Standardized 3D-CT lung volumes for patients with acute exacerbation of rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Fibrotic interstitial lung disease (ILD) is a progressive lung disease characterized by loss of lung volume, resulting in a leading cause of death in patients with RA. Crucially, acute exacerbation (AE) of ILD shows higher morbidity and mortality with rapid deterioration of the lungs. However, a quantitative assessment for physiological changes at AE has yet to be performed. This study hypothesized that quantitative assessments of lung volume (LV) accurately indicate disease severity and mortality risk in patients with AE-RA-ILD. METHODS: This multicentre cohorts study quantitatively assessed physiological changes of RA-ILD at diagnosis (n = 54), at AE (discovery-cohorts; n = 20, and validation-cohort; n = 33), and controls (n = 35) using 3D CT (3D-CT) images. LV was quantitatively measured using 3D-CT and standardized by predicted forced vital capacity. RESULTS: Patients with RA-ILD at diagnosis showed decreased LV, predominantly in lower lobes, compared with controls. Further substantial volume loss was found in upper- and lower lobes at AE compared with those at diagnosis. During AE, decreased standardized 3D-CT LV was associated with a worse prognosis in both cohorts. Subsequently, standardized 3D-CT LV was identified as a significant prognostic factor independent of age, sex and the presence of UIP pattern on CT by multivariate analyses. Notably, a composite model of age and standardized 3D-CT LV successfully classified mortality risk in patients with AE-RA-ILD. CONCLUSION: Volume loss at AE in patients with RA-ILD was associated with increased mortality. Assessing physiological change using standardized 3D-CT might help evaluate disease severity and mortality risk in patients with AE-RA-ILD.

Association of the lung immune prognostic index with the survival of patients with idiopathic interstitial pneumonias.

BACKGROUND AND OBJECTIVE: The lung immune prognostic index (LIPI), a simple index calculated from the blood lactate dehydrogenase level and derived neutrophil-to-lymphocyte ratio, is thought to be associated with host immune status. However, the utility of LIPI in patients with idiopathic interstitial pneumonias (IIPs) is unknown. METHODS: In this multicentre, retrospective, observational study, an association between LIPI and the survival of patients with IIPs was evaluated. RESULTS: Exploratory and validation cohorts consisting of 460 and 414 patients with IIPs, respectively, were included (159 and 159 patients had idiopathic pulmonary fibrosis [IPF], and 301 and 255 had non-IPF, respectively). In the exploratory cohort, patients with IPF and a low LIPI had significantly better survival than those with a high LIPI (median of 5.6 years vs. 3.9 years, p = 0.016). The predictive ability of LIPI for the survival of patients with IPF was validated in the validation cohort (median of 8.5 years vs. 4.4 years, p = 0.003). In a multivariate Cox proportional hazard analysis, LIPI was selected as an independent predictive factor for the survival of IPF patients. There was no significant association between LIPI and survival of non-IPF patients in the exploratory and validation cohorts. CONCLUSION: The LIPI was a predictive factor for the survival of patients with IPF and could aid the management of IPF.

3D-CT-derived lung volumes and mortality risk in patients with fibrotic hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is a complex and heterogenous interstitial lung disease (ILD) that occurs in susceptible individuals due to certain inhaled antigens. Fibrotic-HP is a major underlying disease of progressive pulmonary fibrosis. Therefore, in addition to the radiological features of HP, quantitatively measuring fibrosis is important to evaluate disease severity and progression. The present study aimed to compare three-dimensional computed tomography (3D-CT)-derived lung volumes (LVs) of patients with HP and determine its association with mortality risk. METHODS: In this retrospective and multicenter cohort study, 126 patients diagnosed with HP (fibrotic, n = 72 and non-fibrotic, n = 54) with a confidence level higher than moderate were enrolled. Each lobe LV was measured using 3D-CT at the time of diagnosis and standardized using predicted forced vital capacity. The 3D-CT LV was compared with those of 42 controls and 140 patients with idiopathic pulmonary fibrosis (IPF). RESULTS: Compared to patients with fibrotic-HP, the standardized total LV was significantly higher in controls and patients with non-fibrotic-HP and was similar in patients with IPF. Longitudinal analyses demonstrated that approximately half of the patients with fibrotic-HP had an annual decrease in total LV. Decreased total and lower-lobe LVs were associated with shorter survival, and were independently associated with mortality together with ongoing exposure to inciting antigens. A composite model consisting of ongoing exposure to inciting antigens and total or lower-lobe LV successfully classified mortality risk into three groups. CONCLUSIONS: Quantitatively measuring standardized LV can help determine disease severity, progression, and mortality risk in patients with fibrotic-HP.

Prognostic significance of radiological pleuroparenchymal fibroelastosis in Mycobacterium avium complex lung disease: a multicentre retrospective cohort study.

BACKGROUND: Mycobacterium avium complex (MAC) causes chronic respiratory infectious diseases with diverse clinical features and prognoses. Pleuroparenchymal fibroelastosis (PPFE) is a rare disease characterised by pleural fibrosis with subjacent intra-alveolar fibrosis and alveolar septal elastosis, with unique chest high-resolution CT (HRCT) features (radiological PPFE). An association between recurrent respiratory infections and PPFE formation has been hypothesised; however, the clinical significance of PPFE in MAC lung disease remains unclear. METHODS: This retrospective, multicentre study investigated the prevalence of radiological PPFE in patients with MAC lung disease and its association with clinical features and outcomes. Radiological PPFE was diagnosed on the basis of HRCT findings. Prognostic factors were identified using Cox proportional hazards and Fine-Gray models. RESULTS: Of 850 consecutive patients with definite MAC lung disease, 101 (11.9%) exhibited radiological PPFE. Patients with radiological PPFE had unique characteristics, such as lower body mass index, lower survival rate (5-year cumulative survival rate, 63.1% vs 91.7%; p<0.001) and a higher incidence of respiratory-related death (5-year cumulative incidence, 31.1% vs 3.6%; p<0.001), than those without radiological PPFE. In the multivariable analysis, the presence of radiological PPFE was independently associated with all-cause mortality (adjusted HR, 4.78; 95% CI, 2.87 to 7.95; p<0.001) and respiratory-related death (adjusted HR, 3.88; 95% CI, 2.14 to 7.01; p<0.001). INTERPRETATION: This large-scale study demonstrated that in patients with MAC lung disease, radiological PPFE was common, a phenotype associated with unique clinical features and poor prognosis, particularly respiratory-related death. The specific management of this subgroup should be established.

Cytokine profiling identifies circulating IL-6 and IL-15 as prognostic stratifiers in patients with non-small cell lung cancer receiving anti-PD-1/PD-L1 blockade therapy.

Whether circulating levels of specific cytokines at baseline link with treatment efficacy of immune checkpoint blockade (ICB) therapy in patients with non-small cell lung cancer remains unknown. In this study, serum samples were collected in two independent, prospective, multicenter cohorts before the initiation of ICB. Twenty cytokines were quantified, and cutoff values were determined by receiver operating characteristic analyses to predict non-durable benefit. The associations of each dichotomized cytokine status with survival outcomes were assessed. In the discovery cohort (atezolizumab cohort; N = 81), there were significant differences in progression-free survival (PFS) in accordance with the levels of IL-6 (log-rank test, P = 0.0014), IL-15 (P = 0.00011), MCP-1 (P = 0.013), MIP-1ß (P = 0.0035), and PDGF-AB/BB (P = 0.016). Of these, levels of IL-6 and IL-15 were also significantly prognostic in the validation cohort (nivolumab cohort, N = 139) for PFS (log-rank test, P = 0.011 for IL-6 and P = 0.00065 for IL-15) and overall survival (OS; P = 3.3E-6 for IL-6 and P = 0.0022 for IL-15). In the merged cohort, IL-6high and IL-15high were identified as independent unfavorable prognostic factors for PFS and OS. The combined IL-6 and IL-15 status stratified patient survival outcomes into three distinct groups for both PFS and OS. In conclusion, combined assessment of circulating IL-6 and IL-15 levels at baseline provides valuable information to stratify the clinical outcome of patients with non-small cell lung cancer treated with ICB. Further studies are required to decipher the mechanistic basis of this finding.

A predictive model for acute exacerbation of idiopathic interstitial pneumonias.

BACKGROUND: Acute exacerbation of idiopathic interstitial pneumonias (AE-IIPs) induces permanent pulmonary dysfunction and is potentially lethal. The unpredictable occurrence of AE-IIPs remains an important clinical issue in the management of IIPs. METHODS: In this multicentre, retrospective, observational study, a predictive score for AE-IIPs was designed using clinical factors based on multivariate Fine-Gray analysis in patients with IIPs. RESULTS: Based on multivariate Fine-Gray analysis in an exploratory cohort of 487 patients with IIPs, the predictive score for AE-IIPs was determined as follows: 1 point each was added for honeycombing on high-resolution computed tomography (H), age >75 years (A) and lactate dehydrogenase level >222 U·L-1 (L); the total score ranged from 0 to 3 (HAL score). The HAL score discriminated the risk of AE-IIPs with a C-index of 0.62 (95% CI 0.56-0.67); this discrimination was verified in a validation cohort of 402 patients with IIPs with a C-index of 0.67 (95% CI 0.60-0.73). In a combined cohort, the estimated cumulative risks for AE-IIPs at 1, 2, 3, 5 and 10 years were 1.9%, 3.5%, 5.1%, 7.7% and 12.9%, respectively, in the total score 0 group; 4.7%, 8.3%, 12.0%, 17.7% and 28.4%, respectively, in the total score 1 group; and 8.0%, 14.2%, 19.7%, 28.7% and 43.0%, respectively, in the total score ≥2 group. Subgroup analysis revealed that the HAL score was applicable to patients with and without idiopathic pulmonary fibrosis. CONCLUSIONS: The HAL score discriminated the risk of AE-IIPs and could aid in the management of IIPs.

Geriatric Nutritional Risk Index is a predictor of tolerability of antifibrotic therapy and mortality risk in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung fibrosis of unknown aetiology. Epidemiological studies have suggested that IPF progression may negatively affect nutritional status. Weight loss during antifibrotic therapy is also frequently encountered. The association of nutritional status and outcome has not been fully evaluated in IPF patients. METHODS: This retrospective multicohort study assessed nutritional status of 301 IPF patients receiving antifibrotic therapy (Hamamatsu cohort, n = 151; Seirei cohort, n = 150). Nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI). The GNRI was calculated based on body mass index and serum albumin. The relationship between nutritional status and tolerability of antifibrotic therapy as well as mortality was explored. RESULTS: Of 301 patients, 113 (37.5%) had malnutrition-related risk (GNRI < 98). Patients with malnutrition-related risk were older, had increased exacerbations and worse pulmonary function than those without a GNRI status <98. Malnutrition-related risk was associated with a higher incidence of discontinuation of antifibrotic therapy, particulary due to gastrointestinal disturbances. IPF patients with malnutrition-related risk (GNRI < 98) had shorter survival than those without such risk (median survival: 25.9 vs. 41.1 months, p < 0.001). In multivariate analysis, malnutrition-related risk was a prognostic indicator of antifibrotic therapy discontinuation and mortality, independent of age, sex, forced vital capacity, or gender-age-physiology index. CONCLUSION: Nutritional status has significant effects on the treatment and outcome in patients with IPF. Assessment of nutritional status may provide important information for managing patients with IPF.

Increased serum cholesterol and long-chain fatty acid levels are associated with the efficacy of nivolumab in patients with non-small cell lung cancer.

BACKGROUND: Lipids have immunomodulatory functions and the potential to affect cancer immunity. METHODS: The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab. RESULTS: When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P < 0.001), high-density lipoprotein (HDL)-cholesterol (P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P < 0.001), HDL-cholesterol (P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid. CONCLUSIONS: Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.

Idiopathic pleuroparenchymal fibroelastosis: three-dimensional computed tomography assessment of upper-lobe lung volume.

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a rare interstitial lung disease characterised by predominant upper-lobe fibrosis involving the pleura and subpleural lung parenchyma. Despite its poor prognosis, there is no consensus on prognostic determinants of iPPFE to date. Because volume loss in the upper lobe is a distinct feature of iPPFE, we hypothesised that the lung volume of the bilateral upper lobes (upper-lobe volume) accurately indicates disease severity and mortality risk in iPPFE patients. METHODS: This retrospective study assessed two cohorts of 132 patients with iPPFE (69 in Hamamatsu cohort; 63 in Seirei cohort) and 45 controls. Each lobe volume was quantitatively measured using three-dimensional computed tomography at the time of iPPFE diagnosis and standardised using predicted forced vital capacity. RESULTS: The standardised upper-lobe volume in iPPFE patients was less than half that of controls, whereas the lower-lobe volume did not decrease. iPPFE patients with lower standardised upper-lobe volume had significantly shorter survival rates than those with higher volume (median survival: 6.08 versus 2.48 years, p<0.001). In multivariate analysis, the lower standardised upper-lobe volume was significantly associated with increased mortality adjusting for age, sex and forced vital capacity (HR 0.939). A composite scoring model, including age, sex and standardised upper-lobe volume, better predicted risk of death than the gender-age-physiology model. CONCLUSION: Assessment of upper-lobe volume provides useful information for managing iPPFE by evaluating disease severity and mortality risk in clinical practice.

Erlotinib and bevacizumab in elderly patients ≥75 years old with non-small cell lung cancer harboring epidermal growth factor receptor mutations.

The efficacy and safety of combination therapy with erlotinib and bevacizumab in elderly patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations are unknown. Elderly patients aged ≥75 years old with advanced or recurrent NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) received erlotinib (150 mg, daily) and bevacizumab (15 mg/kg on day 1 of a 21-day cycle) until disease progression or the occurrence of unacceptable toxicities. The primary endpoint was progression-free survival from enrollment. Twenty-five patients were enrolled in this study, and the median age was 80 years. Fifteen (60.0%) and 10 patients (40.0%) had exon 21 L858R mutations and exon 19 deletions, respectively. The median progression-free survival from enrollment was 12.6 months [95% confidence interval (CI): 8.0-33.7 months]. The objective response rate was 88.0% [95% CI: 74.0%-99.0%], and the disease control rate was 100% [95% CI: 88.7%-100%]. Grade 3 or higher adverse events occurred in 12 patients (48.0%), and rash and nausea were the most common. Grade 3 or higher bevacizumab-related toxicities occurred in 4 (16.0%) patients, including proteinuria (n = 2), gastrointestinal perforation (n = 1) and pneumothorax (n = 1). A dose reduction of erlotinib and cessation of bevacizumab was required in 16 (64.0%) and 18 patients (72.0%), respectively. Erlotinib and bevacizumab combination therapy showed a minimal survival benefit with frequent dose reductions and/or treatment discontinuations in elderly patients with EGFR-positive NSCLC.

Pneumothorax in Patients with Idiopathic Pleuroparenchymal Fibroelastosis: Incidence, Clinical Features, and Risk Factors.

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare form of idiopathic interstitial pneumonia that is characterized by predominantly upper lobe pleural and subpleural lung parenchymal fibrosis. Pneumothorax is one of the major respiratory complications in PPFE patients; however, its clinical features are poorly understood. OBJECTIVE: We aimed to investigate the complication of pneumothorax in patients with idiopathic PPFE. METHODS: A retrospective multicenter study involving 89 patients who had been diagnosed with idiopathic PPFE was conducted. We investigated the cumulative incidence, clinical features, and risk factors of pneumothorax after the diagnosis of idiopathic PPFE. RESULTS: Pneumothorax developed in 53 patients (59.6%) with 120 events during the observation period (41.8 ± 35.0 months). The cumulative incidence of pneumothorax was 24.8, 44.9, and 53.9% at 1, 2, and 3 years, respectively. Most events of pneumothorax were asymptomatic (n = 85; 70.8%) and small in size (n = 92; 76.7%); 30 patients (56.6%) had recurrent pneumothorax. Chest drainage was required in 23 pneumothorax events (19.2%), and a persistent air leak was observed in 13 (56.5%). Patients with pneumothorax were predominantly male and frequently had pathological diagnoses of PPFE and prior history of pneumothorax and corticosteroid use; they also had significantly poorer survival than those without pneumothorax (log-rank test; p = 0.001). Multivariate analysis revealed that a higher residual volume/total lung capacity ratio was significantly associated with the development of pneumothorax after the diagnosis. CONCLUSION: Pneumothorax is often asymptomatic and recurrent in patients with idiopathic PPFE, leading to poor outcomes in some cases.

Efficacy of corticosteroid and intravenous cyclophosphamide in acute exacerbation of idiopathic pulmonary fibrosis: A propensity score-matched analysis.

BACKGROUND AND OBJECTIVE: Acute exacerbation (AE) is a leading cause of death in patients with idiopathic pulmonary fibrosis (IPF). Although optimal treatment for AE-IPF remains unclear, high-dose corticosteroids (CS) with/without immunosuppressants, including intravenous cyclophosphamide (IVCY), are often used as empirical therapy. However, the survival benefit of adding IVCY to CS therapy is unknown. We investigated the efficacy of this therapy in patients with AE-IPF. METHODS: Overall, 102 consecutive patients with IPF with a first idiopathic AE were included. Post-AE survival rates and treatment safety were retrospectively assessed. Efficacy of CS + IVCY therapy for the first AE was compared with that of CS monotherapy using a propensity score-matched analysis. RESULTS: The post-AE 90-day survival rate of the entire cohort was 64.7%. On the basis of the propensity scores, 26 matched patient pairs were made. Characteristics of matched patients with AE-IPF treated with CS (matched CS group) and those with CS + IVCY (matched CS + IVCY group) were well balanced. No significant between-group differences were observed in post-AE 90-day survival rates (84.6% vs 76.9%; P = 0.70), cumulative survival rates (P = 0.57 by log-rank test) or incidence of adverse events ≥ CTCAE (Common Terminology Criteria for Adverse Events) v5.0 grade 3 (61.5% vs 65.4%; P = 1.00). CONCLUSION: The propensity score-matched analysis demonstrated that compared with CS monotherapy, CS + IVCY therapy did not significantly improve post-AE survival in patients with AE-IPF. Further studies are warranted to assess the efficacy of CS + IVCY therapy for AE-IPF.

Differences in airway structural changes assessed by 3-dimensional computed tomography in asthma and asthma-chronic obstructive pulmonary disease overlap.

BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical phenotype sharing features of asthma and COPD. Multidetector row computed tomography (MDCT) can be used to evaluate the airway structure; however, differences between asthma and ACO seen on MDCT are poorly understood. OBJECTIVE: To investigate the difference in airway structural between asthma and ACO, using MDCT in patients with clinical asthma. METHODS: Sixty-four patients with asthma were allocated to an asthma group (never smokers and ex-smokers with a smoking history of < 10 pack-years) or an ACO group (patients with a ≥10-pack-year smoking history and forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] < 0.7). The asthma group was further divided into patients with airflow limitation (AL; FEV1/FVC < 0.7) and those without AL. Wall thickness (WT) and airway inner luminal area in the third-generation to fifth-generation bronchi were evaluated using MDCT in both study groups and in 29 healthy controls. RESULTS: Forty-three patients were included in the asthma group (20 with AL, 23 without AL) and 16 in the ACO group. Patients with asthma and ACO had significantly greater WT than the healthy controls. WT in the third-generation bronchi was significantly greater in the ACO group than in the asthma group. The ACO group and the asthma with AL group were matched for age, disease duration, and FEV1/FVC. The WT in the third-generation bronchi was still greater in the ACO group than in the asthma with AL group. CONCLUSION: Patients with ACO have a thicker airway wall than those with asthma, suggesting that airway remodeling is more prominent in ACO than in asthma. UMIN Clinical Trials Registry (UMIN-CTR) system (http://www.umin.ac.jp/ctr/UMIN000028913).

Possibility of using salivary ultra-weak chemiluminescence as a biomarker for feelings of anxiety in hospital settings.

The aim of this study was to assess whether a particular value of noninvasive salivary ultra-weak chemiluminescence (UCL) could be used as a biomarker of psychological stress. Our study covered two groups. Group 1 comprised six healthy volunteers who stayed in a hospital for one night and group 2 comprised 15 patients with lung cancer and 24 patients with respiratory diseases other than lung cancer who were in hospital for an extended stay. First, we evaluated the UCL of saliva from six healthy volunteers before and after one night in hospital. Immunoglobulin A (IgA) concentrations were also measured. The integrated intensity value of UCL was correlated with the IgA concentration (correlation coefficient 0.90). Second, in the case of a long hospital stay, we found that the maximum salivary UCL intensities were higher in patients with lung cancer than in those with respiratory diseases other than lung cancer or in 28 healthy controls. Copyright © 2016 John Wiley & Sons, Ltd.

Efficacy of short-term prednisolone treatment in patients with chronic eosinophilic pneumonia.

In patients with chronic eosinophilic pneumonia (CEP), dramatic improvements are seen in response to corticosteroid therapy; however, relapse is common after treatment has ceased. The optimal duration of corticosteroid therapy remains unclear. In a randomised, open-label, parallel group study, eligible patients with CEP received oral prednisolone for either 3 months (3-month group) or 6 months (6-month group), followed by 2 years observation. All patients were treated with an initial dose of prednisolone of 0.5 mg·kg(-1)·day(-1), which was then tapered and discontinued at either 3 or 6 months. The primary end-point was relapse during the follow-up period. In the final analysis, there were 23 patients in the 3-month group and 21 patients in the 6-month group. All patients showed a good response to prednisolone treatment. There were 12 (52.1%) relapses in the 3-month group and 13 (61.9%) relapses in the 6-month group. No significant difference was found in the cumulative rate of relapse (p=0.56). All relapse cases showed improvement upon resumption of prednisolone treatment. No difference was observed in the rate of relapse between the 3- and 6-month prednisolone treatment groups for patients with CEP.

Nontypeable Haemophilus influenzae exploits the interaction between protein-E and vitronectin for the adherence and invasion to bronchial epithelial cells.

BACKGROUND: Nontypeable Haemophilus influenzae (NTHi) is one of the most common Gram-negative pathogens in otitis media and exacerbation of chronic obstructive pulmonary disease. NTHi has been reported to invade bronchial epithelial cells. This penetration enables NTHi to evade the host immune system and antibiotics, and it seems to be related to the intractable features of these diseases. However, the precise mechanism of the invasion has been unknown. We hypothesized that protein-E, an outer membrane protein of NTHi, plays a role in this penetration into bronchial epithelial cells. RESULTS: We utilized two NTHi strains. NTHi efficiently attached to plate-bound vitronectin (254-309/field at 1,000× magnification) and this attachment was blocked by pretreatment with protein-E peptide (PE84-108). The blockade of adhesion was dependent on the concentration of PE84-108. NTHi strains invaded bronchial epithelial cells and the intracellular bacteria were localized in early endosomes. Furthermore, intracellular invasion of NTHi was also blocked by PE84-108, but not by Arg-Gly-Asp (RGD) peptide. Pretreatment with PE84-108 significantly prevented cells from being invaded by both NTHi strains, which was confirmed by fluorescent microscope observation. In addition, pretreatment with PE84-108 significantly reduced percentages of CFU after gentamicin treatment of cells per input CFU. CONCLUSIONS: These results suggest that NTHi does not directly bind to the cell surface, but binds to host vitronectin that is bound to the cell surface, via bacterial protein-E. Bacterial protein-E and host vitronectin play a role in the attachment to bronchial epithelial cells and is also involved in the subsequent intracellular invasion of NTHi. A novel vaccine or treatment strategy targeting the protein-E-vitronectin axis may prevent respiratory intracellular infection of NTHi and may lead to better clinical outcomes.

Treatment of acute exacerbation of idiopathic pulmonary fibrosis with direct hemoperfusion using a polymyxin B-immobilized fiber column improves survival.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has an extremely poor prognosis and there is currently no effective treatment for this condition. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) improves oxygenation, but it is unclear whether treatment of AE-IPF with PMX-DHP affects survival. This study elucidated the effectiveness and safety of PMX-DHP for the treatment of AE-IPF. METHODS: This study included 31 patients with 41 episodes of AE-IPF. All patients received steroids. Of 31, 14 patients (20 episodes) were treated with PMX-DHP. The laboratory and physiological test results after the start of therapy and survival were retrospectively compared between patients treated with and without PMX-DHP. RESULTS: Patients treated with PMX-DHP had a significantly greater change in PaO2/FiO2 ratio (mean ± SEM, 58.2 ± 22.5 vs. 0.7 ± 13.3, p = 0.034) and a smaller change in white blood cell count (-630 ± 959 /µL vs. 4500 ± 1190 /µL, p = 0.002) after 2 days of treatment than patients treated without PMX-DHP. The 12-month survival rate was significantly higher in patients treated with PMX-DHP (48.2% vs. 5.9%, p = 0.041). PMX-DHP was effective in patients with more severe underlying disease (GAP stages II or III; 12-month survival rate 57.1% with PMX-DHP vs. 0% without PMX-DHP, p = 0.021). Treatment with PMX-DHP was an independent predictor of better prognosis (hazard ratio 0.345, p = 0.037). Mild pulmonary thromboembolism occurred in one patient treated with PMX-DHP. CONCLUSIONS: Treatment of AE-IPF with PMX-DHP is tolerable and improves 12-month survival.

Toll-like receptor-mediated airway IL-17C enhances epithelial host defense in an autocrine/paracrine manner.

IL-17A, IL-17F, and IL-25 belong to the IL-17 family of cytokines, and are well known to play important roles in the host defense against infection and inflammatory diseases. IL-17C, also a member of the IL-17 family, is highly expressed in the epithelium; however, the function and regulatory mechanism of IL-17C in airway epithelium remain poorly understood. In this study, we demonstrate that polyinosinic-polycytidylic acid (polyI:C), the ligand to Toll-like receptor 3, is a potent inducer of IL-17C mRNA and protein expression in primary normal human bronchial epithelial (NHBE) cells. IL-17C induction by polyI:C was both time dependent and dose dependent, and was attenuated by inhibitors of the Toll-IL-1 receptor domain-containing adaptor-inducing INF-ß (TRIF)-NF-κB pathway, Pepinh-TRIF, BAY11, NF-κB inhibitor III, and NF-κB p65 small interfering RNA, suggesting that IL-17C expression is induced by polyI:C via the Toll-like receptor 3-TRIF-NF-κB pathway. Both IL-17C and polyI:C increased the expression of antimicrobial peptides and proinflammatory cytokines, such as human ß-defensin (hBD) 2, colony-stimulating factor 3 (CSF3), and S100A12 in NHBE cells. Knockdown of IL-17 receptor (IL-17R) E, the specific receptor for IL-17C, using IL-17RE small interfering RNA, attenuated polyI:C-induced hBD2, CSF3, and S100A12 expression, without any reduction of polyI:C-induced IL-17C expression, which suggest that IL-17C enhances hBD2, CSF, and S100A12 expression in an autocrine/paracrine manner in NHBE cells. Knockdown of IL-17C also decreased polyI:C-induced hBD2, CSF3, and S100A12 expression. Thus, our data demonstrate that IL-17C is an essential epithelial cell-derived cytokine that enhances mucosal host defense responses in a unique autocrine/paracrine manner in the airway epithelium.

Switching from salmeterol/fluticasone to formoterol/budesonide combinations improves peripheral airway/alveolar inflammation in asthma.

BACKGROUND: Combination therapy with an inhaled corticosteroid (ICS) and a long-acting ß2-agonist (LABA) in a single inhaler is the mainstay of asthma management. We previously showed that switching from salmeterol/fluticasone combination (SFC) 50/250 µg bid to a fixed-dose formoterol/budesonide combination (FBC) 9/320 µg bid improved asthma control and pulmonary functions, but not fractional exhaled nitric oxide (FeNO), in patients with asthma not adequately controlled under the former treatment regimen. OBJECTIVE: To assess whether switching from SFC to FBC improves peripheral airway/alveolar inflammation in asthma (UMIN000009619). METHODS: Subjects included 66 patients with mild to moderate asthma receiving SFC 50/250 µg bid for more than 8 weeks. Patients were randomized into FBC 9/320 µg bid or continued the same dose of SFC for 12 weeks. Asthma Control Questionnaire, 5-item version (ACQ5) score, peak expiratory flow, spirometry, FeNO, alveolar NO concentration (CANO), and maximal NO flux in the conductive airways (J'awNO) were measured. RESULTS: Sixty-one patients completed the study. The proportion of patients with an improvement in ACQ5 was significantly higher in the FBC group than in the SFC group (51.6% vs 16.7%, respectively, p = 0.003). A significant decrease in CANO was observed in the FBC group (from 8.8 ± 9.2 ppb to 4.0 ± 2.6 ppb; p = 0.007) compared to the SFC group (from 7.4 ± 7.8 ppb to 6.4 ± 5.0 ppb; p = 0.266) although there was no significant difference in the changes in pulmonary functions between the 2 groups. Similar significant differences were found in the CANO corrected for the axial back diffusion of NO (FBC, from 6.5 ± 8.2 ppb to 2.3 ± 2.5 ppb; and SFC, from 4.3 ± 5.3 ppb to 3.9 ± 4.3 ppb). There was no difference in the changes in FeNO or J'awNO between the 2 groups. CONCLUSIONS: Switching therapy from SFC to FBC improves asthma control and peripheral airway/alveolar inflammation even though there is no improvement in pulmonary functions, and FeNO in asthmatic patients.