Anti-interferon gamma-inducible protein 16 antibodies: Identification of a novel autoantigen in idiopathic interstitial pneumonia and its clinical characteristics based on a multicenter cohort study.

Autoantibodies are detected in idiopathic interstitial pneumonias (IIPs) without a clear connective tissue disease diagnosis, and their clinical significance is unclear. This study aimed to identify a novel autoantibody in IIPs. We screened 295 IIP patients using a 35S-methionine labeled protein immunoprecipitation assay. Candidate autoantigens were identified via protein array and confirmed by immunoprecipitation. Six sera from 295 IIP patients immunoprecipitated common tetrameric proteins (100 kDa). The protein array identified interferon gamma-inducible protein 16 (IFI16) as the candidate autoantigen. Patients with anti-IFI16 antibodies received immunosuppressants less frequently. Five-year survival rates were 50 %, 69 %, and 63 % (P = 0.60), and acute exacerbation-free rates were 50 %, 96 %, and 84 % (P = 0.15) for patients with anti-IFI16, anti-aminoacyl tRNA antibodies, and others. Anti-IFI16 is a novel autoantibody in IIPs. Patients with this antibody often receive less immunosuppressive therapy and could have a poor prognosis. Further research is needed to refine patient stratification and management.

Evaluation of Bone Mineral Density in Lung Transplant Recipients by Chest Computed Tomography.

INTRODUCTION: Lung transplantation (LT) recipients are at risk of bone mineral density (BMD) loss. Pre- and post-LT BMD loss has been reported in some cross-sectional studies; however, there are limited studies regarding the serial BMD change in LT recipients. The aim of this study was to investigate the serial BMD changes and the clinical characteristics associated with BMD decline. METHODS: This was a single-center, retrospective observational study. BMD was serially measured in thoracic vertebral bodies (Th4, 7, 10) using computed tomography (CT) before and 3 and 12 months after LT. The frequency of osteoporosis and factors associated with pre-LT osteoporosis and post-LT BMD loss were evaluated. The frequency of post-LT compression fracture and its associated factors were also analyzed. RESULTS: This study included 128 adult LT recipients. LT recipients had decreased BMD (151.8 ± 42.2 mg/mL) before LT compared with age-, sex-, and smoking index-matched controls (176.2 ± 35.7 mg/mL). The diagnosis of COPD was associated with pre-LT osteoporosis. LT recipients experience further BMD decline after transplantation, and the percentage of recipients classified as exhibiting osteoporosis increased from 20% at baseline to 43% at 12 months. Recipients who had been taking no or small doses of glucocorticoids before LT had rapid BMD loss after LT. Early bisphosphonate use (within 3 months) after LT attenuated BMD loss and decreased new-onset compression fracture. CONCLUSION: LT recipients are at high risk for BMD loss and compression fracture after LT. Early bisphosphonate use may decrease BMD loss and compression fracture.

Longitudinal assessment of interstitial lung abnormalities on CT in patients with COPD using artificial intelligence-based segmentation: a prospective observational study.

BACKGROUND: Interstitial lung abnormalities (ILAs) on CT may affect the clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), but their quantification remains unestablished. This study examined whether artificial intelligence (AI)-based segmentation could be applied to identify ILAs using two COPD cohorts. METHODS: ILAs were diagnosed visually based on the Fleischner Society definition. Using an AI-based method, ground-glass opacities, reticulations, and honeycombing were segmented, and their volumes were summed to obtain the percentage ratio of interstitial lung disease-associated volume to total lung volume (ILDvol%). The optimal ILDvol% threshold for ILA detection was determined in cross-sectional data of the discovery and validation cohorts. The 5-year longitudinal changes in ILDvol% were calculated in discovery cohort patients who underwent baseline and follow-up CT scans. RESULTS: ILAs were found in 32 (14%) and 15 (10%) patients with COPD in the discovery (n = 234) and validation (n = 153) cohorts, respectively. ILDvol% was higher in patients with ILAs than in those without ILA in both cohorts. The optimal ILDvol% threshold in the discovery cohort was 1.203%, and good sensitivity and specificity (93.3% and 76.3%) were confirmed in the validation cohort. 124 patients took follow-up CT scan during 5 ± 1 years. 8 out of 124 patients (7%) developed ILAs. In a multivariable model, an increase in ILDvol% was associated with ILA development after adjusting for age, sex, BMI, and smoking exposure. CONCLUSION: AI-based CT quantification of ILDvol% may be a reproducible method for identifying and monitoring ILAs in patients with COPD.

Sleep disordered breathing and haemoglobin A1c levels within or over normal range and ageing or sex differences: the Nagahama study.

Recently an association between blood glucose dysregulation and sleep disruption was suggested. The association between sleep disordered breathing, most of which is due to obstructive sleep apnea (OSA) in the general population, and diabetic severity, as well as the impact of antidiabetic treatment, remains unclear. This study aimed to investigate these associations as well as age and sex differences. This cross-sectional study evaluated 7,680 community participants as the main cohort (population-based cohort). OSA was assessed by the 3% oxygen desaturation index from pulse oximetry, which was corrected for sleep duration obtained by wrist actigraphy. For arguing the limitations for using pulse oximetry, 597 hospitalised patients, who were assessed by the apnea-hypopnea index from attended polysomnography, were also evaluated as the validation cohort (hospital-based cohort). Moderate-to-severe OSA was more prevalent as haemoglobin A1c (HbA1c) levels increased (<5.6%/5.6%-<6.5%/6.5%-<7.5%/≥7.5%, respectively) in both cohorts (p < 0.001), but only in those without antidiabetic treatment. The HbA1c level was an independent factor for moderate-to-severe OSA (population-based cohort, odds ratio [OR] 1.26, 95% confidence interval [CI] 1.10-1.45; hospital-based cohort, OR 1.69, 95% CI 1.22-2.33, per 1% increase). These associations were more prominent in the middle-aged (aged <60 years) than in the elderly (aged ≥60 years) and in women than in men in both cohorts. The prevalence of moderate-to-severe OSA in patients with antidiabetic treatment in the hospital-based cohort was ≥75% regardless of HbA1c levels. In conclusion, an association between the prevalence of OSA and HbA1c level even within or over the normal range was found only in patients without antidiabetic treatment and was more prominent in the middle-aged and in women.

Variation in information needs of patients with interstitial lung disease and their family caregivers according to long-term oxygen therapy: a descriptive study.

BACKGROUND: The information needs of patients and their families regarding interstitial lung disease (ILD) have yet to be studied in detail, and few reports have examined the differences in information needs according to patient status. This study aimed to determine whether there are differences in information needs between outpatients with ILD and their family caregivers and whether these differences depend on long-term oxygen therapy use. METHODS: Patients with fibrotic ILDs and their families who visited Kyoto University Hospital between February 2020 and March 2022 were recruited for this descriptive study. Fibrotic ILDs included idiopathic pulmonary fibrosis (IPF), other idiopathic interstitial pneumonias (IIPs) than IPF, connective tissue disease-associated ILD (CTD-ILD), and fibrotic hypersensitivity pneumonia. Data were obtained from electronic patient records and questionnaires. Descriptive data analyses were performed. RESULTS: Sixty-five patients and their family caregivers were analyzed. Twenty-seven (41.5%) patients had IIPs (IPF 9 and other IIPs 18), 34 (52.3%) had CTD-ILD, and 4 (6.2%) had fibrotic hypersensitivity pneumonia. The most common relationship between the patient and their family was a spouse (67.7%), with 80% living together. The primary information needs among patients and their family caregivers were common up to the third rank but differed from the rest. Patients were interested in "when and where to contact health care providers" and "end-of-life care and advanced directives," while family caregivers were interested in "diet and nutrition" and "care and support at home." Patients with long-term oxygen therapy had higher needs for "end-of-life care and advanced directives" and "how to manage breathlessness, cough, and fatigue," while the needs for "drugs for ILD" and "acute exacerbation of ILD" were relatively low. Family caregivers were interested in "diet and nutrition" in the long-term oxygen therapy group and "acute exacerbation of ILD" in the no long-term oxygen therapy group. CONCLUSIONS: This study found that the information needs of patients and their family caregivers were not the same and that the aspect of information needs differed by long-term oxygen therapy status. Healthcare providers should consider the position of the recipient of information, the appropriate time based on the patient's condition, and the necessary information.

Clinical, radiological and pathological features of idiopathic and secondary interstitial pneumonia with pleuroparenchymal fibroelastosis in patients undergoing lung transplantation.

AIMS: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare type of idiopathic interstitial pneumonia, and pathological PPFE is also observed in patients with secondary interstitial pneumonia. This study aimed to evaluate the pathological findings associated with radiological PPFE-like lesions and the clinical and morphological features of patients with pathological PPFE. METHODS AND RESULTS: We retrospectively reviewed the pathology of the explanted lungs from 59 lung transplant recipients with radiological PPFE-like lesions. Pathological PPFE lesions were identified in 14 patients with idiopathic disease and in 12 patients with secondary disease. Pathological PPFE was associated with previous pneumothorax, volume loss in the upper lobes, and a flattened chest. Patients with idiopathic disease and those with secondary disease with pathological PPFE had similar clinical, radiological and pathological findings, whereas fibroblastic foci were more common in patients with idiopathic disease, and patients with secondary disease more frequently showed alveolar septal thickening with elastosis or fibrosis. Post-transplantation survival did not differ between patients with idiopathic and secondary disease with pathological PPFE (log-rank; P = 0.57) and was similar between patients with idiopathic disease with pathological PPFE and those with idiopathic pulmonary fibrosis (IPF) (log-rank; P = 0.62). CONCLUSIONS: Not all patients with interstitial pneumonia with radiological PPFE-like lesions have pathological PPFE. Characteristic clinical features can suggest the presence of pathological PPFE, and idiopathic and secondary cases with pathological PPFE are similar except for fibroblastic foci in idiopathic cases and alveolar septal thickening with elastosis or fibrosis in secondary cases. Patients with pathological PPFE have a similar prognosis to those with IPF after transplantation.

Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by regnase-1.

Regnase-1 is an RNase critical for post-transcriptional control of pulmonary immune homeostasis in mice by degrading immune-related mRNAs. However, little is known about the cell types Regnase-1 controls in the lung, and its relevance to human pulmonary diseases.Regnase-1-dependent changes in lung immune cell types were examined by a competitive bone marrow transfer mouse model, and group 2 innate lymphoid cells (ILC2s) were identified. Then the associations between Regnase-1 in ILC2s and human diseases were investigated by transcriptome analysis and a bleomycin-induced pulmonary fibrosis mouse model. The clinical significance of Regnase-1 in ILC2s was further assessed using patient-derived cells.Regnase-1-deficiency resulted in the spontaneous proliferation and activation of ILC2s in the lung. Intriguingly, genes associated with pulmonary fibrosis were highly upregulated in Regnase-1-deficient ILC2s compared with wild-type, and supplementation of Regnase-1-deficient ILC2s augmented bleomycin-induced pulmonary fibrosis in mice. Regnase-1 suppresses mRNAs encoding transcription factors Gata3 and Egr1, which are potent to regulate fibrosis-associated genes. Clinically, Regnase-1 protein levels in ILC2 negatively correlated with the ILC2 population in bronchoalveolar lavage fluid. Furthermore, idiopathic pulmonary fibrosis (IPF) patients with ILC2s >1500 cells·mL-1 peripheral blood exhibited poorer prognosis than patients with lower numbers, implying the contribution of Regnase-1 in ILC2s for the progression of IPF.Collectively, Regnase-1 was identified as a critical post-transcriptional regulator of the profibrotic function of ILC2s both in mouse and human, suggesting that Regnase-1 may be a novel therapeutic target for IPF.

Cutaneous T-cell-attracting chemokine as a novel biomarker for predicting prognosis of idiopathic pulmonary fibrosis: a prospective observational study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients. METHODS: A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed. RESULTS: In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01-1.07; IL-8, HR = 1.04, 95% CI 1.01-1.08; MIP-1α, HR = 1.19, 95% CI 1.00-1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02-1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01-1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls. CONCLUSIONS: CTACK is a novel prognostic biomarker of IPF. Trial registration None (because of no healthcare intervention).

Prospective associations of sleep apnea, periodic limb movements, and plasma fibrinogen level.

PURPOSE: Our previous cross-sectional study showed that periodic limb movements during sleep (PLMS) were frequently found in patients with obstructive sleep apnea (OSA) and that both OSA and PLMS were associated with higher plasma fibrinogen levels. We explored the longitudinal relationships among these factors. METHODS: Plasma fibrinogen levels were measured in 333 consecutive patients who underwent polysomnography to diagnose OSA. Patients who initiated continuous positive airway pressure (CPAP) underwent follow-up polysomnography after 3 months of CPAP use. They were categorized into groups with good or poor adherence (% days with ≥ 4 h/night of CPAP use ≥ 70% or < 70%, respectively). Changes in sleep parameters and plasma fibrinogen levels during the treatment period were compared between these groups. RESULTS: The cross-sectional analysis of all reviewed 333 patients indicated that fibrinogen levels were associated with the severities of OSA and PLMS. The 60 patients (27 good and 33 poor adherence) who underwent follow-up polysomnography were included in the longitudinal analysis. The median (interquartile range) periodic limb movement index did not change significantly from CPAP titration to the 3-month follow-up (good adherence: 10.5 (0-23.8) to 10.8 (0-70.2) events/h, p = 0.21; poor adherence: 1.2 (0-14.3) to 0.8 (0-15.7) events/h, p = 0.67). However, the plasma fibrinogen level significantly decreased only in the good adherence group (good adherence: baseline 275 ± 46 to follow-up 255 ± 47 mg/dl, p < 0.01; poor adherence: 277 ± 52 to 284 ± 70 mg/dl, p = 0.48). CONCLUSIONS: These results did not support a longitudinal association between PLMS and OSA. However, good adherence to CPAP could reduce plasma fibrinogen levels, thus ameliorating elevations in plasma fibrinogen as a risk factor for future cardiovascular events.

Outcomes of lung transplantation for idiopathic pleuroparenchymal fibroelastosis.

PURPOSE: This study was performed to compare the outcome of lung transplantation (LT) for idiopathic pleuroparenchymal fibroelastosis (IPPFE) with that of LT for idiopathic pulmonary fibrosis (IPF). METHODS: We reviewed, retrospectively, all adult patients who underwent LT for IPPFE or IPF in Japan between 1998 and 2018. RESULTS: There were 100 patients eligible for this study (31 with IPPFE and 69 with IPF). Patients with IPPFE tended to have a significantly lower body mass index (BMI) than those with IPF (median, 16.7 vs. 22.6 kg/m2, respectively; P < 0.01). However, Kaplan-Meier survival curves showed no significant difference in overall survival between the groups. The BMI did not increase in patients with IPPFE, even 1 year after LT (pretransplant, 16.5 ± 3.2 kg/m2 vs. 1 year post-transplant, 15.6 ± 2.5 kg/m2; P = 0.08). The percent predicted forced vital capacity (%FVC) 1 year after LT was significantly lower in the IPPFE group than in the IPF group (48.4% ± 19.5% vs. 68.6% ± 15.5%, respectively; P < 0.01). CONCLUSIONS: Despite extrapulmonary problems such as a flat chest, low BMI, and associated restrictive impairment persisting in patients with IPPFE, patient survival after LT for IPPFE or IPF was equivalent.

Sleep disordered breathing and metabolic comorbidities across sex and menopausal status in East Asians: the Nagahama Study.

It is well known that the prevalence of sleep disordered breathing (SDB) is increased in patients with obesity or metabolic comorbidities. However, the way in which the prevalence of SDB increases in relation to comorbidities according to the severity of obesity remains unclear.This cross-sectional study evaluated 7713 community participants using nocturnal oximetry ≥2 nights. SDB was assessed by the 3% oxygen desaturation index corrected for sleep duration obtained by wrist actigraphy (acti-ODI3%). SDB severity was defined by acti-ODI3%. Obesity was defined as body mass index ≥25 kg·m-2The prevalence of SDB was 41.0% (95% CI 39.9-42.1%), 46.9% (45.8-48.0%), 10.1% (9.5-10.8%) and 2.0% (1.7-2.3%) in normal, mild, moderate and severe SDB, respectively, with notable sex differences evident (males>post-menopausal females>premenopausal females). Comorbidities such as hypertension, diabetes and metabolic syndrome were independently associated with the prevalence of moderate-to-severe SDB, and coincidence of any one of these with obesity was associated with a higher probability of moderate-to-severe SDB (hypertension OR 8.2, 95% CI 6.6-10.2; diabetes OR 7.8, 95% CI 5.6-10.9; metabolic syndrome OR 6.7, 95% CI 5.2-8.6). Dyslipidaemia in addition to obesity was not additively associated with the prevalence of moderate-to-severe SDB. The number of antihypertensive drugs was associated with SDB (p for trend <0.001). Proportion of a high cumulative percentage of sleep time with oxygen saturation measured by pulse oximetry <90% increased, even among moderate-to-severe SDB with increases in obesity.Metabolic comorbidities contribute to SDB regardless of the degree of obesity. We should recognise the extremely high prevalence of moderate-to-severe SDB in patients with obesity and metabolic comorbidities.

Efficacy of plasma exchange in anti-MDA5-positive dermatomyositis with interstitial lung disease under combined immunosuppressive treatment.

OBJECTIVES: Rapidly progressive interstitial lung disease (RP-ILD) with poor prognosis often accompanies anti-melanoma differentiation-associated gene 5 (MDA5)-positive DM. Combined immunosuppressive therapy, including glucocorticoids, calcineurin inhibitors and intravenous cyclophosphamide (IVCY) is reportedly effective in DM with RP-ILD, but some patients remain resistant to therapy. We examined the utility of plasma exchange (PE) in such intractable cases and investigated the prognostic factors of the disease. METHODS: Thirty-eight anti-MDA5-positive DM-ILD patients who received the combined immunosuppressive therapy were retrospectively reviewed. Their serum cytokines were evaluated by multiplex assay before treatment. The patients were divided into two groups: those who achieved remission without exacerbation of respiratory dysfunction (n = 25, group A) and those who progressed to hypoxemia during the treatment (n = 13, group B). RESULTS: PE was carried out in eight group B patients, but none of group A. Five of the eight treated with PE survived, while the five untreated patients died (P =0.04). Higher neutrophil lymphocyte ratio, higher serum ferritin, hypoxemia, high-resolution computed tomography (HRCT) score before treatment and increase of Krebs von Lungen-6 (KL-6) in the first 4 weeks of the treatment were the prognostic factors for disease progression. Serum cytokines such as IL-1, IL-6, IL-8, IL-10, IL-12p70, IL-18 and sCD163 levels were higher in group B than group A. CONCLUSION: PE should be an effective adjuvant treatment in anti-MDA5-positive DM with RP-ILD. Assessment of basal laboratory tests or monocyte/macrophage-derived cytokines and the increase of KL-6, HRCT score and hypoxemia may help us to predict intractable cases and to make early treatment decisions regarding PE in anti-MDA5-positive DM.

Role of serum periostin in severe obstructive sleep apnea with albuminuria: an observational study.

BACKGROUND: Periostin is a matricellular protein and is a useful marker in respiratory diseases. However, the roles of periostin in patients with obstructive sleep apnea (OSA) remain unclear. Several in vitro studies have suggested that mechanical stress, hypoxia, impaired metabolism, and kidney injury, which often accompany OSA, may upregulate the expression of periostin. Meanwhile, serum periostin level has been negatively associated with body mass index (BMI) in the general population. In this study, we hypothesized that a high level of serum periostin despite being overweight/obese may discriminate severe OSA or OSA with comorbidities from mild OSA with obesity alone. We aimed to clarify the roles of periostin in patients with OSA to assist in elucidating the heterogeneity of OSA with comorbidities. METHODS: Among patients diagnosed as OSA, we examined the associations between serum periostin levels and clinical indices, including the severity of OSA, BMI, and comorbidities, using a multifaceted approach. The serum periostin levels and clinical indices were assessed after 3 months of continuous positive airway pressure (CPAP) treatment. RESULTS: In 96 patients with OSA, serum periostin level was negatively correlated with BMI, albeit marginally, and tended to be higher in severe OSA than in others when adjusted for BMI. Cluster analysis identified four clusters, including two severe OSA clusters, one of which was characterized by high serum periostin levels and the presence of comorbidities, including albuminuria. In a comparative analysis of severe OSA cases (n = 53), the level of serum-free fatty acids and the frequency of albuminuria were higher in patients with high serum periostin level of ≥87 ng/mL, which was the highest quintile among all participants, than in those with low serum periostin levels (< 87 ng/mL, n = 41). In patients with severe OSA and high serum periostin levels, the levels of serum periostin and urinary albumin significantly decreased after 3 months of CPAP treatment. CONCLUSIONS: Elevated serum periostin in patients with OSA despite being overweight/obese may be an indicator of severe OSA with comorbidities, particularly albuminuria.

Serum matrix metalloproteinase levels in polymyositis/dermatomyositis patients with interstitial lung disease.

OBJECTIVE: We aimed to clarify the clinical significance of serum levels of MMPs in interstitial lung disease (ILD) complicated with PM/DM (PM/DM-ILD). METHODS: We retrospectively analysed serum levels of seven subsets of MMPs in 52 PM/DM-ILD patients diagnosed at Kyoto University Hospital or Tenri Hospital from January 2005 to December 2014. The patients were sub-grouped based on the presence of anti-amimoacyl-tRNA synthetase antibody (anti-ARS antibody), anti-melanoma differentiation-associated protein 5 antibody (anti-MDA5 antibody) or lack of the antibodies (ARS-ILD, MDA5-ILD and other-ILD groups, respectively) and independently analysed. Eighteen PM/DM patients without ILD and 55 healthy control were also analysed. Associations between serum levels of MMPs and clinical findings including mortality were analysed. RESULTS: Among the MMPs analysed, MMP-7 serum levels in the ARS-ILD group were significantly higher compared with those in any of the other groups of PM/DM patients or in healthy controls. On the other hand, in the MDA5-ILD group, serum MMP-7 levels >5.08 ng/ml were associated with worse overall survival both in univariate (P = 0.017; odds ratio 18.0; 95% CI 1.69, 192.00) and multivariate (P = 0.027; odds ratio 14.60; 95% CI 1.11, 192.00) analyses. Immunohistochemical analysis suggested that MMP-7 was expressed in type II alveolar epithelial cells adjacent to the fibrotic lesions. CONCLUSION: Serum MMP-7 levels were higher in anti-ARS antibody-positive PM/DM-ILD patients, while higher serum MMP-7 levels among anti-MDA5 antibody-positive PM/DM-ILD patients were associated with a worse prognosis. Fibrotic processes may be associated with the elevation of serum MMP-7 levels.

Significance of bronchiolocentric fibrosis in patients with histopathological usual interstitial pneumonia.

AIMS: To evaluate the clinical significance of bronchiolocentric fibrosis (BCF) in patients with a histopathological pattern of usual interstitial pneumonia (UIP). METHODS AND RESULTS: Two hundred and fifty-two patients with pathological UIP pattern were identified. Two hundred and fifteen of these patients (215 of 252) had the multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF). Prospectively defined clinical, radiological and pathological features (including BCF) were recorded, and peripheral blood MUC5B genotype and telomere length were measured. BCF was observed in 38% (96 of 252) of all patients and 33% (72 of 215) of IPF patients; its presence was associated with a non-IPF diagnosis on multivariate analysis (odds ratio = 3.71, 95% confidence interval = 1.68-8.19). BCF was not significantly associated with environmental exposures, gastroesophageal reflux, cigarette smoking or radiological patterns. There was no significant association of BCF with MUC5B genotype or telomere length. BCF has no significant impact on survival time. CONCLUSIONS: Most patients with BCF and a histopathological pattern of UIP have IPF. However, this combined fibrotic pattern is associated with a non-IPF multidisciplinary diagnosis, with approximately one-quarter of these patients being diagnosed as chronic hypersensitivity pneumonia or unclassifiable interstitial fibrosis. The presence of BCF in these patients is not significantly associated with presumed clinical risk factors for bronchiolocentric involvement, radiological findings, MUC5B genotype, telomere length or survival time.

Clinical significance of radiological pleuroparenchymal fibroelastosis pattern in interstitial lung disease patients registered for lung transplantation: a retrospective cohort study.

BACKGROUND: Radiological pleuroparenchymal fibroelastosis (PPFE) lesion is characterized by pleural thickening with associated signs of subpleural fibrosis on high-resolution computed tomography (HRCT). This study evaluated the clinical significance of radiological PPFE as an isolated finding or associated with other interstitial lung diseases (ILDs) in patients having fibrotic ILDs and registered for cadaveric lung transplantation (LT). METHODS: This retrospective study included 118 fibrotic ILD patients registered for LT. Radiological PPFE on HRCT was assessed. The impact of radiological PPFE on clinical features and transplantation-censored survival were evaluated. RESULTS: Radiological PPFE was observed in 30/118 cases (25%): definite PPFE (PPFE concentrated in the upper lobes, with involvement of lower lobes being less marked) in 12 (10%) and consistent PPFE (PPFE not concentrated in the upper lobes, or PPFE with features of coexistent disease present elsewhere) in 18 (15%). Of these, 12 had late-onset non-infectious pulmonary complications after hematopoietic stem-cell transplantation and/or chemotherapy (LONIPCs), 9 idiopathic PPFE, and 9 other fibrotic ILDs (idiopathic pulmonary fibrosis, IPF; other idiopathic interstitial pneumonias, other IIPs; connective tissue disease-associated ILD, CTD-ILD, and hypersensitivity pneumonia, HP). Radiological PPFE was associated with previous history of pneumothorax, lower body mass index, lower percentage of predicted forced vital capacity (%FVC), higher percentage of predicted diffusion capacity of carbon monoxide, less desaturation on six-minute walk test, and hypercapnia. The median survival time of all study cases was 449 days. Thirty-seven (28%) received LTs: cadaveric in 31 and living-donor lobar in six. Of 93 patients who did not receive LT, 66 (71%) died. Radiological PPFE was marginally associated with better survival after adjustment for age, sex, %FVC, and six-minute walk distance < 250 m (hazard ratio 0.51 [0.25-1.05], p = 0.07). After adjustment for covariates, idiopathic PPFE and LONIPC with radiological PPFE was associated with better survival than fibrotic ILDs without radiological PPFE (hazard ratio 0.38 [0.16-0.90], p = 0.03), and marginally better survival than other fibrotic ILDs with radiological PPFE (hazard ratio, 0.20 [0.04-1.11], p = 0.07). CONCLUSIONS: idiopathic PPFE and LONIPC with radiological PPFE has better survival on the wait list for LT than fibrotic ILDs without radiological PPFE, after adjustment for age, sex, %FVC, and six-minute walk distance.

The Clinical Significance of Body Weight Loss in Idiopathic Pulmonary Fibrosis Patients.

BACKGROUND: The significance of the nutritional status in idiopathic pulmonary fibrosis (IPF) is largely unknown. Temporal body weight (BW) change, a dynamic index of nutrition status, can detect the malnutrition more accurately than the conventional single-point body mass index evaluation. OBJECTIVE: To investigate how the temporal BW change influences the clinical courses of IPF. METHODS: This multicenter study enrolled IPF patients from four referral hospitals of interstitial lung diseases in Japan (the Japanese cohort, the derivation cohort) and the Royal Brompton Hospital (the UK cohort, the validation cohort). The annual rate of BW change from the initial presentation was evaluated. A > 5% decrease of BW was defined as a significant BW loss. RESULTS: Twenty-seven out of 124 patients in the Japanese cohort and 13 out of 86 patients in the UK cohort showed significant BW loss. Patients with BW loss showed significantly worse survival in both cohorts. Multivariate analyses revealed that BW loss was an independent factor for decreased survival (Japanese cohort: p = 0.047, UK cohort: p = 0.013). A 6.1% loss of BW was chosen as the optimal cutoff value to predict the 2-year mortality from the initial presentation. The stratified analysis revealed that a 6.1% or greater BW loss could predict worse survival specifically in cases without a greater than 10% decline in forced vital capacity (FVC). CONCLUSIONS: BW loss is independently associated with the survival of IPF patients, particularly when a decline in the FVC was not observed. Further studies are needed to understand the mechanisms underlying BW loss in IPF.

Role of mitochondrial hydrogen peroxide induced by intermittent hypoxia in airway epithelial wound repair in vitro.

The airway epithelium acts as a frontline barrier against various environmental insults and its repair process after airway injury is critical for the lung homeostasis restoration. Recently, the role of intracellular reactive oxygen species (ROS) as transcription-independent damage signaling has been highlighted in the wound repair process. Both conditions of continuous hypoxia and intermittent hypoxia (IH) induce ROS. Although IH is important in clinical settings, the roles of IH-induced ROS in the airway repair process have not been investigated. In this study, we firstly showed that IH induced mitochondrial hydrogen peroxide (H2O2) production and significantly decreased bronchial epithelial cell migration, prevented by catalase treatment in a wound scratch assay. RhoA activity was higher during repair process in the IH condition compared to in the normoxic condition, resulting in the cellular morphological changes shown by immunofluorescence staining: round cells, reduced central stress fiber numbers, pronounced cortical actin filament distributions, and punctate focal adhesions. These phenotypes were replicated by exogenous H2O2 treatment under the normoxic condition. Our findings confirmed the transcription-independent role of IH-induced intracellular ROS in the bronchial epithelial cell repair process and might have significant implications for impaired bronchial epithelial cell regeneration.

Chronic Kidney Disease Predicts Survival in Patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: The prevalence of chronic kidney disease (CKD) increases with age as with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We assessed the prevalence of CKD (stages 3-5) and investigated the relationship of CKD to clinical features and outcomes in patients with IPF. METHODS: This study comprised 123 patients with IPF; 61 subjects with chronic obstructive pulmonary disease (COPD), which was reportedly associated with CKD, were also enrolled as a disease control. CKD (stages 3-5) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. RESULTS: Thirty-seven patients (30%) with IPF and 14 controls (23%) with COPD were diagnosed with CKD, and these frequencies were not significantly different. The patients with IPF and CKD were older (p < 0.01) and had a higher frequency of hypertension (p = 0.048) and ischemic heart disease (p = 0.02) than those with IPF but without CKD. Furthermore, the diffusing capacity of the lung for carbon monoxide (DLCO) and the 6-min walking distance in the patients with CKD were significantly lower (40.0 ± 13.2 vs. 45.9 ± 14.4%, p = 0.04, and 416 ± 129 vs. 474 ± 84 m, p = 0.01, respectively) than in the patients without CKD. The outcome of the patients with CKD showed significantly worse survival compared with the patients without CKD (p = 0.04). Moreover, eGFR remained an independent predictor of survival after adjusting for age and pulmonary function data. CONCLUSION: A substantial percentage of IPF patients have CKD. CKD with a low eGFR was associated with decreased survival in IPF.

Changes in Energy Metabolism after Continuous Positive Airway Pressure for Obstructive Sleep Apnea.

RATIONALE: Disrupted energy homeostasis in obstructive sleep apnea (OSA) may lead to weight gain. Paradoxically, treating OSA with continuous positive airway pressure (CPAP) may also promote weight gain, although the underlying mechanism remains unclear. OBJECTIVES: To explore the underlying mechanism by which patients with OSA gain weight after CPAP. METHODS: A comprehensive assessment of energy metabolism was performed in 63 newly diagnosed OSA study participants (51 men; 60.8 ± 10.1 yr; apnea-hypopnea index >20 h(-1)) at baseline, CPAP initiation, and at a 3-month follow-up. Measurements included polysomnography, body weight, body composition, basal metabolic rate (BMR), hormones (norepinephrine, cortisol, leptin, ghrelin, insulin-like growth factor-1), dietary intake, eating behavior, and physical activity. MEASUREMENTS AND MAIN RESULTS: BMR significantly decreased after CPAP (1,584 kcal/d at baseline, 1,561 kcal/d at CPAP initiation, and 1,508 kcal/d at follow-up; P < 0.001), whereas physical activity and total caloric intake did not significantly change. In multivariate regression, baseline apnea-hypopnea index, Δurine norepinephrine, and CPAP adherence were significant predictors of ΔBMR. The weight gainers had higher leptin levels, lower ghrelin levels, and higher eating behavior scores than the non-weight gainers, indicating a positive energy balance and disordered eating behavior among the weight gainers. Among the parameters related to energy metabolism, increased caloric intake was a particularly significant predictor of weight gain. CONCLUSIONS: Although a reduction in BMR after CPAP predisposes to a positive energy balance, dietary intake and eating behavior had greater impacts on weight change. These findings highlight the importance of lifestyle modifications combined with CPAP. Clinical trial registered with http://www.umin.ac.jp/english/ (UMIN000012639).