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Rationale The Sarcoidosis Health Questionnaire (SHQ) is the first sarcoidosis-specific health status questionnaire ever developed. Worse health status, as evaluated by the SHQ, may indicate higher risk for deterioration in the following 5 years. Objectives To evaluate the association between SHQ scores and deterioration defined clinically at 5-year follow-up. Methods 122 patients with biopsy-supported sarcoidosis completed the SHQ and underwent evaluation with respect to organ involvement, chest radiograph, electrocardiogram, serum biomarker measurements, pulmonary function tests, and echocardiogram. Of these 122, 88 (72.1%) were available for pulmonary, cardiac, and non-pulmonary, non-cardiac deterioration assessment during the following 5 years. Measurements and main results Five-year deterioration was observed in 20 patients (23%). The SHQ total score was significantly associated with 5-year deterioration, after adjusting for cardiac involvement at baseline, with adjusted odds ratio (OR) of 0.54 (95% confidence interval [95% CI], 0.29–0.99). The association of the total SHQ with 5-year outcome was not significant when adjusted for left ventricular ejection fraction (LVEF) at baseline (adjusted OR, 0.61 [0.32–1.16]), whereas LVEF was significantly associated with 5-year outcome (adjusted OR, 0.92 [0.86–0.99]). The association between total SHQ score and 5-year deterioration was marginal when adjusted for baseline usage of systemic corticosteroid (CS)/immunosuppressive (IS) agents (adjusted OR, 0.58 [0.31–1.10]), whereas systemic CS/IS usage significantly predicted 5-year deterioration (adjusted odds ratio [OR], 3.46 [1.12–10.7]). There was a marginal correlation between the total SHQ and LVEF (rho = 0.19, p = 0.07) and a weak association between the total SHQ and systemic CS/IS usage (rho = −0.23, p = 0.03). The Physical Functioning domain scores of the SHQ were significantly associated with 5-year deterioration (adjusted OR, 0.45–0.51). Conclusions Worse health status, as assessed by the SHQ score, can be a risk factor for 5-year deterioration of sarcoidosis, although usage of the CS/IS at baseline and lower LVEF at baseline are more predictive of 5-year deterioration.

Summary Background Polymyositis and dermatomyositis-associated interstitial lung disease (PM/DM-ILD) can have variable courses. We evaluated the prognostic value of high-resolution computed tomography (HRCT) in PM/DM-ILD. Methods The cases of 51 patients newly diagnosed with PM/DM-ILD were retrospectively reviewed. HRCT images at diagnosis were categorized into four radiological patterns based on the major findings and distributions of these abnormalities, and the disease extent on HRCT was scored. The impact of HRCT findings and other clinical parameters on day 90 and overall mortality were analyzed. Results Of the 51 patients (11 with polymyositis and 40 with dermatomyositis), the lower consolidation/ground-glass attenuation (GGA) pattern was observed in 21 patients (41%), lower reticulation was observed in 23 patients (45%), random GGA was observed in four patients (8%), and other patterns were observed in three patients (6%). Twenty-one patients (42%) were positive for anti-CADM-140. The lower consolidation/GGA pattern, clinically amyopathic dermatomyositis, fever (≥38.0 °C), ferritin levels >500 ng/mL, and the presence of anti-CADM-140 were significantly associated with 90-day mortality in univariate analysis. Multivariate analysis revealed that the lower consolidation/GGA pattern (odds ratio, 23.1; P = 0.02) and the presence of anti-CADM-140 (odds ratio, 14.1; P = 0.03) were independent predictors of 90-day mortality. This HRCT pattern was also associated with a higher 90-day morality rate among anti-CADM-140-positive patients. The lower consolidation/GGA pattern was also associated with overall mortality in univariate analysis, whereas only the presence of anti-CADM-140 was an independent determinant of overall mortality in multivariate analysis. Conclusion HRCT patterns at diagnosis can help predict the prognosis of patients with PM/DM-ILD as well as the presence of anti-CADM-140.

Summary Background Recent epidemiological evidence indicates an association between cardiovascular diseases and pulmonary fibrosis. The vascular endothelium acts to maintain vascular homeostasis through multiple mechanisms and impaired endothelial function can contribute to the development, progression and clinical expression of atherosclerosis. Methods We consecutively recruited 39 newly-diagnosed chronic interstitial pneumonitis/fibrosis patients without any specific etiology. We assessed endothelium-dependent vasodilator response of patients using digital pulse amplitude tonometry and compared the reactive hyperemia index (RHI) with age-, sex- and body mass index-matched control subjects ( n = 30). We further investigated the relationships between RHI and clinical characteristics, laboratory cardiovascular risk factors, disease-related factors and circulating levels of inflammatory biomarkers. Results RHI was significantly lower in patients with chronic interstitial pneumonitis/fibrosis than in control subjects ( p = 0.02). While circulating levels of total cholesterol, triglycerides, HbA1c and fasting glucose did not differ significantly between groups, patients with chronic interstitial pneumonitis/fibrosis had significantly lower high density lipoprotein levels and higher low density lipoprotein levels as compared with control subjects. Regarding disease-related factors, RHI was significantly associated with the diffusing capacity for carbon monoxide, alveolar-arterial oxygen pressure difference, 6-min walk distance and end-exercise oxygen saturation. Additionally, circulating levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were inversely correlated with RHI. Conclusions We confirmed a possible link between pulmonary fibrosis and cardiovascular disease by demonstrating an impairment of endothelium-dependent vasodilator response, which was significantly associated with the severity of pulmonary fibrosis and circulating levels of adhesion molecules.

Rationale Anti-aminoacyl transfer RNA synthetase antibodies (anti-ARS) are a group of myositis-specific autoantibodies that are detected in the sera of patients with polymyositis and dermatomyositis (PM/DM) and also in those of patients with idiopathic interstitial pneumonias without any connective tissue disease (CTD), including PM/DM. Although we reported the clinical characteristics of interstitial lung disease with anti-ARS antibodies (ARS-ILD) with and without PM/DM, the long-term prognosis of ARS-ILD remains undetermined. As our previous studies revealed that ARS-ILD without PM/DM was similar to CTD-associated ILD, and that ARS-ILD with PM/DM was radiologically suggestive of a nonspecific interstitial pneumonia (NSIP) pathological pattern, we hypothesized that the prognosis of ARS-ILD might be distinct from that of idiopathic pulmonary fibrosis (IPF) without anti-ARS. Objectives To elucidate the long-term outcome of ARS-ILD with and without PM/DM and compare it to that of IPF. Methods A two-center retrospective study was conducted. The study population comprised 36 patients with ARS-ILD (8 with PM, 12 with DM, and 16 without myositis throughout the course), 100 patients with IPF without anti-ARS, and 7 patients with NSIP without anti-ARS. The presence of anti-ARS was determined by RNA immunoprecipitation using the sera obtained at the time of diagnosis before specific treatment. Measurements and main results During the observational period (median 49 months; range, 1–114 months), 7 patients with ARS-ILD (19%; 3 with PM, 1 with DM, and 3 without PM/DM) and 51 patients with IPF (51%) died. Patients with ARS-ILD had better overall survival than those with IPF (log-rank test, P P = 0.59). The prognosis for patients with ARS-ILD was similar between those with and without myositis (log-rank test, P = 0.91). At the median follow-up time of 76.5 months, 14 of the 36 patients with ARS-ILD had deteriorated. Both a decline in forced vital capacity or an initiation of long-term oxygen therapy during the course (odds ratio [OR], 5.34) and acute exacerbation (OR, 28.4) significantly increased the mortality risk. Conclusions The long-term outcome of ARS-ILD was significantly better than that of IPF regardless of the presence or absence of myositis.

Summary Background Anti-CADM-140 antibody (anti-CADM-140), also referred to as anti-melanoma differentiation-associated gene 5 (MDA5) antibody, is a myositis-specific antibody identified in the sera of patients with clinically amyopathic dermatomyositis (C-ADM) and is associated with a worse prognosis in dermatomyositis-associated interstitial lung disease (DM-ILD). We sought to determine high-resolution computed tomography (HRCT) features of DM-ILD with anti-CADM-140. Methods Twenty-five patients newly diagnosed with DM-ILD at Kyoto University Hospital between 2005 and 2009 were retrospectively reviewed. Serum anti-CADM-140 was measured in all patients at their first visit. Chest HRCT images taken prior to treatment were classified based on the dominant findings and their distribution, and compared between patients with and without the antibody. Results Of 25 DM-ILD patients, 12 were positive and 13 were negative for anti-CADM-140. HRCT patterns differed significantly between anti-CADM-140-positive and negative patients ( P = 0.002). Lower consolidation or ground-glass attenuation (GGA) pattern (50.0%) and random GGA pattern (33.3%) were the predominant patterns in anti-CADM-140-positive cases, while lower reticulation pattern (69.2%) was frequently seen in anti-CADM-140-negative cases. Anti-CADM-140-positive cases were also significantly characterized by the absence of intralobular reticular opacities (0% in anti-CADM-140 (+) vs. 84.6% in anti-CADM-140 (−), P Conclusions Anti-CADM-140-positive DM-ILD was characterized by lower consolidation or GGA pattern, random GGA pattern, and the absence of intralobular reticular opacities.

SummaryBackgroundThe level at which arterial carbon dioxide tension (PaCO2) a few months after introduction of long-term non-invasive positive pressure ventilation (NPPV) is associated with a favorable prognosis remains uncertain.MethodsData on 184 post-tuberculosis patients with chronic restrictive ventilatory failure who were receiving long-term domiciliary NPPV were examined retrospectively. Average PaCO2 3–6 months after NPPV (3- to 6-mo PaCO2) and potential confounders were analyzed with discontinuation of long-term NPPV as the primary outcome. The effects of 3- to 6-mo PaCO2 on annual hospitalization rates due to respiratory deterioration from 1 year before to 3 years after the initiation of NPPV were examined. The effect of the difference between the PaCO2 value at the start of NPPV (0-mo PaCO2) and the PaCO2 value 3- to 6-mo later (d-PaCO2) on continuation rates for NPPV was also assessed in patients who initiated NPPV while in a chronic state.ResultsPatients with relatively low 3- to 6-mo PaCO2 values maintained a relatively low PaCO2 6–36 months after NPPV (p

Summary Background Long-term noninvasive positive pressure ventilation (NPPV) is associated with an excellent survival rate, especially in post-tuberculosis patients. Nothing is currently known on which method of ventilatory support is associated with a better continuation of long-term NPPV, which itself might lead to longer survival. Methods One hundred and eighty four post-tuberculosis patients, who started NPPV at the Kyoto University Hospital group and the National Tokyo Hospital from June 1990 to August 2007, were examined retrospectively. Ventilator mode (an assisted mode or a pure controlled mode) and potential confounders were examined with the discontinuation of NPPV as the primary outcome. Results Patients treated with a pure controlled mode had significantly better continuation rates (hazard ratio, 3.09; 95% confidential interval, 1.75–5.47; p =0.0001) and better survival rates (Log-rank test; p =0.0031) than those treated with an assisted mode. Female gender and no pulmonary lesions were also associated with a significantly better probability of continuing NPPV. The five- and ten-year probabilities of continuing NPPV for 106 patients with a pure controlled mode were 68.3% and 41.4%, respectively, while those for 76 patients with an assisted mode were 46.7% and 12.7%, respectively. Conclusions Patients treated with pure controlled ventilation had significantly better continuation rates and survival rates than those treated with assisted ventilation. Prospective randomized controlled trials are needed to verify the effectiveness of a pure controlled mode in patients with not only restrictive thoracic disease but also other diseases including chronic obstructive pulmonary disease.

Background: We hypothesized that the factors which may influence health status would differ in patients at different disease stages of chronic obstructive pulmonary disease (COPD). The present study investigated how impairments in health status were distributed in male patients at each disease stage according to the British Thoracic Society (BTS) guidelines, and analysed the contribution of the clinical indices, the dyspnoea rating and the psychological status to the health status of patients at the three disease stages of COPD.Methods: A total of 218 consecutive male patients with stable COPD were recruited from our outpatient clinic. All eligible patients completed pulmonary function testing, progressive cycle ergometry, a dyspnoea rating [Medical Research Council (MRC) dyspnoea scale], an assessment of their anxiety and depression [Hospital Anxiety and Depression Scale (HADS)], and an assessment of their health status [the St. George's Respiratory Questionnaire (SGRQ)]. The patients were categorized into three groups: mild COPD with a FEV1at 60–79% of the predicted value, moderate COPD at 40–59% of the predicted value, and severe COPD at below 40% of the predicted value.Results: Twenty-five patients (11%) had mild COPD, 72 patients (33%) had moderate COPD, and 121 patients (56%) had severe COPD. Significant differences were observed for the total score and for three components on the SGRQ among patients at the three stages (one-way ANOVA, P

Summary Background Obstructive sleep apnea (OSA) has both systemic and local effects partly through the increased oxidative stress caused by intermittent hypoxia and reoxygenation. However, lung-specific biomarkers in OSA have not been fully assessed in comparison with systemic biomarkers such as C-reactive protein (CRP), although results of a recent study having a small sample size indicated KL-6 as one candidate. Methods Subjects of the present study were 197 patients suspected to have OSA. In addition to polysomnography, we also measured serum levels of KL-6, surfactant protein-D (SP-D) and CRP and pulmonary function. We examined the relationships of different biomarkers with OSA severity and pulmonary function. Results The apnea/hypopnea index (AHI) was significantly positively correlated with serum KL-6 levels even after adjustment for body mass index (BMI) and smoking ( p = 0.03), but not with SP-D and CRP. Also, a significant trend for an increase in serum KL-6 was noted in accordance with the severity of OSA even after adjustment for BMI and smoking ( β coefficient = 0.18, p = 0.02). Additionally, elevated KL-6 levels were significantly associated with restrictive lung function disturbance and gas exchange derangement after adjustment for obesity and smoking, which contrasted with CRP whose elevations were significantly associated with worsened airflow limitation and increased lung volume. Conclusions Serum KL-6 levels may reflect the degree of subclinical lung injury associated with OSA independently of obesity or smoking, unlike CRP. We consider that KL-6 can be a potential candidate as a lung-specific biomarker of OSA and might provide complementary information on systemic biomarkers in assessing OSA.

Summary Significant relationships between the psychological status and poor asthma outcomes are often reported. However, most of these studies are cross-sectional and none have evaluated how the psychological status progresses over time during the management of asthma patients. Therefore, we examined the longitudinal changes in the psychological status of asthma patients, and compared them with changes in other clinical measurements. Eighty-seven outpatients with stable asthma after 6 months of treatment were enrolled in this study. The psychological status was evaluated using the Hospital Anxiety and Depression Scale (HADS), the health status using the Asthma Quality of Life Questionnaire (AQLQ) and the St. George's Respiratory Questionnaire (SGRQ). The patient's pulmonary function, peak expiratory flow values and airway hyperresponsiveness were measured at entry and every year thereafter over a 5-year period. Using mixed effects models to estimate the slopes, the HADS anxiety and depression scores did not change significantly over time ( p =0.71 and 0.72, respectively). The changes in the HADS scores correlated noticeably with changes in the AQLQ and SGRQ scores, but not with changes in the physiological measurements. The baseline HADS anxiety and depression scores were significantly correlated to the subsequent annual changes in each measurement. The psychological status remained clinically stable over the 5-year study period in patients with stable asthma. Changes in the psychological status were significantly correlated to changes in the health status. The baseline HADS scores were a useful indicator in detecting patients who would show subsequent deterioration in their psychological status.

Summary Goals of effective management of patients with chronic obstructive pulmonary disease (COPD) include relieving their symptoms and improving their health status. We examined how such patient reported outcomes would change longitudinally in comparison to physiological outcomes in COPD. One hundred thirty-seven male outpatients with stable COPD were recruited for the study. The subjects health status was evaluated using the St. George's Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Disease Questionnaire (CRQ). Their dyspnoea using the modified Medical Research Council (MRC) scale and their psychological status using the Hospital Anxiety and Depression Scale (HADS) were assessed upon entry and every 6 months thereafter over a 5-year period. Pulmonary function and exercise capacity as evaluated by peak oxygen uptake \( V ˙ O 2 \) on progressive cycle ergometry were also followed over the same time. Using mixed effects models to estimate the slopes for the changes, scores on the SGRQ, the CRQ, the MRC and the HADS worsened in a statistically significant manner over time. However, changes only weakly correlated with changes in forced expiratory volume in 1s (FEV 1 ) and peak V ˙ O 2 . We demonstrated that although changes in pulmonary function and exercise capacity are well known in patients with COPD, patient reported outcomes such as health status, dyspnoea and psychological status also deteriorated significantly over time. In addition, deteriorations in patient reported outcomes only weakly correlated to changes in physiological indices. To capture the overall deterioration of COPD from the subjective viewpoints of the patients, patient reported outcomes should be followed separately from physiological outcomes.

SummaryDyspnoea measurements in chronic obstructive pulmonary disease (COPD) can be broadly divided into two categories: those that assess breathlessness during exercise, and those that assess breathlessness during daily activities. We investigated the relationships between dyspnoea at the end of exercise and during daily activities with clinical measurements and mortality in COPD patients.We examined 143 male outpatients with moderate to very severe COPD. The peak Borg score at the end of progressive cycle ergometry was used for the assessment of peak dyspnoea rating during exercise, and the Baseline Dyspnea Index (BDI) score was used for dyspnoea with activities of daily living. Relationships between these dyspnoea ratings with other clinical measurements of pulmonary function, exercise indices, health status and psychological status were then investigated. In addition, their relationship with the 5-year mortality of COPD patients was also analyzed to examine their predictive ability.Although the BDI score was significantly correlated with airflow limitation, diffusing capacity, exercise indices, health status and psychological status, the Borg score at the end of exercise had non-existent or only weak correlations with them. The BDI score was strongly significantly correlated with mortality, whereas the Borg score was not.Dyspnoea during daily activities was more significantly correlated with objective and subjective measurements of COPD than dyspnoea at the end of exercise. In addition, the former was more predictive of mortality. Dyspnoea with activities of daily living is considered to be a better measurement for evaluating the disease severity of COPD than peak dyspnoea during exercise.