Effect of inspiratory muscle training on cough strength in older people with frailty: a single-blind randomized controlled trial.

OBJECTIVES: To investigate the effect of inspiratory muscle training (IMT) on cough strength in older people with frailty. DESIGN: Single-blind randomized controlled trial. SETTING: Day health care centers at two sites. PARTICIPANTS: Older people with frailty. INTERVENTIONS: Eligible people were randomized to receive IMT program in addition to general exercise training (IMT group), or general exercise training alone (control group). The IMT group performed training using a threshold IMT device with the load set at 30% of maximum inspiratory mouth pressure in addition to the general exercise training program throughout the 8 weeks. The IMT took place twice a day and each session consisted of 30 breaths. MAIN OUTCOME MEASURE: Primary outcome was cough strength, measured as the cough peak flow (CPF), at the beginning and the end of the program. RESULTS: Data from 52 participants (26 in each group) were available for the analysis. The mean age was 82.6 years, 33% were male. The change in CPF at the end of the program was 28.7 ± 44.4 L/min in the IMT group and -7.4 ± 26.6 L/min in the control group. A linear regression model showed that the presence or absence of IMT was associated with changes in CPF (mean difference between groups: 36.3, 95%CI: 16.7 to 55.9, effect size: 0.99). CONCLUSION: IMT may be a useful intervention to improve cough strength in frail older people.

Drug-induced interstitial lung disease caused by olaparib: three case reports and review of the Japanese Adverse Drug Event Report database and literature.

BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated effectiveness in treating ovarian, breast, and other cancers, particularly those with specific molecular subtypes including, but not limited to, BRCA1/2 mutations. Consequently, its utilization is expected to increase in the future. For this reason, it is important to acknowledge the potential for adverse events associated with olaparib, including the relatively rare but significant risk of drug-induced interstitial lung disease (DIILD). Since DIILD can lead to fatal outcomes, its early detection is crucial. The dissemination of knowledge regarding DIILD can be facilitated through case reports; however, specific reports of DIILD caused by olaparib have only been published in Japanese. To the best of our knowledge, this is the first report in English of our experience with three cases of DIILD caused by olaparib. CASE PRESENTATION: Cases 1, 2, and 3 involved Japanese women with ovarian cancer who had been receiving olaparib at a dose of 600 mg/day. Case 1, a 72-year-old woman who had been on olaparib for 4 months, and case 2, a 51-year-old woman who had been on olaparib for 8 months, reported fever and general malaise. Chest computed tomography (CT) revealed pale ground glass opacity (GGO) similar to hypersensitivity pneumonitis. The severity grade was 2 in both cases. Case 3, a 78-year-old woman who had been on olaparib for 3 weeks, presented with cough and reported dyspnea on exertion. Chest CT revealed non-specific interstitial pneumonia and organizing pneumonia-like shadows. The severity grade was 4. Olaparib was discontinued in all cases. Case 1 received 0.6 mg/kg of prednisolone due to mild hypoxia, while prednisolone was not administered in case 2 due to the absence of hypoxia. Case 3 received steroid pulse therapy due to severe hypoxia. Olaparib administration was not resumed in any patient. CONCLUSION: DIILD caused by olaparib in Japan, including the present three cases, commonly presents with GGO, similar to hypersensitivity pneumonitis on chest CT. The prognosis for the majority of patients is favorable; however, there have been instances of severe cases. Early recognition of drug-induced lung injury and further accumulation of cases is important.

Lung Involvement in Adult T-Cell Lymphoma Diagnosed Using Bronchoscopic Cryobiopsy: A Case Report and Review of the Literature.

The diagnosis of pulmonary lymphoma using small tissue samples is difficult and often requires surgical procedures; thus, a less invasive sampling method is desirable. Moreover, pulmonary involvement in adult T-cell lymphoma (ATL) is often difficult to diagnose, especially in cases without characteristic flower cells. Here, we present the case of a 78-year-old man, in whom pathological examination of the transbronchial lung biopsy (TBLB) specimen did not reveal malignant findings; therefore, transbronchial lung cryobiopsy (TBLC) in combination with endobronchial ultrasonography (EBUS) was used to diagnose ATL based on the pathological findings. A literature review identified 18 cases of pulmonary lymphomas diagnosed using TBLC. Among the 19 cases, including our own, 16 cases were of B-cell lymphoma (84.2%), and the present case is the first case of ATL diagnosed using TBLC. Eighty percent of the cases underwent a biopsy (more than two samples) of the middle or lower lobe and were diagnosed without major complications. EBUS was used with TBLC in three cases to identify the location of the pulmonary lesions. In the present case, EBUS was also useful for avoiding vascular biopsy. Although large-scale prospective studies are required to establish precise guidelines for diagnosing pulmonary lymphomas using TBLC, our case report and review contributes to a deeper understanding of the diagnosis of rare diseases.

Underbody blankets have a higher heating effect than overbody blankets in lithotomy position endoscopic surgery under general anesthesia: a randomized trial.

BACKGROUND: Surgery under general anesthesia results in temperature decrease due to the effect of anesthetics and peripheral vasodilation on thermoregulatory centers. Perioperative temperature control is therefore an issue of high importance. In this study, we aimed to compare the warming effect of underbody and overbody blankets in patients undergoing surgery in the lithotomy position under general anesthesia. METHODS: From September 2018 to October 2019, 99 patients undergoing surgery for colorectal cancer in the lithotomy position were included in this randomized controlled trial and assigned to the intervention group (underbody blanket) or control group (overbody blanket). RESULTS: The central temperature was significantly higher in the underbody blanket group than in the overbody blanket group at 90 min after the beginning of the surgery (p = 0.02); also in this group, the peripheral temperature was significantly higher 60 min after the beginning of the surgery (p = 0.02). Regarding postoperative factors, the underbody blanket group had a significantly lower frequency of postoperative shivering (p < 0.01) and a significantly shorter postoperative hospital stay (p = 0.04) than the overbody blanket group. CONCLUSIONS: We recommend the use of underbody blankets for intraoperative temperature control in patients undergoing surgery in the lithotomy position under general anesthesia. Underbody blankets showed improved rise and maintenance of central and peripheral temperature, decreased the incidence of postoperative shivering, and shortened the postoperative length of hospital stay.

Autoimmune pulmonary alveolar proteinosis exacerbated by steroid therapy due to misdiagnosis as anti-aminoacyl-tRNA synthetase (ARS) antibody positive- interstitial pneumonia: a case report.

BACKGROUND: Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are myositis-specific autoantibodies that have been identified in a subset of patients with interstitial pneumonia who do not present with dermatomyositis or polymyositis. Anti-ARS antibody-positive interstitial pneumonia is commonly treated with steroids or immunosuppressive agents and is usually responsive to these therapies. Here, we present in detail a case in which respiratory failure of a patient diagnosed with anti-ARS antibody-positive interstitial pneumonia was exacerbated by treatment with steroids and immunosuppressive agents. Further examination revealed misdiagnosis of this patient and a subsequent diagnosis of autoimmune pulmonary alveolar proteinosis. CASE PRESENTATION: A 66-year-old man presented to the hospital with dyspnea on exertion, which resulted in the detection of interstitial pneumonia. Serum anti-ARS antibodies were detected; however, there were no other findings suggestive of myositis. Pulmonary alveolar proteinosis (PAP) was suspected based on the marked increase in serum KL-6 and chest computed tomography findings. The bronchoalveolar lavage revealed no milky changes in the lavage fluid. After treatment with steroids and initiation of immunosuppressive agents for anti-ARS antibody-positive interstitial pneumonia, respiratory failure and chest imaging findings showed worsening of the condition. Bronchoscopy was repeated, and milk-like alveolar lavage fluid was collected; serum anti-granulocyte macrophage colony-stimulating factor antibody was identified. Steroids and immunosuppressive agents were gradually tapered and discontinued, and the patient's condition stabilized after repeated alveolar lavage under general anesthesia. CONCLUSION: Due to similar presentation, PAP can be misdiagnosed as interstitial pneumonia. If pulmonary lesions due to interstitial pneumonia are exacerbated by immunosuppressive treatment, physicians should reconsider the diagnosis and include PAP in the differential diagnosis.

A comparative study of the sarcopenia screening in older patients with interstitial lung disease.

BACKGROUND: The Asian Working Group for Sarcopenia 2019 (AWGS 2019) is the gold standard diagnostic criteria for sarcopenia in Asian populations. The calf circumference (CalF), the strength, assistance in walking, rising from a chair, climbing stairs, and falls (SARC-F) and the SARC-CalF questionnaires for sarcopenia screening have been used by AWGS 2019. The aim of this study was to assess accuracy of these three sarcopenia screening tools in patients with interstitial lung disease. METHODS: In this cross-sectional study, stable patients with interstitial lung disease were enrolled. The SARC-F, SARC-CalF, and CalF, used in patients with interstitial lung disease, were compared to the diagnostic criteria proposed by AWGS 2019. The accuracy of screening tools was compared using sensitivity and specificity. Moreover, areas under the receiver operating characteristic curves (AUC) were computed. RESULTS: Seventy eight patients were analyzed, and sarcopenia was identified in 25 (32.1%) patients with interstitial lung disease by the AWGS 2019 criteria. The sensitivity of the CalF was highest (96%) of the three screening tools, while the specificity was 60%. The sensitivity of SARC-F and SARC-CalF were 24% and 68%, while the specificity were 92% and 66%, respectively. The AUCs of CalF, SARC-F, and SARC-CalF in all patients were 0.78, 0.58, and 0.67, respectively. CONCLUSIONS: The CalF is most suitable for screening sarcopenia in patients with interstitial lung disease, while SARC-F and SARC-CalF are not.

Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro.

Excessive extracellular matrix deposition, in particular collagen, is an important cause of lung fibrosis. Heat shock protein 47 (HSP47), a collagen-binding protein, plays an important role in the intracellular processing of procollagen. A small molecule that blocks the collagen chaperone function of HSP47 has been reported as an HSP47 inhibitor. The aim of this study was to assess the effect of the HSP47 inhibitor on collagen synthesis and other fibrotic process in vitro. We evaluated collagen expression by western blot, and determined cell viability and migration by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and scratch test, respectively, in human and mouse lung fibroblasts. Treatment of lung fibroblasts with HSP47 siRNA decreased collagen type I expression. Similarly, the HSP47 inhibitor decreased collagen type I expression in transforming growth factor beta 1 (TGF-ß1)-treated lung fibroblasts in a dose-dependent manner. The inhibitor also decreased the viability and cell migration ability of TGF-ß1-treated lung fibroblasts. Overall, we demonstrated that HSP47 is a potential therapeutic target for pulmonary fibrosis. The small molecule HSP47 inhibitor may mediate antifibrotic effects by suppressing the overexpression of collagen, and inhibiting the viability and migration of fibroblasts. Further research is needed to clarify the therapeutic potential of this HSP47 inhibitor for pulmonary fibrosis.

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.

Pneumoconiosis with a Sarcoid-Like Reaction Other than Beryllium Exposure: A Case Report and Literature Review.

Background: Chronic beryllium disease (CBD) is a granulomatous disease that resembles sarcoidosis but is caused by beryllium. Clinical manifestations similar to those observed in CBD have occasionally been reported in exposure to dusts of other metals. However, reports describing the clinical, radiographic, and pathological findings in conditions other than beryllium-induced granulomatous lung diseases, and detailed information on mineralogical analyses of metal dusts, are limited. Case presentation: A 51-year-old Japanese man with rapidly progressing nodular shadows on chest radiography, and a 10-year occupation history of underground construction without beryllium exposure, was referred to our hospital. High-resolution computed tomography showed well-defined multiple centrilobular and perilobular nodules, and thickening of the intralobular septa in the middle and lower zones of both lungs. No extrathoracic manifestations were observed. Pathologically, the lung specimens showed 5-12 mm nodules with dust deposition and several non-necrotizing granulomas along the lymphatic routes. X-ray analytical electron microscopy of the same specimens revealed aluminum, iron, titanium, and silica deposition in the lung tissues. The patient stopped smoking and changed his occupation to avoid further dust exposure; the chest radiography shadows decreased 5 years later. Conclusion: The radiological appearances of CBD and sarcoidosis are similar, although mediastinal or hilar lymphadenopathy is less common in CBD and is usually seen in the presence of parenchymal opacities. Extrathoracic manifestations are also rare. Despite limited evidence, these findings are similar to those observed in pneumoconiosis with a sarcoid-like reaction due to exposure to dust other than of beryllium. Aluminum is frequently detected in patients with pneumoconiosis with a sarcoid-like reaction and is listed as an inorganic agent in the etiology of sarcoidosis. It was also detected in our patient and may have contributed to the etiology. Additionally, our case suggests that cessation of dust exposure may contribute to improvement under the aforementioned conditions.

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.

The acoustic characteristics of fine crackles predict honeycombing on high-resolution computed tomography.

BACKGROUND: Honeycombing on high-resolution computed tomography (HRCT) is a distinguishing feature of usual interstitial pneumonia and predictive of poor outcome in interstitial lung diseases (ILDs). Although fine crackles are common in ILD patients, the relationship between their acoustic features and honeycombing on HRCT has not been well characterized. METHODS: Lung sounds were digitally recorded from 71 patients with fine crackles and ILD findings on chest HRCT. Lung sounds were analyzed by fast Fourier analysis using a sound spectrometer (Easy-LSA; Fukuoka, Japan). The relationships between the acoustic features of fine crackles in inspiration phases (onset timing, number, frequency parameters, and time-expanded waveform parameters) and honeycombing in HRCT were investigated using multivariate logistic regression analysis. RESULTS: On analysis, the presence of honeycombing on HRCT was independently associated with onset timing (early vs. not early period; odds ratios [OR] 10.407, 95% confidence interval [95% CI] 1.366-79.298, P = 0.024), F99 value (the percentile frequency below which 99% of the total signal power is accumulated) (unit Hz = 100; OR 5.953, 95% CI 1.221-28.317, P = 0.029), and number of fine crackles in the inspiratory phase (unit number = 5; OR 4.256, 95% CI 1.098-16.507, P = 0.036). In the receiver-operating characteristic curves for number of crackles and F99 value, the cutoff levels for predicting the presence of honeycombing on HRCT were calculated as 13.2 (area under the curve [AUC], 0.913; sensitivity, 95.8%; specificity, 75.6%) and 752 Hz (AUC, 0.911; sensitivity, 91.7%; specificity, 85.2%), respectively. The multivariate logistic regression analysis additionally using these cutoff values revealed an independent association of number of fine crackles in the inspiratory phase, F99 value, and onset timing with the presence of honeycombing (OR 33.907, 95% CI 2.576-446.337, P = 0.007; OR 19.397, 95% CI 2.311-162.813, P = 0.006; and OR 12.383, 95% CI 1.443-106.293, P = 0.022; respectively). CONCLUSIONS: The acoustic properties of fine crackles distinguish the honeycombing from the non-honeycombing group. Furthermore, onset timing, number of crackles in the inspiratory phase, and F99 value of fine crackles were independently associated with the presence of honeycombing on HRCT. Thus, auscultation routinely performed in clinical settings combined with a respiratory sound analysis may be predictive of the presence of honeycombing on HRCT.

Serum Soluble Interleukin-2 Receptor Is a Biomarker for Pneumocystis jirovecii Pneumonia among Patients with Rheumatoid Arthritis under Methotrexate Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic joint inflammation and may manifest as interstitial pneumonia (IP). Methotrexate (MTX) is one of the main therapeutic drugs used for RA, but MTX could cause severe side effects, including Pneumocystis jirovecii pneumonia (PCP) and IP. Owing to similar symptoms, it is sometimes difficult to discriminate MTX therapy-associated PCP (MTX-PCP) and MTX therapy-associated IP (MTX-IP). Soluble interleukin-2 receptor (sIL-2R) is considered a marker of T-cell activation, and serum sIL-2R levels are elevated in RA and PCP. This led us to hypothesize that serum sIL-2R is a potential biomarker for discriminating MTX-PCP and MTX-IP. Accordingly, we carried out a retrospective analysis of 20 MITX-PCP cases, 30 MTX-IP cases, and as controls, 16 patients with RA-associated IP (RA-IP) and 13 patients with PCP without MTX treatment (PCP group). C-reactive protein and alveolar-arterial oxygen differences were higher in the MTX-PCP group than those in the RA-IP and MTX-IP groups. Importantly, serum levels of sIL-2R in MTX-PCP were significantly higher than those in other three groups. Based on the receiver operating characteristic curve, the cut-off level of sIL-2R resulting in the highest diagnostic accuracy for MTX-PCP was 1,311.5 U/mL, discriminating between MTX-PCP and other groups with 91.7% sensitivity and 78.6% specificity. Thus, patients with MTX-PCP show a higher degree of systemic inflammation, severe hypoxemia, and increased sIL-2R levels compared with those in MTX-IP cases. In conclusion, serum sIL-2R could be a biomarker for PCP diagnosis among patients with RA under MTX therapy.

Elevated α-defensin levels in plasma and bronchoalveolar lavage fluid from patients with myositis-associated interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is a prognostic indicator of poor outcome in myositis. Although the pathogenesis of myositis-associated ILD is not well understood, neutrophils are thought to play a pivotal role. Neutrophils store azurophil granules that contain defensins, which are antimicrobial peptides that regulate the inflammatory response. Here, we evaluated levels of the human neutrophil peptides (HNPs) α-defensin 1 through 3 in patients with myositis-associated ILD to determine whether HNPs represent disease markers and play a role in the pathogenesis of myositis-associated ILD. METHODS: HNP levels were measured in the plasma and bronchoalveolar lavage fluid (BALF) of 56 patients with myositis-associated ILD and 24 healthy controls by enzyme-linked immunosorbent assay. RESULTS: Analysis revealed significantly higher HNP levels in plasma and BALF samples from patients with myositis-associated ILD as compared to those of healthy controls; however, plasma HNPs were significantly correlated with total cell counts in BALF. Additionally, BALF HNP levels were positively correlated with serum surfactant protein-A and the percentage of neutrophils in BALF, and BALF HNP levels correlated with the percentage of reticular opacities in high-resolution computed tomography results for patients with anti-aminoacyl-tRNA synthetase (ARS) antibody positive myositis-associated ILD. Survival did not differ between patients with higher and lower levels of plasma and BALF HNPs. CONCLUSIONS: Plasma and BALF HNPs might reflect the disease activities of myositis-associated ILD, especially in patients with anti-ARS antibody positive myositis-associated ILD. However further studies are necessary to clarify whether HNPs represent disease markers and play roles in disease pathogenesis.

Premedication with Clarithromycin Is Effective against Secondary Bacterial Pneumonia during Influenza Virus Infection in a Pulmonary Emphysema Mouse Model.

Secondary bacterial pneumonia (SBP) during influenza increases the severity of chronic obstructive pulmonary disease (COPD) and its associated mortality. Macrolide antibiotics, including clarithromycin (CAM), are potential treatments for a variety of chronic respiratory diseases owing to their pharmacological activities, in addition to antimicrobial action. We examined the efficacy of CAM for the treatment of SBP after influenza infection in COPD. Specifically, we evaluated the effect of CAM in elastase-induced emphysema mice that were inoculated with influenza virus (strain A/PR8/34) and subsequently infected with macrolide-resistant Streptococcus pneumoniae CAM was administered to the emphysema mice 4 days prior to influenza virus inoculation. Premedication with CAM improved pathologic responses and bacterial load 2 days after S. pneumoniae inoculation. Survival rates were higher in emphysema mice than control mice. While CAM premedication did not affect viral titers or exert antibacterial activity against S. pneumoniae in the lungs, it enhanced host defense and reduced inflammation, as evidenced by the significant reductions in total cell and neutrophil counts and interferon (IFN)-γ levels in bronchoalveolar lavage fluid and lung homogenates. These results suggest that CAM protects against SBP during influenza in elastase-induced emphysema mice by reducing IFN-γ production, thus enhancing immunity to SBP, and by decreasing neutrophil infiltration into the lung to prevent injury. Accordingly, CAM may be an effective strategy to prevent secondary bacterial pneumonia in COPD patients in areas in which vaccines are inaccessible or limited.

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.

Effect of long-term treatment with corticosteroids on skeletal muscle strength, functional exercise capacity and health status in patients with interstitial lung disease.

BACKGROUND AND OBJECTIVE: Corticosteroids are occasionally used in the treatment of ILD. Chronic corticosteroid administration induces skeletal muscle weakness. However, it is unclear whether chronic corticosteroid treatment could further reduce skeletal muscle strength in patients with ILD who are weaker than healthy controls. The aim of this study was to determine the effects of chronic corticosteroid administration on skeletal muscle strength, exercise capacity, activities of daily living (ADL) and health status in ILD patients. METHODS: Forty-seven ILD patients treated with corticosteroids and 51 Medical Research Council dyspnea grade-matched ILD patients not treated with corticosteroids were assessed by isometric quadriceps muscle force (QF) and handgrip force (HF), pulmonary function, 6-min walk distance, ADL score and health status (Medical Outcomes Study 36-Item Short-Form Health Survey), and the two groups' results were compared. RESULTS: QF and HF were significantly lower in subjects on corticosteroids than in the control patients (QF, 52.6 ± 25.6 vs 77.1 ± 33.3 %predicted, P < 0.001; HF, 63.8 ± 22.4 vs 81.8 ± 28.3 %predicted, P < 0.001, respectively). There were no significant differences in the 6MWD, ADL score and all subscales of the SF-36 between the groups. Inverse correlations were found between skeletal muscle strength and total amount of corticosteroids administered (QF, r = -0.401, P = 0.005; HF, r = -0.403, P = 0.005). On multiple regression analysis, the total amount of corticosteroids was an independent predictor of HF. CONCLUSION: Chronic cor3ticosteroid treatment contributes to muscle weakness in ILD patients, and muscle weakness is inversely correlated to the total amount of corticosteroids administered.

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.

Association of elevated α-defensin levels with interstitial pneumonia in patients with systemic sclerosis.

BACKGROUND: Interstitial lung disease (ILD) is the leading cause of mortality in patients with systemic sclerosis (SSc). Although the pathogenesis of SSc-ILD is not well understood, neutrophils may play a pivotal role in this process. Neutrophils store azurophil granules that contain defensins, antimicrobial peptides that function in regulating the inflammatory response, and IL-8, a potent chemoattractant for neutrophils. The present study evaluated the levels of defensins and IL-8 in patients with SSc-ILD to determine their roles in disease pathogenesis. METHODS: Defensins (also known as human neutrophil peptides, HNPs) and IL-8 levels were measured in the serum and bronchoalveolar lavage fluid (BALF) of 33 patients with SSc-ILD and in 20 healthy controls by using ELISA. RESULTS: BALF analysis revealed a significant increase in HNPs in SSc-ILD patients (median; 240.0 pg/mL) than that of healthy controls (79.7 pg/mL). Additionally, IL-8 levels were higher in SSc-ILD patient serum and BALF as compared to healthy controls (16.4 pg/mL vs. 5.8 pg/mL and 15.4 pg/mL vs. 14.5 pg/mL, respectively). However, plasma HNPs levels were relatively unchanged. HNP and IL-8 levels in patient BALF displayed a significant positive correlation significantly correlated (r = 0.774, p <0.01), and which also correlated with clinical disease parameters--such as ILD biomarkers, pulmonary function tests, ratio of neutrophils and eosinophils in BALF, tricuspid regurgitation peak gradient (TRPG), and the extent of high-resolution computed tomography (HRCT) findings in the lung. Levels of plasma HNPs and serum IL-8 did not show a significant correlation with any clinical parameter. SSc-ILD progression was evaluated by pulmonary function tests, but no association was observed between VC change ratios and HNPs or IL-8 levels. CONCLUSIONS: BALF levels of HNPs and IL-8 were higher in SSc-ILD than in healthy controls, and are associated with various clinical disease parameters. Further studies are needed to clarify the role of defensins and IL-8 in SSc-ILD pathogenesis.

Comparison of pulmonary involvement between patients expressing anti-PL-7 and anti-Jo-1 antibodies.

Anti-PL-7 is an anti-tRNA synthetase antibody, and interstitial lung disease (ILD) is the most frequent complication of anti-PL-7-associated antisynthetase syndrome. However, the features of ILD have not been fully elucidated. The present study retrospectively compares 7 and 15 patients who were positive for anti-PL-7 and anti-Jo-1 antibodies, respectively. The features of ILD did not significantly differ between the two groups, but the ratio of lymphocytes in bronchoalveolar lavage fluid was higher in the Jo-1 than in the PL-7 group. High-resolution computed tomography revealed nonspecific interstitial pneumonia in all patients in the PL-7 group and organizing pneumonia in four of the 15 patients in the Jo-1 group. These findings suggest that pulmonary complications slightly differ between patients expressing anti-PL-7 and anti-Jo-1 antibodies. Further studies are required to clarify the features of ILD associated with PL-7.

Serum interferon-α is a useful biomarker in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis.

OBJECTIVE: We have tried to clarify the clinical importance of the measurement of serum type-I interferon (IFN) in patients with anti-melanoma differentiation-associated gene 5 Ab (MDA5 Ab)-positive dermatomyositis (DM). METHODS: We studied 30 patients with DM: 10 were anti-MDA5 Ab-positive and 20 were anti-MDA5 Ab-negative. At each patient's initial visit, serum IFN-α, IFN-ß, interleukin 18 (IL-18), ferritin, and the titer of anti-MDA5 Ab were measured using enzyme-linked immunosorbent assays (ELISAs). The associations between the IFNs and with the other variables were examined. RESULTS: Rapidly progressive interstitial lung disease (RPILD) was confirmed in 10 patients, most of whom were complicated in the anti-MDA5 Ab-positive DM patients. The presence of clinically amyopathic dermatomyositis (CADM) as well as the serum concentrations of IFN-α and ferritin was significantly higher in the anti-MDA5 Ab-positive DM patients. Serum concentration of IL-18 did not differ between anti-MDA5 Ab-positive and anti-MDA5 Ab-negative groups; however, a positive correlation was found between IFN-α and IL-18 in the anti-MDA5 Ab-positive DM patients (r = 0.8139, p = 0.0146). CONCLUSION: Serum IFN-α can be used as a useful biomarker in patients with anti-MDA5 Ab-positive DM, which may reflect the presence of RPILD.