Kohei Ikezoe

Treatment with Methotrexate and Low-dose Corticosteroids in Sarcoidosis Patients with Cardiac Lesions

The Authors Reply There are several weaknesses of the study in respect to the examined number of patients. However, regarding the diagnosis of sarcoidosis, we carefully checked the involved lesions (including the sites and severity) according to the 2006 Japanese guidelines (1). The patients cannot be diagnosed with any other disease, even if sarcoidosis is removed from the differential diagnosis. Based on our experience with more than 2,000 sarcoidosis patients, we selected typical cases that have a substantial amount of clinical evidence of sarcoidosis lesions. All cases satisfied the major criteria according to the 2006 Japanese guidelines (1). This guideline is approved by another reviewer (2). In addition, basal thinning of the interventricular septum was detected in 15 patients; two patients without basal thinning had other positive findings that satisfied the diagnostic criteria. Positron emission tomography negative cases also showed abnormalities related to the presence of the cardiac lesions due to sarcoidosis. Ischemic heart diseases were actively differentiated during their time courses. We explained the specific treatment for all patients with cardiac sarcoidosis. The importance of the new treatment was to reduce the adverse effects of standard corticosteroid therapy. However, some patients showed a hesitation to receive the novel therapy using methotrexate and therefore were treated with corticosteroid therapy only. Other patients were treated with the two drugs. We selected age-matched patients between two groups. Therefore, after removing the age-mismatched patients (younger patients), the number of the cases became smaller. In the comparison between the two groups, there were no statistically significant differences in the forced expiratory volume one second (FEV1) or any other parameters. Regarding the FEV1, the smallest value in our patients was 1.39 L and this patient showed mild airflow limitation with mild fibrotic lesions. Therefore, it was difficult to relate the airflow lesion to heart dysfunction. We analyzed differences in the outcome indices (including the left ventricular ejection fraction) between the groups at various time points and found statistical significance after 3 years. There were no clear results that stabilized the cardiac function two years after treatment with either the standard dose or a high dose of corticosteroid therapy (3). There was also a slight increase in the cardio-thoracic ratio associated with an increase of the N-terminal fragment pro-brain natriuretic peptide. These findings may be attributed directly to the treatment method, as there was no apparent ischemic heart disease or hypertension.

Total lesion glycolysis as an IgG4-related disease activity marker

Abstract Objectives. 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) was reported to be useful for monitoring immunoglobulin G4-related disease (IgG4-RD); however, a quantitative FDG-PET/CT analysis such as total lesion glycolysis (TLG) has not yet been conducted. This study aimed to investigate whether TLG would correlate with serum markers in IgG4-RD, and the utility of TLG for disease monitoring. Methods. This retrospective study included 17 patients (12 men; median age, 62 years) who were followed up at Kyoto University Hospital and underwent FDG-PET/CT from April 2009 to November 2013. TLG was calculated for the involved lesions. Correlations between serum markers [IgG4, soluble IL-2 receptor (sIL-2R), lactate dehydrogenase (LDH), and C-reactive protein (CRP)] and TLG concomitant with FDG-PET/CT scans were investigated. Serial changes in TLG were assessed in patients who underwent follow-up FDG-PET/CT (n = 6). Results. The calculated median (IQL) TLG value was 154.8 (63.7–324.4). A significant correlation was found between the sIL-2R level and TLG (P = 0.001, rs = 0.763). In contrast, no correlations were found between the IgG4, LDH, or CRP levels and TLG. Increased or decreased TLG corresponded with clinical disease improvement or worsening. Conclusions. TLG correlated significantly with the serum sIL-2R level and may be useful for disease monitoring in IgG4-RD.

Aquaporin-3 potentiates allergic airway inflammation in ovalbumin-induced murine asthma

Oxidative stress plays a pivotal role in the pathogenesis of asthma. Aquaporin-3 (AQP3) is a small transmembrane water/glycerol channel that may facilitate the membrane uptake of hydrogen peroxide (H2O2). Here we report that AQP3 potentiates ovalbumin (OVA)-induced murine asthma by mediating both chemokine production from alveolar macrophages and T cell trafficking. AQP3 deficient (AQP3−/−) mice exhibited significantly reduced airway inflammation compared to wild-type mice. Adoptive transfer experiments showed reduced airway eosinophilic inflammation in mice receiving OVA-sensitized splenocytes from AQP3−/− mice compared with wild-type mice after OVA challenge, consistently with fewer CD4+ T cells from AQP3−/− mice migrating to the lung than from wild-type mice. Additionally, in vivo and vitro experiments indicated that AQP3 induced the production of some chemokines such as CCL24 and CCL22 through regulating the amount of cellular H2O2 in M2 polarized alveolar macrophages. These results imply a critical role of AQP3 in asthma, and AQP3 may be a novel therapeutic target.

Evaluation of Bone Mineral Density by Computed Tomography in Patients with Obstructive Sleep Apnea.

STUDY OBJECTIVES Clinical studies have investigated whether obstructive sleep apnea (OSA) can modulate bone metabolism but data are conflicting. Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry is the standard technique for quantifying bone strength but has limitations in overweight patients (body mass index [BMI] ≥ 25 kg/m(2)). The aim of this study was to examine the association between OSA and BMD by examining CT images that allow true volumetric measurements of the bone regardless of BMI. METHODS Lumbar vertebrae BMD was evaluated in 234 persons (180 males and 54 females) by CT scan. The method was calibrated by a phantom containing a known concentration of hydroxyapatite. RESULTS BMD was lower in male patients with severe OSA (apnea-hypopnea index [AHI] ≥ 30/h) than non OSA (AHI < 5; p < 0.05), while OSA and BMD had no association in females. Linear and multiple regression analyses revealed that age (p < 0.0001, β = -0.52), hypertension (p = 0.0068, β = -0.17), and the alveolar-arterial oxygen pressure difference (A-aDO2) (p = 0.012, β = -0.15) in males were associated with BMD, while only age (p < 0.0001, β = -0.68) was associated with BMD in females. CONCLUSION Males with severe OSA had a significantly lower BMD than non OSA participants. Age, hypertension, and elevation of A-aDO2 were significant factors for BMD by CT imaging. The usefulness of measuring BMD in OSA patients by CT scanning should be studied in future.

Clinical relevance of plasma prostaglandin F2α metabolite concentrations in patients with idiopathic pulmonary fibrosis.

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology with few current treatment options. Recently, we determined an important role of prostaglandin F2α (PGF2α) in pulmonary fibrosis by using a bleomycin-induced pulmonary fibrosis model and found an abundance of PGF2α in bronchoalveolar lavage fluid of IPF patients. We investigated the role of PGF2α in human IPF by assessing plasma concentrations of 15-keto-dihydro PGF2α, a stable metabolite of PGF2α. METHODS We measured plasma concentrations of 15-keto-dihydro PGF2α in 91 IPF patients and compared these values with those of controls (n = 25). We further investigated the relationships of plasma 15-keto-dihydro PGF2α concentrations with disease severity and mortality. RESULTS Plasma concentrations of 15-keto-dihydro PGF2α were significantly higher in IPF patients than controls (p<0.001). Plasma concentrations of this metabolite were significantly correlated with forced expiratory volume in 1 second (Rs [correlation coefficient] = -0.34, p = 0.004), forced vital capacity (Rs = -0.33, p = 0.005), diffusing capacity for carbon monoxide (Rs = -0.36, p = 0.003), the composite physiologic index (Rs = 0.40, p = 0.001), 6-minute walk distance (Rs = -0.24, p = 0.04) and end-exercise oxygen saturation (Rs = -0.25, p = 0.04) when patients with emphysema were excluded. Multivariate analysis using stepwise Cox proportional hazards model showed that a higher composite physiologic index (relative risk = 1.049, p = 0.002) and plasma 15-keto-dihydro PGF2α concentrations (relative risk = 1.005, p = 0.002) were independently associated with an increased risk of mortality. CONCLUSIONS We demonstrated significant associations of plasma concentrations of PGF2α metabolites with disease severity and prognosis, which support a potential pathogenic role for PGF2α in human IPF.

Importance of serial changes in biomarkers in idiopathic pulmonary fibrosis

The clinical significance of serial changes in serum biomarkers in patients with idiopathic pulmonary fibrosis (IPF) remains to be established. This retrospective study was conducted to clarify the associations of serial changes in serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) with changes in physiological indices and overall mortality in IPF. The study subjects were 75 patients with IPF. The 6 month change in serum KL-6 was significantly correlated with changes in the percentage of the predicted forced vital capacity (FVC % pred) and the percentage of the predicted diffusing capacity of the lung for carbon monoxide (% DLCO), while the 6 month change in serum SP-D was correlated only with % DLCO. During the mean follow-up period of 647 days, 22 (29.3%) patients died. An increase in serum KL-6 over a 6 month period was a significant predictor of mortality even after adjustment for %FVC, % DLCO and serum KL-6 at the baseline (hazard ratio 1.10 per 100 U·mL−1, 95% CI 1.01–1.18, p=0.03), whereas the 6 month increase in serum SP-D was not significant. Serial measurements of serum KL-6 may provide additional prognostic information compared to that provided by physiological parameters in patients with IPF. Serial changes in serum KL-6 are associated with changes in physiological variables and can predict survival in IPF http://ow.ly/hCkb30eauLg

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.

Serial perfusion in native lungs in patients with idiopathic pulmonary fibrosis and other interstitial lung diseases after single lung transplantation.

Lung perfusions after single lung transplantation (SLT) have not been fully clarified in patients with interstitial lung disease (ILD). The present study aimed to investigate temporal changes in native lung perfusion and their associated clinical factors in patients with ILD who have undergone SLT.

Neutrophil gelatinase-associated lipocalin in idiopathic pulmonary fibrosis

To the Editor: Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kD lipocalin that is covalently bound to matrix metalloproteinase (MMP)-9 produced by neutrophils [1]. NGAL in blood or bronchoalveolar lavage fluid (BALF) may reflect neutrophilic inflammation in the lungs [2, 3], and it is highly induced in injured epithelial cells, including those in the lung [4]. Possible roles for neutrophilic inflammation and epithelial injury have been reported in idiopathic pulmonary fibrosis (IPF). Thus, we hypothesised that NGAL may be associated with the pathogenesis of IPF. To investigate the roles of NGAL in IPF, we used immunohistochemical staining for lung specimens and measured plasma and BALF NGAL levels. Our study was approved by the Ethics Committee of Kyoto University (approval No. E438), and written informed consent was obtained from all study participants. First, we immunohistochemically stained the lung tissue specimens of six IPF patients, two nonspecific interstitial pneumonia (NSIP) patients, and a control (normal area distant from the lesion of surgically diagnosed organising pneumonia) for NGAL using a conventional method [5]. We also performed sequential immunofluorescent staining for NGAL and MMP-9. Immunohistochemical staining showed that NGAL was abundantly expressed in airway epithelial cells that covered the honeycomb cysts in IPF (fig. 1a and b). Further, histologically normal bronchioles in the fibrotic lesions also exhibited abundant NGAL expression, although apparently normal alveolar walls exhibited little NGAL expression. NGAL was also expressed in macrophages, neutrophils and some alveolar epithelial cells. Figure 1– Immunohistochemical staining results for neutrophil gelatinase-associated lipocalin (NGAL) in lung specimens from: a and b) idiopathic pulmonary fibrosis (IPF) …

Prognostic factors and outcomes in Japanese lung transplant candidates with interstitial lung disease

Objective Young patients with advanced interstitial lung disease (ILD) are potential candidates for cadaveric lung transplantation. This study aimed to examine clinical features, outcomes, and prognostic factors in Japanese ILD patients awaiting lung transplantation. Methods We investigated the clinical features and outcomes of 77 consecutive candidates with ILD who were referred to Kyoto University Hospital and subsequently actively listed for lung transplant in the Japan Organ Transplant Network between 2010 and 2014. Results Of the 77 candidates, 33 had idiopathic pulmonary fibrosis (IPF) and 15 had unclassifiable ILD. During the observational period, 23 patients (30%) received lung transplantations and 49 patients (64%) died before transplantation. Of the 33 patients with IPF, 13 (39%) had a family history of ILD and 13 (39%) had an “inconsistent with usual interstitial pneumonia pattern” on high-resolution computed tomography (HRCT). The median survival time from registration was 16.7 months, and mortality was similar among patients with IPF, unclassifiable ILD, and other ILDs. Using a multivariate stepwise Cox proportional hazards model, 6-min walking distance was shown to be an independent prognostic factor in candidates with ILD (per 10 m, hazard ratio (HR): 0.97; 95% confidence interval (CI): 0.95–0.99, p<0.01), while lower body mass index (HR: 0.83; 95% CI: 0.72–0.95, p < 0.01) independently contributed to mortality in patients with IPF. Conclusions Japanese patients with ILD awaiting transplantation had very poor outcomes regardless of their specific diagnosis. A substantial percentage of IPF patients had an atypical HRCT pattern. 6-min walking distance in ILD patients and body mass index in IPF patients were independent predictors of mortality.