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Disinhibition is sometimes experienced during bronchoscopy with sedation. However, data on disinhibition during bronchoscopy are scarce. We examined the prevalence and characteristics of disinhibition during bronchoscopy with midazolam.This retrospective study analyzed consecutive patients who underwent bronchoscopy between November 2019 and December 2020. The severity of disinhibition was defined as follows: mild, disinhibition sometimes requiring restraints by assistants; moderate, disinhibition always requiring restraints by assistants; and severe, disinhibition requiring antagonization of sedation by flumazenil to continue bronchoscopy.Among 251 eligible patients who were sedated using midazolam, 36 (14.3%; 95% confidence interval [CI], 10.5%-19.2%), 42 (16.7%; 95% CI, 12.6%-21.8%), and 7 (2.8%; 95% CI, 1.4%-5.6%) experienced mild, moderate, and severe disinhibition, respectively. Depression (odds ratio [OR] 2.77; 95% CI, 1.20-6.41), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (OR 10.23; 95% CI, 1.02-103.01, referred to brushing/bronchial washing/observation), and increased administration of midazolam (OR 1.20; 95% CI, 1.02-1.42, per 1-mg increase) were independently associated with moderate-to-severe disinhibition. Patients experiencing moderate disinhibition reported significantly better scores for discomfort during bronchoscopy. Besides the maximum systolic and diastolic blood pressures during bronchoscopy, the changes in hemodynamic and respiratory statuses during bronchoscopy or complications did not significantly differ between patients experiencing moderate-to-severe disinhibition and those experiencing none-to-mild disinhibition.Moderate-to-severe disinhibition occurred in 19.5% of patients during bronchoscopy with midazolam. We should focus on disinhibition when patients have depression or are planning to undergo EBUS-TBNA, and sparing the administration of midazolam might reduce the occurrence of disinhibition.UMIN000038571.

Background IL1RL1 (ST2) is involved in Th2 inflammation including eosinophil activation. Single nucleotide polymorphisms (SNPs) of the IL1RL1 gene are associated with asthma development and increased peripheral blood eosinophil counts. However, the association between IL1RL1 SNPs and eosinophilic phenotype among adults with asthma remains unexplored. Methods In a primary cohort of 110 adult Japanese patients with stable asthma, we examined the associations between IL1RL1 SNPs and clinical measurements including forced expiratory volume (FEV 1 ), airway reversibility of FEV 1 , exhaled nitric oxide (FeNO), serum soluble-ST2 (sST2) levels, peripheral blood eosinophil differentials and serum total IgE level. The findings in the primary cohort were confirmed in a validation cohort of 126 adult Japanese patients with stable asthma. Results Patients with minor alleles in 3 SNPs (rs17026974, rs1420101, and rs1921622) had high FeNO, blood eosinophil differentials, and reversibility of FEV 1 , but low levels of serum sST2 and FEV 1 . Minor alleles of rs1041973 were associated with low serum sST2 levels alone. In the validation cohort, minor alleles of rs1420101 were associated with high FeNO and blood eosinophil differentials, whereas minor alleles of rs17026974 and rs1921622 were associated with high blood eosinophil differentials and FeNO, respectively. Multivariate analyses revealed that the minor allele of rs1420101 additively contributed to the FeNO, blood eosinophil differentials, and reversibility of FEV 1 . Conclusions The minor alleles of IL1RL1 SNPs were associated with high FeNO and peripheral blood eosinophilia among adult Japanese patients with stable asthma. IL1RL1 SNPs may characterize the eosinophilic phenotype with greater eosinophilic inflammation in the Japanese asthma cohort.

Background The Severe Respiratory Insufficiency (SRI) Questionnaire was originally developed in German to assess health-related quality of life (HRQL) and was validated as a multidimensional instrument with high psychometric properties in chronic hypercapnic respiratory failure (CHRF) patients receiving noninvasive ventilation (NIV). We aimed to investigate the intercultural adaptation of the Japanese SRI Questionnaire and whether it is a reliable and valid HRQL questionnaire to administer to those patients. Methods The SRI Questionnaire was adapted to Japanese using a translation and back-translation procedure, followed by equivalency assessment. It was validated in 56 stable outpatients receiving NIV for CHRF, primarily due to chronic obstructive pulmonary disease (COPD) and/or pulmonary tuberculosis sequelae. Results Examination of the frequency distribution of the Japanese SRI Questionnaire showed that the subscales and summary were approximately normally distributed and well balanced. There were no significant differences in SRI scores between patients with COPD and pulmonary tuberculosis sequelae. Cronbach׳s α values representing internal consistency of seven SRI subscales ranged from 0.56 to 0.80; attendant symptoms and sleep had the lowest values. Cronbach׳s α value was 0.92 for the SRI summary. The SRI summary score was significantly related to all eight subscales of the Medical Outcomes Study 36-item short form, with correlation coefficients of 0.41–0.66. Conclusions The Japanese SRI Questionnaire was produced using a standardized procedure and an equivalency study. It has high psychometric properties with internal consistency and concurrent validity. The Japanese SRI Questionnaire can be used to assess HRQL in patients on NIV for CHRF.

Relapsing polychondritis (RP) is characterized by recurrent systemic inflammation of the cartilages and is accompanied by central airway collapse. We report a case wherein three-dimensional imaging of respiratory system resistance (Rrs) and respiratory system reactance (Xrs) by using MostGraph (CHEST M.I., Tokyo, Japan), a forced oscillation system, revealed that Rrs and Xrs in the inspiratory and expiratory phases correlated with proximal airway collapse. The degree of difference in Rrs and Xrs between the supine and sitting positions reflected airway collapse more closely than did the pulmonary function test. MostGraph could be a useful tool for assessing airway collapse in RP.

Background Chronic cough involves airway remodeling associated with cough reflex hypersensitivity. Whether cough itself induces these features remains unknown. Methods Guinea pigs were assigned to receive treatment with citric acid (CA), saline (SA), or CA+dextromethorphan (DEX). All animals were exposed to 0.5M CA on days 1 and 22. On days 4–20, the CA and CA+DEX groups were exposed to CA, and the SA group to saline thrice weekly, during which the CA+DEX group was administered DEX pretreatment to inhibit cough. The number of coughs was counted during each 10-min CA or SA exposure. Terbutaline premedication was started to prevent bronchoconstriction. Bronchoalveolar lavage and pathology were examined on day 25. Average cough number for 10 CA exposures was examined as "cough index" in the CA group, which was divided into frequent (cough index>5) and infrequent ( Results The number of coughs significantly increased in the CA group from day 13 onwards. In the CA+DEX and SA groups, the number of coughs did not differ between days 1 and 22, while average number of coughs during days 4–20 was significantly lower than at days 1 and 22. Bronchoalveolar cell profiles were similar among the four groups. The smooth muscle area of small airways was significantly greater in the frequent-cough subgroup than in the other groups (in which it was similar), and highly correlated with cough index in CA group. Conclusion Repeated cough induces airway smooth muscle remodeling associated with cough reflex hypersensitivity.

We report the first case of non-specific interstitial pneumonia (NSIP) in a patient with cancer-associated myositis (CAM) that emerged along with the recurrence of the cancer. A 60-year-old woman, with a history of partial gastrectomy for gastric cancer 11 years ago, presented with exertional dyspnea with anti-Jo-1 antibody-positive myositis. Surgical lung biopsy showed NSIP with metastatic gastric cancer. Accordingly, her condition was diagnosed as CAM with cancer recurrence. In patients with a history of cancer, development of myositis may indicate cancer recurrence; therefore, careful observation would be necessary.

Background Alpha 1 -antitrypsin (ΑAT) deficiency (AATD), a condition of little or no AAT in the serum, is believed to be extremely rare in Japan. However, no such nationwide epidemiological survey has been conducted. The Respiratory Research Failure Group and Japanese Respiratory Society (JRS) cooperated to conduct this survey. Methods The survey questionnaire was sent by post to 1598 hospitals that have 200 or more beds (excluding mental hospitals), and by e-mail to members of the JRS. Hospitals failing to respond were followed-up by phone. Results 1467 hospitals replied [response rate=91.8% (1467/1598)], and 114 members responded. Of the 14 probands registered from 10 hospitals and one local practitioner, 9 had severe and 5 had mild AATD. Eleven of these patients were diagnosed with COPD, 1 with COPD and bronchiectasis, 1 with pulmonary emphysema without airflow obstruction, and the remaining 1 with bronchiectasis without airflow obstruction. Mutation analysis of the SERPINA1 gene was performed in 7 patients, 6 of whom (85.7%) had homozygous PI * S iiyama . The prevalence of AATD in Japan was thus estimated to be 24 patients, with a 95% confidence interval (22, 27). When asked if they would prescribe AAT augmentation therapy, 6 of the 10 (60.0%) of respondent attending physicians answered affirmatively if health insurance would cover the treatment. Conclusions This nationwide survey confirmed that AATD is extremely rare in Japan. Six of 10 care-giving physicians would offer AAT augmentation therapy if the therapy were covered by health insurance in Japan.

Background In lymphangioleiomyomatosis (LAM), predicting lung disease progression is essential for treatment planning. However, no previous Japanese studies have attempted to predict the reductions in pulmonary function that occur in LAM patients. Methods The data for 89 LAM patients who had undergone ≥3 spirometry tests and whose data had been registered in the Japanese National Research Project on Intractable Diseases database between October 2009 and March 2014 were analyzed after excluding patients who had undergone (1) a lung transplant; (2) mTOR inhibitor treatment; or (3) thoracic drainage, pleurodesis, surgery, or thoracic duct ligation during the study period. The rates of change (slope) in pulmonary parameters were calculated, and their associations with clinical background factors were investigated. Results Among the whole study population, the median (quartiles) slope of forced expiratory volume in one second (FEV 1 ) was −46.7 (−95.2; −15.0)mL per year. Episodes of conservatively treated pneumothorax during the study period were found to be associated with rapid reductions in FEV 1 (% predicted). Pregnancy during the study period was associated with a reduction in FEV 1 (% predicted). When the patients were divided into those who exhibited initial FEV 1 (% predicted) values of >70% (Group A) and ≤70% (Group B), Group B displayed significantly faster reductions in FEV 1 (% predicted) than Group A. Conclusions LAM patients whose initial FEV 1 (% predicted) values are ≤70% subsequently exhibit rapid reductions in their FEV 1 values, and hence, require treatment. However, the FEV 1 reduction rate varies markedly among individuals and should be monitored in all cases.

Background Cough and sputum production (symptoms of bronchitis) are common in chronic obstructive pulmonary disease (COPD). Extrapulmonary comorbidities, such as gastroesophageal reflux disease (GERD) and post-nasal drip, also cause bronchitis symptoms. The impact of extrapulmonary comorbidities on the severity of bronchitis symptoms in COPD is unknown. The aim of this study was to quantify bronchitis symptoms and assess the impact of GERD and nasal symptoms on the severity of bronchitis symptoms in COPD. Methods In this cross-sectional study, stable COPD patients were recruited and completed the COPD assessment test (CAT) and Cough and Sputum Assessment Questionnaire (CASA-Q) to quantify bronchitis symptoms. To evaluate extrapulmonary comorbidities, the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and nasal symptom questionnaire were completed. The impact of these comorbidities on the severity of bronchitis symptoms was analyzed. Results Ninety-nine COPD patients were recruited. The presence of GERD symptoms (24.2% in the study population) was associated with more sputum symptoms. The presence of nasal discharge (43.4%) was associated with more cough and sputum symptoms, whereas post-nasal drip (13.1%) was associated with more sputum symptoms. On multivariate analyses, nasal discharge was associated with more cough symptoms. GERD and post-nasal drip were associated with more sputum symptoms. Conclusion This study showed that the presence of GERD and/or nasal symptoms is associated with an increase in bronchitis symptoms. Careful assessment of extrapulmonary comorbidities is necessary in the evaluation of bronchitis symptoms in COPD patients.

Shoko Matsui, Hiroshi Yamamoto, Seijiro Minamoto, Yuko Waseda, Michiaki Mishima, Keishi Kubo Health Administration Center, University of Toyama, Gofuku 3190, Toyama-shi, Toyama 930-8555, Japan Shinshu University School of Medicine, Japan Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Japan Kanazawa University Graduate School of Medical Science, Japan Graduate School of Medicine, Kyoto University, Japan Nagano Prefectural Hospital Organization, Japan

Background In 1999, a Japanese epidemiological survey of chronic hypersensitivity pneumonitis (HP) showed that summer-type HP was the most prevalent variant of the disease. The number of reported cases of chronic HP has recently been increasing, and the clinical features of the disease seem to have changed. We conducted another nationwide epidemiological survey of chronic HP in Japan to determine better estimates of the frequency and clinical features of the disease. Methods A questionnaire was sent to qualified hospitals throughout Japan, and data on cases of chronic HP diagnosed between 2000 and 2009 were collected. Results In total, 222 cases of chronic HP from 22 hospitals were studied. Disease subtypes included bird-related HP ( n =134), summer-type HP ( n =33), home-related HP ( n =25), farmer's lung ( n =4), isocyanate-induced HP ( n =3), and other types ( n =23). The median proportion of lymphocytes in bronchoalveolar lavage fluid was high (24.5%). The primary findings of computed tomography of the chest were ground-glass attenuation and interlobular septal thickening. Centrilobular fibrosis was the major pathological finding on examination of surgical lung biopsy specimens from 93 patients. The median survival time was 83 months. Conclusions The proportion of bird-related HP was higher than that in the previous epidemiological survey, and the proportions of isocyanate-induced HP and farmer's lung were lower. A crucial step in diagnosing chronic HP is to thoroughly explore the possibility of antigen exposure.

Fractional exhaled nitric oxide (FeNO) is considered an alternative marker of eosinophilic airway inflammation and is sometimes incorporated in the diagnosis of asthma. However, many patients with cough variant asthma (CVA) demonstrate an FeNO in the normal range. Therefore, additional information is needed to confirm the diagnosis of CVA, particularly in patients with low FeNO levels. We aimed to investigate the feasibility of using cough triggers to help diagnose CVA.We studied 163 patients presenting with prolonged/chronic cough alone (including 104 CVA patients) who underwent FeNO measurements and an airway responsiveness test, and answered a questionnaire listing 18 cough triggers. The sensitivity and specificity of FeNO levels and cough triggers for the diagnosis of CVA were determined.CVA patients showed higher FeNO levels than non-CVA patients. When the cut-off value of FeNO levels for the diagnosis of CVA was set at 22ppb, its sensitivity was 57%. CVA patients more frequently responded to "cold air" and "talking" as cough triggers than non-CVA patients. When the analysis was confined to those with a low FeNO (22ppb) group, the sensitivity and positive predictive values of "cold air" and "talking" for the diagnosis of CVA were 36% and 70% for "cold air", and 44% and 74% for "talking", respectively. Their specificity was 81%. "Cold air" was associated with airway hyperresponsiveness in all patients with an emphasis on those with low FeNO levels."Cold air" and/or "talking" as cough triggers could be signs for the diagnosis of CVA, particularly when FeNO levels are low.

The transforming growth factor-β superfamily signaling pathway is thought to be involved in the pathogenesis of pulmonary arteriovenous malformation (PAVM). However, the association between bone morphogenetic protein receptor type 2 (BMPR2) gene mutations and PAVM remains unclear. We present a case of concurrent PAVM and pulmonary arterial hypertension (PAH), with a deletion mutation in exon 6 and exon 7 of the BMPR2 gene. Drug treatment for PAH improved the patient's hemodynamics and exercise capacity, but worsened oxygenation. This case suggests that BMPR2 gene mutation may be associated with the complex presentation of PAVM combined with PAH.