Kinetics of pro- and anti-inflammatory spike-specific cellular immune responses in long-term care facility residents after COVID-19 mRNA primary and booster vaccination: a prospective longitudinal study in Japan.

BACKGROUND: The magnitude and durability of cell-mediated immunity in older and severely frail individuals following coronavirus disease 2019 (COVID-19) vaccination remain unclear. A controlled immune response could be the key to preventing severe COVID-19; however, it is uncertain whether vaccination induces an anti-inflammatory cellular immune response. To address these issues, a 48-week-long prospective longitudinal study was conducted. A total of 106 infection-naive participants (57 long-term care facility [LTCF] residents [median age; 89.0 years], 28 outpatients [median age; 72.0 years], and 21 healthcare workers [median age; 51.0 years]) provided peripheral blood mononuclear cell (PBMC) samples for the assessment of spike-specific PBMC responses before primary vaccination, 24 weeks after primary vaccination, and three months after booster vaccination. Cellular immune responses to severe acute respiratory syndrome coronavirus 2 spike protein were examined by measuring interferon (IFN)-γ, tumor necrosis factor (TNF), interleukin (IL)-2, IL-4, IL-6, and IL-10 levels secreted from the spike protein peptide-stimulated PBMCs of participants. RESULTS: LTCF residents exhibited significantly lower IFN-γ, TNF, IL-2, and IL-6 levels than healthcare workers after the primary vaccination. Booster vaccination increased IL-2 and IL-6 levels in LTCF residents comparable to those in healthcare workers, whereas IFN-γ and TNF levels in LTCF residents remained significantly lower than those in healthcare workers. IL-10 levels were not significantly different from the initial values after primary vaccination but increased significantly after booster vaccination in all subgroups. Multivariate analysis showed that age was negatively associated with IFN-γ, TNF, IL-2, and IL-6 levels but not with IL-10 levels. The levels of pro-inflammatory cytokines, including IFN-γ, TNF, IL-2, and IL-6, were positively correlated with humoral immune responses, whereas IL-10 levels were not. CONCLUSIONS: Older and severely frail individuals may exhibit diminished spike-specific PBMC responses following COVID-19 vaccination compared to the general population. A single booster vaccination may not adequately enhance cell-mediated immunity in older and severely frail individuals to a level comparable to that in the general population. Furthermore, booster vaccination may induce not only a pro-inflammatory cellular immune response but also an anti-inflammatory cellular immune response, potentially mitigating detrimental hyperinflammation.

Management Reality of Female Patients with COPD: A Multicenter Cross-Sectional CAP Study in Japan.

Background: Reports from Europe and North America suggest that female chronic obstructive pulmonary disease (COPD) patients have a higher symptom burden and mortality than male patients. However, little is known about the management reality of female patients with COPD in Japan. Patients and Methods: We compared the clinical characteristics of female COPD patients with those of male using the cohort of the COPD Assessment in Practice study, which is a cross-sectional multicenter observational study. Results: Of the 1168 patients, 133 (11.4%) were female. A history of never smoking was higher in females than males (p<0.01). Although there was no difference in age or forced expiratory volume in one second (FEV1) % predicted between the groups, modified medical research council dyspnea scale (mMRC) and number of frequent exacerbators were higher in females (mMRC≥2: p<0.01; number of exacerbations≥2: p=0.011). The mean forced vital capacity and FEV1 values in females were lower than those in males (p<0.0001 and p<0.0001, respectively). Females were more likely to use long-term oxygen therapy and inhaled corticosteroids than males (p=0.016 and p<0.01, respectively). The prevalence of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups B, C, D (ABCD GOLD 2017 classification), and E (ABE GOLD 2023 classification) was higher in females than in males. Conclusion: The disease burden of female patients with COPD is higher than that of male patients in Japan, suggesting the importance of interventions considering female-dominant features such as lower absolute FVC and FEV1, respiratory failure, and asthma-like conditions.

Relief of Airflow Limitation and Airway Inflammation by Endoscopic Sinus Surgery in a Patient with Severe Asthma with Eosinophilic Chronic Rhinosinusitis.

Although endoscopic sinus surgery (ESS) is beneficial in improving asthma symptoms, its impact on the lung function in patients with asthma and chronic rhinosinusitis remains unclear. We herein report a case of severe asthma with eosinophilic chronic rhinosinusitis, in which ESS substantially improved airflow limitation and concomitantly reduced fractional exhaled nitric oxide and blood eosinophil counts. ESS likely relieved airflow limitation by suppressing type 2 inflammatory pathways. This case highlights ESS as a promising strategy for achieving clinical remission in patients with severe asthma and chronic rhinosinusitis.

Kinetics of COVID-19 mRNA primary and booster vaccine-associated neutralizing activity against SARS-CoV-2 variants of concern in long-term care facility residents: a prospective longitudinal study in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19) remains a threat to vulnerable populations such as long-term care facility (LTCF) residents, who are often older, severely frail, and have multiple comorbidities. Although associations have been investigated between COVID-19 mRNA vaccine immunogenicity, durability, and response to booster vaccination and chronological age, data on the association of clinical factors such as performance status, nutritional status, and underlying comorbidities other than chronological age are limited. Here, we evaluated the anti-spike IgG level and neutralizing activity against the wild-type virus and Delta and Omicron variants in the sera of LTCF residents, outpatients, and healthcare workers before the primary vaccination; at 8, 12, and 24 weeks after the primary vaccination; and approximately 3 months after the booster vaccination. This 48-week prospective longitudinal study was registered in the UMIN Clinical Trials Registry (Trial ID: UMIN000043558). RESULTS: Of 114 infection-naïve participants (64 LTCF residents, 29 outpatients, and 21 healthcare workers), LTCF residents had substantially lower anti-spike IgG levels and neutralizing activity against the wild-type virus and Delta variant than outpatients and healthcare workers over 24 weeks after the primary vaccination. In LTCF residents, booster vaccination elicited neutralizing activity against the wild-type virus and Delta variant comparable to that in outpatients, whereas neutralizing activity against the Omicron variant was comparable to that in outpatients and healthcare workers. Multiple regression analyses showed that age was negatively correlated with anti-spike IgG levels and neutralizing activity against the wild-type virus and Delta variant after the primary vaccination. However, multivariate regression analysis revealed that poor performance status and hypoalbuminemia were more strongly associated with a lower humoral immune response than age, number of comorbidities, or sex after primary vaccination. Booster vaccination counteracted the negative effects of poor performance status and hypoalbuminemia on the humoral immune response. CONCLUSIONS: LTCF residents exhibited suboptimal immune responses following primary vaccination. Although older age is significantly associated with a lower humoral immune response, poor performance status and hypoalbuminemia are more strongly associated with a lower humoral immune response after primary vaccination. Thus, booster vaccination is beneficial for older adults, especially those with a poor performance status and hypoalbuminemia.

Detection of impaired gas exchange using the 1-minute sit-to-stand test in patients with interstitial lung disease.

BACKGROUND: Although pulmonary function tests (PFTs) are important in patients with interstitial lung disease (ILD), they cannot be easily performed in a primary healthcare setting. This study aimed to examine the usefulness of the difference between pulse oxygen saturation (SpO2) at rest and the lowest SpO2 during the 1-min sit-to-stand test (delta SpO2-1STST) for predicting pulmonary function impairment. METHODS: We retrospectively reviewed 116 patients with ILD who underwent 1STST and PFTs. RESULTS: The delta SpO2-1STST and diffusing capacity for carbon monoxide (DLco) strongly correlated (ρ = 0.70). The delta SpO2-1STST was effective in predicting impaired gas exchange (cut-off value, -4%; AUC, 0.86; sensitivity, 74%; specificity, 87%). CONCLUSIONS: The Delta SpO2-1STST may be a reasonable tool for predicting abnormalities in PFTs.

Investigating the role of heat shock protein 47 in fibrosis in Crohn's disease.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share similar genetic risk factors. However, while fibrotic stricture of the intestine is a major characteristic of CD; it is rarely observed in UC. Deposition of collagen in the extracellular matrix contributes to the formation of fibrotic strictures in CD, but the underlying mechanisms are unknown. In the present study, we found that heat shock protein 47 (HSP47), a stress-response protein that acts as a molecular chaperone during the processing and secretion of collagen, expressed in the intestinal tissue from patients with CD. Serum HSP47 levels and anti-HSP47 antibody titers were significantly higher in patients with CD than in those with UC. Furthermore, anti-HSP47 antibody levels correlated significantly with fibrosis in CD. In addition, HSP47 inhibition significantly suppressed collagen production in fibroblasts in vitro. These findings suggest that HSP47 is a biomarker for differentiating fibrotic from non-fibrotic forms of CD. Additionally, we propose that HSP47 could be a potential target for treating fibrosis in patients with CD.

Invasive thymoma extending to the right atrium with superior vena cava syndrome presenting massive intracardiac thrombosis immediately after the start of chemotherapy: an autopsy case report.

Invasive thymomas with intraluminal tumor thrombi are rare. Removal of the thymoma and infiltration of the superior vena cava (SVC) is a curative alternative. We report an autopsy case of invasive thymoma with intraluminal growth into the intracardiac right atrium extension. Furthermore, the patient died of massive intracardiac thrombosis 5 days after the start of chemotherapy. A 66-year-old man with SVC syndrome was referred to our hospital. He had been aware of swelling of the face for 6 months. The patient was diagnosed with invasive thymoma by a CT-guided needle biopsy of the anterior mediastinal mass. Contrast-enhanced chest computed tomography showed a mass in the anterior mediastinum extending to the SVC and right atrium. As a result of discussion with surgeons and radiotherapists, we planned a multidisciplinary treatment in which neoadjuvant chemotherapy would reduce the tumor size, and surgery and postoperative radiotherapy were followed by chemotherapy. He was administered neo-adjuvant chemotherapy with CBDCA + PTX (carboplatin, area under the curve = 6, and paclitaxel, 200 mg/m2). On the 4th day of chemotherapy, he suddenly developed obstructive shock due to intracardiac thrombosis in the right ventricle. We believe that chemotherapy may trigger rapid thrombus formation. If an invasive thymoma spreads into a large vessel or the right atrium, surgical treatment should be considered if possible. However, if surgery is impossible, administration of anticoagulants should be considered to prevent thrombus formation before chemotherapy.

Antineutrophil cytoplasmic antibody-negative granulomatosis with polyangiitis localized to the lungs.

Patients with granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, sometimes exhibit no clinical features. Here, we describe a case of antineutrophil cytoplasmic antibody (ANCA)-negative GPA presenting with only lung granuloma. A 55-year-old woman with a right upper lung mass underwent lobectomy for suspected lung cancer; however, only granuloma was detected, and the etiology was not identified. Serum ANCA results were negative. Four years postoperatively, another pulmonary nodule appeared in the left lung's apex. The kidneys and sinuses were not impaired, but re-examination of the resected specimen revealed necrotizing vasculitis and granulomas around the vessels. Thus, the patient was diagnosed with GPA localized to the lungs. Although this was a non-life-threatening disease, the patient was administered oral prednisolone (PSL) and intravenous cyclophosphamide (IVCY) to prevent fatal complications of GPA as she was non-elderly and had no comorbidities, leading to a decrease in the mass size. Detailed re-examination by expert pulmonary pathologists could aid in GPA diagnosis when clinical features are absent, as in our case. In patients with granulomas of unknown etiology, a careful multidisciplinary approach is pivotal in the diagnosis. If patients tolerate adverse effects, a PSL and IVCY combination may prevent fatal outcomes, even in patients with non-life-threatening disease.

Improved Prognostic Prediction by Combination of Early Initiation of Polymyxin B Hemoperfusion with Modified Gender-Age-Physiology Index in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

INTRODUCTION: Respiratory failure from acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with high mortality. Direct hemoperfusion with polymyxin B-immobilized fiber column (PMX-DHP) has been reported to have beneficial effects on patients with AE-IPF. Whether patient characteristics influence the extent of this benefit remains unclear. METHODS: We retrospectively examined the records of 30 patients with AE-IPF who underwent PMX-DHP. The favorable factors of survival were determined using Cox proportional hazards analyses. RESULTS: The 1- and 12-month survival rates after PMX-DHP were 70.0% and 50.0%, respectively. The multivariate analysis revealed that low modified Gender-Age-Physiology (GAP) index (≤8 points) (hazard ratio [HR] 0.317, p = 0.015) and PMX-DHP received within 48 h of steroid pulse (HR 0.289, p = 0.012) were favorable factors. Notably, even in the patients with high modified GAP index (>8 points), that is, more advanced IPF, those who received PMX-DHP within 48 h of steroid pulse had a better prognosis than those who did after 48 h of the steroid pulse (p = 0.032). CONCLUSIONS: Early PMX-DHP initiation in patients with AE-IPF, specifically within 48 h after the steroid pulse therapy, may improve prognosis regardless of the severity of chronic phase of IPF before AE-IPF.

Presence of heat shock protein 47-positive fibroblasts in cancer stroma is associated with increased risk of postoperative recurrence in patients with lung cancer.

BACKGROUND: Heat shock protein 47 (HSP47), a collagen-binding protein, has a specific role in the intracellular processing of procollagen production. HSP47 expression is associated with cancer growth and metastasis in several types of cancers. However, none of the studies have assessed whether HSP47 expression is associated with the risk of postoperative recurrence of lung cancer until now. Therefore, we aimed to assess this association. METHODS: The study population consisted of a cohort of consecutive patients who underwent surgery for lung cancer at Nagasaki University Hospital, Nagasaki, Japan, from January 2009 to December 2010. Patient characteristics, survival and disease-free survival (DFS), and laboratory findings were compared between patients who tested positive and negative for HSP47 expression in lung cancer cells and between those who showed high and low numbers of HSP47-positive fibroblasts in cancer stroma. RESULTS: A total of 133 patients underwent surgery for lung cancer. Sixty-seven patients (50.4%) had HSP47-positive cancer cells, and 91 patients (68.4%) had a higher number of HSP47-positive fibroblasts. The patients with a high number of HSP47-positive fibroblasts had a shorter DFS than those with a low number of HSP47-positive fibroblasts. Multivariate analysis identified only the presence of a high number of HSP47-positive fibroblasts as an independent risk factor for recurrence of lung cancer after surgery (odds ratio, 4.371; 95% confidence interval, 1.054-29.83; P = 0.042). CONCLUSION: The present study demonstrated that the presence of a high number of HSP47-positive fibroblasts in the cancer stroma was a risk factor for recurrence of lung cancer after surgery.

Comparison of lung microbiota between antineutrophil cytoplasmic antibody-associated vasculitis and sarcoidosis.

Microbial involvement in the pathogenesis have been suggested in both antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and sarcoidosis, both of which have lung involvement. However, exhaustive research to assess the bacteria in the lung in AAV and in sarcoidosis have not been performed. We sought to elucidate the distinct dysbiotic lung microbiota between AAV and sarcoidosis. We used 16S rRNA gene high-throughput sequencing to obtain the bacterial community composition of bronchoalveolar lavage fluid (BALF) in patients with AAV (n = 16) compared to patients with sarcoidosis (n = 21). The patients had not undergone therapy with immunosuppressive medication when their BALF was acquired. No difference was observed in α-diversity between patients with AAV and patients with sarcoidosis when using all the detected taxa. We defined the taxa of the oral cavity by using the data of oral microbiota of healthy individuals from the Human Microbiome Project (HMP). The analysis using only oral taxa made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. Besides, the analysis using detected taxa except for oral taxa also made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. A linear negative relationship between the α-diversity and Birmingham vasculitis activity score (BVAS) was detected in the AAV group. The observed p-value for the effect of the disease groups on the ß-diversity was small while the effect of other factors including sex and smoking status did not have small p-values. By excluding oral taxa from all the detected taxa, we found a cluster mainly consisted of sarcoidosis patients which was characterized with microbial community monopolized by Erythrobacteraceae family. Our results suggested the importance of considering the influence of oral microbiota in evaluating lung microbiota.

Prediction of Anti-Cancer Drug-Induced Pneumonia in Lung Cancer Patients: Novel High-Resolution Computed Tomography Fibrosis Scoring.

BACKGROUND AND OBJECTIVE: Pre-existing interstitial lung disease (ILD) in lung cancer patients is considered a risk factor for anti-cancer drug-induced pneumonia; however, a method for evaluating ILD, including mild cases, has not yet been established. We aimed to elucidate whether the quantitative high-resolution computed tomography fibrosis score (HFS) is correlated with the risk of anti-cancer drug-induced pneumonia in lung cancer patients, even in those with mild pre-existing ILD. METHODS: The retrospective single-institute study cohort comprised 214 lung cancer patients who underwent chemotherapy between April 2013 and March 2016. The HFS quantitatively evaluated the grade of pre-existing ILD. We extracted data regarding age, sex, smoking history, and coexisting factors that could affect the incidence of anti-cancer drug-induced pneumonia. Cox proportional hazard models were used to analyze the effects of the HFS and other factors on the risk of anti-cancer drug-induced pneumonia. RESULTS: Pre-existing ILD was detected in 61 (29%) of 214 patients, while honeycombing and traction bronchiectasis were observed in only 15 (7.0%) and 10 (4.7%) patients, respectively. Anti-cancer drug-induced pneumonia developed in 19 (8.9%) patients. The risk of anti-cancer drug-induced pneumonia increased in proportion to the HFS (hazard ratio, 1.16 per point; 95% confidence interval, 1.09-1.22; p < 0.0001). CONCLUSIONS: The quantitative HFS was correlated with the risk of developing anti-cancer drug-induced pneumonia in lung cancer patients, even in the absence of honeycombing or traction bronchiectasis. The quantitative HFS may lead to better management of lung cancer patients with pre-existing ILD.

Postoperative acute exacerbation of interstitial pneumonia in pulmonary and non-pulmonary surgery: a retrospective study.

BACKGROUND: Acute exacerbation of interstitial pneumonia (AE-IP) is a serious complication of pulmonary surgery in patients with IP. However, little is known about AE-IP after non-pulmonary surgery. The aim of this study was to determine the frequency of AE-IP after non-pulmonary surgery and identify its risk factors. METHODS: One hundred and fifty-one patients with IP who underwent pulmonary surgery and 291 who underwent non-pulmonary surgery were retrospectively investigated. RESULTS: AE-IP developed in 5 (3.3%) of the 151 patients in the pulmonary surgery group and 4 (1.4%) of the 291 in the non-pulmonary surgery group; the difference was not statistically significant. A logistic regression model showed that serum C-reactive protein (CRP) was a predictor of AE-IP in the non-pulmonary surgery group (odds ratio 1.187, 95% confidence interval 1.073-1.344, P = 0.002). CONCLUSIONS: This is the first study to compare the frequency of AE-IP after pulmonary surgery with that after non-pulmonary surgery performed under the same conditions. The results suggest that the frequency of AE-IP after non-pulmonary surgery is similar to that after pulmonary surgery. A high preoperative C-reactive protein level is a potential risk factor for AE-IP after non-pulmonary surgery.

Clinical Features of Anti-MDA5 Antibody-positive Rapidly Progressive Interstitial Lung Disease without Signs of Dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody is associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis (CADM) or dermatomyositis (DM). We herein report three Japanese cases of anti-MDA5 antibody-positive RP-ILD without signs of CADM or DM. High-resolution computed tomography revealed patchy or subpleural distribution of consolidations and/or ground-glass opacities accompanied by traction bronchiectasis. All patients succumbed to respiratory failure within two months. Anti-MDA5 antibody-positive RP-ILD without signs of CADM or DM should be included in the differential diagnosis of acute/subacute ILD. Measurement of anti-MDA5 antibody and an intensive immunosuppressive regimen might rescue these patients from RP-ILD.

Pulmonary Alveolar Proteinosis with Ulcerative Colitis.

A 65-year-old Japanese man was referred to our hospital for the further assessment of cough and dyspnea. He had a history of ulcerative colitis for which he was receiving treatment. Chest computed tomography showed a crazy-paving pattern. His bronchoalveolar lavage fluid had a milky appearance, and a transbronchial lung biopsy specimen revealed acellular periodic acid-Schiff stain-positive bodies. The serum anti-granulocyte macrophage-colony stimulating factor (GM-CSF) antibody titer was elevated. The diagnosis was autoimmune pulmonary alveolar proteinosis (PAP). There are few reports of autoimmune PAP in patients with ulcerative colitis. Some reports suggest that PAP and inflammatory bowel disease might have a common pathogenesis involving the anti-GM-CSF antibody.

Lymphocytic focus score is positively related to airway and interstitial lung diseases in primary Sjögren's syndrome.

OBJECTIVE: Although high-resolution computed tomography (HRCT) is useful for the characterization of minute morphological changes in the lungs, no study has investigated risk factors for lung involvement detected by HRCT in patients with Sjögren's syndrome with or without respiratory symptoms. The aim of the current study was to investigate risk factors for lung involvement in patients with primary Sjögren's syndrome detected by HRCT, with a particular focus on airway and interstitial lung diseases. METHODS: We performed a retrospective cohort study of patients with primary Sjögren's syndrome and investigated risk factors for lung involvement detected by HRCT. A total of 101 patients with primary Sjögren's syndrome with initial HRCT examinations were enrolled. RESULTS: Higher age, dry mouth, and higher labial gland biopsy focus scores (≥4) were risk factors for airway diseases (odds ratio [OR] 1.064 confidence interval [CI] 1.026-1.102, OR 8.795 CI 2.317-33.378 and OR 3.261 CI 1.100-9.675, respectively) in the multivariable analysis. Higher age, male sex, and higher labial gland biopsy focus scores (≥4) were risk factors for interstitial lung diseases (OR 1.078 CI 1.032-1.127, OR 12.178 CI 1.121-132.307 and OR 3.954 CI 1.423-10.987, respectively) in the multivariable analysis. The presence of anti-T-lymphotropic virus type 1 antibodies was significantly more common in patients with airway diseases. CONCLUSIONS: This study showed significant associations of labial gland biopsy focus scores and dry mouth with pulmonary manifestations in patients with primary Sjögren's syndrome. Focus scores as well as dry mouth may reflect lymphoproliferative activity in the lungs in patients with primary Sjögren's syndrome.

The surgical outcomes of lung cancer combined with interstitial pneumonia: a single-institution report.

PURPOSE: Several studies have reported that an acute exacerbation (AE) of idiopathic interstitial pneumonia (IIP) can occur after lung resection in patients with non-small cell lung cancer (NSCLC); however, the perioperative management strategy is controversial. METHODS: The data of lung cancer patients at Nagasaki University Hospital from June 1994 to October 2013 were retrospectively reviewed. RESULTS: Among all 1701 NSCLC patients who underwent lung resection, 59 (3.5%) had IIP. Five patients (8.5%) had an AE of IIP following lung resection, three (60%) of whom died in hospital. Univariate and multivariate analyses were performed to identify possible risk factors for AE. The univariate analyses identified LDH and the volume of blood loss as risk factors. The multivariate analysis identified no factors. The treatment for an AE included steroid pulse therapy and neutrophil elastase inhibitor therapy. Direct hemoperfusion with polymyxin B immobilized the fiber column and immunosuppressant therapy was attempted in some of the patients who did not respond to these treatments. CONCLUSION: Patients with lung cancer and IIP have a higher risk of chest surgery and a poor prognosis. Very careful surgery and perioperative management are needed, because AEs are often difficult to AE predict.

Interstitial Lung Disease Induced by Pazopanib Treatment.

Although pneumothorax has been reported to be a major pulmonary adverse event in patients treated with pazopanib, a multikinase inhibitor, drug-induced interstitial lung disease (DILD) has not been reported. A 74-year-old Japanese man who received pazopanib for the treatment of femoral leiomyosarcoma and lung metastasis presented with dyspnea and fatigue. He had mild interstitial pneumonia when pazopanib treatment was initiated. Chest computed tomography revealed progressive bilateral ground-glass opacity (GGO) and traction bronchiectasis. We diagnosed DILD due to pazopanib. The patient's pazopanib treatment was interrupted and a steroid was administered. The symptoms and GGO were improved with treatment. Physicians should be aware of DILD due to pazopanib in patients with pre-existing interstitial lung disease.

Risk factors for an acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis are major causes of morbidity and mortality among patients with idiopathic pulmonary fibrosis. However, acute exacerbations remain unpredictable. The aim of this study was to investigate risk factors for acute exacerbations of idiopathic pulmonary fibrosis. METHODS: We performed a retrospective cohort study of patients with idiopathic pulmonary fibrosis who visited our institutions from January 1999 to September 2014. We investigated risk factors for acute exacerbations in patients with idiopathic pulmonary fibrosis diagnosed retrospectively based on the official 2011 idiopathic pulmonary fibrosis ATS/ERS/JRS/ALAT Update Statement. RESULTS: The idiopathic pulmonary fibrosis study cohort included 65 subjects. The median follow-up period was 2.6 years. During follow-up, 24 patients (36.9 %) experienced acute exacerbations. A Kaplan-Meier curve demonstrated that the 1-year, 2-year, and 3-year incidences of acute exacerbation were 9.6, 19.2 and 31.0 %, respectively. Acute exacerbation exerted a significant impact on overall survival among those with the disease. A log-rank test showed that baseline cardiovascular diseases, higher GAP (gender, age, physiology) stage (≥II), higher serum lactate dehydrogenase level (≥180 U/L), higher serum surfactant protein-D level (≥194.7 ng/mL), higher neutrophil (≥1.77 %) and eosinophil (≥3.21 %) percentages in bronchoalveolar lavage fluid samples, and treatment with an immunosuppressive agent after diagnosis were associated with poor acute exacerbation-free probability. In the Cox analysis adjusted for treatment with an immunosuppressive agent, baseline cardiovascular diseases, higher GAP stage (≥II), and higher eosinophil percentage (≥3.21 %) in bronchoalveolar lavage fluid samples were predictors of an acute exacerbation of idiopathic pulmonary fibrosis. CONCLUSIONS: This study demonstrated that baseline cardiovascular diseases, higher GAP stage (≥II), and higher eosinophil percentage (≥3.21 %) in bronchoalveolar lavage fluid samples were associated with the onset of an acute exacerbation of idiopathic pulmonary fibrosis.

Identification of Helicobacter pylori VacA in human lung and its effects on lung cells.

OBJECTIVE: Prior reports suggested that infection with Helicobacter pylori was associated with respiratory diseases; pathogenetic mechanisms however, were not defined. We tested the hypothesis that VacA, an exotoxin of H. pylori, a gastric pathogen, was aspirated into the lung and could stimulate secretion of inflammatory cytokines by lung epithelial cells. METHODS: The presence of VacA was determined by immunohistochemistry in surgical lung biopsy tissue samples from 72 patients with interstitial pneumonia. The effects of VacA on A549 human alveolar epithelial adenocarcinoma cells and normal human bronchial epithelial cells were determined. After incubation with VacA, the secretions of cytokines were measured by Multiplex Luminex(®) Assays. RESULTS: VacA was detected with anti-VacA antibodies in bronchial epithelial cells and alveolar epithelial cells from 10 of 72 patients with interstitial pneumonia. VacA was more prevalent in lungs of patients with collagen vascular disease-associated interstitial pneumonia than in those of patients with idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia and cryptogenic organizing pneumonia. Incubation of A549 cells and normal human bronchial epithelial cells with VacA for 24 h was cytotoxic, and resulted in vacuolation. VacA induced interleukin-8 production by A549 cells and normal human bronchial epithelial cells and interleukin-6 production by A549 cells. Based on multiplex screening, interleukin-8 and interleukin-6 were the primary secretory products induced by VacA. CONCLUSIONS: H. pylori VacA is present in human lung and can induce interleukin-8 and interleukin-6 production by human lung cells. VacA could have a role in the pathogenesis of respiratory diseases by its cytotoxic effects and by inducing the secretion of interleukin-8 and interleukin-6 by targeted airway epithelial cells.