BACKGROUND: Patients sometimes misidentify upper respiratory tract secretions or saliva as "sputum." The objective of this study was to investigate the prevalence of such misidentification and its clinical associations. METHODS: We conducted a cross-sectional study of adults with cough and/or sputum symptoms, examining how often patients referred to upper respiratory tract secretions or saliva as "sputum," and explored related clinical features. RESULTS: Of 72 patients with sputum symptoms, 32% and 13% referred to upper respiratory tract secretions and saliva, respectively, as "sputum." Patients who misidentified upper respiratory secretions more often reported post-nasal drip (41.2% vs. 6.1%) and rhinitis (64.7% vs. 26.5%) than those who did not, which remained significant after adjustment for covariates (p < 0.05). Saliva misidentification was more common in older patients (p = 0.03). CONCLUSIONS: 32% of the patients with sputum production referred to upper respiratory tract secretions as "sputum," highlighting a potential source of miscommunication in clinical practice.

BACKGROUND: Treprostinil has been approved for pulmonary hypertension associated with interstitial lung disease (PH-ILD) in Japan. This report aimed to evaluate long-term effects of inhaled treprostinil in Japanese patients with PH-ILD based on observation over 52 weeks. METHODS: Inhaled treprostinil was administered via a nebulizer from 18 μg (three breaths, four times daily) to 72 μg (12 breaths, four times daily) at minimum 3-day intervals. World Health Organization (WHO) functional class, clinical worsening, adverse events, pulmonary function and ILD-related biomarkers were evaluated throughout the trial. RESULTS: Among 20 patients, 16 and 13 completed the 52-week and 100-week observation periods, respectively. Eleven patients continued on the trial until transitioning to a commercially available product. The reasons of discontinuation in nine patients were adverse events in six patients (including four adverse drug reactions (ADRs)), withdrawal of consent in two patients, and lung transplantation in one patient. The median observation period was 107.5 weeks (interquartile range, 61.4-128.8 weeks) in 20 patients. Among 13 patients observed until week 100, WHO functional class was maintained in 69.2 % (9/13), and improved from class III to class II in 30.8 % (4/13). The main ADRs included cough, malaise, and blood pressure decreased. At the final measurement timepoint in each patient, 70.0 % (14/20) and 83.3 % (15/18) maintained had no absolute decline of forced vital capacity ≥5 % and diffusing capacity for carbon monoxide ≥10 %, respectively. CONCLUSION: Considering its long-term clinical benefits and tolerability, inhaled treprostinil is a promising treatment option for patients with PH-ILD. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT), jRCT2051210016. (first registered: May 7, 2021).

OBJECTIVE: Progressive pulmonary fibrosis (PPF) is a chronic interstitial lung disease (ILD) characterised by fibrotic progression and poor prognosis, with effective treatment strategies for previously untreated patients remaining unclear. This study evaluated the efficacy and safety of upfront combination therapy with anti-inflammatory and antifibrotic agents in previously untreated PPF patients. METHODS: This multicentre, single-arm phase 2 study enrolled 34 patients with ILD (including unclassifiable idiopathic interstitial pneumonia, idiopathic nonspecific interstitial pneumonia, fibrotic hypersensitivity pneumonitis and rheumatoid arthritis-associated ILD) all with evidence of PPF. Tacrolimus (0.0375 mg·kg-1 twice daily) and prednisolone (10 mg once daily) were initiated on day 1, with nintedanib (150 mg twice daily) added on day 8. The tacrolimus dosage was adjusted to maintain blood trough levels. The primary end-point was the change in the relative decline slope for forced vital capacity % predicted (%FVC) between before and after treatment. RESULTS: The protocol treatment was associated with a substantial improvement in the relative %FVC decline slope, from -20.9% per year before to +11.2% per year after treatment. Subgroup analysis revealed greater improvement in patients with an increased lymphocyte percentage in bronchoalveolar lavage fluid or elevated blood biomarkers. Adverse events, such as diarrhoea (67.6%) and hepatic dysfunction (29.4%), were manageable, with no severe cases or treatment discontinuations. CONCLUSION: Early combination therapy with tacrolimus, prednisolone and nintedanib was associated with improved pulmonary function and was well tolerated in previously untreated PPF patients. Our findings suggest the potential of this regimen as an initial treatment strategy, but further validation in larger randomised controlled trials is warranted.

【はじめに】特発性胸膜肺実質線維弾性症（iPPFE）に対する呼吸リハビリテーション（呼吸リハ）の介入方法は確立されていない． 【症例】64歳女性．心肺運動負荷試験Peak O₂/W: 9.8 ml/min/kg，定常負荷試験耐久時間（Endurance time: ET）：3分21秒，呼吸困難（修正Borg Scale; mBS）6であった．超音波診断装置を用いて横隔膜変位量（DE）を評価した．深吸気でDEは，座位19.7 mm，背臥位40.1 mmであった． 【理学療法】DEの結果から，背臥位で下肢筋力増強，仰臥位用負荷量可変式エルゴメーターによる持久力運動を実施した． 【結果】Peak O₂/Wが 12.5 ml/min/kg，ETが5分15秒，呼吸困難はmBS3へ改善した． 【結論】iPPFE患者に対する背臥位での運動療法は，より効果的に運動耐容能や呼吸困難を改善する可能性が示唆された．

BACKGROUND: The INCREASE trial, conducted in the United States, showed that inhaled treprostinil improved exercise capacity in pulmonary hypertension associated with interstitial lung disease (PH-ILD). However, hemodynamic and pharmacokinetic measurements were not performed in the trial. The objective of this trial was to evaluate the efficacy on hemodynamics and exercise capacity, safety, and pharmacokinetics (PK) of inhaled treprostinil in Japanese patients with PH-ILD. METHODS: This trial was a multicenter, non-randomized, open-label, single-arm trial of patients with PH-ILD. Inhaled treprostinil was administered at 3 breaths (18 μg)/session four times daily, and the dose was gradually increased to a maximum of 12 breaths (72 μg)/session. The primary endpoints were the change of pulmonary vascular resistance index (PVRI) and peak 6-min walking distance (6MWD) from baseline to week 16. Endpoints also included other efficacy parameters, safety, and PK. RESULTS: Twenty patients received inhaled treprostinil. At week 16, PVRI decreased from baseline by -40.1% (95% CI, -53.1 to -27.2) and peak 6MWD increased by 13.0 m (95% CI, -15.0 to 49.0). The most frequently reported adverse events related with treprostinil were cough, malaise and blood pressure decreased. PK was similar to those in pulmonary arterial hypertension (PAH) patients. CONCLUSIONS: Treatment with inhaled treprostinil using the same dosing regimen as in the INCREASE trial resulted in improvements in hemodynamics and exercise capacity with a favorable tolerability and safety profile in Japanese patients with PH-ILD.

BACKGROUND: Pulmonary arterial hypertension (PAH)-specific therapies are generally ineffective in patients with pulmonary hypertension associated with lung disease (PH-LD). The aim of this preliminary study was to evaluate the potential efficacy of selexipag, titrated according to individual tolerance, in patients with PH-LD. METHODS: Consecutive patients diagnosed with PH-LD between October 2016 and March 2019, who received selexipag treatment, were retrospectively evaluated. Specific parameters, including changes in hemodynamic parameters, 6-min walk distance (6MWD), and partial pressure of atrial oxygen/fraction of inspiratory oxygen (PaO2/FiO2) were evaluated. Patients whose 6MWD improved ≥20 m were defined as responders. RESULTS: Eight patients with PH-LD were included, comprising four with chronic obstructive pulmonary disease (COPD), two with interstitial lung disease (ILD) related to rheumatoid arthritis, one with ILD related to systemic sclerosis, and one with pulmonary Langerhans cell histiocytosis. No statistically significant improvements in hemodynamic parameters and 6MWD were noted following selexipag treatment. However, four patients showed improvements in 6MWD ≥20 m at follow-up and were considered responders. They had a higher body mass index (BMI) and lower PaO2/FiO2 at baseline than non-responders (p = 0.02 and p = 0.04, respectively). No Grade 3 or 4 adverse events were observed. CONCLUSIONS: Selexipag was effective in half of the PH-LD cases, emphasizing higher BMI and lower PaO2/FiO2 as possible indicators for favorable response. Since selexipag starting at a low dose with subsequent titration may reduce the risk of early adverse events, it can be considered a treatment option for PH-LD. Further large-scale studies are warranted to confirm these findings.

Objective Inspiratory muscle training (IMT) is used to improve inspiratory muscle strength in patients with chronic obstructive pulmonary disease (COPD). However, the effect of IMT on diaphragmatic function has not yet been thoroughly evaluated. This study aimed to evaluate the effect of IMT on maximum diaphragmatic excursion (DE_max) using ultrasonography in patients with COPD. Methods This was a single-center, randomised, prospective, parallel-group, unblinded controlled trial involving 38 participants with stable COPD. Participants underwent a standardised 12-week pulmonary rehabilitation (PR) program followed by a 12-week IMT program, consisting of home-based IMT and low-frequency outpatient PR sessions supervised by physiotherapists (once every 2 weeks),versuslow-frequency outpatient PR alone as a control. The DE_maxand exercise tolerance were measured. Results Out of the 38 patients initially enrolled in the PR program, 33 successfully completed it and were subsequently randomised to the IMT program. Finally, 15 (94%) and 14 (88%) patients from the IMT and control groups, respectively, completed the study. Following the IMT program, DE_maxincreased in the IMT group (50.1±7.6 mm to 60.6±8.0 mm, p<0.001), but not in the control group (47.4±7.9 mm to 46.9±8.3 mm, p=0.10). Changes in DE_maxand exercise tolerance (peak VO₂) were greater in the IMT group than in the control group (both p<0.01). Conclusions IMT following the PR program improved DE_maxand exercise tolerance. Therefore, DE_maxmay be an important outcome of IMT.

BACKGROUND: Acute exacerbations (AEs) of fibrotic idiopathic interstitial pneumonia (fIIP) that require hospitalization occur in some patients. During hospitalization, these patients can develop hospital-acquired pneumonia (HAP), a common hospital-acquired infection with a high mortality rate. However, the characteristics of HAP in AE-fIIP remain unknown. The purpose of this study was to determine the incidence, causative pathogens, and outcomes of HAP in patients with AE-fIIP. METHODS: The medical records of consecutive patients who were hospitalized with AE-fIIP from January 2008 to December 2019 were analyzed for the incidence, causative pathogen, and survival of HAP. The records of patients with an obvious infection-triggered AE were excluded from analysis. RESULTS: There were 128 patients with AE-fIIP (89 with idiopathic pulmonary fibrosis [IPF] and 39 with non-IPF fIIP) who were hospitalized a total of 155 times (111 with IPF and 44 with non-IPF fIIP). HAP occurred in 49 patients (40 with IPF and 9 with non-IPF fIIP). The incidence and the in-hospital mortality rates of HAP in patients with AE-fIIP were high, at 32.2% and 48.9%, respectively. Corynebacterium spp. was the most common causative pathogen, which was followed by human cytomegalovirus (HCMV). CONCLUSIONS: The incidence and the in-hospital mortality rates of HAP in patients with AE-fIIP are high. To improve their survival, patients with fIIP who had AEs and HAP should receive prompt empirical treatment for possible infections with Corynebacterium spp. and testing for HCMV.

BACKGROUND: Recent guidelines discourage the use of pulmonary arterial hypertension (PAH)-targeted therapies in patients with pulmonary hypertension (PH) associated with respiratory diseases. Therefore, stratifications of the effectiveness of PAH-targeted therapies are important for this group. OBJECTIVES: The authors aimed to identify phenotypes that might benefit from initial PAH-targeted therapies in patients with PH associated with interstitial pneumonia and combined pulmonary fibrosis and emphysema. METHODS: We categorized 270 patients with precapillary PH (192 interstitial pneumonia, 78 combined pulmonary fibrosis and emphysema) into severe and mild PH using a pulmonary vascular resistance of 5 WU. We investigated the prognostic factors and compared the prognoses of initial (within 2 months after diagnosis) and noninitial treatment groups, as well as responders (improvements in World Health Organization functional class, pulmonary vascular resistance, and 6-minute walk distance) and nonresponders. RESULTS: Among 239 treatment-naive patients, 46.0% had severe PH, 51.8% had mild ventilatory impairment (VI), and 40.6% received initial treatment. In the severe PH with mild VI subgroup, the initial treatment group had a favorable prognosis compared with the noninitial treatment group. The response rate in this group was significantly higher than the others (48.2% vs 21.8%, ratio 2.21 [95% CI: 1.17-4.16]). In multivariate analysis, initial treatment was a better prognostic factor for severe PH but not for mild PH. Within the severe PH subgroup, responders had a favorable prognosis. CONCLUSIONS: This study demonstrated an increased number of responders to initial PAH-targeted therapy, with a favorable prognosis in severe PH cases with mild VI. A survival benefit was not observed in mild PH cases. (Multi-institutional Prospective Registry in Pulmonary Hypertension associated with Respiratory Disease; UMIN000011541).

BACKGROUND: Obstructive sleep apnea (OSA) is one of the major co-morbidities and aggravating factors of asthma. In OSA-complicated asthma, obesity, visceral fat, and systemic inflammation are associated with its severity, but the role of bronchial hyperresponsiveness (BHR) is unclear. We investigated the involvement of BHR and mediastinal fat width, as a measure of visceral fat, with OSA severity in patients with OSA and asthma-like symptoms. METHODS: Patients with OSA who underwent BHR test and chest computed tomography scan for asthma-like symptoms were retrospectively enrolled. We evaluated the relationship between apnea-hypopnea index (AHI) and PC20 or anterior mediastinal fat width, stratified by the presence or absence of BHR. RESULTS: OSA patients with BHR (n = 29) showed more obstructive airways and frequent low arousal threshold and lower mediastinal fat width, and tended to show fewer AHI than those without BHR (n = 25). In the overall analysis, mediastinal fat width was significantly positively correlated with AHI, which was significant even after adjustment with age and gender. This was especially significant in patients without BHR, while in OSA patients with BHR, there were significant negative associations between apnea index and airflow limitation, and hypopnea index and PC20. CONCLUSIONS: Risk factors for greater AHI differed depending on the presence or absence of BHR in OSA patients with asthma-like symptoms. In the presence of BHR, severity of asthma may determine the severity of concomitant OSA.

BACKGROUND: Decreased respiratory muscle strength and muscle mass is key in diagnosing respiratory sarcopenia. However, the role of reduced diaphragm activity, expressed as the maximal level of diaphragmatic excursion (DEmax), in diagnosing respiratory sarcopenia in patients with chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to characterize patients with COPD and low DEmax and maximal inspiratory pressure (MIP), a measure of inspiratory muscle strength, and assess the role of DEmax in respiratory sarcopenia. METHODS: Patients with COPD underwent spirometry, exercise tolerance (VO2peak) test, and MIP measurement. DEmax and sternocleidomastoid thickness at the maximal inspiratory level (TscmMIL) were assessed using ultrasound sonography. RESULTS: Overall, 58 patients with COPD (median age, 76 years; median %FEV1, 51.3 %) were included, 28 of whom showed a %MIP of ≥80 %, defined as having preserved MIP. Based on the %MIP of 80 % and median value of DEmax (48.0 mm) as thresholds, the patients were stratified into four groups: both-high (n = 18), %MIP-alone low (n = 11), DEmax-alone low (n = 10), and both-low (n = 19) groups. The both-low group exhibited the lowest %FEV1, Δinspiratory capacity, VO2peak, and TscmMIL, and these values were significantly lower than those of the both-high group. Except for %FEV1, these values were significantly lower in the both-low group than in the %MIP-alone low group despite adjusting DEmax level for body mass index. CONCLUSION: Measuring DEmax along with MIP can characterize patients with COPD, reduced exercise capacity, and decreased accessory respiratory muscle mass and can help diagnose respiratory sarcopenia.

Background and objective Dynamic lung hyperinflation (DLH) can play a central role in exertional dyspnoea in patients with chronic obstructive pulmonary disease (COPD). Chest X-ray is the basic tool for assessing static lung hyperinflation in COPD. However, the predictive capacity of DLH using chest X-ray remains unknown. This study was conducted to determine whether DLH can be predicted by measuring the height of the right diaphragm (dome height) on chest X-ray. Methods This single-centre, retrospective cohort study included patients with stable COPD with pulmonary function test, cardiopulmonary exercise test, constant load test, and pulmonary images. They were divided into two groups according to the median of changes of inspiratory capacity (ΔIC=IC lowest − IC at rest). The right diaphragm dome height and lung height were measured on plain chest X-ray. Results Of the 48 patients included, 24 were classified as having high DLH (ΔIC≤−0.59 L from rest; −0.59 L, median of all) and 24 as having low DLH. Dome height correlated with ΔIC (r=0.66, p<0.001). Multivariate analysis revealed that dome height was associated with high DLH independent of %low attenuation area on chest computed tomography and %FEV₁. Furthermore, the area under the receiver operating characteristic curve of dome height to predict high DLH was 0.86, with sensitivity and specificity of 83% and 75%, respectively, at a cutoff of 20.5 mm. Lung height was unrelated to ΔIC. Conclusion Diaphragm dome height on chest X-ray may adequately predict high DLH in patients with COPD.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance. RESEARCH QUESTION: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression? METHODS: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52. RESULTS: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019). INTERPRETATION: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time. TRIAL REGISTRATION NUMBER: UMIN000026376.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) have a slowly progressive clinical course, although some develop acute exacerbations (AEs). An easily obtained composite score is desirable for predicting the survival rate in patients with AE of IPF (AE-IPF). We investigated the quick sequential organ failure assessment (qSOFA), originally developed to identify sepsis, as a predictor of mortality in patients with AE-IPF and compared it to other composite assessments. METHODS: Consecutive patients with IPF admitted for their first AE between 2008 and 2019 were recruited retrospectively. The association between the qSOFA score obtained at admission and mortality was investigated. RESULTS: During the study period, 97 patients with AE-IPF were hospitalized. The hospital mortality was 30.9%. Multivariate logistic regression analysis revealed that both the qSOFA and the Japanese Association for Acute Medicine (JAAM)-disseminated intravascular coagulation (DIC) scores were significant predictors of hospital mortality (odds ratio [OR] 3.86, 95% confidence interval [CI] 1.43-10.3; p = 0.007 and OR 2.71, 95% CI 1.56-4.67; p = 0.0004; respectively). Kaplan-Meier survival curves showed that both scores were consistently associated with survival. Furthermore, the sum of the two scores was a more effective predictor than the individual scores. CONCLUSIONS: The qSOFA score of patients admitted with AE-IPF was associated with both in-hospital and long-term mortality, which was also true for the JAAM-DIC score. The qSOFA score plus the JAAM-DIC score should be determined during the diagnostic evaluation of a patient with AE-IPF. Both scores combined may be more effective at predicting outcomes than individual scores.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have difficulties inhaling as the diaphragm becomes flattened and weakened due to lung hyperinflation. This weakened respiratory function is compensated for by the increased activity of the accessory respiratory muscles, such as the sternocleidomastoid muscle (SCM). OBJECTIVES: This study aimed to evaluate the difference in the SCM thickening fraction (SCM TF) of each respiratory phase (end-expiration, resting inspiration, and end-inspiration), as measured using ultrasonography (US), between patients with COPD and control subjects. We also evaluate the correlation between the SCM TF of each respiratory phase and exercise tolerance in patients with COPD. METHODS: Patients with COPD (n = 44) and age-matched controls (n = 20) underwent US for determination of the SCM TF. Ventilation parameters, including the peak oxygen uptake (peak VO2) and the change in the inspiratory capacity, were measured during cardiopulmonary exercise testing. The SCM thickness and TF was measured during end-expiration, resting breathing, and end-inspiration. RESULTS: The SCM was significantly thinner in patients with COPD than in controls at end-expiration. The increase in the SCM TF from end-expiration to end-inspiration in patients with COPD did not differ significantly from that in control subjects. In contrast, the SCM TF from end-expiration to resting inspiration was significantly greater in patients with COPD than in control subjects. The peak VO2 was strongly positively correlated with the SCM TF from end-expiration to end-inspiration in patients with COPD (r = 0.71, p < 0.01). CONCLUSIONS: The SCM may be thinner in patients with COPD than in controls. The SCM TF may also be associated with exercise tolerance.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is diagnosed incidentally in some patients with minimal or no respiratory symptoms. The clinical features of such patients are unknown. Herein we aimed to clarify the prevalence, clinical course, and prognostic factors of patients who were incidentally diagnosed with IPF. METHODS: The files of consecutive patients with newly diagnosed IPF were retrospectively reviewed to determine the methods involved in their diagnosis, and their outcomes. RESULTS: Among a total of 107 patients with newly diagnosed IPF, 35 (32.7%) were diagnosed incidentally, including 18 undergoing annual health check-ups and 17 undergoing assessment for other medical problems. The median survival from the time of diagnosis was 4.9 years for the 35 patients diagnosed incidentally, which was comparable to the median survival of 3.9 years for the 72 who were not diagnosed incidentally. The body mass index (BMI) was the sole independent predictor of survival (hazard ratio 0.78, 95% confidence interval 0.65-0.93, p = 0.006) in patients diagnosed incidentally. CONCLUSIONS: Nearly one third of patients with IPF were diagnosed incidentally, and their survival was still poor. Identifying patients during the earliest stage of IPF, particularly those with a low BMI, is warranted.

We describe a case of asymptomatic lung toxocariasis in a man in whom severe eosinophilia (WBC count: 4,780 /μL; Eosinophils: 35.0%) detected during a medical check-up led to the diagnosis. The patient gave a history of habitually consuming the raw livers of cows, even after this was legally banned in Japan. His chest computed tomography (CT) revealed nodules with halos and ground-glass opacities in the lungs; the nodules migrated over time before treatment was started. Immunoserological examination by microplate-enzyme-linked immunosorbent assay showed a high optical density for specific antibody against Toxocara spp. excretory secretory antigen (TcES). A positive reaction for TcES was also confirmed by Western blotting. Based on these findings, the patient was diagnosed with lung toxocariasis. He was successfully treated with albendazole, which led to improvement of the eosinophilia and resolution of the abnormal opacities on the chest CT. The antibody titer against TcES also decreased. Even though ingestion of the raw livers of cows has been legally banned in Japan, the possibility of toxocariasis should be considered in the differential diagnosis of patients with severe eosinophilia.

Background: Idiopathic pulmonary fibrosis (IPF) is a form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, with a poor prognosis. We previously showed the antifibrotic effects of a novel phosphodiesterase 4 (PDE4) inhibitor, AA6216. In this study, we examined the effect of AA6216 on the pulmonary accumulation of segregated-nucleus-containing atypical monocytes (SatMs), which produce tumor necrosis factor (TNF)-α and are involved in murine lung fibrosis. Methods: Mice were treated with bleomycin intratracheally at day 0 and either 10 mg/kg AA6216, 100 mg/kg nintedanib, or vehicle orally once daily from day 0 to 8. On day 9, we isolated the bronchoalveolar lavage fluid and analyzed the SatM ratio. In addition, we evaluated the effect of AA6216 on TNF-α production from SatMs isolated from murine bone marrow. Results: AA6216, and not the antifibrotic agent nintedanib, significantly suppressed the pulmonary accumulation of SatMs (AA6216: 68.3 ± 5.4%, Nintedanib: 129.8 ± 19.7%). Furthermore, AA6216 dose-dependently inhibited the production of TNF-α by SatMs. Conclusions: AA6216 suppresses pathogenic SatMs in the lung, which contributes to its antifibrotic effects.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), the maximum level of diaphragm excursion (DEmax) is correlated with dynamic lung hyperinflation and exercise tolerance. This study aimed to elucidate the utility of DEmax to predict the improvement in exercise tolerance after pulmonary rehabilitation (PR) in patients with COPD. METHODS: This was a prospective cohort study. Of the 62 patients with stable COPD who participated in the outpatient PR programme from April 2018 to February 2021, 50 completed the programme. Six-minute walk distance (6MWD) was performed to evaluate exercise tolerance, and ultrasonography was performed to measure DEmax. Responders to PR in exercise capacity were defined as patients who demonstrated an increase of > 30 m in 6MWD. The receiver operating characteristic (ROC) curve was used to determine the cut-off point of DEmax to predict responses to PR. RESULTS: Baseline levels of forced expiratory volume in 1 s, 6MWD, maximum inspiratory pressure, DEmax and quadriceps muscle strength were significantly higher, and peak dyspnoea of modified Borg (mBorg) scale score was lower in responders (n = 30) than in non-responders (n = 20) to PR (p < 0.01). In multivariate analysis, DEmax was significantly correlated with an increase of > 30 m in 6MWD. The area under the ROC curve of DEmax to predict responders was 0.915, with a sensitivity and specificity of 83% and 95%, respectively, at a cut-off value of 44.9 mm of DEmax. CONCLUSION: DEmax could adequately predict the improvement in exercise tolerance after PR in patients with COPD.

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

BACKGROUND: A recent paper reported that low muscle mass in the erector spinae muscles (ESM) was strongly associated with poor prognosis and declining muscle mass over time in subjects with COPD. However, effects of pulmonary rehabilitation (PR), if any, on ESM mass have not been reported. We hypothesized that PR reduces the annual decline in ESM mass. METHODS: This was a retrospective cohort study. Thirty-nine subjects with COPD who received PR and underwent chest computed tomography before and after PR were evaluated (rehabilitation group). We also evaluated 39 age-matched subjects with COPD who did not receive PR (nonrehabilitation group). Data were collected from August 2010 until March 2020 in both groups. The ESM cross-sectional area (ESMCSA) was measured using axial computed tomography images, and annual changes were calculated. The 6-min walk distance (6MWD) was measured before and after PR; the minimum clinically important difference was defined as 30 m. RESULTS: ESMCSA declined in the nonrehabilitation group over time (-116.0 ± 141.2 mm2/y) but increased in the PR group (51.0 ± 95.3 mm2/y; P < .001). The annual increase in ESMCSA was significantly higher among subjects with an increase in 6MWD that exceeded the minimum clinically important difference compared with nonresponders in the rehabilitation group. The annual change in ESMCSA was negatively correlated with comorbidity index, and triple therapy (long-acting β2-agonist/long-acting muscarinic antagonist/inhaled corticosteroid) had a favorable effect on annual change in ESMCSA. Multiple regression analysis revealed that only PR was an independent factor for annual change in ESMCSA. CONCLUSIONS: ESM mass was shown to decline yearly in subjects with COPD. The annual decline in muscle mass was reduced by PR.

Background: Pulmonary rehabilitation causes short-term improvement in exercise capacity, dyspnoea and health-related quality of life in idiopathic pulmonary fibrosis (IPF); however, long-term maintenance of the improvement is difficult. Nintedanib, an antifibrotic drug, has been shown to delay the worsening of pulmonary function in IPF. Therefore, the concomitant use of nintedanib with pulmonary rehabilitation is anticipated to contribute to the long-term maintenance of the pulmonary rehabilitation effects. The long-term effect of pulmonary rehabilitation under nintedanib treatment in IPF (FITNESS) study is a multicenter, randomised, prospective, parallel-group, open-label trial. Methods: The study will enrol 84 patients with IPF who have been treated with nintedanib. Patients in the pulmonary rehabilitation group will receive a programmed short-term induction pulmonary rehabilitation programme, followed by a maintenance home-based pulmonary rehabilitation programme, while patients in the control group will receive usual outpatient care. Patients in both groups will continue to receive nintedanib treatment throughout the study period. The primary end-point of the study is to compare the change in the 6-min walk distance from the baseline to 12 months between the pulmonary rehabilitation and control groups. The main secondary end-point is endurance exercise time, measured using a bicycle ergometer. Discussion: FITNESS is the first randomised controlled study to evaluate the long-term effects of pulmonary rehabilitation in IPF treated with nintedanib. This study will address the hypothesis that concomitant use of nintedanib contributes to the maintenance of long-term effects of pulmonary rehabilitation, thus leading to a comprehensive therapeutic approach of "nintedanib and pulmonary rehabilitation" in the antifibrotic era.

Dysphagia is frequently observed in patients with chronic obstructive pulmonary disease (COPD). Decreased tongue strength is one of the causes of dysphagia, and it is often observed in patients with sarcopenia. Sarcopenia is also frequently observed in COPD patients. We hypothesized that tongue strength is lower in COPD patients compared to normal subjects. This was a single-center, observational, cross-sectional study. Maximum tongue pressure (MTP) was measured in 27 patients with COPD and 24 age-matched control subjects. We also evaluated handgrip strength, gait speed, and appendicular skeletal muscle mass to define subjects as having sarcopenia. We used bioelectrical impedance analysis to assess body composition. The eating assessment test-10 was used to diagnose dysphagia. MTP was significantly lower in COPD patients than in control subjects (33.8 ± 8.4 vs 38.0 ± 5.3; p = 0.032). All measures of muscle and fat free body mass, handgrip strength, and gait speed were also significantly lower in COPD patients compared to control subjects (p < 0.01). The prevalence of sarcopenia in COPD patients was higher than that in control subjects (6/27 versus 0/24; p = 0.007), but the prevalence of dysphagia was not different between groups (COPD: 5/27, versus control: 1/24; p = 0.112). MTP was moderately correlated with skeletal muscle mass index (r = 0.56, p = 0.003) and handgrip strength (r = 0.43, p = 0.027) in COPD patients. Tongue strength was lower in COPD patients compared to normal subjects, and decreased tongue strength may be correlated with sarcopenia in COPD patients.

BACKGROUND: The utility of bronchoscopy for patients with suspected immune checkpoint inhibitor (ICI)-related pneumonitis is currently debatable. The purpose of this study was to examine the findings of bronchoalveolar lavage (BAL) analysis and transbronchial lung biopsy (TBLB) in non-small cell lung cancer (NSCLC) patients with ICI-related pneumonitis, and to elucidate the clinical significance of bronchoscopy for this health condition. PATIENTS AND METHODS: Consecutive NSCLC patients treated with ICIs, diagnosed with ICI-related pneumonitis after undergoing bronchoscopy between October 2015 and March 2019 were retrospectively screened. Findings of BAL fluid analysis and/or TBLB specimen histology were reviewed. RESULTS: Twelve patients underwent bronchoscopy for the diagnosis of ICI-related pneumonitis, ten of whom underwent BAL. An increase in the proportion of lymphocytes higher than 20% was observed in all ten patients. An increase in the proportion of neutrophils (> 10%) and eosinophils (> 10%) was observed in two and one patient, respectively. TBLB specimens were analyzed for eight patients. Major histologic findings included alveolitis in seven (87.5%) and organizing pneumonia (OP) in five (62.5%) patients. Other findings included acute lung injury and fibrosis. All twelve patients demonstrated favorable outcomes. CONCLUSION: A major characteristic of BAL analysis in ICI-related pneumonitis with NSCLC was an increased proportion of lymphocytes. The histologic features of lung tissue included alveolitis and/or OP. Acute lung injury and fibrosis were observed. Although the necessity of bronchoscopy should be determined on a case-by-case basis, it is necessary to assess these parameters when proper differential diagnosis is needed.

BACKGROUND: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis.Methods and Results:Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI. CONCLUSIONS: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.

Some patients with idiopathic pulmonary fibrosis (IPF) undergo recurrent acute exacerbations (AEs). This study aimed to elucidate the risk factors for recurrent AEs of IPF (AE-IPF). Consecutive patients with IPF admitted for their first AE-IPF between January 2008 and December 2018 were retrospectively recruited. Of 63 patients admitted for an AE-IPF and discharged alive, 9 (14.3%) developed a recurrence of AE within 1 year. The mean time to recurrence was 233 ± 103 days. Total doses (mg/month and mg/kg/month) of corticosteroids administered over day 1 to 30 after the AE were significantly higher in patients without recurrences of AE-IPF (5185 ± 2414 mg/month, 93.5 ± 44.0 mg/kg/month) than the doses in patients with recurrences (3133 ± 1990 mg/month, 57.2 ± 37.7 mg/kg/month) (p = 0.02 and p = 0.03, respectively). However, no differences were observed between the total doses of corticosteroids administered over days 31 to 60, 61 to 90, 91 to 120, and 151 to 180 after the AE. Furthermore, differences between the administration rates of immunosuppressive and antifibrotic treatments administered to the 2 patient groups were not significant. An increased total dose of corticosteroid administered over day 1 to 30 after an AE-IPF was associated with a decreased risk of subsequent recurrence of AE-IPF within 1 year after the first AE.

Some patients with idiopathic pulmonary fibrosis (IPF) require hospitalization due to pneumonia. Although predictive scoring tools have been developed and validated for community-acquired pneumonia (CAP), their usefulness in IPF is unknown. The Confusion, Urea, Respiratory Rate, Blood Pressure and Age (CURB-65) score and the Pneumonia Severity Index (PSI) are validated for CAP. The quick Sequential Organ Failure Assessment (qSOFA) is also reported to be useful. The aim of this study was to investigate the ability of these tools to predict pneumonia mortality among hospitalized patients with IPF. A total of 79 patients with IPF and pneumonia were hospitalized for the first time between January 2008 and December 2017. The hospital mortality rate was 15.1%. A univariate logistic regression analysis revealed that the CURB-65 (odds ratio 4.04, 95% confidence interval 1.60-10.2, p = 0.003), PSI (4.00, 1.48-10.7, 0.006), and qSOFA (5.00, 1.44-1.72, 0.01) scores were significantly associated with hospital mortality. There was no statistically significant difference between the three receiver operating characteristic curves (0.712, 0.736, and 0.692, respectively). The CURB-65, PSI, and qSOFA are useful tools for predicting pneumonia mortality among hospitalized patients with IPF. Because of its simplicity, the qSOFA may be most suitable for early assessment.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) are at risk of acute exacerbations (AEs) that manifest as respiratory distress. However, the clinical course after AEs of IPF (AE-IPFs) has not been well described. Therefore, we aimed to elucidate the clinical course and prognosis in survivors of AE-IPFs. METHODS: Consecutive patients with IPF who presented to our institution with their first AE-IPFs between January 2008 and December 2019 were included in this study. Data were retrospectively collected, and the clinical course, survival, and cause of death were further analyzed. RESULTS: Ninety-seven patients were included in this retrospective study. Among them, 67 (69.1%) were discharged alive, with a median survival time after discharge of 1081 days. AE recurrence and pneumonia were the most common causes of death, each accounting for 22.2% of cases among survivors of AE-IPFs. AEs were the most frequent during the first 3 years after discharge, whereas pneumonia was more common thereafter. CONCLUSIONS: Survivors of AE-IPFs have a relatively favorable long-term prognosis. Among the survivors of first AE-IPFs, AE recurrence and pneumonia were the most common causes of death after discharge. Therefore, preventing AE recurrence and lung infections is crucial for prolonging survival in survivors of AE-IPFs.

BACKGROUND: Some patients with idiopathic pulmonary fibrosis (IPF) develop pneumothorax. However, the characteristics of pneumothorax in patients with IPF have not been elucidated. The purpose of this study was to clarify the clinical course, actual management, and treatment outcomes of pneumothorax in patients with IPF. METHODS: Consecutive patients with IPF who were admitted for pneumothorax between January 2008 and December 2018 were included. The success rates of treatment for pneumothorax, hospital mortality, and recurrence rate after discharge were examined. RESULTS: During the study period, 36 patients with IPF were admitted with pneumothorax a total of 58 times. During the first admission, 15 patients (41.7%) did not receive chest tube drainage, but 21 (58.3%) did. Of the 21 patients, 8 (38.1%) received additional therapy after chest drainage. The respective treatment success rates were 86.6% and 66.7% in patients who underwent observation only vs chest tube drainage. The respective hospital mortality rates were 13.3% and 38.0%. The total pneumothorax recurrence rate after hospital discharge was 34.6% (n = 9). CONCLUSIONS: Pneumothorax in patients with IPF was difficult to treat successfully, had a relatively poor prognosis, and showed a high recurrence rate.

BACKGROUND: Some patients with idiopathic pulmonary fibrosis (IPF) must be hospitalized because of heart failure (HF), including HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF). The association between IPF and HF has not been clarified. We retrospectively investigated the clinical features and outcomes of patients with IPF who required nonelective hospitalization because of HF. METHODS: We examined data from IPF patients who required nonelective hospitalization for HF at the Kindai University Hospital from January 2008 to December 2018. We divided the patients into 3 groups: those with HFpEF without elevated right ventricular systolic pressure (RVSP), those with HFpEF and elevated RVSP, and those with HFrEF. The recurrence rates of HF after discharge and the 30- and 90-day mortality rates of the patients were evaluated. RESULTS: During the study period, 37 patients with IPF required hospitalization because of HF. Among the 34 patients included in the study, 17 (50.0%) were diagnosed with HFpEF without elevated RVSP, 11 (32.3%) with HFpEF and elevated RVSP, and 6 (17.6%) with HFrEF. Patients with HFrEF had significantly higher values for B-type natriuretic peptide (BNP) and left ventricular (LV) end-systolic and end-diastolic diameters than patients with the 2 types of HFpEF (BNP: P = 0.01 and P = 0.0004, LV end-systolic diameter: P <0.0001 and P <0.0001, and LV end-diastolic diameter: P = 0.01 and P = 0.0004, respectively). Notably, the difference between the LVEFs of the patients with 2 types of HFpEF was not significant. The patients with HFpEF without elevated RVSP had the lowest 30- and 90-day mortality rates (0%, P = 0.02 and 11.7%, P = 0.11, respectively). CONCLUSIONS: Among patients with IPF, HFpEF without elevated RVSP was the most common type of HF that required hospitalization. Patients with HFpEF without elevated RVSP survived longer than the patients with the other 2 types of HF.

Background: Although the pathophysiological mechanisms involved in the development of dyspnoea and poor exercise tolerance in patients with COPD are complex, dynamic lung hyperinflation (DLH) plays a central role. Diaphragmatic excursions can be measured by ultrasonography (US) with high intra- and interobserver reliability. The objective of this study was to evaluate the effect of diaphragmatic excursions as assessed by US on exercise tolerance and DLH in patients with COPD. Methods: Patients with COPD (n=20) and age-matched control subjects (n=20) underwent US, which was used to determine the maximum level of diaphragmatic excursion (DEmax). Ventilation parameters, including the change in inspiratory capacity (ΔIC), were measured in the subjects during cardiopulmonary exercise testing (CPET). We examined the correlations between DEmax and the ventilation parameters. Results: The DEmax of patients with COPD was significantly lower than that of the controls (45.0±12.8 mm versus 64.6±6.3 mm, respectively; p<0.01). The perception of peak dyspnoea (Borg scale) was significantly negatively correlated with DEmax in patients with COPD. During CPET, oxygen uptake/weight (V'O2 /W) and minute ventilation (V'E) were significantly positively correlated with DEmax, while V'E/V'O2 and V'E/carbon dioxide output (V'CO2 ) were significantly negatively correlated with DEmax in patients with COPD. DEmax was also significantly positively correlated with ΔIC, reflecting DLH, and with V'O2 /W, reflecting exercise capacity. Conclusion: Reduced mobility of the diaphragm was related to decreased exercise capacity and increased dyspnoea due to dynamic lung hyperinflation in COPD patients.

Idiopathic pulmonary fibrosis (IPF) is an intractable disease with poor prognosis, and therapeutic options are limited. While the pathogenic mechanism is unknown, cytokines, such as transforming growth factor (TGF)-β, and immune cells, such as monocytes and macrophages, that produce them, seem to be involved in fibrosis. Some phosphodiesterase 4 (PDE4) inhibitors reportedly have anti-fibrotic potential by acting on these disease-related factors. Therefore, we evaluated the effect of a novel PDE4 inhibitor, AA6216, on nonclinical IPF-related models and samples from IPF patients. First, we examined the inhibitory effect of AA6216 on the production of TGF-β1 from a human monocytic cell line, THP-1. Second, we analyzed the impact of AA6216 on TNF-α production by human alveolar macrophages collected from patients with IPF. Finally, we investigated the anti-fibrotic potency of AA6216 on bleomycin-induced lung fibrosis in mice. We found that AA6216 significantly inhibited TGF-β1 production by THP-1 cells. It also significantly suppressed TNF-α production by alveolar macrophages from patients with IPF. In the mouse model of bleomycin-induced pulmonary fibrosis, therapeutic administration of AA6216 significantly reduced fibrosis scores, collagen-stained areas, and TGF-β1 in bronchoalveolar lavage fluid. AA6216 may represent a new agent for the treatment of IPF with a distinct mechanism of action from that of conventional anti-fibrotic agents.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Chronic idiopathic interstitial pneumonia (c-IIP) is a group of lung diseases consisting mainly of fibrotic IIPs, and IPF is a type of c-IIP. Some patients with c-IIP undergo respiratory-related hospitalizations (RHs). With the hypothesis that the characteristics of patients who undergo RHs are related to the number of hospitalizations, we reviewed and investigated the RHs of patients with c-IIP. METHODS: We retrospectively examined the data of patients with c-IIP who were admitted to Kindai University Hospital between January 2008 and December 2018 for respiratory-related causes. RESULTS: During the study period, 243 patients with c-IIP were hospitalized a total of 544 times because of respiratory-related causes. The most common reasons for the first RH were acute exacerbation (48.1%) followed by pulmonary infection (32.5%). The most frequent reason for subsequent RHs was pulmonary infection. The in-hospital and 90-day mortality rate of patients with pulmonary infection increased with increasing numbers of RHs. Patients with multiple RHs had significantly worse long-term survival than patients hospitalized a single time. CONCLUSIONS: Pulmonary infection was the most frequent reason for repeated RHs. The proportion of all patients hospitalized for pulmonary infection at each RH increased with increasing numbers of RHs, along with the mortality rate of patients with pulmonary infections. Furthermore, repeated RHs were associated with poor survival.

BACKGROUND: The characteristics and significance of respiratory-related hospitalization in patients with idiopathic pulmonary fibrosis (IPF) in Asian countries remain unknown. The purpose of this study was to define the characteristics of respiratory-related hospitalization and to inspect the relationship between respiratory-related hospitalization and subsequent survival in patients with IPF in Japanese general practice. METHODS: Patients with IPF who underwent clinical evaluation between February 2008 and August 2017 were screened. Only those who had undergone evaluation within 1 year after the diagnosis of IPF were included in the study. The post-diagnosis pulmonary function tests were considered the registration point. We then performed a 6-month landmark analysis including only patients who were alive 6 months after the registration. The characteristics of respiratory-related hospitalizations during the 6 months after registration and the association between respiratory-related hospitalization and survival were investigated. RESULTS: A total of 106 patients with IPF were included in the study. The mean forced vital capacity (FVC) at registration was 80.2 ± 25.1% predicted. Seventeen patients (16.0%) had respiratory-related hospitalization during the 6 months after registration. Pneumonia was the most frequent reason for hospitalization (47.0%), followed by acute exacerbation of IPF (29.4%). In multivariate analysis, % predicted FVC (hazard ratio: 0.98, 95% confidence interval: 0.96-0.99, p = 0.004), 6-month decrease in % predicted FVC (1.05, 1.02-1.08, 0.005), and respiratory-related hospitalization (2.45, 1.24-4.85, 0.009) were significantly associated with survival. CONCLUSIONS: Pneumonia is the most frequent cause of respiratory-related hospitalization in Japanese IPF patients. Furthermore, respiratory-related hospitalization is significantly associated with subsequent poor survival.

BACKGROUND: Although evidence of a disseminated intravascular coagulation (DIC)-like reaction has been identified in the lung parenchyma of patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF), an association between DIC and IPF outcome has not been elucidated. Therefore, we retrospectively investigated the association between the Japanese Association for Acute Medicine (JAAM)-DIC score and mortality in patients with acute exacerbation of fibrosing idiopathic interstitial pneumonia (AE-fIIP). METHODS: Between January 2008 and December 2016, consecutive patients with chronic fIIP who were admitted for the first time for AE-fIIP were recruited into the study. Associations between clinical data and JAAM-DIC score at the time of admission and mortality were examined. RESULTS: During the study period, a total of 91 patients with fIIP (73.0±8.4 y.o.) were hospitalized for AE-fIIP for the first time. The 30-day and hospital mortality were 8.7% and 17.5%, respectively. A multivariate analysis showed that the JAAM-DIC score on admission was an independent predictor of 30-day mortality (odds ratio [OR] 2.57, 95% confidential interval [CI] 1.50-4.40, P = 0.0006). The APACHE II score (OR 1.29, 95% CI 1.01-1.63, P = 0.03) and the JAAM-DIC score (OR 3.47, 95% CI 1.73-6.94, P = 0.0004) were independent predictors of hospital mortality. CONCLUSIONS: The JAAM-DIC scoring system can predict survival in patients with AE-fIIP. The role of DIC in the pathogenesis of AE-fIIP merits further investigation.

<p>閉塞性細気管支炎（以下；BO）は，気管支領域を主病変とする慢性のびまん性肺疾患である．移植医療の進歩とともに疾患数が増加傾向である．しかし，BO患者に対する呼吸リハビリテ―ション（以下；呼吸リハ）のエビデンスは確立されていない．今回，BO患者に対する12週間の外来呼吸リハを施行し，運動療法中心の介入にて6分間歩行試験の歩行距離，等尺性膝伸展筋力，身体活動量が改善した1例を経験した．移植片対宿主病に伴うBO患者では，長期的なステロイド内服にて筋力低下が生じやすく，運動療法の重要性が高いと考える．今後は症例数を増やしてBOに対する呼吸リハのエビデンスを確立していく事が必要と考える．</p>

BACKGROUND: We obtain summary estimates of the accuracy of additional objective tests for the diagnosis of adult asthma using systematic review and meta-analysis of diagnostic test accuracy studies. METHODS: Medline, Embase, and other relevant electronic databases were searched for papers published between January 1989 and December 2016. Studies were included if they evaluated the diagnostic accuracy of objective tests, including airway reversibility (AR), airway hyperresponsiveness (AHR), and fractionated exhaled nitric oxide (FeNO) for the diagnosis of adult asthma in patients with symptoms suggestive of asthma. If papers were assessed appropriate using the adapted QUADAS-2 tool, meta-analysis was conducted using the hierarchical bivariate model. This hierarchical model accounts for both within and between study variability. RESULTS: Sixteen studies reported the performance of the evaluated objective tests at presentation. For diagnosis of adult asthma, overall sensitivity and specificity for AR were 0.39 (95% confidence interval [CI] 0.18 to 0.66) and 0.95 (95% CI 0.86 to 1.00); for AHR, 0.86 (95% CI 0.61 to 1.00) and 0.95 (95% CI 0.77 to 1.00); for FeNO, 0.65 (95% CI 0.53 to 0.77) and 0.83 (95% CI 0.75 to 0.90). Comprehensive comparison of three diagnostic tools for adult asthma using the back-calculated likelihood rate (LR) showed that AR and AHR corresponded to a higher LR+, and AHR gave a lower LR-. CONCLUSIONS: In the current situation of no gold standard for diagnosis of adult asthma, AR and AHR are appropriate for ruling-in the true diagnosis, and AHR is superior for ruling-out a diagnosis. Since each objective test had a specific characteristic, it should be chosen depending on the situation, such as the capacity of the institution and the conditions of patients.

BACKGROUND: Few studies have reported the diagnostic variability in patients with a possible usual interstitial pneumonia (UIP) pattern on high-resolution CT (HRCT) who underwent surgical lung biopsy (SLB), and the prognostic factors for these patients have not been fully evaluated. We retrospectively investigated the frequency of idiopathic pulmonary fibrosis (IPF) and prognostic factors in patients with possible UIP pattern on HRCT. METHODS: Consecutive patients who had a possible UIP pattern on HRCT, underwent SLB, and had a diagnosis of IIPs before SLB were retrospectively recruited from 10 hospitals. Diagnoses were made based on multidisciplinary discussion using the criteria for current IPF guidelines and multidisciplinary classification for IIPs in each hospital. RESULTS: 179 patients who underwent SLB were enrolled. The diagnoses were IPF in 91 patients (51%), unclassifiable IIPs in 47 (26%), idiopathic NSIP in 18 (10%), and chronic hypersensitivity pneumonia in 17 (9%). One-year FVC changes showed significant differences between IPF and non-IPF (-138.6 mL versus 18.2 mL, p = 0.014). Patients with IPF had a worse mortality than those with non-IPF (Logrank test, p = 0.025). Multivariable Cox regression analysis demonstrated that diagnoses of IPF (HR, 2.961; 95% CI, 1.183-7.410; p = 0.02), high modified MRC score (HR, 1.587; 95% CI, 1.003-2.510; p = 0.049), and low %FVC (HR, 0.972; 95% CI, 0.953-0.992; p = 0.005). CONCLUSIONS: About a half of patients with a possible UIP pattern on HRCT had diagnoses other than IPF, and patients with IPF had a worse mortality than those with an alternative diagnosis. We reaffirmed that multidisciplinary discussion is crucial in patients with possible UIP pattern on HRCT.

A 52-year-old woman was referred to our hospital presenting with epigastric pain and weight loss. A contrast- enhanced abdominal computed tomography (CT) scan showed a low-density mass in the body of the pancreas, indicative of a malignancy. Endoscopic ultrasound-guided fine needle aspiration of the pancreatic mass was performed three times and showed no specific findings. A distal pancreatectomy was performed, and a pathological examination revealed epitheli- oid cell granulomas and necrosis. Ziehl-Neelsen staining did not reveal acid-fast bacilli in the pancreatic mass. A diagnosis of tuberculosis or sarcoidosis of the pancreas was con- sidered; however, the patient chose to undergo a follow-up examination without therapeutic intervention because the pancreatic mass had been removed completely and she had recovered well. Four months after the operation, the patient was readmitted to our hospital for insulin therapy for pancreatic diabetes. She presented with a fever and a productive cough, and a chest CT scan showed multiple nodules in both upper lobes. A bronchoscopy was performed and bronchoalveolar lavage fluid cultures for Mycobacterium tuberculosis were positive. The patient received antitubercular quadri-therapy and showed symptomatic and radiologic improvement. At the initial examination, we had been unable to establish the correct diagnosis; however, the detection of pulmonary lesions led to the time-delayed diagnosis of pancreatic tuber- culosis. Owing to its rarity, it is difficult to diagnose pancreatic tuberculosis using clinical symptoms and radiological imaging modalities; thus, pathologic and bacteriologic confirmation is essential. To avoid performing an unnecessary laparotomy in patients with pancreatic tuberculosis, increased vigilance and an accurate diagnostic approach are required.

【背景と目的】慢性呼吸器疾患患者の日常生活訓練を実施する際，指導を正しく理解できないことや，自身の動作に固執することをしばしば経験する．慢性閉塞性肺疾患（以下COPD）患者で前頭葉機能が低下していると報告はあるが，間質性肺炎（以下IP）患者の報告はない．そこで，IP患者を対象に前頭葉機能を検討し，COPD患者やコントロール患者と比較した．【対象と方法】当院で入院や外来通院しているIP患者20名，COPD患者48名，コントロール患者12名を対象とした．前頭葉機能検査はFrontal Assessment Battery（以下FAB）を用いて検討した．【結果】FAB合計点数はコントロール群（16.8±1.3点）と比較して，IP群（14.2±1.7点），COPD群（14.5±1.7点）ともに低値であった．FAB項目のなかでは，類似性，語の流暢性課題がIP群，COPD群ともに低値で，GO/NO-GO課題はCOPD群で低値であった．【結語】COPD患者と同様に，IP患者の前頭葉機能は低下していた．項目別でも，IP患者とCOPD患者の低下パターンは類似していた．

[Abstract] OBJECTIVE : Spirometry is used to investigate airflow limitation in patients with asthma ; however, this method is burdensome for elderlysubjects. An impulse oscillation system (IOS) allows examinations to be performed quickly and with little burden and can be used to evaluate the resistance of total airway (R5), large airway (R20), small airway (R5-R20), reactance (X5), and resonant frequency of reactance (Fres). The airway resistance of elderly and non-elderly patients with asthma was compared using IOS. METHODS : IOS was performed for 51 elderly (65 years old or older) and 58 non-elderly (below 65 years old) patients with asthma. RESULTS : R5, R5-R20, and Fres were significantly higher in the elderly group. X5 was significantly lower in the elderly group. CONCLUSION : These results suggest that IOS can be used to reveal small airway lesions in elderly patients with asthma and is useful as a method of evaluating airway lesions in patients with asthma.

64歳女。6歳時に頸椎・胸椎カリエスのため手術を施行した。徐々に進行する労作時呼吸困難が出現し、精査目的で入院となった。5日間の入院で非侵襲的陽圧人工呼吸器(NPPV)が導入され、退院後外来で呼吸リハビリテーションが開始となった。外来通院で実施した呼吸リハビリテーションプログラムは、週2回、休憩も含め1回約90分実施した。退院後NPPVと同時に労作時は在宅酸素療法(HOT)を導入していたが、介入後2ヵ月でHOTの離脱が可能であった。週2回の外来呼吸リハビリテーションと夜間睡眠時のNPPV導入により呼吸機能や運動耐容能、夜間睡眠時のSpO2が改善し、さらに、労作時の酸素療法を中止できた。運動前に実施した全身調整訓練の目的は、胸郭コンプライアンスの改善や呼吸補助筋のリラクセーションを行うことで効率の良い呼吸を獲得することとした。呼吸機能や夜間のSpO2の改善を認めた。

安静時PaO2 70 Torr以上を呈し運動時SpO2低下をきたす未治療の臨床的特発性肺線維症患者8例を対象に経鼻カヌラ4 L/分酸素投与の6分間歩行試験における効果を検討した．患者背景は年齢74.0±8.8歳，男性7例，％FVC 77.1±17.6％，％DLco 72.7±19.6％，安静室内気PaO2 88.4±12.5 Torrなどであった．6分間歩行距離は401.1±100.6 mから438.4±90.4 mへ有意に延長し（P＜0.01），延長量は37.3±22.6 m（最小11.0 m，最大75.0 m）であった．最大心拍数や最大呼吸困難感，最大下肢疲労感に有意な改善を認めなかったが，最低SpO2，最大呼吸数は有意に改善した．6分間歩行距離延長量と患者背景因子や最大心拍数，最低SpO2，最大呼吸数，最大呼吸困難感，最大下肢疲労感それぞれの変化量，そしてベースラインの6分間歩行距離との間にはいずれも有意な相関を認めなかった．特発性肺線維症患者における運動時酸素投与によって運動耐容能改善効果が得られる可能性が示唆されたが，その効果が得られる患者背景因子や機序は明らかにならなかった．

We retrospectively reviewed 9 consecutive cases of primary pulmonary cryptococcosis having no comorbidity. At diagnosis, seven had no subjective symptoms and two had subtle symptom. Chest CT scan showed nodular shadows in 8, while 3 cases had infiltrative shadows. Eight of the nine were diagnosed with histopathology obtained by transbronchial lung biopsy or CT-guided needle aspiration biopsy. We also assessed PHA and Con A lymphocyte stimulation tests to measure cellular immune function in 6, four of whom showed decreased reaction of lymphocytes. We successfully treated seven of the nine with fluconazole alone and used fluconazole as a maintenance regimen in two. No relapse or treatment failure was seen after completion of antifungal treatment. Six cases were seropositive for serum cryptococcus antigen titer at diagnosis and only one showed seroconversion. We concluded that the duration of therapy for primary pulmonary cryptococcosis should not be necessarily determined by serum cryptococcus antigen seroconversion.

The purpose of this study was to evaluate the effect of gefitinib on quality of life (QOL) in patients with advanced non-small cell lung cancer in general practice. In order to do this, we retrospectively reviewed data of all patients who received a single course of treatment with gefitinib at Tosei General Hospital from July 2002 until May 2004, and evaluated their QOL based on The European Organization for Research and Treatment of Cancer's QLQ-C30 before and 4 weeks after initiation of treatment. Data for 45 patients were analyzed. Many QOL scores improved in patients who responded to treatment, though such improvement was not statistically significant. In addition many QOL scores improved in patients in whom the disease was stable, and many deteriorated in patients in whom it was progressing, though such changes were not statistically significant. In conclusion, a good response to gefitinib treatment can improve QOL in patients with advanced non-small cell lung cancer even if they have experienced a relapse or the disease has been refractory with 1 st or 2 nd line treatment. Pharmacists should take these findings into consideration when providing pharmaceutical advice to patients.

The purposes of this study were: (1) to examine the short-term (10 weeks) and the long-term (1 year) effects of exercise training at high work rate on exercise tolerance in patients with chronic obstructive pulmonary disease, and (2) to detect the baseline physical conditions of patients who had shown decrease in exercise tolerance during the maintenance period. Fifty-seven patients underwent the exercise training, and were evaluated at baseline and 10 weeks and 1 year after the training. A significant improvement in 6-min walk distance was observed at 10 weeks and 1 year compared to the baseline. However, 6-min walk distance at 10 weeks was less than that at 1 year. Compare with patients who had not shown a decrease in 6-min walk distance, patients who had indicated the decrease (less than 54m) exhibited poorer pulmonary functions, less 6-min walk distance, and poorer ADL and Health Related QOL at baseline in the former group. Furthermore, there was a significant correlation between changes in 6-min walk distance and those in ADL score. The results suggest that poorer baseline physical condition may be an indicator of a decrease in 6-min walk distance during the maintenance period, although exercise training at high work rate improves 6-min walk distance. Moreover, a change in 6-min walk distance was significantly associated with a change in ADL score, which suggests that exercise training at the early stage can lead to long-term maintenance in improved in exercise tolerance.

The purpose of this study was to determine whether supplemental oxygen can improve exercise capacity in chronic obstructive pulmonary disease (COPD) patients without exercise-induced hypoxemia. Ten stable COPD patients with resting PaO_2 more than 55 mmHg and exercise O_2 saturation not less than 88% were included in the study. The patients underwent constant load exercise tests without oxygen and receiving oxygen (4 L/min) in different days. Endurance time, breathlessness, leg fatigue, and the maximum heart rate were evaluated. As results, no improvements in all these variables were observed when oxygen was given. We conclude that supplemental oxygen does not improve exercise capacity in nonhypoxemic COPD patients.

To evaluate irreversible airflow limitation in asthmatics, we studied 168 patients admitted to our hospital with acute exacerbation of asthma. All patients were given intravenous methylprednisolone for at least 7 days to maximum 14 days and the best of PEF(% of predicted)was evaluated. In all subjects, the best of PEF showed significant correlations with both the patients'age(r=-0.411, p<0.0001)and the duration of asthma(r=-0.494, p<0.0001). A significant correlations between the best of PEF and the duration of asthma were also observed in both patients over 60 years old(r=-0.157, p<0.0001)and non-smokers(r=-0.568, p<0.0001). We conclude that asthma may develop irreversible airflow limitation in itself and the degree of impairment of lung function correlated with the duration of the disease.

We reviewed the records of 823 patients who underwent fiberoptic bronchoscopy to determine the various causes of hemoptysis. Chest roentgenograms were normal in 559 patients (67.9%) and abnormal in 264 (32.1%). Specific diagnosis could be identified in 100 patients (17.9%) with normal chest roentgenograms and 196 patients (74.2%) with any abnormal findings on chest roentgenograms. Bacterial infection (54 patients, 9.7%), bronchiectasis (10 patients, 1.8%), and pulmonary vascular abnormalities (10 patients, 1.8%) accounted for the majority of hemoptysis of patients with normal chest roentgenograms. Malignant neoplasms were diagnosed in 5 patients (0.9%). In contrast, bronchogenic carcinoma (66 patients, 15.9%), mycobacterial infection (32 patients, 14.0%), old tuberculosis (33 patients, 12.5%), bacterial infection (32 patients, 12.1%), and bronchiectasis (19 patients, 7.2%) accounted for the majority of causes of hemoptysis of patients with any abnormal findings on chest roentgenograms. Malignant neoplasms were diagnosed in 50 patients (18.9%). All 5 patients with malignant neoplasms and normal chest roentgenograms were over 55 years old. But malignant neoplasms were diagnosed in even young patients under 40 years old with any abnormal findings on chest roentgenograms. We conclude that following patients with hemoptysis shoud be examined using fiberoptic bronchoscopy to rule out malignancy ; (1) all patients with abnormal findings on chest roentgenograms and (2) patients with higher age even without abnormal findings on chest roentgenograms.

【目的】
呼吸リハビリテーションを継続しているCOPD患者を対象に運動耐容能，呼吸困難，健康関連QOLなどの各指標の経年的変化を検討する．
【対象】
呼吸リハビリテーションプログラムを施行し2年以上の観察期間があるCOPD患者で本研究参加の同意を得た48例，年齢69.3±7.0歳，FEV1(pred) 43.0±14.8％である．
【方法】
呼吸リハビリテーションは週2回・10週間の集中的なプログラムにて行い，以降は週1回の頻度で継続した．プログラムの内容は下肢トレーニング，上下肢筋力トレーニング，Threshold による吸気筋トレーニングからなる運動療法を主軸とした．評価は6MWD，6MWD時最低SpO₂，呼吸困難 (BDI)，健康関連QOL(SGRQ;西村浩一訳)，呼吸筋力 (PImax)，肺機能検査はFEV1(pred)とした．10週間前後と前より1年後および2年後で評価を行い，経年的変化は多変量分散分析にて検討した．
【結果】
6MWDは前後(447.6±100.9m→488.2±91.1m)で有意に改善し，1年後（472.7±106.3m）も維持されていた．2年後（459.5±111.5m）は前値に復する傾向にあった．6MWD時最低SpO₂は前後（86.1±6.8→84.4±7.7％），1年後（82.3±8.2％），2年後（83.0±8.3％）で有意に悪化した．BDIは前後（6.9±1.6→7.8±1.5）で有意に改善し，1年後（7.5±1.5）も維持されていたが，2年後（6.8±1.6）は前値に復する傾向にあった．SGRQは前後（46.0±14.9→43.0±14.6）で有意に改善したが，1年後（47.5±16.1），2年後（48.0±16.3）には悪化する傾向にあった．PImaxは前後（62.4±28.1→74.7±27.8cmH₂O），1年後（79.7±27.7cmH₂O），2年後（83.0±29.0cmH₂O）も有意に改善していた．FEV1(pred)は1年後（42.5±14.5％），2年後（42.6±16.3％）と悪化する傾向にあるが有意差はなかった．
【考察】
運動耐容能や呼吸困難の改善は1年後も維持されており，PImaxにおいては2年後も有意に改善していた．また運動耐容能や呼吸困難は2年後には前値に復する傾向にあり，6MWD時最低SpO₂は経年的に有意に悪化していた．運動療法の継続により，1年後までは改善が維持できているものの，2年後には前値に復する傾向にあった．COPDは慢性疾患であり，長期的に運動耐容能や呼吸困難，健康関連QOLを維持していくには，再プログラムの実施を検討し，かつ酸素療法や薬物療法なども考慮にいれ包括的に管理していく必要があると考えられた．

目的.paclitaxel (TXL)とdocetaxel (TXT)は同じtaxn系化合物であるが,完全な交差耐性を示さない薬剤であることが,基礎研究,臨床研究において報告されている.また,2nd lineのdocetaxel治療で約10%の奏効率が報告され,生存延長も期待されている.TXLの投与方法については3週間毎投与が標準治療とされているが,海外の報告ではweekly投与の場合,奏効率が単剤で30〜50%と優れ,また,3週間毎投与に比較し,骨髄毒性,脱毛,末梢神経障害,粘膜炎等の副作用が少ないとされている.今回は進行非小細胞肺癌症例に対するTXT+Carboplatin (CBDCA)併用化学療法の無効・再発症例に対し,Weekly TXL投与法の有効性と安全性について検討した.目的.Primary endpointは奏効率,有害事象発現率とし,secondary endpointはQOL・Survivalとした.方法.進行非小細胞肺癌症例に対するTXT+CBDCA併用化学療法(RTも含む)の無効・再発症例に対し,TXL80mg/m^2の毎週投与6コース終了後,2週間休薬しこれを1クールとした.結果.36症例が登録され,男女比は22/14,ECOG performance statusは0が19例,1が13例,2が4例,組織型は腺癌29例,扁平上皮癌6例,腺扁平上皮癌1例,IIIB8例IV28例.PR/SD/PD/NE : 5/20/9/2例で奏効率13.8%であった.G3 (MCI-CTC)以上の副作用は好中球減少が36%,血小板減少は0%,過敏反応(G2)を1例に認めた.QLQ C-30による健康関連QOLは痛みと食欲不振の項目が改善した.結論.TXLはTXTと同じタキサン系化合物であるが,TXT無効・再発症例にもTXLの毎週投与は有効であることが示唆された.

令和5年度は、喘息例での胸部CT所見（気管支拡張・細気管支炎像の有無，進展度）等と遺伝子多型との関係を中心に解析した。候補遺伝子としてびまん性汎細気管支炎や非若齢発症喘息のリスク遺伝子であり、分泌型ムチンをコードするHCG22遺伝子の一塩基多型（SNP）rs2523870に着目した。喘息106例において、rs2523870のgenotypeはTT 37名、CT 45名、CC 24名であった。リスクアレルのホモ接合体であるCC型と他との２群比較で、喘息発症年齢、呼吸機能、mReiff score(気管支拡張像の進展度)との関係はなかったが、CC型で好酸球性副鼻腔炎併存率、過去の血液好酸球数、過去の吸入ステロイド量、過去及び直近の胸部CTで細気管支炎罹患葉数が有意に多かった。IL4RA rs8832、IL13 rs20541についても解析を行ったが、mReiff scoreや細気管支炎の罹患葉数との関連は認めなかった。本研究でCC型での細気管支病変が、好酸球性か否かは確認できなかったが、好酸球性副鼻腔炎の併存率から推察すると一定の割合で好酸球性細気管支炎も存在すると考えられる。喘息の細気管支病変例で、好中球性気道炎症を呈するびまん性汎細気管支炎と同様のリスク多型が確認されたことは、分泌型ムチンの異常、気道クリアランスの障害が、炎症型を問わず細気管支病変の形成に寄与する可能性が推察される（J Allergy Clin Immunol 2023 Epub ahead of print）。