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Background Tobacco smoking causes a variety of smoking-related diseases, death, and economic damage. Despite targeted anti-smoking campaigns, tobacco-related deaths are expected to increase in Japan. We investigated the current state of non-cancerous lung diseases such as idiopathic interstitial pneumonias (IIPs), chronic obstructive pulmonary disease (COPD), and combined pulmonary fibrosis and emphysema (CPFE), which are known to be highly related to tobacco smoking. Methods This prospective multi-institutional observational study involved 29 major hospitals within the Fukuoka Prefecture area (Fukuoka tobacco-related lung disease registry study group). Patients diagnosed with IIPs, including CPFE and COPD, registered from September 1, 2013 to April 30, 2016 were included. Clinical background information, laboratory and pulmonary function test results, findings of imaging tests, including chest radiography and chest computed tomography, and DNA isolated from peripheral blood were collected from each patient. Follow-up surveillance involved collection of data regarding the exacerbation of disease and death until 5 years of registration. In the present study, we report the baseline characteristics of the patients registered in this surveillance study. Results Overall, 1016 patients (524 with IIPs, including 145 CPFE and 492 with COPD) were enrolled. Among the patients with COPD, 96.8% were current or former smokers. Among the patients with IIPs, 69.9% were current or former smokers. Conclusion This study revealed the current status of lung diseases potentially related to tobacco smoking in Fukuoka Prefecture. Both COPD and CPFE were highly related to tobacco smoking, whereas 30% of patients with IIPs had never smoked.

Background The relationship between the histological pattern and survival in systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unclear. In patients with SSc-ILD, we investigated whether the clinical data obtained by non-invasive examinations could be used for prognostic evaluation, and attempted to clarify whether complicating acute exacerbation (AE) and the selection of pharmacological therapy were associated with survival. Methods Thirty-five patients with SSc-ILD, who had not been diagnosed by surgical lung biopsy were analyzed, retrospectively. The HRCT findings were evaluated by 2 radiologists and classified into "CT-UIP" or "CT-inconsistent with UIP" patterns based on whole lung interpretations. HRCT scores were calculated based on the extent of abnormality evidenced by HRCT. The log-rank test was used to determine variables, including clinical parameters and histories. Results Twelve (34%) of the 35 patients died during a median follow-up period of approximately 7.9 years. The log-rank test showed that a higher mortality was associated with higher age, a CT-UIP pattern, a higher score for ground-glass attenuation with traction bronchiectasis on HRCT, and complicating AE, whereas a lower mortality was significantly associated with the use of immunosuppressants. A CT-UIP pattern was significantly associated with a higher incidence of later AE. Conclusion Treatment with immunosuppressants was associated with a longer survival, and complicating AE is a predictor of shortened survival in SSc-ILD patients. Among the clinical parameters determined by non-invasive examinations, a CT-UIP pattern and the extent of fibrotic lesions on HRCT, but not a histological pattern of UIP, may be predictors of shortened survival.

SummaryMyeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) is a well known marker for small vessel vasculitis. Recent reports have demonstrated that interstitial pneumonia (IP) may rarely be associated with serum MPO-ANCA. Yet, little is known about the histological features.We reviewed surgical lung biopsy from nine patients with IP of uncertain etiology with serum MPO-ANCA.There was a male predominance (6:3) with a median age of 62.1. Histologically, eight patients presented with a usual interstitial pneumonia (UIP) pattern of pulmonary fibrosis, frequently accompanied by areas of nonspecific interstitial pneumonia (NSIP) pattern. One patient showed diffuse alveolar damage (DAD), and two patients showed mixture of UIP and DAD reflecting acute exacerbation of UIP. Microscopic honeycomb cysts were common, but fibroblastic foci were inconspicuous. The most frequent additional findings were small airway disease (9/9), and lymphoid follicles (7/9). Neither capillaritis nor vasculitis was seen in any of our cases. Three patients had microscopic hematuria, but none progressed to microscopic polyangiitis during the follow up. Mortality rate was 44% (median follow up 39.1 months).IP associated with MPO-ANCA showed characteristic histology dominated by UIP pattern. Vasculitis was not identified in our cohort, but small airways disease and lymphoid follicles were present in most cases. IP associated with MPO-ANCA may be a histologically distinctive disease from idiopathic pulmonary fibrosis. Mortality was relatively high and life threatening acute exacerbation may occur.

Background We are occasionally presented with patients with unclassifiable interstitial pneumonia of unknown etiology. Idiopathic pulmonary upper lobe fibrosis (IPUF) does not fit any of the currently defined subsets of idiopathic interstitial pneumonias (IIPs). This study was performed to examine clinical, functional, and pathological characteristics of IPUF. Methods We present 9 cases of histologically confirmed IPUF. The clinical and histological characteristics of the 9 patients were evaluated. The baseline respiratory function of all patients was measured. There were 7 patients whose forced vital capacity (FVC) had been monitored for at least a year who were selected to quantify the yearly decline in FVC. Results All patients were slender, with a body mass index of 16.0–19.8kg/m 2 . Seven patients had a history of pneumothorax. Six patients died 1.8 to 5.7 years after the onset of the first symptoms. Fundamental histological features were intraalveolar collagen deposition and densely packed elastic fibers in the subpleural areas. These findings are the same as those seen in pleuroparenchymal fibroelastosis. However, the visceral pleura was thickened with dense collagen in only 2 patients, and pleural thickening was localized, if present, in the remaining 7 patients. Ventilatory impairment was also a characteristic. The time course decline of FVC was rapid and almost linear. The median yearly decline in FVC was −20.3% (range, −7.7% to −26.5%), which was more rapid than that reported for chronic fibrosing interstitial pneumonias such as idiopathic pulmonary fibrosis. Conclusions IPUF is a unique pulmonary fibrosis that results in rapid deterioration of ventilatory function and poor prognosis.

Idiopathic interstitial pneumonias (IIPs) are histopathologically classified into several types, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and cryptogenic organising pneumonia (COP). We investigated whether periostin, a matrix protein, could be used as a biomarker to assess histopathological types of IIPs. We performed immunohistochemical analyses in each histopathological type of IIP, examined serum levels of periostin in IIP patients and analysed the relationship between serum levels of periostin and the pulmonary functions in patients with idiopathic pulmonary fibrosis (IPF). Periostin was strongly expressed in lungs of UIP and fibrotic NSIP patients, whereas expression of periostin was weak in the lungs of cellular NSIP and COP patients, as well as in normal lungs. Serum levels of periostin in IPF were significantly higher than those of healthy subjects and COP patients. Furthermore, periostin levels in IPF patients were inversely correlated with their pulmonary functions. Thus, we have found that periostin is a novel component of fibrosis in IIP. Periostin may be a potential biomarker to distinguish IIP with fibrosis.

Background and objective: The usefulness of two tests in the serodiagnosis of chronic pulmonary aspergillosis (CPA) was compared. The tests were the serum Aspergillus galactomannan antigen test (Platelia (R) Aspergillus) by enzyme-linked immunoassay (EIA) using old and new cut-off indexes, and the Aspergillus precipitating antibody test. Methods: Both Aspergillus-precipitating antibody and Platelia Aspergillus EIA positivity were measured in the sera of 28 patients at the time of diagnosis of CPA. Results: Serum Aspergillus precipitating antibody positivity was 89.3% (25/28) in CPA patients. Serum Platelia Aspergillus EIA positivity was 21.4% (6/28) using the old cut-off index (≥1.5) and 50% (14/28) using the new cut-off index (≥0.5)—still less than that for Aspergillus precipitating antibody. Three of the 28 CPA patients had positive reactions in the Platelia Aspergillus EIA using the old cut-off index but not in the Aspergillus precipitating antibody test. Positivity for (1,3) β-d glucan was 15.4%, and that for culture on CHROMagar Candida was 17.9%. One patient with pulmonary actinomycosis had a false-positive reaction in the Platelia Aspergillus test with the new cut-off index. Conclusions: For the diagnosis of CPA, Aspergillus precipitating antibody testing is more sensitive than the Platelia Aspergillus EIA, even with the new cut-off index. False-positive reactions are observed with the Platelia Aspergillus EIA in patients with conditions such as pulmonary actinomycosis. Results should be interpreted with care when patients are positive for the Platelia Aspergillus EIA but negative for Aspergillus precipitating antibody.

Background The histological pattern of pleuroparenchymal fibroelastosis (PPFE) is well defined, but its clinical features remain unclear. Methods We retrospectively examined the predominantly involved lung-fields (based on abnormal opacities on computed tomography [CT] images), and the initial value and annual decline of respiratory function in patients with pulmonary fibrosis presenting with histologically confirmed PPFE. Results Thirteen female and nine male subjects were included. Eleven interpreters independently analyzed 231 CT image series. One-third of the CT series (78/231) was interpreted as demonstrating equal involvement of the upper and lower lung fields, i.e., six out of 21 patients had equal involvement of the upper and lower lung fields, based on a majority decision of the interpreters. The residual volume/total lung capacity (RV/TLC) was increased and correlated inversely with forced vital capacity (FVC) at the initial measurement. FVC followed two patterns of decline over time: a gradual decline over a follow-up period of more than 6 years (−55mL/year, R 2 =0.799), and a relatively rapid decline over a shorter period (−364mL/year, R 2 =0.855) as determined by mixed-effect linear regression. Conclusions The predominantly involved sites seen on CT images of PPFE were not limited to the upper lobes. In some cases, upper lung fields were predominantly involved, but in other cases, both upper and lower lung fields were equally involved. Two patterns of FVC decline exists: a rapid decline over a short period and a slow decline over a longer period, suggesting that the disease follows a heterogeneous clinical course.

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is a major interstitial lung disease (ILD). Recently, we established a new mouse model for ILD in which daily administration of interleukin (IL)-18 with IL-2 induces lethal lung injury, suggesting that IL-18 is involved in the pathogenesis of ILD. Here, utilizing immunohistochemistry, we have analyzed IL-18 and IL-18 receptor (IL-18R) alpha expression in the lungs of 18 patients with IPF/UIP and 13 control subjects by using monoclonal anti-IL-18 antibodies and a new monoclonal antibody for IL-18Ralpha (H44). IL-18 was expressed in bronchoalveolar epithelium, alveolar macrophages, and the endothelium of small vessels in control subjects, and was abundantly expressed in the majority of pulmonary cells in patients with IPF. IL-18Ralpha was expressed in bronchoalveolar epithelium and alveolar macrophages in control subjects, and was strongly expressed in interstitial cells in patients with IPF, especially in the fibroblastic foci (FF). Interestingly, IL-18Ralpha expression was only weakly observed in areas showing established fibrosis. Semiquantitative analysis revealed that the histologic FF score was significantly correlated with the IL-18Ralpha expression level in FF lesions. Moreover, IL-18 levels in the serum and bronchoalveolar lavage fluid of patients with IPF were significantly higher than those in control subjects. Our findings suggest IL-18 and IL-18R are involved in the pathogenesis of IPF/UIP.

Aims To investigate the histological evolution in the development of pleuroparenchymal fibroelastosis (PPFE). Methods and results We examined four patients who had undergone surgical lung biopsy twice, or who had undergone surgical lung biopsy and had been autopsied, and in whom the histological diagnosis of the first biopsy was not PPFE, but the diagnosis of the second biopsy or of the autopsy was PPFE. The histological patterns of the first biopsy were cellular and fibrotic interstitial pneumonia, cellular interstitial pneumonia (CIP) with organizing pneumonia, CIP with granulomas and acute lung injury in cases 1, 2, 3, and 4, respectively. Septal elastosis was already present in the non-specific interstitial pneumonia-like histology of case 1, but a few additional years were necessary to reach consolidated subpleural fibroelastosis. In case 3, subpleural fibroelastosis was already present in the first biopsy, but only to a small extent. Twelve years later, it was replaced by a long band of fibroelastosis. The septal inflammation and fibrosis and airspace organization observed in the first biopsies were replaced by less cellular subpleural fibroelastosis within 3–12 years. Conclusions Interstitial inflammation or acute lung injury may be an initial step in the development of PPFE.

Background The process of airway inflammation in the lungs of nonsmokers who die of asthma (fatal asthma) has not been reported in detail. Objective To examine nonsmokers who had died of asthma to exclude chronic obstructive pulmonary disease and investigate pulmonary inflammatory cells and the expression of interleukin-18 (IL-18) and its receptor in lung tissues compared with those in patients with well-controlled mild asthma and nonsmokers. Methods Lung tissues were obtained at autopsy examination from 12 nonsmokers with fatal asthma, excluding cases of chronic obstructive pulmonary disease, and from 5 nonsmokers with well-controlled mild asthma and 10 nonsmokers who had undergone surgical resection for lung cancer. Pulmonary inflammatory cells were examined and the expression of the proinflammatory cytokine IL-18 and its receptor in the lungs was evaluated. Results The numbers of eosinophils and lymphocytes, but not basophils or macrophages, were significantly increased in the lungs of patients with fatal asthma compared with the other 2 groups. The lung neutrophil count did not differ significantly between the fatal and mild asthma groups but was significantly higher in the fatal asthma group than in nonsmokers. CD8 + T cells, but not CD4 + T cells, were significantly increased in the lungs of the fatal asthma group compared with the other 2 groups. IL-18 protein and IL-18 receptor were strongly expressed in the lungs in the fatal asthma group. Conclusion Caspase-1 inhibitors, anti–IL-18 antibodies, anti–IL-18 receptor antibodies, IL-18 binding protein, or inhibitors of genes downstream of the IL-18 signal transduction pathway may be of clinical benefit for the treatment of patients with severe asthma.

A 49-year-old man with dyspnea was found to have reticular opacities and ground-glass attenuation with traction bronchiectasis or bronchiolectasis on computed tomography. The patient met the criteria for lungdominant connective tissue disease (LD-CTD) and histopathologically exhibited a chronic fibrotic interstitial pneumonia illustrating framework of a usual interstitial pneumonia-like pattern. Due to worsening of the disease, therapy was initiated with corticosteroids in combination with cyclosporine A. However, treatment with these drugs was ineffective. Pirfenidone and intravenous cyclophosphamide therapy also proved ineffective. The cyclosporine A was therefore switched to tacrolimus, and the patient's disease improved, allowing for a reduction in the dose of the corticosteroids. Our experience in this case suggests that treatment with tacrolimus might be useful for treating refractory LD-CTD even when histopathologically chronic fibrotic interstitial pneumonia is evident., Internal Medicine, 52(5), pp.605-609; 2013

Background It is difficult to predict survival in patients with idiopathic pulmonary fibrosis. Recently, several proteins, such as surfactant protein (SP) and KL-6, have been reported to be useful biologic markers for prediction of prognosis for interstitial pneumonias. It is not clear whether there is any relationship between expression of these proteins in regenerative/hyperplastic alveolar epithelial cells and prognosis of idiopathic interstitial pneumonias (IIPs). Objectives This study aimed to elucidate the clinical significance of the expression of such lung secretory proteins as SP-A and KL-6 in lung tissues of patients with IIPs. Methods We retrospectively investigated the immunohistochemical expression of SP-A, KL-6, cytokeratin (CK), and epithelial membrane antigen (EMA) in alveolar epithelial cells in lung tissues obtained from surgical lung biopsy in 43 patients with IIPs, and analyzed the correlation between expression of these markers and the prognosis of each IIP patient. CK and EMA were used as general markers for epithelial cells. Results In patients with usual interstitial pneumonia (UIP), the ratio of SP-A positive epithelial cells to all alveolar epithelial cells (SP-A positive ratio) in the collapsed and mural fibrosis areas varied, ranging from cases where almost all alveolar epithelial cells expressed SP-A to cases where only a few did. On the other hand, in many patients with nonspecific interstitial pneumonia (NSIP), many of the alveolar epithelial cells in the diseased areas expressed SP-A. The SP-A positive ratio was significantly lower in patients who died from progression of UIP than in patients with UIP who remained stable or deteriorated but did not die. In NSIP patients, a similar tendency was noted between the SP-A positive ratio and prognosis. Conclusions The results suggest that the paucity of immunohistochemical SP-A expression in alveolar epithelial cells in diseased areas (i.e. regenerative/hyperplastic alveolar epithelial cells) may predict a worse prognosis for patients with IIPs, especially patients with UIP. A prospective study is needed to confirm these results.

OBJECTIVE Oxidant stress is thought to be involved in the establishment of idiopathic interstitial pneumonia (IIP). Thioredoxin 1 (TRX1) plays a role as a strong antioxidant in vivo, suggesting that TRX1 may be involved in the pathogenesis of IIPs. However, there is no report on TRX1 levels in the sera of IIPs. In addition, TRX1 expression in the lungs of non-specific interstitial pneumonia (NSIP) and cryptogenic organizing pneumonia (COP) patients also has not been reported. Here, we investigated whether or not TRX1 levels are altered in the lungs and sera of patients with idiopathic pulmonary fibrosis (IPF), NSIP, and COP. METHODS Immunohistochemical analysis was performed to examine the expression of TRX1. TRX1 levels in sera were measured using an ELISA kit. RESULTS TRX1 was expressed in the bronchiole-alveolar epithelium, especially with regenerative or metaplastic feature, and in alveolar macrophages in usual interstitial pneumonia (UIP) and fibrotic NSIP. TRX1 was weakly expressed in the lungs of cellular NSIP and COP. TRX1 producing cells in UIP (n=16), fibrotic NSIP (n=15), cellular NSIP (n=4), and COP (n=5) were significantly increased when compared to nonsmokers (n=7). TRX1 producing cells in UIP and fibrotic NSIP were significantly increased when compared to cellular NSIP and COP. TRX1 levels in the sera of the patients with IPF (n=32; 74.2 ± 7.5 ng/mL), fibrotic NSIP (n=7; 82.5 ± 18.4 ng/mL), cellular NSIP (n=3; 62.2 ± 3.2 ng/mL) and COP (n=17; 88.8 ± 19.7 ng/mL) were significantly higher than those of control subjects (n=74; 35.3 ± 2.7 ng/mL). Furthermore, TRX1 levels in the sera of IPF patients who later showed acute exacerbation (n=7; 106.6 ± 16.3 ng/mL) were significantly higher than those of IPF patients without acute exacerbation (n=25; 65.1 ± 7.6 ng/mL). CONCLUSION Overproduction of TRX1 in the lungs and sera may play an important role in the pathogenesis of IIPs.

Chronic obstructive pulmonary disease (COPD) is believed to be an inflammatory cytokine-driven disease, but a causal basis that can be associated with a specific cytokine has not been directly demonstrated. We have previously reported that proinflammatory cytokine IL-18 expression is important in the pathogenesis of pulmonary inflammation and lung injury in mice. Our results demonstrate that IL-18 overproduction in the lungs can induce lung diseases, such as pulmonary inflammation, lung fibrosis, and COPD.We analyzed the role of IL-18 in the pathogenesis of COPD.Using the human surfactant protein C promoter to drive expression of mature mouse IL-18 cDNA, we developed two different lines of transgenic (Tg) mice that overproduced mouse mature IL-18 in the lungs either constitutively or in response to doxycycline.Constitutive overproduction of IL-18 in the lungs resulted in the increased production of IFN-gamma, IL-5, and IL-13, and chronic pulmonary lung inflammation with the appearance of CD8+ T cells, macrophages, neutrophils, and eosinophils. Increased lung volume, severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension were observed in (more than 15-wk-old) Tg mice. Interestingly, disruption of the IL-13 gene, but not the IFN-gamma gene, prevented emphysema and pulmonary inflammation in Tg mice. Moreover, when IL-18 production was induced in lung tissues for 4 weeks through the use of a doxycycline-dependent surfactant protein C promoter, interstitial inflammation was induced.Our results indicate that IL-18 and IL-13 may have an important role in the pathogenesis of COPD.