe dyspnea and right heart failure. Although pulmonary tumor thrombotic microangiopathy typically occurs in patients with untreated and/or advanced cancer, its occurrence in patients who are responding well to medical therapy is poorly documented. CASE PRESENTATION: A 68-year-old Japanese woman who had received four cycles of immuno-chemotherapy (pembrolizumab, carboplatin, and pemetrexed) followed by three cycles of maintenance therapy (pembrolizumab and pemetrexed) for advanced non-small cell lung cancer and had achieved a partial response with a stable clinical course was admitted to the emergency ward because of worsening breathlessness and general fatigue for 1 week. Chest computed tomography showed no evidence of tumor progression or any new lung lesion. Two-dimensional transthoracic echocardiography demonstrated right atrial and ventricular dilatation, tricuspid regurgitation, and a high trans-tricuspid pressure gradient of 65 mmHg. Despite her percutaneous oxygen saturation being 96% on room air at the time of admission, it worsened rapidly; the patient requiring 8 L/min of oxygen within 4 h. Repeat computed tomography with contrast medium revealed no evidence of pulmonary embolism. The patient developed progressive respiratory failure that was unresponsive to optimal cardio-pulmonary supportive therapy. An autopsy revealed tumorous clusters in pre-capillary lung vessels, whereas the primary lesion had shrunk to the point of almost complete resolution. CONCLUSION: Pulmonary tumor thrombotic microangiopathy occurs not only in patients with advanced and/or uncontrolled cancer but also in those whose primary lesion seems to have been well controlled by medical treatment.

Bilobectomy for synchronous multiple lung cancer after COVID-19 pneumonia: a case report.

Coronavirus disease 2019 (COVID-19) is a novel emerging disease and a major risk factor for postoperative complications, especially in thoracic surgery. However, it is unclear how previous COVID-19 infection may affect perioperative management of lung resection patients. A 70-year-old woman visited her primary doctor complaining of chest pain. Chest computed tomography (CT) revealed three abnormal nodules in the right upper and middle lung lobes and synchronous triple primary cancer was suspected. Before we could assess the patient for surgery, she developed a persistent fever. A second chest CT scan revealed newly emerged subpleural ground-glass opacities (GGO) in the right lung. The patient was diagnosed with COVID-19 pneumonia and hospitalized. She was treated for COVID-19 (Clinical Trial: jRCTs031200196) and discharged in a satisfactory condition 10 days later. A right upper and middle bilobectomy was performed 60 days after the patient's initial COVID-19 diagnosis without any complications. Histopathological examination of the nodules identified synchronous triple primary lung cancer. The subpleural right upper and middle lung lobe tissue showed peribronchial lymphocyte infiltration and interstitial thickening. However, immunohistochemical staining for the SARS-CoV-2 antigen and PCR testing for SARS-CoV-2 were both negative. In this case, bilobectomy for triple primary lung cancer was performed safely after COVID-19 pneumonia. Further studies are needed to establish a safe and appropriate perioperative management system for thoracic surgery in patients recovering from COVID-19 pneumonia.

A case of thoracic air leak syndrome with pleural parenchymal fibroelastosis after treatment for hematologic malignancy while awaiting lung transplantation: Imaging and pathological findings of rapid loss in lung volume.

We report the case of a 29-year-old man who underwent umbilical cord blood transplantation for chronic myelogenous leukemia 14 years previously. He was diagnosed with secondary pleuroparenchymal fibroelastosis (sPPFE) following treatment for hematologic malignancies (sPPFE after HM-Tx) 2.5 years ago. On computed tomography, pleural thickening in the upper lobe, lung volume loss, and recurrent bilateral pneumothorax were detected. Although he waited for cadaveric lung transplantation (LTx) for 1.5 years, his respiratory failure worsened, and he died. Pathological autopsy and clinical course indicated sPPFE. After diagnosing sPPFE after HM-Tx, the timing for deciding LTx is critical, especially when pneumothorax recurs.

Clinical Characteristics and Risk Factors of Lung Injury Induced by Nab-Paclitaxel.

Background/Aim: Nab-paclitaxel (Nab-PTX) has been widely used to treat several advanced cancers. Nab-PTX can cause drug-induced lung injury (DILI); however, its clinical and radiographic features have not been clarified. We aimed to assess the clinical characteristics of Nab-PTX-induced lung injury and identify its associated risk factors. Patients and Methods: We retrospectively investigated 304 patients who received Nab-PTX at Chiba University Hospital between November 2010 and November 2017. We obtained information regarding the clinical course, laboratory findings, and chest computed tomography findings from their medical records. Results: Forty-one patients (13%) developed DILI. Grade 1 lung injury occurred in 27 patients (8.8%), grade 2, 8 patients (2.6%); grade 3, 3 patients (0.9%); grade 4, 1 (0.3%); and grade 5, 2 (0.6%). Multivariate analysis revealed that age >56 years (odds ratio [OR]: 3.0), pre-existing interstitial lung changes (OR: 3.2), and combined drugs with gemcitabine (OR: 2.7) were independent risk factors for DILI owing to Nab-PTX administration. Conclusion: Nab-PTX-induced lung injury is not rare; however, most cases are asymptomatic (grade 1). Older age, pre-existing interstitial lung changes, and combined drugs with gemcitabine could increase the incidence of Nab-PTX-induced lung injury; such patients should be treated with greater care.

What are the factors affecting the recovery rate of bronchoalveolar lavage fluid?

BACKGROUND: Bronchoalveolar lavage (BAL) is a useful examination for the evaluation of interstitial lung disease. A high BAL fluid (BALF) recovery rate is desirable because low recovery rates lead to inaccurate diagnoses and increased adverse events. Few studies have explored whether BALF recovery rates are influenced by clinical factors. OBJECTIVES: This study aimed to identify the clinical parameters affecting the recovery rates of BALF and the extent of their effects. METHOD: Data from patients who underwent BAL at the Chiba University Hospital between 2013 and 2019 were retrospectively reviewed. BAL was performed with three aliquots of 50-ml physiological saline. The potential association of the BALF recovery rate with clinical parameters such as age, sex, smoking status, underlying disease, bronchus used for the procedure and pulmonary function, was analysed. RESULTS: Eight hundred twenty-six patients had undergone BAL. The average recovery rate was 52.4%. Factors affecting BALF recovery rates included male sex (odds ratio [OR]: 0.32, 95% confidence interval [CI]: 0.20-0.53, p < 0.001); age ≥ 65 years (OR: 0.50, 95% CI: 0.33-0.76, p < 0.001); use of the left bronchus (OR: 0.46, 95% CI: 0.30-0.71, p = 0.001) and bronchi other than the middle lobe bronchus or lingula (OR: 0.41, 95% CI: 0.25-0.65, p < 0.001); and forced expiratory volume in 1 s divided by forced vital capacity <80% (OR: 0.42, 95% CI: 0.40-1.00, p < 0.001). CONCLUSION: Sex, age, bronchus used for the procedure and pulmonary function may be useful as pre-procedural predictors of BALF recovery rates.

Coronary artery calcium score may be a novel predictor of COVID-19 prognosis: a retrospective study.

BACKGROUND: Although several studies have reported an association between atherosclerosis-related diseases and COVID-19, the relationship between COVID-19 severity and atherosclerosis progression remains unclear. The aim of this study is to determine the coronary artery calcium score (CACS) prognostic value in patients with COVID-19 using indices such as deterioration in oxygenation and CT images of the chest. METHODS: This was a single-centre retrospective study of 53 consecutive patients with COVID-19 in Narita who were admitted to our hospital between March 2020 and August 2020. CACS was calculated based on non-gated CT scans of the chest performed on admission day. The patients were divided into the following two groups based on CACS: group 1 (CACS ≥180, n=11) and group 2 (CACS <180, n=42). Following univariate analysis of the main variables, multivariate analysis of variables that may be associated with COVID-19 progression was performed. RESULTS: Multivariable logistic regression analysis of age, sex, smoking history, diabetes, hypertension, dyslipidaemia, number of days from symptom onset to hospitalisation and CACS of ≥180 was performed. It revealed that unlike CACS of <180, CACS of ≥180 is associated with exacerbation of oxygenation or CT images of the chest during hospitalisation (OR: 12.879, 95% CI: 1.399 to 380.401). Furthermore, this model of eight variables showed good calibration (Hosmer-Lemeshow p=0.119). CONCLUSION: CACS may be a prognosis marker of COVID-19 severity. Although coronary artery calcification is not typically assessed in pneumonia cases, it may provide a valuable clinical indicator for predicting severe COVID-19 outcomes.

Risk factors for acute exacerbation following bronchoalveolar lavage in patients with suspected idiopathic pulmonary fibrosis: A retrospective cohort study.

INTRODUCTION: Bronchoalveolar lavage (BAL) is useful for diagnosing diffuse lung disease and excluding other conditions. However, acute exacerbations (AEs) are recognized as important complications of BAL in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to identify risk factors for BAL-induced AEs in patients with IPF. MATERIAL AND METHODS: We retrospectively analyzed the data of 155 patients with suspected IPF who had undergone BAL between January 2013 and December 2018. BAL-related AE was defined as the development of AE within 30 days after the procedure. We compared clinical features and parameters between patients with AE (AE group) and without AE (non-AE group). We also reviewed the relevant reported literature. RESULTS: Among the 155 patients, 5 (3.2%) developed AE within 30 days after BAL. The average duration from BAL to AE onset was 7.8 days (2-16 days). Results from the univariate analysis revealed PaO2 < 75 mm Hg (p = 0.036), neutrophil content in BAL ≥ 7% (p = 0.0061), %DLCO < 50% (p = 0.019), Gender-Age-Physiology (GAP) stage III (p = 0.034), and BAL recovery rates < 30% (p < 0.001) as significant risk factors for post-BAL AE. All five patients who developed AE recovered and were discharged. CONCLUSIONS: Disease severity, high neutrophil levels in BAL, and poor BAL recovery rates may be risk factors for BAL-induced AEs.

Bronchiolitis obliterans after stem cell transplantation for hematologic malignancies rescued by lung transplantation: A report of two cases.

Bronchiolitis obliterans syndrome (BOS) occurring after hematopoietic stem cell transplantation (HSCT) for hematologic malignancies is a progressive and refractory disease, and lung transplantation (LTx) seems to be the only promising treatment. We report two cases of BOS after HSCT, which showed distinct clinical courses and were successfully treated with LTx. The respiratory symptoms and function of the two patients progressively deteriorated to a critical level during the waiting period. In one patient, recurrent and intractable pneumothoraxes consistent with thoracic air-leak syndrome (TALS) occurred, which were associated with pleuroparenchymal fibroelastosis. TALS could accelerate clinical deterioration, thus permitting a shorter waiting period for LTx.

The Japanese respiratory society guidelines for the management of cough and sputum (digest edition).

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.

Potential patient screening for late-onset Pompe disease in suspected sleep apnea: a rationale and study design for a Prospective Multicenter Observational Cohort Study in Japan (PSSAP-J Study).

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the acid α-glucosidase (GAA) enzyme. GAA deficiency induces progressive glycogen accumulation which leads to weakness of the respiratory muscle including the diaphragm. Pompe disease is one of the few myopathies, for which an established therapy is available. Thus, earlier detection of potential late-onset Pompe disease (LOPD) and earlier intervention would have a significant clinical impact. PURPOSE: Our hypothesis is that sleep problems including sleep disordered breathing (SDB) and clinical symptoms may indicate an early stage of LOPD since decreased respiratory muscle activity generally first presents during sleep. Thus, the aims of this prospective, multicenter observational cohort study in Japan (PSSAP-J) are to demonstrate a higher prevalence of LOPD in a sleep lab-based population (primary outcome), and to identify predictive factors for LOPD from findings in diagnostic polysomnography (PSG) and clinical symptoms (secondary outcomes). METHODS: The study design is a prospective multicenter observational cohort study. Consecutive patients who present to sleep labs due to suspected SDB for an overnight PSG will be enrolled. All patients will be measured for creatine kinase, GAA activity, and if necessary, genetic analysis of GAA. Furthermore, chest X-ray, pulmonary function test, and arterial blood gas analysis will be collected. Then, prevalence and specific findings of LOPD will be assessed. RESULT: Congenital myopathy shows a shift from slow-deep to rapid-shallow breathing during transition from wakefulness to sleep accompanying a symptom of waking with gasping (actual further results are pending). DISCUSSION: The distribution in respiratory physiology between during wakefulness and sleep specific to LOPD may provide insights into early-stage detection. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

The Gender-Age-Physiology system as a prognostic model in patients with idiopathic pulmonary fibrosis treated with nintedanib: a longitudinal cohort study.

INTRODUCTION: The Gender-Age-Physiology (GAP) system is a tool for predicting prognosis in patients with idiopathic pulmonary fibrosis (IPF). Yet, to date, the GAP system has not been evaluated in patients with IPF who received nintedanib. MATERIAL AND METHODS: This single-center retrospective study included 89 patients with IPF who received Nintedanib for at least 3 months. All-cause mortality was set as the end point. Clinical parameters, including the GAP stage, were statistically analyzed for risk factors leading to mortality using the Cox proportional hazard model. RESULTS: The median follow-up was 16.4 months (range 3.7-37.4 months), during which 23 patients died. Univariate analysis revealed that the GAP stage (hazard ratio [HR] 3.00, 95% confidence interval [CI] 1.52-5.92, p = 0.0014) and PaO2 (HR 0.95, 95% CI 0.92-0.98, p = 0.0063) were significant prognostic factors. Multivariate analysis revealed that the GAP stage was a significant prognostic factor (HR 2.26, 95% CI 1.07-4.78, p = 0.031). Log-rank analysis revealed that there were no significant differences in "Gender" (p = 0.47) and "Age" (p = 0.18) factors. However, there were significant differences in "Physiology" factors (% of forced vital capacity, p = 0.018; % of diffusing capacity of lung carbon monoxide, p < 0.001). The cumulative incidences of mortality at 1 and 2 years were as follows: GAP I: 5.1% and 6.8%; GAP II: 9.5% and 29.3%; and GAP III: 18.9% and 84.2%. CONCLUSIONS: The GAP system is useful as a prognostic tool in patients with IPF who have been treated with nintedanib.

Nocturnal Hypoxemia and High Circulating TNF-α Levels in Chronic Thromboembolic Pulmonary Hypertension.

Objective Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by persistent thromboemboli of the pulmonary arteries, and one of its etiological factors may be inflammation. Sleep disordered breathing (SDB) is reportedly an important complication of pulmonary hypertension. However, the association between SDB and inflammation in CTEPH has been undefined. This prospective observational study analyzed the association between the severity of SDB, pulmonary hemodynamic parameters and the systemic inflammation level in patients with CTEPH. Methods CTEPH patients admitted for a right heart catheter (RHC) examination were consecutively enrolled from November 2017 to June 2019 at the pulmonary hypertension center in Chiba University Hospital. Patients with idiopathic pulmonary arterial hypertension (IPAH) were also enrolled as a control group. All patients underwent a sleep study using a WatchPAT 200 during admission. Results The CTEPH patients showed worse nocturnal hypoxemia, oxygen desaturation index (ODI), and apnea-hypopnea index than the IPAH patients. Among these factors, only the nocturnal mean percutaneous oxygen saturation (SpO2) was negatively correlated with the pulmonary hemodynamic parameters. The circulating tumor necrosis factor-alpha (TNF-α) level was also high in the CTEPH group, and a multivariate analysis showed that the nocturnal mean SpO2 was the most important predictive factor for a high TNF-α level. Conclusion We showed that CTEPH patients had high serum TNF-α levels and that the nocturnal mean SpO2 was a predictive factor for serum TNF-α levels. Further investigations focused on nocturnal hypoxemia and the TNF-α level may provide novel insight into the etiology and new therapeutic strategies for CTEPH.

Feasibility and accuracy of rapid on-site evaluation of touch imprint cytology during transbronchial biopsy.

BACKGROUND: Rapid on-site evaluation (ROSE) of cytologic material is widely performed because it provides clinicians with instant diagnostic information. However, the utility of ROSE of touch imprint cytology (ROSE-TIC) during transbronchial biopsy (TBB) remains unclear. The aim of this study was to evaluate the feasibility and accuracy of ROSE-TIC for TBB. METHODS: A retrospective study was performed on patients who underwent diagnostic bronchoscopy combined with ROSE-TIC. The results of ROSE-TIC, diagnosed as either positive or negative for malignancy, were compared with the histological findings and final diagnosis. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were calculated. The success rate of molecular testing on TBB specimens was also assessed. RESULTS: Overall, 460 patients underwent bronchoscopy with ROSE-TIC. Of these, 377 cases (82.0%) were malignant and 83 cases (18.0%) were non-malignant in the final diagnosis. Compared with the histological findings, ROSE-TIC showed sensitivity, specificity, PPV, NPV, and diagnostic accuracy values of 91.1%, 90.4%, 94.8%, 84.0%, and 90.9%, respectively. Compared with the final diagnosis, ROSE-TIC showed sensitivity, specificity, PPV, NPV, and diagnostic accuracy values of 75.3%, 91.6%, 97.6%, 45.0%, and 78.3%, respectively. Seven discordant cases (1.5%) were positive on ROSE-TIC and negative on final diagnosis. The success rates for molecular analysis from TBB samples were 96.6% for EGFR mutation, 87.3% for ALK rearrangement, 93.1% for ROS1 rearrangement, and 96.2% for PD-L1 expression. CONCLUSIONS: The accuracy of ROSE-TIC is high. It can be useful for obtaining instant diagnosis, contributing to a high success rate of molecular analysis for targeted therapy.

Clinical characteristics and risk factors of drug-induced lung injury by ALK tyrosine kinase inhibitors: A single center retrospective analysis.

BACKGROUND: If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effective treatment. However, the details of drug-induced lung injury (DILI) caused by ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK-TKIs in clinical practice. METHODS: The clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK-TKIs was compared between the DILI onset group and the non-onset group. RESULTS: A total of seven cases were diagnosed with DILI due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute. CONCLUSIONS: Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern. KEY POINTS: Significant findings of the study: Extra caution is needed when recommending ALK-TKIs for patients over 64 years of age or those with decreased renal function. Computed tomography images of the majority of patients with DILI by ALK-TKIs show an OP pattern. WHAT THIS STUDY ADDS: The same or a different ALK-TKI may be considered as a treatment option after the onset of DILI, based on careful judgment.

Tolerability of nintedanib-related diarrhea in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Nintedanib is an important drug for the treatment of idiopathic pulmonary fibrosis (IPF). However, the drug is discontinued in some patients who present with diarrhea. In this study, we aimed to assess the drug continuation rate in patients who developed diarrhea during nintedanib therapy and to evaluate if antidiarrheal drugs or nintedanib dose reductions improved clinical tolerability and efficacy. METHODS: Eighty-six patients with IPF were treated in our institution between December 2015 and March 2018. Among them, 50 patients who experienced nintedanib-related diarrhea were analyzed regarding tolerability and persistence rate. RESULTS: In 50 patients who experienced nintedanib-related diarrhea, 26 (n = 11, without reduction and n = 15, with reduction) continuously received nintedanib. Meanwhile, the drug was discontinued in 24 patients (n = 13, without reduction and n = 11, with reduction). In 9 of 24 patients, the drug was discontinued due to diarrhea. The annual rate of decline in forced vital capacity and the duration of nintedanib administration were not significantly different between groups with and without dosage reduction. Moreover, 23, 13, 8, and 2 patients received 1, 2, 3, and 4 agents, respectively. Clostridium butyricum is a probiotic bacterium most commonly used as an antidiarrheal agent. In this study, it was used in 28 of 46 patients. The total durations of nintedanib administration differed significantly according to the number of antidiarrheal drugs taken: 853 ± 221 days, more than three agents; 424 ± 365 days, without an agent (p = 0.043); and 460 ± 142, one agent (p = 0.0003). CONCLUSIONS: When diarrhea occurs within a year after using nintedanib, the dose reduction may be acceptable without affecting pulmonary function. Moreover, treatment with multiple antidiarrheals may be a practical option to maintain the use of nintedanib therapy compared with monotherapy and no therapy.

A novel biosimulator based on ex vivo porcine lungs for training in peripheral tissue sampling using endobronchial ultrasonography with a guide sheath.

BACKGROUND: Although radial probe endobronchial ultrasonography (EBUS) with a guide sheath (GS; EBUS-GS) is widely used for sampling peripheral pulmonary lesions (PPLs), a standard training model for EBUS-GS remains to be developed. The purpose of this study was to evaluate the feasibility of a novel pulmonary biosimulator for hands-on training in peripheral tissue sampling using EBUS-GS. METHODS: We established a novel biosimulator for EBUS-GS using porcine lungs. The simulator was equipped with multiple pseudo PPLs that were created using blue agar solution injected through GS inserted in a bronchoscope. A total of 12 voluntary trainees participated in a hands-on training course using the biosimulator. The size of samples acquired using biopsy forceps were compared between initial and post-training biopsies, and trainee satisfaction with the biosimulator and training program were evaluated using a questionnaire. RESULTS: Under the guidance of a trainer, all trainees successfully detected pseudo PPLs using radial probe EBUS before the initial biopsy, and 11 trainees acquired samples from the target lesions during the initial biopsy. Post-training biopsy samples were larger than the initial samples for eight trainees. The results of the questionnaire revealed that all trainees were satisfied with the biosimulator. Moreover, eight trainees who had previously participated in another hands-on EBUS-GS training program involving a synthetic phantom model showed greater satisfaction for the biosimulator. CONCLUSIONS: A hands-on training program using the novel biosimulator assessed in this study could aid clinicians in improving their skills for EBUS-GS and acquiring larger peripheral tissue samples using biopsy forceps inserted through GS.

Differences in tolerability of pirfenidone between elderly and younger patients with idiopathic pulmonary fibrosis.

PURPOSE: Although pirfenidone (PFD) is a key drug for the treatment of idiopathic pulmonary fibrosis (IPF), differences in tolerability between elderly and young patients remain unclear. This study aimed to investigate age-related differences in adverse drug reactions to PFD and to evaluate whether patient age influences the safety and tolerability of PFD in clinical practice. PATIENTS AND METHOD: One hundred fifty-four patients with IPF were treated with PFD in our institution between May 2009 and April 2017; these patients were classified into 2 groups on the basis of age: ≥75 years of age (elderly patients) and <75 years of age (younger patients). In each group, the clinical course, laboratory data, radiographic findings, adverse events, and tolerability of PFD at 6 months and 1 year after administration were retrospectively analyzed. RESULTS: Among the 120 patients examined in this study, 31 patients (26%) were ≥75 years of age. The continuation rate of PFD at 1 year in the elderly patient group was significantly lower (n=11 [35%] vs 57 [64%], p=0.007) than in the younger patient group. Regarding adverse drug reactions to PFD, the incidence of gastrointestinal disorders including anorexia (n=24 [77%] vs 40 [45%], p=0.002) and the discontinuation caused by gastrointestinal disorders (n=11 [35%] vs 13 [15%], p=0.019) were significantly higher in elderly patients than those in younger patients. However, with the exception of gastrointestinal disorders, other adverse drug reactions did not significantly differ between elderly and younger patients. CONCLUSIONS: Compared with younger patients, elderly patients with IPF had a higher incidence of gastrointestinal disorders, along with an increased discontinuation rate of PFD. More careful management of gastrointestinal disorders may be required to ensure continuation of PFD in elderly patients.

Transbronchial evaluation of peripheral pulmonary lesions using ultrasonic spectrum analysis in lung cancer patients.

BACKGROUND AND OBJECTIVE: Analysis of the endobronchial ultrasound (EBUS) radiofrequency spectrum has been used for convex-probe EBUS technology. Quantitative imaging analysis is also warranted for guided bronchoscopy using radial-probe EBUS (RP-EBUS) targeting peripheral pulmonary lesions (PPL). This study aimed to determine the feasibility of radiofrequency spectrum analysis for distinguishing malignant and benign PPL during diagnostic bronchoscopy. METHODS: Raw RP-EBUS images with radiofrequency data, including backscatter signals, were prospectively recorded. The ultrasonic spectral parameters, such as intercept, midband-fit and slope within the region of interest, were retrospectively computed by linear regression analysis and compared with the final diagnosis. RESULTS: A total of 71 PPL, including 45 malignant and 26 benign lesions, were analysed. Malignant PPL showed a significantly lower intercept (P < 0.0001), lower midband-fit (P < 0.0001) and higher slope (P = 0.014) than benign PPL. Analyses of the area under the curve of receiver operating characteristic plots demonstrated that the intercept showed the best diagnostic performance among three parameters (0.87, 0.77 and 0.69 for intercept, midband-fit and slope, respectively). The sensitivity, specificity, accuracy, positive likelihood and negative likelihood were 75.6%, 96.2%, 83.1%, 19.6 and 0.25 for the intercept; 88.9%, 57.7%, 77.5%, 2.1 and 0.19 for the midband-fit; and 68.9%, 73.1%, 70.4%, 2.6 and 0.43 for the slope. CONCLUSION: Spectrum analysis of EBUS radiofrequency can be used as a novel non-invasive predictor of malignant or benign PPL. Analysis of the 'intercept' of the targeted lesion may provide useful supporting data for real-time sampling from PPL during diagnostic bronchoscopy.