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RNA therapeutics is an emerging field that widens the range of treatable targets and would improve disease outcome through bypassing the antibiotic bactericidal targets to kill Mycobacterium tuberculosis (M.tb).We screened for microRNA with immune-regulatory functions against M.tb by next generation sequencing of peripheral blood mononuclear cells, followed by validation in an independent cohort.Twenty three differentially expressed microRNAs were identified between 12 active pulmonary TB patients and 4 healthy subjects, and 35 microRNAs before and after 6-month anti-TB therapy. Enriched predicted target pathways included proteoglycan, HIF-1 signaling, longevity-regulating, central carbon metabolism, and autophagy. We validated miR-431-3p down-regulation and miR-1303 up-regulation accompanied with corresponding changes in their predicted target genes in an independent validation cohort of 46 active TB patients, 30 latent TB infection subjects, and 24 non-infected healthy subjects. In vitro experiments of transfections with miR-431-3p mimic/miR-1303 short interfering RNA in THP-1 cells under ESAT-6 stimuli showed that miR-431-3p and miR-1303 were capable to augment and suppress autophagy/apoptosis/phagocytosis of macrophage via targeting MDR1/MMP16/RIPOR2 and ATG5, respectively.This study provides a proof of concept for microRNA-based host-directed immunotherapy for active TB disease. The combined miR-431-3p over-expression and miR-1303 knock-down revealed new vulnerabilities of treatment-refractory TB disease.

BackgroundAdult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity.MethodsEnvironmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case–control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables.FindingsIn the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28–3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108–0.311, p2.5exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (pInterpretationThese results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.

Background The Interaction between anti-tuberculous and immunosuppressive drugs which may increase the risk of graft rejections is a major challenge in managing transplant recipients with tuberculosis (TB). Instead of rifampicin (RFM), most guidelines recommended the use of rifabutin (RFB) because of its reduced capacity to induce immunosuppressant metabolism while maintaining the same efficacy as RFM against TB. However, there has been no available data directly comparing the outcome of RFB from RFM-based anti-TB regimens in liver transplant patients with TB. This study aimed to compare the effects of RFB from RFM-based treatment in terms of the drug interaction with immunosuppressants, as well as the safety, efficacy and clinical outcomes of living donor liver transplant (LDLT) recipients with active TB. Patients and methods A retrospective study was conducted on all adult LDLT recipients diagnosed with active TB from June 1994 to May 2016 that had concurrently and continuously received either RFB or RFM-based treatment and immunosuppressants. Results Twenty-two patients were included. Twelve (55%) patients were in the RFM group. Ten (45%) patients were in the RFB group. RFB group showed a lesser rate of immunosuppressant trough level reduction (20% vs 50%, p = 0.009) during TB treatment. There was no TB recurrence and no significant change in platelet or leukocyte count in either group. Acute cellular rejection (ACR), rate of TB-treatment completion and overall survival, rates were excellent and statistically similar in both groups. Conclusion The use of RFB in LDLT recipients with active TB, had a lesser drug interaction than when RFM was used. However, RFB did not significantly reduced the rate of ACR. RFB and RFM are both effective and safe to use in LDLT recipients with active TB.

Objectives Acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) can affect health status, hospitalization and readmission rates, and disease progression. This study aimed to identify independent markers associated with COPD AEs. Methods This study included male patients with COPD and collected data regarding their AEs and baseline clinical parameters. Results We included 149 male patients. Among them, 58 were included in the year 0 high-AE group and 91 in the low-AE group. Multivariate analysis revealed that the high-AE group had higher white blood cell count, lower serum albumin level, and post-bronchodilator (BD) forced expiratory volume in one second (FEV1) (%) with a combined receiver operating characteristic curve (ROC) of 0.721 ( p < 0.001). Additionally, 34 patients were included in the year 1 high-AE group and 70 in the low-AE group ( p < 0.001). Multivariate analysis revealed that the high-AE group had higher platelet count, positive asthma history, and lower pre-BD FEV1 (%) with a combined ROC of 0.782 ( p < 0.001). Conclusion In male patients with COPD, baseline white blood cell count, albumin level, and post-BD FEV1 (%) were correlated with year 0 AE; on the other hand, baseline platelet count, positive asthma history, and pre-BD FEV1 (%) were associated with year 1 AE.

We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ZNF323 (− 296), and hypomethylated SEPT8 (− 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (− 173) gene and hypomethylated CYSLTR1 (+ 348)/CCDC88C (+ 125,722)/ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (− 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (− 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2′-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.

Background: Adult asthma is phenotypically heterogeneous with unclear etiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity. Methods: Environmental risk was evaluated by assessing the records of National Health Insurance Research database (NHIRD) and residence-based air pollution [PM2.5 and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)], integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case-control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-SNE integrating 18 clinical and demographic variables. Findings: In the NHIRD dataset, a modest increase in the relative risk with time-lag effect for emergency (N=209,837) and outpatient visits (N=638,538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH originated from multiple sources, posing a significant risk for current asthma and its severity, correlating with the level of oxidative stress markers, notably Ne-(hexanoyl)-lysine (HEL) as a marker of response in both cases and controls. Further, levels of circulating sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) were found to discriminate asthma, correlating with the levels of exposure to PAH and metals, respectively, and both correlating with a panel of circulating inflammatory markers. Stratification of the combined datasets by 6 phenotypic clusters among 1,163 asthmatic subjects and those with comorbid T2DM revealed cluster-selective environmental risks and biosignatures. Interpretation: These results suggest the potential contribution of environmental factors, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity. Funding Information: This work was supported, in part, by grants from National Health Research Institutes, Taiwan (EOPP10-014, EOSP07-014 and NHRI-102A1-PDCO-03010201) and Ministry of Health, Taiwan (EODOH01), National Science Council (NSC 102-2314-B-037-052), Ministry of Health (EODOH01), Ministry of Science and Technology (MOST 103-2320-B-110-001), and Academic Sinica (BM-102021170), Taiwan. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: All eligible subjects were enrolled in the study after signing the informed consent approved by the respective recruitment hospitals.

Objectives This study aims to explore the role of M2a polarization and formyl peptide receptor (FPR) regulation in the reactivation of Mycobacterium tuberculosis (Mtb) infection. Methods M1/M2a monocyte percentage and FPR1/2/3 protein expression of blood immune cells were measured in 38 patients with sputum culture (+) active pulmonary TB disease, 18 subjects with latent TB infection (LTBI), and 28 noninfected healthy subjects (NIHS) using flow cytometry method. Results M1 percentage was decreased in active TB versus either NIHS or LTBI group, while M2a percentage and M2a/M1 percentage ratio were increased. FPR1 expression on M1/M2a, FPR2 expression on M1, and FPR3 expression of M1 were all decreased in active TB versus LTBI group, while FPR1 over FPR2 expression ratio on NK T cell was increased in active TB versus either NIHS or LTBI group. In 11 patients with active TB disease, M1 percentage became normal again after anti-TB treatment. In vitro Mtb-specific antigen stimulation of monocytic THP-1 cells resulted in M2a polarization in association with increased FPR2 expression on M2a. Conclusions Increased M2a and decreased M1 phenotypes of blood monocyte may serve as a marker for active TB disease, while decreased FPR1 on blood monocyte may indicate LTBI status.

BACKGROUND This study aimed to determine clinical outcomes using various drugs during tuberculosis (TB) treatment among living donor liver transplant (LDLT) recipients with TB and to assess the impact of performing LDLT in patients with active TB at the time of LDLT. MATERIAL AND METHODS Out of 1313 LDLT performed from June 1994 to May 2016, 26 (2%) adult patients diagnosed with active TB were included in this study. Active TB was diagnosed using either TB culture, PCR, and/or tissue biopsy. RESULTS The median age was 56 years and the male/female ratio was 1.6: 1. Most patients had pulmonary TB (69.2%), followed by extrapulmonary and disseminated TB (15.4% each). Fourteen (53.8%) patients underwent LDLT even with the presence of active TB. All patients concurrently received anti-TB [Rifampicin-based: 13 (50%); Rifabutin-based: 12 (46.2%); INH-based: 1 (3.8%)] and immunosuppressive drugs [Tacrolimus-based: 6 (23%); Sirolimus/Everolimus-based: 20 (77%)]. During treatment, adverse drug reactions (ADR) occurred in 34.6% of patients: acute rejection in 6 (23.1%), hepatotoxicity in 2 (7.7%), and blurred vision in 1 (3.8%). Twenty-three (88%) patients completed their TB treatment. Neither TB recurrence nor TB-specific mortality were observed. Three (11.5%) patients died of non-TB-related causes. The overall 5-year survival rate was 86.2%. Patients with ADRs had a higher incidence of incomplete TB treatment (log-rank: p=0.012). Furthermore, patients with incomplete treatment were significantly associated with decreased overall survival (log-rank: p

CD14+ monocytes contain precursors for macrophages and fibrocytes, known to be involved in regulating airway remodeling in human asthma and distinguishable by the PM-2K marker. We sought to identify circulating subsets of PM-2K+ macrophage-like cells and evaluate their relationships to lung function, severity and control status. Circulating PM-2K+ macrophage-like cells and fibrocytes could be identified and distinguished between normal individuals (N = 152) and asthmatic subjects (N = 133) using multi-parametric flow cytometry. PM-2K+ macrophage-like cells were found to be significantly lower in asthmatic subjects, particularly noted for the CD14−PM-2K+ subset and PM-2K+CCR7−CD86+ cells in subjects with poor lung function (FEV%/FVC% −CD86+ subset distribution was significantly different in subjects with varying severity. Moreover, exogenous transforming growth factor beta 1 (TGF-β1) was found to inhibit the generation of PM-2K+ macrophage-like cells, but promote the growth of fibrocytes, from CD14+ monocytes, and monocyte-derived TGF-β1 was found to correlate with the lung function, severity and control status in asthmatic patients. Collectively, aberrant differentiation of monocytes into PM-2K+ macrophage-like cell subsets and fibrocytes, together with increased monocyte-derived TGF-β1, characterized patients with severe asthma.

Exposure to polycyclic aromatic hydrocarbons (PAHs) associated with ambient air particulate matter (PM) poses significant health concerns. Several modeling approaches have been developed for simulating ambient PAHs, but no hourly intra-urban spatial data are currently available. The aim of this study is to develop a new modeling strategy in simulating, on an hourly basis, grid-scale PM2.5-PAH levels. PM and PAHs were collected over a one-year time frame through an established air quality monitoring network within a metropolitan area of Taiwan. Multivariate linear regression models, in combination with correlation analysis and PAH source identification by principal component analysis (PCA), were performed to simulate hourly grid-scale PM2.5-PAH concentrations, taking criteria pollutants and meteorological variables selected as possible predictors. The simulated levels of 72-h personal exposure were found to be significantly (R=0.729**, p

Objectives Previous studies reported that environmental factors, particularly the work environment, were related to quality of life (QoL) in patients with asthma. However, the pathway that links workplace and QoL in adults with asthma is still not clear. The aim of this study was to explore the comprehensive environmental factors, asthma control, and QoL pathways in patients with asthma. Study design and setting Two cohorts of patients with asthma were established, including a prospective phase cohort in 2006 and a cross-sectional phase cohort in 2012. The Asthma Control Test was used to determine the level of disease control, and QoL was assessed by using the Taiwanese version of an asthma quality-of-life questionnaire. In 2014, a structural equation model was applied to explore the pathways from the risk factors to QoL. Results The structural equation model for predicting QoL provided a good fit (χ(2) [degrees of freedom] = 43.81 [38]; root mean square error of approximation 0.021 [90% confidence interval, 0.001-0.044]) after combining the two cohorts. The wheeze frequency, allergic response frequency, parental asthma, and asthma control were directly associated with QoL. We found that patients who were obese and who worked in poor environments had increased work symptoms and wheeze frequency during the previous year in a cross-sectional phase cohort. However, we did not find that body mass index was a significant factor in a prospective cohort. The patients with obesity and with frequent work symptoms, which induced poor asthma control, were possible mechanisms in the pathway from workplace exposure to poor QoL in the observed adults with asthma in our combined data. Conclusion Body mass index, the work environment, and the wheeze frequency should be considered when assessing asthma control and QoL in adult patients with asthma. Patients who reduce their body weight or avoid exposure to poor workplaces may find this useful for their asthma control and improvement of their QoL.

Background Controversy exists in previous studies on macrophage M1/M2 polarization in chronic obstructive pulmonary disease (COPD). We hypothesized that formyl peptide receptor (FPR), a marker of efferocytosis and mediator of M1/M2 polarization, may be involved in the development of COPD. Methods We examined FPR 1/2/3 expressions of blood M1/M2a monocyte, neutrophil, natural killer (NK) cell, NK T cell, T helper (Th) cell, and T cytotoxic (Tc) cell by flowcytometry method in 40 patients with cigarette smoking-related COPD and 16 healthy non-smokers. Serum levels of five FPR ligands were measured by ELISA method. Results The COPD patients had lower M2a percentage and higher percentages of NK, NK T, Th, and Tc cells than the healthy non-smokers. FPR2 expressions on Th/Tc cells, FPR3 expressions of M1, M2a, NK, NK T, Th, and Tc cells, and serum annexin A1 (an endogenous FPR2 ligand) levels were all decreased in the COPD patients as compared with that in the healthy non-smokers. FPR1 expression on neutrophil was increased in the COPD patient with a high MMRC dyspnea scale, while FPR2 expression on neutrophil and annexin A1 were both decreased in the COPD patients with a history of frequent moderate exacerbation (≥ 2 events in the past 1 year). In 10 COPD patients whose blood samples were collected again after 1-year treatment, M2a percentage, FPR3 expressions of M1/NK/Th cells, FPR2 expression on Th cell, and FPR1 expression on neutrophil were all reversed to normal, in parallel with partial improvement in small airway dysfunction. Conclusions Our findings provide evidence for defective FPR2/3 and annexin A1 expressions that, associated with decreased M2a polarization, might be involved in the development of cigarette smoking induced persistent airflow limitation in COPD.

Chronic exposure to ambient polycyclic aromatic hydrocarbons (PAHs) is associated with asthma, but its regulatory mechanisms remain incompletely defined. We report herein that elevated levels of urinary 1-hydroxypyrene, a biomarker of PAH exposure, were found in asthmatic subjects (n = 39) as compared to those in healthy subjects (n = 43) living in an industrial city of Taiwan, where indeno[1,2,3-cd]pyrene (IP) was found to be a prominent PAH associated with ambient PM2.5. In a mouse model, intranasal exposure of mice with varying doses of IP significantly enhanced antigen-induced allergic inflammation, including increased airway eosinophilia, Th2 cytokines, including IL-4 and IL-5, as well as antigen-specific IgE level, which was absent in dendritic cell (DC)-specific aryl hydrocarbon receptor (AhR)-null mice. Mechanistically, IP treatment significantly altered DC’s function, including increased level of pro-inflammatory IL-6 and decreased generation of anti-inflammatory IL-10. The IP’s effect was lost in DCs from mice carrying an AhR-mutant allele. Taken together, these results suggest that chronic exposure to environmental PAHs may pose a significant risk for asthma, in which IP, a prominent ambient PAH in Taiwan, was shown to enhance the severity of allergic lung inflammation in mice through, at least in part, its ability in modulating DC’s function in an AhR-dependent manner.

Background Asthma is a heterogeneous disease with complex mechanisms and involves many risk factors and in vivo cellular molecules. It is notable that sex differences may have a potential effect on asthma phenotype. Objective To identify sex-specific phenotypes and health outcomes of asthma. Methods We conducted the Taiwanese Adult Asthma Cohorts study to enroll female (n = 421) and male (n = 299) adult patients with stable asthma. Eight variables were selected by a factor analysis. We further performed a 2-step sensitivity cluster analysis to classify asthma clusters. The risks of asthma-related outcomes among the clusters were assessed using simple logistic regressions. Results Three different clusters were identified in males and females. In the female clusters, atopy/eosinophil-predominant (cluster 2), and obesity/neutrophil-predominant pattern (cluster 3) had more than a 2-fold risk of asthma exacerbations (odds ratio, 2.51; 95% CI, 1.12-5.59 and odds ratio, 2.22; 95% CI, 1.01-4.93). In the male clusters, current smoker/neutrophilic atopic cluster (cluster 5) and ex-smoker/eosinophil-predominant or mixed inflammatory pattern (cluster 6) also had a higher risk of asthma exacerbations. Conclusions This study identified heterogeneous characteristics between sexes. In females, the analysis showed atopy with eosinophil-predominant and obese with neutrophil-predominant inflammation. Two distinct asthma phenotypes were found in current and ex-smokers in males. Understanding asthma phenotypes and explaining the potentially biological pathways have become important.

Nai-Ying Kuo,1,2 Mei-Lien Tu,1,3 Tsai-Yi Hung,1 Shih-Feng Liu,4 Yu-Hsiu Chung,4 Meng-Chih Lin,4 Chao-Chien Wu41Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital; 2Kaohsiung Medical University; 3Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, TaiwanBackground: Patient-ventilator asynchrony is a common problem in mechanically ventilated patients; the problem is especially obvious in COPD. Neutrally adjusted ventilatory assist (NAVA) can improve patient-ventilator asynchrony; however, the effect in COPD patients with prolonged mechanical ventilation is still unknown. The goals of this study are to evaluate the effect of NAVA and conventional weaning mode in patients with COPD during prolonged mechanical ventilation.Methods: The study enrolled a total of 33 COPD patients with ventilator dependency for more than 21 days in the weaning center. A diaphragm electrical activity (Edi) catheter was inserted in patients within 24 hours after admission to the respiratory care center, and patients were randomly allocated to NAVA or conventional group. A spontaneous breathing trial was performed every 24 hours. The results correlated with the clinical parameters.Results: There were significantly higher asynchrony incidence rates in the whole group after using Edi catheter (before vs post-Edi catheter insertion =60.6% vs 87.9%, P

Elafin inhibits serine proteases, such as human neutrophil elastase and proteinase 3, to prevent excessive damage during inflammation. However, the relationship between elafin and asthma is still unclear. Microarray technology was used to evaluate smoking- and asthma-related biomarkers in a discovery-driven manner. We identified candidate genes, e.g., proteinase inhibitor 3 (PI3), related to asthma and smoking from gene expression microarray data sets and evaluated their potential as biomarkers for asthma.We used human genome microarray data sets from smoking- and asthma-related gene expression data sets and performed real-time quantitative polymerase chain reaction to measure and validate differences in gene expression. We also recruited adult patients with asthma and age- and sex-matched control patients who were administered a structured questionnaire and evaluated for lung function and plasma elafin levels, which are encoded by the PI3 gene.Six significantly altered candidate genes, PI3, protein kinase C iota, phosphoserine phosphatase, IQ motif-containing GTPase activating protein 1, interleukin 13 receptor α 1, and signal transducing adaptor molecule SH3 domain and ITAM motif 2, were identified from comparisons across the four asthma- and four smoking-related data sets included in this study. An in vitro study of human airway epithelial cells (A549) and a human monocytic cell line (THP-1) demonstrated that PI3 messenger RNA levels were significantly altered by nicotine exposure. Elafin concentration was significantly higher in control patients than in patients with asthma (p0.001). The plasma elafin concentration in the highest quartile (≥12.69 ng/mL) was inversely associated with asthma (adjusted odds ratio 0.122 [95% confidence interval, 0.053-0.278]) compared with the lowest quartile (5.82 ng/mL) after adjusting for age, sex, smoking status, waist-to-hip ratio, percentage predicted forced expiratory volume in 1 second, cockroaches in the home, incense burning, and family history.Our study revealed that high elafin levels identified in smoking- and asthma-related microarray data sets and an epidemiologic study significantly reduced the risk of asthma. Further studies of elafin as a potential therapy for asthma are warranted.

BACKGROUND The methods of differentiation and management of incidental small pulmonary nodules (ISN) in candidates for living donor liver transplantation (LDLT) are not well clarified. We aimed to share our experience and investigate the role of nodular size in application of ISN. MATERIAL AND METHODS From October 2009 to December 2012, 360 primary adult LDLTs were performed. Thirty-seven candidates with ISN and follow-up of over 2 years were collected. Subjects with pathologic reports of malignancy or infection composed group A, and those with pathologic reports of benign disease or stable lesions on CT image within 3~6 months composed group B. RESULTS Nodular size was significantly different between group A and B (7.68±3.77 mm versus 4.10±1.37 mm, respectively, p

High-sensitivity C-reactive protein (hs-CRP) concentrations and obesity are proposed to have a significant relationship with impairment of lung function, but little has been reported to date on the association between CRP gene and lung function. We studied the association of three tagSNPs (tag single nucleotide polymorphisms) of CRP gene and their interactions with central obesity on lung function. A total of 384 asthmatic adults and 384 controls who were 1:1 matched by sex and age were recruited for this study. Three tagSNPs polymorphisms for CRP rs1417938, rs1800947 and rs1205 were selected from HapMap data and genotyping by using TaqMan allelic discrimination assay. A questionnaire interview, body composition and pulmonary function tests were performed. CRP single nucleotide polymorphisms (SNPs) did not increase the risk of asthma, but CRP rs1205 CC genotype significantly decreased the predictive value of forced vital capacity (FVC) in the asthma group (adjusted mean change = −7.54%, 95% CI = −13.82 to −1.25%). Waist-to-hip ratio, not body mass index, also decreased the predictive value of FVC in asthmatics. The subjects with central obesity who carried CRP SNPs have a significant reduction effect in lung function. The current results suggest that central obesity may play a major role in lung function, and these effects were modified significantly by the polymorphisms for CRP gene.

Background: Adult asthma is caused by interaction effects of multiple genetic and environmental factors. Some studies have suggested that antioxidant enzyme activity and gene polymorphisms may play important roles in the context of asthma. Therefore, our study objectives were to investigate the association between asthma, antioxidant activities and the polymorphisms of manganese superoxide dismutase (Mn-SOD) or catalase (CAT). Materials and Methods: A case-control study, for which we recruited 250 asthmatic adults and 250 age- and sex-matched controls. All subjects completed a questionnaire. Waist and hip circumference measurements, a lung function test and DNA genotyping were performed. In total, 50 incident cases and 50 matched controls who were non-smokers or had quit smoking for at least 1 year were selected in order to investigate SOD and CAT activity levels. Results: In our study, we did not find a significant association between Mn-SOD Ala16Val, CAT C–262T and asthma. The level of SOD activity in new-onset asthma patients was significantly lower than in control subjects (p < 0.0005). The level of CAT activity in new-onset asthma patients was significantly higher than in control subjects (p < 0.0005). Conclusions: The levels of SOD and CAT activity were significantly related to adult asthma. SOD and CAT activity may be good tools to differentiate potential asthma sufferers. This would enable us to further investigate the mechanism of defective antioxidant enzymes in the context of asthma pathogenesis.

Objective:To identify patients at high risk of relapse after anti-tuberculosis (TB) therapy or with poor long-term outcomes.Methods:Fifty-one patients with pulmonary TB: 7 were classified as high association with both cavitations on initial chest radiography and positive sputum smear/cultures after two months of anti-TB treatment (HA group); 19 medium association (MA, one risk alone); and 25 low association (LA, neither risk). Serum interferon (IFN)-γ-inducible protein 10 (IP-10), interleukin-17 (IL-17), and C-reactive protein levels were investigated.Results:There was a trend towards higher serum IP-10 levels (p= 0.042) for HA patients throughout the 6-month treatment period. Month-2 IP-10 levels were higher in the HA than in the MA/LA group (656.2 ± 234.4 vs. 307.6 ± 258.5 pg/ml, adjustedp= 0.005). Receiver operating characteristic curves showed that the risk of relapse was well-captured by month-2 IP-10 levels at a cut-off value of 431 pg/ml (AUC=0.857, 95% CI 0.75–0.97,p= 0.003). Month-2 serum IL-17 levels were lower in non-survivors than survivors (15.7 ± 2.9 pg/ml vs. 24.6 ± 8.2 pg/ml,p= 0.001). Multivariate analysis demonstrated that a month-2 serum IL-17 level of ≤ 17 pg/ml (p= 0.026) was independently associated with all-cause mortality.Conclusions:Serum IP-10 and IL-17 levels after 2 months of anti-TB treatment may be biomarkers for estimating risk of both cavitation and delayed sputum conversion, and for predicting long-term mortality, respectively.

Summary Background Several studies have suggested that the association between obesity and asthma may be stronger in females than in males, but the reason is still unclear. Objective The aim of this study was to investigate whether differences in high-sensitivity C-reactive protein (hs-CRP) levels explain why obesity is associated with asthma in females but not in males. Methods This study prospectively enrolled 754 subjects 18 years old from hospital-based asthma patients and population-based controls. We measured adiposity factors [body mass index (BMI), waist circumference and waist-hip ratio], hs-CRP and total IgE levels. Results After adjusting for potential confounding factors, we found a significant association between BMI and asthma in females with a significant interaction of gender and BMI on asthma (χ2=10.2, P=0.004). If hs-CRP was added to the logistic model, the interaction was attenuated but still significant (χ2=7.02, P=0.03). After adjusting for BMI, we did not find that circulating hs-CRP concentrations were significantly associated with asthma in males and females. Conclusion We found that BMI was associated with asthma in females, but our results do not support the suggestion that hs-CRP levels contribute significantly to the link between obesity and asthma with respect to gender disparity. Cite this as: T.-N. Wang, M.-C. Lin, C.-C. Wu, M.-S. Huang, S. Y. Leung, C.-C. Huang, P.-S. Ho and Y.-C. Ko, Clinical & Experimental Allergy, 2011 (41) 72–77.

Asthma is often work-related and can be classified as atopic or nonatopic on the basis of its pathogenesis. Few studies have reported an association between exposure to occupational asthmogens and asthma with and without atopy.We investigated, in adults with asthma, whether occupational exposure to asthmogens influenced the risk of having atopic or nonatopic asthma, and their level of lung function.We recruited 504 hospital-based adults with current asthma, 504 community-based control subjects, and 504 hospital-based control subjects in southern Taiwan. Asthma with atopy was defined as having asthma in combination with an increase in total IgE (≥100 U/ml) or a positive Phadiatop test (≥0.35 Pharmacia arbitrary unit/L) (Pharmacia ImmunoCAP; Pharmacia, Uppsala, Sweden). Occupational exposure to asthmogens was assessed with an asthma-specific job exposure matrix.We found a significant association between atopic asthma and exposure to high molecular weight asthmogens (adjusted odds ratio [AOR], 4.0; 95% confidence interval [CI], 1.8-8.9). Nonatopic asthma was significantly associated with exposure to low molecular weight asthmogens (AOR, 2.6; 95% CI, 1.6-4.3), including industrial cleaning agents and metal sensitizers. Agriculture was associated with both atopic and nonatopic asthma (AOR, 7.8; 95% CI, 2.8-21.8; and AOR, 4.1; 95% CI, 1.3-13.0, respectively). The ratio of FEV₁ to FVC in the high-risk group was significantly lower than in the no-risk group (P = 0.026) in currently employed patients with asthma.In adults with asthma, occupational exposure to high and low molecular weight asthmogens appears to produce differential risks for atopic and nonatopic asthma.

Background and objective:Little is known about the usefulness of lymphocyte subsets as early predictors of anti-tuberculosis (TB) treatment response in immuno-competent patients.Methods:Among a total of 64 patients with culture positive pulmonary TB, 29 remained sputum smear/culture positive or had delayed resolution on CXR (slow responders (SR)), and 35 had sputum culture conversion to negative and rapid resolution on CXR (fast responders (FR)) after two months of anti-tuberculosis treatment. Clinical parameters and lymphocyte subsets were investigated.Results:A larger proportion of patients in the SR group had cavities on CXR, bilateral lung involvement, positive acid-fast bacilli stains, and complaint of cough at diagnosis than those in the FR group. Absolute counts of CD3+T cells (p= 0.016) and CD8+T cells (p= 0.012) at diagnosis were both significantly higher in the SR group. This trend was present throughout the 6-month treatment course. Absolute T cell counts (odds ratio (OR) 1.002, 95% confidence interval (CI) 1.0–1.004), positive sputum acid fast bacilli stain (OR 6.69, 95% CI 1.37–32.77) and bilateral lung involvemment on CXR (OR 13.114, 95% CI 1.87–92.14) at diagnosis were independent predictors for a slow response. Combining these three predictors, a prediction score (PS) could be calculated to display an optimal discrimination for slow response (area under the curve (AUC) = 0.855,p< 0.001) whereas absolute T cell counts yielded the highest discriminative value on an individual level (AUC = 0.676,p= 0.015).Conclusions:A higher T cell count at diagnosis in patients with TB may predict a slow response to two months of treatment. The calculation of a PS further increased predictive accuracy and performance.

There has been no previously reported case series study regarding chest radiographic (CXR) presentations in dengue hemorrhagic fever (DHF) patients. We retrospectively studied 363 DHF patients from June to December 2002 in southern Taiwan, and a total of 468 CXRs were obtained and reviewed. More than 50% of these showed abnormalities after the 3rd day, with infiltration only and small pleural effusion as the major findings. Progressive changes during the first week and improvements during the second week were observed in these abnormal CXRs. The CXR presentation was also significantly correlated with laboratory findings (white blood cell count, platelet levels, activated partial thromboplastin time, and alanine aminotransferase and albumin levels), as well as the clinical course (renal insufficiency, liver function impairment, upper gastrointestinal bleeding, combination bacterial infection, and duration of admission) and outcome (mortality). The CXR may therefore be a modality for evaluating the clinical course of DHF and should be made during first week after the onset of illness.

To investigate clinical course and outcome of dengue with acute respiratory failure (ARF), and to identify related risk factors for acquiring ARF in dengue, we retrospectively studied 11 dengue patients with ARF. From June to December 2002, a total of 606 adult patients were diagnosed as having dengue. Eleven (1.8%) of 606 dengue patients had complications of ARF. The main causes of ARF were sepsis (n = 6, 54.5%) and upper gastrointestinal (UGI) bleeding (n = 3, 27.3%). The mortality rate was 72.7% (n = 8). Additionally, univariate analysis showed that age, dyspnea, cough, prothrombin time, activated partial thromboplastin time, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, albumin, renal insufficiency, acute renal failure, acute hepatic failure, UGI bleeding, and combination bacterial infection were significantly predictive variables associated with dengue patients with ARF.

Objective.We conducted an epidemiologic investigation at the beginning of a nosocomial outbreak of severe acute respiratory syndrome (SARS) to clarify the dynamics of SARS transmission, the magnitude of the SARS outbreak, and the impact of the outbreak on the community.Methods.We identified all potential cases of nosocomially acquired SARS, linked them to the most likely infection source, and described the hospital containment measures.Setting.A 2,300-bed medical center in Kaohsiung, Taiwan.Results.A total of 55 cases of SARS were identified, and 227 hospital workers were quarantined. The index patient and neighboring patients were isolated. A chest physician team reviewed medical charts and chest radiographs and monitored the development of SARS in patients staying in the ward. The presence of underlying lung disease and immunocompromise in some patients made the diagnosis of SARS difficult. Some cases of SARS were diagnosed after the patients had died. Medical personnel were infected only if they cared for patients with unrecognized SARS, and caretakers played important roles in transmission of SARS to family members. As the number of cases of nosocomial SARS increased, the hospital closed the affected ward and expedited construction of negative-pressure rooms on other vacated floors for patient cohorting, and the last case in the hospital was identified 1 week later.Conclusions.Timely recognition of SARS is extremely important. However, given the limitations of SARS testing, possible loss of epidemic links, and the nonspecific clinical presentations in hospitalized patients, it is very important to establish cohorts of persons with low, medium, and high likelihoods of SARS acquisition. Rapid closure of affected wards may minimize the impact on hospital operations. Establishment of hospitals dedicated to appropriate treatment of patients with SARS might minimize the impact of the disease in future epidemics.

Background A genome-wide association study uncovered Chitinase 3 like 1 (CHI3L1) as a candidate gene for asthma susceptibility. CHI3L1, which encodes the YKL-40 protein, is associated with asthma in Western European and American populations and with atopy in a Korean population. However, asthma-associated polymorphisms remain unknown for a Taiwanese population. Methods We enrolled 628 adult asthmatic patients and 1:1 age-sex matched community-based controls in southern Taiwan and performed a combined effect sizes analysis to test if CHI3L1 polymorphisms were related to genetic risks for asthma in the Asian population. Ten tagSNP polymorphisms for the CHI3L1 gene were selected from the HapMap database and genotyped using a TaqMan allelic discrimination assay. Results Adjusted odds ratios of the CHI3L1 rs1538372 CC genotype (aOR = 1.97, 95% CI: 1.23–3.14) and the rs10399931 GG genotype (aOR = 1.77, 95% CI: 1.13–2.77) were significantly associated with asthma in the Taiwanese populations. Predictive values of forced expiratory volume in the first second of the forced vital capacity (12.37%, P = 0.03) and of forced vital capacity (12.10%, P = 0.036) decreased in conjunction with an increase in YKL-40 levels among CHI3L1 rs1538372 CC carriers; these values were 16.1% (P = 0.004) and 14.5% (P = 0.011), respectively, among CHI3L1 rs10399931 GG carriers. Furthermore, steroid use by asthma patients did not affect serum YKL-40 levels, but both polymorphisms had significant effects on YKL-40 levels in asthma patients who used steroids. Conclusions Our findings suggest that the CHI3L1 polymorphisms rs1538372 and rs10399931 can be used as genetic markers for predicting asthma risk in the Taiwanese population.

Summary Objectives Toll-like receptor 2 (TLR2) is a major mediator of innate immunity against tuberculosis (TB). This study aimed to determine if TLR2 promoter DNA methylation is associated with pulmonary TB. Methods The DNA methylation levels of 20 CpG sites over the TLR2 promoter region and TLR2 gene/protein expressions of immune cells of the blood were examined in 99 sputum culture-positive pulmonary TB patients and 77 healthy subjects (HS). Results TB patients had higher methylation levels over five CpG sites (3, 7, 9, 13, and 18), lower TLR2 gene expression, lower TLR2 expression on monocyte, higher TLR2 expression on NK cell, and higher serum TNF-α/IFN-γ levels than HS after adjusting for confounding factors. Patients with a high bacillary load had lower methylation levels at CpG-15, -17, and -20. Patients with drug-resistant TB had higher CpG-18 methylation levels and lower TLR2 expression on NK cell. Patients with far advanced lesion on chest radiograph had higher serum TNF-α level and higher TLR2 expression on NK cell. Patients with a high TLR2 expression on NK cell had lower one-year survival. CpG-18 methylation level, TLR2 expressions on monocyte/NK cell, and TNF-α/IFN-γ levels were all reversed to normal after 6-month anti-TB treatment. Conclusions Aberrant methylation of certain CpG sites over TLR2 promoter region is associated with active pulmonary TB or its phenotypes, probably through the down-regulation of TLR2 expression.

National Health Research Institutes National Science Council, Taiwan National Institute for Health Research (NIHR) Biomedical Research Centre and Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust King's College London Background: Betel nut is commonly used in many countries. Despite evidence suggesting an association with asthma, few studies have investigated the connection between betel nut use and asthma; thus, the underlying mechanism for the association with asthma is also unclear. the aim of this study was to investigate the association between betel chewing and asthma as well as the associations of plasma arecoline (a biomarker for exposure) and eotaxin-1 (a potential mediator) with asthma and lung function.Methods: We recruited 600 hospital-based asthmatic patients and 1200 age- and gender-matched community controls in southern Taiwan. To clarify the mechanism of action for eotaxin-1 in the association between betel chewing and asthma, we also designed an in vitro experiment to study the functional associations between arecoline exposure and eotaxin-1 levels.Results: A significant association was found between asthma and current betel chewing (adjusted odds ratio 2.05, 95% CI = 1.12-3.76), which was independent of potential confounders but was attenuated following adjustment for eotaxin-1. Arecoline and eotaxin-1 levels were positively correlated (Spearman r = 0.303, p = 0.02), while arecoline and arecaidine were negatively correlated with lung function. Functionally, arecoline alone does not induce eotaxin-1 release in vitro from dermal and gingival fibroblasts. However, in the presence of IL-4 and TNF-alpha, arecoline at 100 mg/ml induced more eotaxin-1 release than arecoline at 0 mu g/ml (2700 +/- 98 pg/ml vs 1850 +/- 142 pg/ml, p = 0.01 in dermal fibroblast cells, and 1489 +/- 78 pg/ml vs 1044 +/- 95 pg/ml, p = 0.03 in gingival fibroblast cells, respectively).Conclusion: Betel chewing is associated with asthma in this population, with arecoline induction of eotaxin-1 supported as a plausible causal pathway. Kaohsiung Med Univ, Coll Hlth Sci, Dept Publ Hlth, Kaohsiung, Taiwan Kaohsiung Med Univ, Ctr Excellence Environm Med, Kaohsiung, Taiwan Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Coll Med, Dept Internal Med,Div Pulm & Crit Care Med & Geri, Kaohsiung, Taiwan Chang Gung Univ, Chang Gung Mem Hospital, Coll Med, Med Ctr,Dept Med,Div Pulm & Critical Care Med, Kaohsiung, Taiwan Kaohsiung Med Univ, Dept Med & Appl Chem, Kaohsiung, Taiwan Kaohsiung Chang Gung Mem Hosp, Dept Dermatol, Kaohsiung, Taiwan Chang Gung Univ, Coll Med, Kaohsiung, Taiwan Kaohsiung Med Univ, Coll Dent Med, Sch Dent, Kaohsiung, Taiwan China Med Univ Hosp, Environment Omics Dis Res Ctr, Taichung, Taiwan China Med Univ, Grad Inst Clin Med Sci, Taichung, Taiwan Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Coll Med, Fac Med,Dept Internal Med,Div Pulm & Crit Care Me, Kaohsiung, Taiwan Chung Shan Med Univ, Chung Shan Med Univ Hosp, Sch Med, Inst Med,Dept Psychiat, Taichung, Taiwan Universidade Federal de São Paulo, Dept Psychobiol, São Paulo, Brazil Kings Coll London, Inst Psychiat, London, England Universidade Federal de São Paulo, Dept Psychobiol, São Paulo, Brazil National Health Research Institutes: NHRI-CN-PD9611P National Science Council, Taiwan: NSC96-2314-B-037-040-MY3 National Science Council, Taiwan: NSC100-2314-B-037-025-MY3 Web of Science

BackgroundTo investigate whether the toll-like receptor 2 polymorphisms could influence susceptibility to pulmonary TB, its phenotypes, and blood lymphocyte subsets.MethodsA total of 368 subjects, including 184 patients with pulmonary TB and 184 healthy controls, were examined for TLR2 polymorphisms over locus -100 (microsatellite guanine-thymine repeats), -16934 (T>A), -15607 (A>G), -196 to -174 (insertion>deletion), and 1350 (T>C). Eighty-six TB patients were examined to determine the peripheral blood lymphocyte subpopulations.ResultsWe newly identified an association between the haplotype [A-G-(insertion)-T] and susceptibility to pulmonary TB (p = 0.006, false discovery rate q = 0.072). TB patients with systemic symptoms had a lower -196 to -174 deletion/deletion genotype frequency than those without systemic symptoms (5.7% vs. 17.7%; p = 0.01). TB patients with the deletion/deletion genotype had higher blood NK cell counts than those carrying the insertion allele (526 vs. 243.5 cells/μl, p = 0.009). TB patients with pleuritis had a higher 1350 CC genotype frequency than those without pleuritis (12.5% vs. 2.1%; p = 0.004). TB patients with the 1350 CC genotype had higher blood NK cell counts than those carrying the T allele (641 vs. 250 cells/μl, p = 0.004). TB patients carrying homozygous short alleles for GT repeats had higher blood NK cell counts than those carrying one or no short allele (641 vs. 250 cells/μl, p = 0.004).ConclusionsTLR2 genetic polymorphisms influence susceptibility to pulmonary TB. TLR2 variants play a role in the development of TB phenotypes, probably by controlling the expansion of NK cells.

The aim of this study was to investigate genetic effects on the pathogenesis of chronic obstructive pulmonary disease (COPD). The study was conducted as a prospective case-control study in a medical center in southern Taiwan. The patient group consisted of 145 male patients with smoking-related COPD and a control group of 139 resistant smokers from July 2004 to September 2009. We compared allele and genotype frequencies of three tag single nucleotide polymorphisms (SNP) of the TNF-alpha gene promoter region at -308, -863, and -1031 in all subjects. We also analyzed the influence of each genetic variant on pulmonary function parameters, body mass index (BMI), serum TNF-alpha levels, and outcomes among heavy smokers with or without COPD. COPD patients had a significantly lower A allele frequency (9.7 vs. 15.1%, OR = 0.6, p = 0.048, false discovery rate q = 0.144) and a significantly lower A carrier genotype frequency (19.3 vs. 30.2%, OR = 0.52, p = 0.042, q = 0.135) than resistant smokers. The -863 CA genotype was associated with a better FEV(1)/FVC ratio (79 vs. 71.5%, p = 0.034), and higher BMI (24.9 vs. 23.6 kg/m(2), p = 0.048). In addition, COPD patients with the -1031 C carrier genotype had higher serum TNF-alpha levels (20.9 vs. 16.2 pg/ml, p = 0.01). BMI (hazard ratio = 0.84, 95% CI = 0.74-0.96, p = 0.008) was the only independent predictor for mortality. The TNF-alpha -863 A allele may confer a degree of resistance to the susceptibility to and muscle wasting of COPD among heavy smokers.

To compare the clinical and laboratory characteristics and disease severity between adults and children with dengue in Taiwan in 2002, we retrospectively studied 661 serologically confirmed dengue-infected patients (606 adults and 55 children) admitted between June and December 2002 to a single medical centre. The medical charts of the patients were reviewed for demographic, clinical, laboratory and imaging information. Compared with children, adult patients were found to have: higher incidences of arthralgia (P

Lipopolysaccharide (LPS) induces acute lung injury (ALI) via Toll-like receptor 4 (TLR4)-mediated MAPK activation. The lipid A fraction of LPS is considered to be the active moiety, but whether the lipid A-TLR4 interaction accounts completely for ALI-associated MAPK activation in vivo has not been determined. The lipid A fraction of LPS induces a discrete MAPK activation pattern in murine ALI. Mice (C57BL/6J, C3H/HeJ) were treated with intratracheal instillations of purified lipid A or LPS (10, 30, and 100 μg per mouse) or vehicle. ALI was assessed by histology. Chromogenic myeloperoxidase (MPO) activity was measured in lung homogenates. MAPK expression was quantified by immunoblotting. In vitro ERK inhibitor studies using thioglycollate-elicited macrophages were also performed. MPO increased in a dose- and time-responsive fashion. Notably, MPO was 2.4-fold greater after lipid A compared with LPS and vehicle at 6 h after instillation (lipid A, 0.88 ± 0.25 vs. LPS, 0.37 ± 0.21 optical density units·min−1·mg−1; P < 0.05). However, ALI scores were comparable at 6 and 24 h between LPS and lipid A. MPO was also comparable in vehicle-treated or C3H/HeJ mice treated with LPS or lipid A at 6 and 24 h. Phospho-ERK activation was pronounced at 6 and 24 h after lipid A but not LPS treatment. In vitro studies confirmed the relationship between phospho-ERK activation and cytokine expression in macrophage stimulated with either LPS or lipid A. Compared with whole LPS, the lipid A fraction is associated with amplified whole lung MPO and ERK activation 6 h after intratracheal instillation in mice.

In Taiwan, lung cancer is the second most common cause of cancer death and its incidence has been rising for the last 50 years. Shifts in histological types and differences in gender distribution have also accompanied the changed incidence of lung malignancies.A total of 590 lung cancer patients were interviewed at Kaohsiung Chang-Gung Memorial Hospital, a medical center of Southern Taiwan, in 1997 and 2002. A retrospective investigation confirmed the age-adjusted incident rate in the hospital and demographic variations by different histological types for both genders. The statistical differences were evaluated using the heterogeneity chi-squared test and Cox regression.Results indicated that from 1997 to 2002, the age-adjusted rates of lung cancer decreased by 3.64% at the hospital. The largest percentage of increases in the age-adjusted rate was observed for small cell lung cancer (approximately 8.18%), whereas it decreased by 31.2% for squamous cell carcinoma and increased by 1.62% for adenocarcinoma. Female patients were found to be younger and had longer survival duration. The frequency was the highest for lesions in the upper lobe and patients had more advanced stage in all histological types. The 6-month relative survival rate between the two time-periods did not change appreciably.The age-adjusted incidence rate of adenocarcinoma at the hospital has increased, as well as small cell lung carcinoma. During the study period, early-staging diagnosis and 6-months survival rate did not change appreciably for the different histological lung cancer patients, suggesting that therapeutic and diagnostic advances, prevention or screening procedures had mild effects in southern Taiwan. Further studies are needed for confirmation of our results.

To investigate the disease characteristics of sarcoidosis in southern Taiwan, and to investigate diagnostic methods.We retrospectively reviewed the medical records of all patients diagnosed with sarcoidosis at Chang Gung Memorial Hospital, Kaohsiung, from March 1988 to February 2002.A total of 12 patients (3 men, 9 women), with a mean age of 44.5 years, and a diagnosis of sarcoidosis by positive histology and either a typical chest roentgenogram or clinical presentation were included. All 12 patients had intrathoracic involvement (hilar or mediastinal lymph nodes, 12; lungs, 5), eight had skin involvement, and two had extrathoracic lymph node involvement. The most frequent biopsy specimens were from the skin (n = 10), followed by the intrathoracic lymph nodes (n = 4), lungs (n = 2), and extrathoracic lymph nodes (n = 2). Four patients had positive biopsies from two organs. Our data showed an older age distribution and a greater female predominance of the disease compared with Western countries. A higher rate of intrathoracic and skin involvement was also found, but the reason for this was not clear.Greater awareness of possible skin involvement may enable chest physicians and clinical practitioners to suspect this condition earlier. A histologic diagnosis from skin biopsy should then be made, rather than using more invasive procedures.