BACKGROUND:Acute exacerbation (AE) is defined as acute deterioration in the respiratory status that can lead to a fatal outcome. It may occur in various types of interstitial lung disease (ILD). However, its incidence and clinical picture in patients with primary Sjögren's syndrome-associated interstitial lung disease (pSjS-ILD) remain unclear. Therefore, this study aimed to examine the incidence and clinical significance of AE in patients with pSjS-ILD. METHODS:This study included 101 consecutive patients with pSjS-ILD. The clinical findings at diagnosis, AE development, and outcome were analyzed. Furthermore, the prognostic significance of AE was evaluated via Cox proportional-hazards analysis with time-dependent covariates. The Fine-Gray subdistribution hazard model was employed to identify factors associated with AE development. RESULTS:Of the 101 patients, 17 (17 %) developed AE during their clinical course. The cumulative incidence rates of AE were 2.0 %, 11.2 %, and 18.1 % at 1, 5, and 10 years, respectively. Multivariate analysis revealed that AE development was significantly associated with poor prognosis (hazard ratio: 3.69; P = 0.01) as well as age, male sex, and %FVC. Moreover, the serum levels of surfactant protein-D at diagnosis were significantly associated with AE development. Of the 17 patients demonstrating AE, 8 died, with a 60-day post-AE mortality rate of 47 %. The age and serum C-reactive protein level at AE onset were significantly associated with 60-day mortality in patients with AE of pSjS-ILD. CONCLUSION:AE occurs with a certain frequency and is strongly associated with poor outcome in patients with pSjS-ILD.

A 79-year-old woman with severe asthma developed chronic eosinophilic pneumonia (CEP). After CEP resolved with oral prednisolone at 30 mg/day, prednisolone was tapered and discontinued under introduction of benralizumab for her severe asthma. However, 8 weeks later, symptoms and bilateral patchy infiltrates on chest radiography appeared. Lymphocytosis without eosinophilia was seen in bronchoalveolar lavage fluids, and transbronchial biopsy indicated organizing pneumonia. Cryptogenic organizing pneumonia (COP) was diagnosed and resolved with prednisolone at 30 mg/day. Prednisolone was tapered to 3 mg/day without relapse of CEP or COP. This case suggests the overlap and similar pathogenesis of CEP and COP.

症例は79歳女性，検診で胸部異常陰影を指摘され来院した．発熱，腹部膨満感も認めていた．腹部CTで虫垂の腫脹，周囲脂肪織濃度の上昇とリンパ節腫大を認めた．急性虫垂炎を疑い，抗菌薬の点滴投与で症状は軽快したが，約1カ月後のCTでは虫垂の壁肥厚が増強し，虫垂腫瘍疑いで腹腔鏡下手術を施行した．腹腔内は腹腔腸管漿膜全面にわたり1 mm程度の粟粒性の播種性病変で覆い尽くされていた．虫垂には炎症性の変化や腫瘍を疑う所見は認めなかった．腹膜の播種性病変の生検にて非乾酪性の類上皮肉芽腫を認め，腹膜サルコイドーシスと診断した．約半年後に出現した両下腿の皮下結節から類上皮多核巨細胞を認め，皮膚サルコイドーシスの合併も認めた．約1年後に急性虫垂炎で施行した腹腔鏡下手術では，腹腔内の粟粒性の播種性病変は肉眼的に消失しており，腹膜サルコイドーシスの腹腔内所見は自然軽快していた．腹腔内所見の肉眼的改善を観察し得た腹膜サルコイドーシスは稀であり報告する．

BackgroundMucociliary clearance (MCC) is an essential defense mechanism in airway epithelia for removing pathogens from the respiratory tract. Impaired ciliary functions and MCC have been demonstrated in asthma and chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators, which are used for treating asthma and COPD; however, the effects of LAMAs on ciliary function remain unclear. This study aimed to identify the effects of LAMAs on airway ciliary functions.MethodsWild-type BALB/c mice were treated with daily intranasal administrations of glycopyrronium for 7 days, and tracheal samples were collected. Cilia-driven flow and ciliary activity, including ciliary beat frequency (CBF), ciliary beating amplitude, effective stroke velocity, recovery stroke velocity and the ratio of effective stroke velocity to recovery stroke velocity, were analyzed by imaging techniques. Using in vitro murine models, tracheal tissues were transiently cultured in media with/without LAMAs, glycopyrronium or tiotropium, for 60 min. Cilia-driven flow and ciliary activity were then analyzed. Well-differentiated normal human bronchial epithelial (NHBE) cells were treated with glycopyrronium, tiotropium, or vehicle for 60 min, and CBF was evaluated. Several mechanistic analyses were performed.ResultsIntranasal glycopyrronium administration for 7 days significantly increased cilia-driven flow and ciliary activity in murine airway epithelium. In the murine tracheal organ culture models, treatment with glycopyrronium or tiotropium for 60 min significantly increased cilia-driven flow and ciliary activity in airway epithelium. Further, we confirmed that 60-min treatment with glycopyrronium or tiotropium directly increased CBF in well-differentiated NHBE cells. In the mechanistic analyses, neither treatment with glycopyrronium nor tiotropium affected intracellular calcium ion concentrations in well-differentiated NHBE cells. Glycopyrronium did not increase protein kinase A activity in well-differentiated NHBE cells. Moreover, glycopyrronium had no effect on extracellular adenosine triphosphate concentration.ConclusionsLAMAs exert a direct effect on airway epithelium to enhance ciliary function, which may improve impaired MCC in asthma and COPD. Further investigations are warranted to elucidate the underlying mechanisms of the effects of LAMAs on the promotion of airway ciliary function.

Introduction: Although recent advances in chemotherapy for lung cancer are remarkable, most clinical trials have excluded patients with interstitial lung disease (ILD) due to the concern of developing acute exacerbation (AE) of ILD. Hence, accumulating original evidence of cancer treatment for this population is important. Methods: Between 2016 and 2020, a prospective observational study was conducted across 11 Japanese hospitals. Patients with chemotherapy- naïve, inoperable, advanced lung cancer with ILD were included. The primary outcome was the frequency of AE-ILD after registration; the secondary outcomes were the risk factor of AE-ILD and the efficacy of chemotherapy. Results: Among 124 patients enrolled, 109 patients who received chemotherapy were analyzed. The median age was 72 years, and the majority showed usual interstitial pneumonia (UIP)/probable UIP pattern upon chest computed tomography. The median percent-predicted forced vital capacity (%FVC) was 81% (interquartile range: 66–95%). After registration, 23 patients (21.1%; 95% confidence interval [CI]: 14.4–29.7%) developed AE-ILD. The logistic analysis revealed that lower %FVC slightly but significantly increased the risk of AE-ILD (odds ratio per 10% decrease: 1.27; 95% CI: > 1.00–1.62). Overall response rates/median overall survival times in non-small-cell lung cancer and small-cell lung cancer for the first-line chemotherapy were 41% (95% CI: 31–53)/8.9 months (95% CI: 7.6–11.8) and 91% (95% CI: 76–98)/12.2 months (95% CI: 9.2–14.5), respectively. Conclusion: AE-ILD during chemotherapy is a frequent complication among patients with lung cancer with ILD, particularly those with lower %FVC. Conversely, even in this population, passable treatment response can be expected.

ABSTRACTBackground and objectiveThe efficacy of combination therapy with corticosteroids and CNI, TAC and CsA, for PM/DM‐ILD has been described retrospectively. However, it remains unknown which CNI treatment regimens, TAC or CsA regimens, are more effective as initial treatments for patients with PM/DM‐ILD.MethodsWe conducted a prospective multicentre, open‐label, randomized, 52‐week phase 2 trial. Patients with PM/DM‐ILD were randomly allocated to receive PSL plus TAC (TAC group) or PSL plus CsA (CsA group). The primary endpoint was PFS rate in the intention‐to‐treat population at 52 weeks. The secondary endpoints were OS rate at 52 weeks, changes in pulmonary function tests from baseline to 52 weeks and AE.ResultsFifty‐eight patients were randomly assigned to the TAC group (n = 30) and the CsA group (n = 28). The PFS rates at 52 weeks were 87% in the TAC group and 71% in the CsA group (P = 0.16). The OS rates at 52 weeks were 97% in the TAC group and 93% in the CsA group (P = 0.50). The %FVC at 52 weeks in the per‐protocol populations significantly increased in both groups. None of the patients discontinued the treatment due to AE.ConclusionPSL plus TAC treatment may achieve a better short‐term PFS rate compared with PSL plus CsA treatment. Further studies must be conducted to evaluate the long‐term efficacy and safety of such treatment.

BACKGROUND:Viral respiratory tract infections, such as influenza A virus (IAV), are common and life-threatening illnesses worldwide. The mechanisms by which viruses are removed from the respiratory tract are indispensable for airway host defense. Mucociliary clearance is an airway defense mechanism that removes pathogens from the respiratory tract. The coordination and modulation of the ciliary beating of airway epithelial cells play key roles in maintaining effective mucociliary clearance. However, the impact of respiratory virus infection on ciliary activity and mucociliary clearance remains unclear.METHODS:Tracheal samples were taken from wild-type (WT) and Toll-like receptor 3 (TLR3)-knockout (KO) mice. Transient organ culture of murine trachea was performed in the presence or absence of IAV, polyI:C, a synthetic TLR3 ligand, and/or reagents. Subsequently, cilia-driven flow and ciliary motility were analyzed. To evaluate cilia-driven flow, red fluorescent beads were loaded into culture media and movements of the beads onto the tracheal surface were observed using a fluorescence microscope. To evaluate ciliary motility, cilia tips were labeled with Indian ink diluted with culture medium. The motility of ink-labeled cilia tips was recorded by high-speed cameras.RESULTS:Short-term IAV infection significantly increased cilia-driven flow and ciliary beat frequency (CBF) compared with the control level in WT culture. Whereas IAV infection did not elicit any increases of cilia-driven flow and CBF in TLR3-KO culture, indicating that TLR3 was essential to elicit an increase of cilia-driven flow and CBF in response to IAV infection. TLR3 activation by polyI:C readily induced adenosine triphosphate (ATP) release from the trachea and increases of cilia-driven flow and CBF in WT culture, but not in TLR3-KO culture. Moreover, blockade of purinergic P2 receptors (P2Rs) signaling using P2R antagonist, suramin, suppressed polyI:C-mediated increases of cilia-driven flow and CBF, indicating that TLR3-mediated ciliary activation depended on released extracellular ATP and the autocrine ATP-P2R loop.CONCLUSIONS:IAV infection readily increases ciliary activity and cilia-driven flow via TLR3 activation in the airway epithelium, thereby hastening mucociliary clearance and "sweeping" viruses from the airway as an initial host defense response. Mechanically, extracellular ATP release in response to TLR3 activation promotes ciliary activity through autocrine ATP-P2R loop.

Objective: Interstitial lung disease (ILD) is a condition characterized by a higher mortality rate in primary Sjogren's syndrome (pSS). However, factors influencing the outcome of patients with pSS-associated ILD remain unclear. The aim of the present study was to evaluate predictive factors associated with a worse prognosis in pSS-ILD. Methods: This retrospective study included 99 consecutive patients with pSS-ILD. Clinical characteristics, laboratory findings, and pulmonary function tests at the time of diagnosis were analyzed. Chest HRCT images were reviewed by two experienced chest radiologists. Prognostic factors were assessed by univariate and multivariate analyses, using Cox proportional hazards regression model. Results: Median age was 68 years (73% women). In the total patient population, the 5- and 10-year survival rates were 89.8% and 79.0%, respectively. Univariate analysis revealed a significant association between prognosis and age, serum Krebs von den Lungen-6 (KL-6) levels, and %FVC. None of the chest HRCT findings were related to patient outcomes. Based on multivariate analyses adjusted by age and gender, lower levels of %FVC and higher levels of KL-6 were significantly associated with poor outcomes. Using optimal cutoff levels, according to receiver operating characteristic curve analyses, KL-6 > 800 U/mL were significantly associated with worse prognosis (HR: 2.91, 95% CI: 1.04-8.10). Patients with elevated serum KL-6 levels (>800 U/mL) showed a higher mortality rate than those without elevated serum KL-6 levels (p = 0.02). Conclusions: Lower %FVC and higher serum KL-6 levels are predictive factors for poor outcome in patients with pSS-ILD.

An 85-year-old, never-smoking man presented with exertional dyspnea. He had been exposed to silica dust in the work place. Chest computed tomography revealed bronchial wall thickening without emphysema. A pulmonary function test showed airflow obstruction without impaired gas transfer. Airway hyperresponsiveness and reversibility were not evident. A transbronchial lung biopsy showed findings suggestive of mineral dust exposure, such as fibrosis and slight pigmentation of bronchioles. He was diagnosed with non-smoking chronic obstructive pulmonary disease (COPD) due to occupational exposure to silica dust. His symptoms were improved using an inhaled long-acting bronchodilator. The clinical characteristics of non-smoking COPD are discussed in this report.

An 83-year-old man, who was a former smoker, with anti-ribonucleoprotein (RNP) antibody-positive combined pulmonary fibrosis and emphysema presented with a cough and dyspnea. A chest radiograph showed bilateral pleural effusions. His laboratory data showed proteinuria and elevated levels of anti-nuclear antibodies, anti-double strand DNA antibodies, and CA125, with decreased serum complement levels. Thoracentesis showed an exudative pleural effusion with an increased lymphocyte count and elevated CA125 levels. A thoracoscopic biopsy specimen showed proliferation of CA125-positive mesothelial cells. Systemic lupus erythematosus was diagnosed. His symptoms and pleural effusion resolved after the initiation of systemic corticosteroid therapy. The detection of anti-RNP antibody and CA125 levels are helpful in the diagnosis of lupus pleuritis.

Rationale: Pulmonary diseases due to non-tuberculous mycobacteria(pNTM) has been increasing in Japan. The diagnosis of Mycobacterium avium-complex pulmonary disease (MAC-PD) is complicated. Objectives: Our aim of this study was to evaluate a serodiagnosis of MAC-PD using anti-glycopeptidolipid(GPL) core antigen IgA antibody. Methods and Results: Between April 2012 and December 2012, the levels of serum anti-glycopeptidolipid(GPL) core antigen IgA antibody were measured in 69 patients in our hospital: 53 patients with MAC-PD, 4 with non-MAC pNTM (M.kansasii, M.Scrofulaceum, M.goldonae, M.abscessus), 7 with pulmonary tuberculosis, and 5 with lung cancer. The MAC-PD group included infections with M. avium (n =28), and M. intracellulare (n = 25). The patients of MAC-PD and non-MAC pNTM fulfilled the American Thoracic Society (ATS) criteria for the diagnosis of NTM infection. None of the patients was seropositive for HIV type1 or 2. The level of serum IgA antibody to GPL core antigen was quantified using the ELISA kit. Setting the cutoff point at 0.7 U/ml resulted in 71.7% sensitivity and 93.8% specificity of diagnosing MAC-PD. Of the 4 patients with Non-MAC pNTM group, only one patient with M.abscessus had positive result. All the patients of tuberculosis and lung cancer had negative results for anti-glycopeptidolipid core antigen IgA antibody. Conclusion: The ELISA kit of serum IgA antibody specific for GPL core antigen is useful for the rapid diagnosis of MAC-PD.

Vibrio vulnificus感染症の多くは肝機能障害を有する患者が罹患し,「時間」単位で進行し致死率が高い.症例は85歳,男性.多発性骨髄腫に対する外来化学療法中に腰痛~下腿部痛と嘔吐を主訴に来院.血圧低下を認め,緊急入院し敗血症性ショックの治療を開始した.第4病日に血液培養でVibrio vulnificusが同定された.この頃より右下腿に蜂巣炎・壊死性筋膜炎を認めるようになったが,治療の経過とともに病変は縮小し回復した.本症の危険因子として免疫不全状態が挙げられており,血液疾患患者への注意も必要である.