Tuberculous pleural effusion (TPE) leads to residual pleural opacity (RPO) in a significant proportion of cases. The aim of this study was to investigate which TPE patients would have RPO following the treatment. This study was performed prospectively for a total of 60 TPE patients, who underwent pleural fluid analysis on the initial visit and chest radiographs and computed tomography (CT) scans before and after the administration of antituberculous medication. At the end of antituberculous medication, the incidence of RPO was 68.3% (41/60) on CT with a range of 2-50 mm. Compared with the non-RPO group, the RPO group had a longer symptom duration and lower pleural fluid glucose level. On initial CT, loculation, extrapleural fat proliferation, increased attenuation of extrapleural fat, and pleura-adjacent atelectasis were more frequent, and parietal pleura was thicker in the RPO group compared with the non-RPO group. By multivariate analysis, extrapleural fat proliferation, loculated effusion, and symptom duration were found to be predictors of RPO in TPE. In conclusion, RPO in TPE may be predicted by the clinico-radiologic parameters related to the chronicity of the effusion, such as symptom duration and extrapleural fat proliferation and loculated effusion on CT.
Computed Tomography; Pleural Effusion; Residual Thickening; Tuberculosis
Thoracoscopic pleural biopsy is often required for rapid and confirmative diagnosis in patients with suspected pleural tuberculosis (PL-TB). However, this method is more invasive and costly than its alternatives. Therefore, we evaluated the clinical utility of the chest computed tomography (CT)-based bronchial aspirate (BA) TB-polymerase chain reaction (PCR) test in such patients.
Bronchoscopic evaluation was performed in 54 patients with presumptive PL-TB through diagnostic thoracentesis but without a positive result of sputum acid-fast bacilli (AFB) smear, pleural fluid AFB smear, or pleural fluid TB-PCR test. Diagnostic yields of BA were evaluated according to the characteristics of parenchymal lesions on chest CT.
Chest radiograph and CT revealed parenchymal lesions in 25 (46%) and 40 (74%) of 54 patients, respectively. In cases with an absence of parenchymal lesions on chest CT, the bronchoscopic approach had no diagnostic benefit. BA TB-PCR test was positive in 21 out of 22 (95%) patients with early-positive results. Among BA results from 20 (37%) patients with patchy consolidative CT findings, eight (40%) were AFB smear-positive, 18 (90%) were TB-PCR-positive, and 19 (95%) were culture-positive.
The BA TB-PCR test seems to be a satisfactory diagnostic modality in patients with suspected PL-TB and patchy consolidative CT findings. For rapid and confirmative diagnosis in these patients, the bronchoscopic approach with TB-PCR may be preferable to the thoracoscopy.
Tuberculosis, Pleural; Bronchoscopy; Polymerase Chain Reaction; Thoracoscopy
The pneumonia severity index (PSI) and CURB-65 are widely used tools for the prediction of community-acquired pneumonia (CAP). This study was conducted to evaluate validation of severity scoring system including the PSI and CURB-65 scores of Korean CAP patients. In the prospective CAP cohort (participated in by 14 hospitals in Korea from January 2009 to September 2011), 883 patients aged over 18 yr were studied. The 30-day mortalities of all patients were calculated with their PSI index classes and CURB scores. The overall mortality rate was 4.5% (40/883). The mortality rates per CURB-65 score were as follows: score 0, 2.3% (6/260); score 1, 4.0% (12/300); score 2, 6.0% (13/216); score 3, 5.7% (5/88); score 4, 23.5% (4/17); and score 5, 0% (0/2). Mortality rate with PSI risk class were as follows: I, 2.3% (4/174); II, 2.7% (5/182); III, 2.3% (5/213); IV, 4.5% (11/245); and V, 21.7% (15/69). The subgroup mortality rate of Korean CAP patients varies based on the severity scores and CURB-65 is more valid for the lower scores, and PSI, for the higher scores. Thus, these variations must be considered when using PSI and CURB-65 for CAP in Korean patients.
Pneumonia; Prognosis; Severity Index
The relationship of mast cells to the pathogenesis of lung fibrosis remains undefined despite recognition of their presence in the lungs of patients with pulmonary fibrosis. This study was performed to characterize the relationship of mast cells to fibrotic lung diseases.
Methods and results
Lung tissues from patients with idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP), systemic sclerosis (SSc)-related interstitial lung disease (ILD) and normal individuals were subjected to chymase immunostaining and the mast cell density quantified. Eosinophils were quantified by immunostaining for eosinophil peroxidase. Changes in lung function were correlated with mast cell density. Lung tissue obtained from IPF patients had a higher density of chymase-immunoreactive mast cells than that from patients with HP, SSc-related ILD or normal lungs. IPF lung tissue had a higher density of eosinophils than normal lung. There was no correlation between mast cell density and eosinophil density in IPF lung. IPF patients with high mast cell density had a slower rate of decline in forced vital capacity (FVC) than IPF patients with low mast cell density.
Mast cell density in IPF lungs is higher than in other fibrotic lung diseases and normal lungs. Increased mast cell density in IPF may predict slower disease progression.
chloroacetate esterase; eosinophil; hypersensitivity pneumonitis; idiopathic interstitial pneumonia; systemic sclerosis
Reported herein is an adult case of Fisher syndrome (FS) that occurred as a complication during the course of community-acquired pneumonia caused by Mycoplasma pneumoniae. A 38-yr-old man who had been treated with antibiotics for serologically proven M. pneumoniae pneumonia presented with a sudden onset of diplopia, ataxic gait, and areflexia. A thorough evaluation including brain imaging, cerebrospinal fluid examination, a nerve conduction study, and detection of serum anti-ganglioside GQ1b antibody titers led to the diagnosis of FS. Antibiotic treatment of the underlying M. pneumoniae pneumonia was maintained without additional immunomodulatory agents. A complete and spontaneous resolution of neurologic abnormalities was observed within 1 month, accompanied by resolution of lung lesions.
Mycoplasma pneumoniae; Fisher Syndrome; Anti-GQ1b Antibody
Multicentric Castleman's disease (CD) is a rare atypical lymphoproliferative disorder, which is characterized by various systemic manifestations. Some patients with multicentric CD may have concomitant lung parenchymal lesions, for which lymphoid interstitial pneumonia (LIP) is known to be the most common pathologic finding. Follicular bronchiolitis and LIP are considered to be on the same spectrum of the disease. We describe a case of multicentric CD with pulmonary involvement, which was pathologically proven as follicular bronchiolitis.
Bronchiolitis; Lung Diseases, Interstitial; Multi-centric Castleman's Disease
A genome-wide association study has identified the 15q25 region as being associated with the risk of chronic obstructive pulmonary disease (COPD) in Caucasians. This study intended as a confirmatory assessment of this association in a Korean population. The rs6495309C > T polymorphism in the promoter of nicotinic acetylcholine receptor alpha subunit 3 (CHRNA3) gene was investigated in a case-control study that consisted of 406 patients with COPD and 394 healthy control subjects. The rs6495309 CT or TT genotype was associated with a significantly decreased risk of COPD when compared to the rs6495309 CC genotype (adjusted odds ratio = 0.69, 95% confidence interval = 0.50-0.95, P = 0.023). The effect of the rs6495309C > T on the risk of COPD was more evident in moderate to very severe COPD than in mild COPD under a dominant model for the variant T allele (P = 0.024 for homogeneity). The CHRNA3 rs6495309C > T polymorphism on chromosome 15q25 is associated with the risk of COPD in a Korean population.
CHRNA3; Pulmonary Disease, Chronic Obstructive; Polymorphism
Stress of the endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR) and alveolar epithelial cell (AEC) apoptosis may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our objectives were to determine whether circulating caspase-cleaved cytokeratin-18 (cCK-18) is a marker of AEC apoptosis in IPF, define the relationship of cCK-18 with activation of the UPR, and assess its utility as a diagnostic biomarker.
IPF and normal lung tissues were stained with the antibody (M30) that specifically binds cCK-18. The relationship between markers of the UPR and cCK-18 was determined in AECs exposed in vitro to thapsigargin to induce ER stress. cCK-18 was measured in serum from subjects with IPF, hypersensitivity pneumonitis (HP), nonspecific interstitial pneumonia (NSIP), and control subjects.
cCK-18 immunoreactivity was present in AECs of IPF lung, but not in control subjects. Markers of the UPR (phosphorylated IRE-1α and spliced XBP-1) were more highly expressed in IPF type II AECs than in normal type II AECs. Phosphorylated IRE-1α and cCK-18 increased following thapsigargin-induced ER stress. Serum cCK-18 level distinguished IPF from diseased and control subjects. Serum cCK-18 was not associated with disease severity or outcome.
cCK-18 may be a marker of AEC apoptosis and UPR activation in patients with IPF. Circulating levels of cCK-18 are increased in patients with IPF and cCK-18 may be a useful diagnostic biomarker.
Idiopathic interstitial pneumonia; idiopathic pulmonary fibrosis; lung fibrosis; ER stress; apoptosis
Cystic fibrosis (CF) is one of the most common hereditary disorders among Caucasians. The most common mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been well established among Caucasian populations. In Koreans, however, there are very few cases of genetically confirmed CF thus far, and the spectrum of mutations seems quite different from that observed in Caucasians.
In the present study, we describe the cases of 2 Korean CF patients, present sequencing results identifying mutations in their CFTR gene, and summarize the results of CFTR mutational spectrum from previously reported Korean CF patients. The mutations described were identified by performing direct sequencing analysis of the complete coding regions and flanking intronic sequences of the CFTR gene, followed by multiplex ligation-dependent probe amplification (MLPA) analysis in order to detect gene deletions or duplications that could not be identified by a direct sequencing method.
Three CFTR mutations were identified in the 2 patients, including p.Q98R, c.2052delA, and c.579+5G>A. In an analysis of 9 Korean CF patients that included the 2 patients presented in this study, p.Q98R mutation was the only recurrently observed mutation with a frequency of 18.8% (3/16 alleles). Furthermore, only one of the mutations (c.3272-26A>G) was found among the 32 common mutations in the screening panel for Caucasians from the Cystic Fibrosis Mutation Database.
Sequencing of the entire CFTR gene followed by MLPA analysis, rather than using the targeted sequencing-based screening panel for mutations commonly found in Caucasian populations, is recommended for genetic analysis of Korean CF patients.
CFTR; Cystic fibrosis transmembrane conductance regulator; Cystic fibrosis; Mutations; Koreans; Sequencing; MLPA
This study was conducted to evaluate the performance of a whole-blood interferon-gamma release assay in inpatients who were admitted to the emergency department (ED) with pulmonary infiltrates who required a differential diagnosis with pulmonary tuberculosis (TB).
The patients with pulmonary infiltrates who received a QuantiFERON (QFT) test in the ED were included as an inpatient group and were divided into TB and non-TB group based on the final diagnosis. Patients with pulmonary TB who were tested in the outpatient department served as a control group.
In total, 377 QFT tests were analyzed. Of the 284 inpatient QFT tests, 29.6% had an indeterminate result (35.2% in the 196 patients with non-TB and 17.0% in the 88 patients with TB). In contrast, only 1.1% of the 93 outpatients with TB returned an indeterminate result (p < 0.001). The indeterminate QFT results in the inpatient group were independently associated with lymphocytopenia, hypoalbuminemia, and high C-reactive protein levels. Non-positive QFT results in inpatients with TB were associated with lymphocytopenia and hypoalbuminemia, while non-positive QFT results in outpatients with TB were associated with high erythrocyte sedimentation rates and radiographically more severe diseases.
QFT tests in ED-based inpatients with pulmonary infiltrate return indeterminate results relatively frequently. In addition, inpatients and outpatients with pulmonary TB may differ in terms of the risk factors on non-positive QFT results.
Increased apoptosis of alveolar epithelial cells and impaired apoptosis of myofibroblasts have been linked to the pathogenesis of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). Fas, a death receptor of the TNF-receptor superfamily, has been implicated in apoptosis of both cell types, though the mechanisms are poorly understood. The goals of this study were: (1) to examine the localization of Fas-associated death-domain-like IL-1β-converting enzyme inhibitory protein (c-FLIP), an NF-κB–dependent regulator of Fas-signaling, in lung tissues from IPF/UIP patients and control subjects; and (2) to compare c-FLIP expression with epithelial cell and myofibroblast apoptosis, proliferation, and NF-κB activation. c-FLIP expression was restricted to airway epithelial cells in control lung tissues. In contrast, in patients with IPF/UIP, c-FLIP was also expressed by alveolar epithelial cells in areas of injury and fibrosis, but was absent from myofibroblasts in fibroblastic foci and from alveolar epithelial cells in uninvolved areas of lung tissue. Quantification of apoptosis and proliferation revealed an absence of apoptotic or proliferating cells in fibroblastic foci and low levels of apoptosis and proliferation by alveolar epithelial cells. Quantification of NF-κB expression and nuclear translocation revealed strong staining and translocation in alveolar epithelial cells and weak staining and minimal nuclear translocation in myofibroblasts. These findings suggest that: (1) c-FLIP expression is induced in the abnormal alveolar epithelium of patients with IPF/UIP, (2) the resistance of myofibroblasts to apoptosis in patients with IPF/UIP occurs independently of c-FLIP expression, and (3) increased NF-κB activation and c-FLIP expression by the alveolar epithelium may be linked.
idiopathic pulmonary fibrosis; c-FLIP; lung, epithelium; myofibroblast
In 2007, the Korean Interstitial Lung Disease Society had collected clinical data of patients who have diagnosed as Lymphangioleiomyomatosis (LAM) since 1990 through nationwide survey, which showed that LAM patients had increased sharply after 2004. The present study was performed to show the clinical features of Korean patients with LAM, and to establish the reason for the recent increase in the diagnosis. All 63 patients were women and the mean age at diagnosis was 36 yr. The most common presenting symptom was dyspnea and 8 patients had tuberous sclerosis complex. The survival rate at 5 yr after diagnosis was 84%. Compared with patients diagnosed after 2004 (n=34), the patients diagnosed before 2004 (n=29) complained with dyspnea more (P=0.016) and had lower FEV1% predicted (P=0.003), and DLco% predicted (P=0.042). The higher proportion of patients diagnosed after 2004 showed the normal chest radiography, and they were detected by routine chest CT screening (P=0.016). This study showed that clinical features of Korean patients with LAM were not different from those reported elsewhere. It is concluded that the reason for the increase of newly diagnosed patients is the result of increase in detection of the early stage LAM by the widespread use of chest CT screening.
Lymphangioleiomyomatosis; Korea; Registries; Respiratory Function Tests
Although TP53 mutations have been widely studied in lung cancer, the majority of studies have focused on exons 5-8 of the gene. In addition, TP53 mutations in Korean patients with lung cancers have not been investigated. We searched for mutations in the entire coding exons, including splice sites of the gene, in Korean patients with non-small cell lung cancer (NSCLC). Mutations of the gene were determined by direct sequencing in 176 NSCLCs. Sixty-nine mutations (62 different mutations) were identified in 65 tumors. Of the 62 mutations, 12 were novel mutations. TP53 mutations were more frequent in males, ever-smokers and squamous cell carcinomas than in females, never-smokers and adenocarcinomas, respectively (all comparisons, P<0.001). Missense mutations were most common (52.2%), but frameshift, nonsense, and splice-site mutations were frequently observed at frequencies of 18.8%, 15.9% and 10.1%, respectively. Of the 69 mutations, 9 (13.0%) were found in the oligomerization domain. In addition, the proportion of mutations in the oligomerization domain was significantly higher in adenocarcinomas than in squamous cell carcinomas (23.5% vs. 2.9%, P=0.01). Our study provides clinical and molecular characteristics of TP53 mutations in Korean patients with NSCLCs.
Lung Neoplasms; Mutation; Genes, p53
Idiopathic pulmonary alveolar proteinosis (PAP) is a rare disorder in which lipoproteinaceous material accumulates within alveoli. There were few reports on Asian populations with idiopathic PAP. We retrospectively reviewed 38 patients with idiopathic PAP in Korea. We assessed clinical features, therapeutic efficacy and outcomes of whole lung lavage in patients with idiopathic PAP. The mean age at diagnosis was 52 yr. Eighty six percent of patients were symptomatic at diagnosis. Dyspnea and cough were the most common symptoms. Crackles were the most common physical examination finding. On pulmonary function test, a mild restrictive ventilatory defect was common, with a predicted mean forced vital capacity (FVC) of 77% and forced expiratory volume in one second (FEV1) of 84.6%. Diffusing capacity was disproportionately reduced at 67.7%. Arterial blood gas analysis revealed hypoxemia with a decreased PaO2 of 69.0 mmHg and an increased D(A-a)O2 of 34.2 mmHg. After whole lung lavage, PaO2, D(A-a)O2 and DLCO were significantly improved, but FVC and total lung capacity (TLC) were not different. This is the first multicenter study to analyze 38 Korean patients with idiopathic PAP. The clinical features and pulmonary parameters of Korean patients with idiopathic PAP are consistent with reports in other published studies. Whole lung lavage appears to be the most effective form of treatment.
Pulmonary Alveolar Proteinosis; Irrigation; Treatment Outcome; Koreans
In patients undergoing major orthopedic surgery, data of deep venous thrombosis (DVT) and pulmonary embolism (PE) are lacking as studied by computed tomographic (CT) pulmonary angiography and indirect CT venography (CTPA-CTV). A prospective observational study was performed for 363 Korean patients undergoing major orthopedic surgery to determine the incidence of venous thromboembolism (VTE), especially proximal DVT and PE. The incidence of VTE was 16.3% (n=59). Of them, 8 patients (2.2%) were symptomatic. The rate of VTE was the highest in patients who underwent total knee replacement (40.4%), followed by hip fracture surgery (16.4%), and total hip replacement (8.7%; P<0.001). The incidence of PE was 6.6% (n=24). Of them, 4 patients (1.1%) were symptomatic. Forty-one patients (11.3%) were in the proximal DVT or PE group. Based on multivariate analysis, total knee replacement and age ≥65 yr were significant risk factors for proximal DVT or PE in patients undergoing major orthopedic surgery (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1-5.1; P=0.025; and OR, 2.1; 95% CI, 1.0-4.4; P=0.046, respectively). Taken together, the overall incidence of PE was 6.6% and rate of symptomatic PE rate was 1.1%. Knee joint replacement and age ≥65 yr were significant risk factors for proximal DVT or PE.
Orthopedics; Venous Thromboembolism; Pulmonary Embolism; Computed Tomography
A number of genome-wide linkage analyses have identified the 2q33.3-2q37.2 region as most likely to contain the genes that contribute to the susceptibility to chronic obstructive pulmonary disease (COPD). It was hypothesized that the SERPINE2 gene, which is one of the genes located at the 2q33.3-2q37.2 region, may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, the association of four SERPINE2 single nucleotide polymorphisms (SNPs; rs16865421A>G, rs7583463A>C, rs729631C>G, and rs6734100C>G) with the risk of COPD was investigated in a case-control study of 311 COPD patients and 386 controls. The SNP rs16865421 was associated with a significantly decreased risk of COPD in a dominant model for the polymorphic allele (adjusted odds ratio [OR]=0.66, 95% confidence interval [CI]=0.45-0.97, P=0.03). In haplotype analysis, the GACC haplotype carrying the polymorphic allele at the rs16865421 was associated with a significantly decreased risk of COPD when compared to the AACC haplotype (adjusted OR=0.58, 95% CI=0.38-0.89, P=0.01), and this effect was evident in younger individuals (adjusted OR=0.30, 95% CI=0.14-0.64, P=0.002). This study suggests that the SERPINE2 gene contributes to the susceptibility to COPD.
Serpine2; Polymorphism; Pulmonary Disease, Chronic Obstructive
Pulmonary accumulation of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis/usual interstitial pneumonia (IFP/UIP) has been linked to (1) increased migration of a circulating pool of fibrocytes, (2) cell proliferation, and (3) resistance to apoptosis. The mechanism of physiologic apoptosis of lung fibroblasts is poorly understood. Using normal and fibrotic human lung fibroblasts and the human lung fibroblast cell line, MRC-5, we examined the regulation of Fas-induced apoptosis by the proinflammatory cytokines TNF-α and IFN-γ. Herein, we show that the basal resistance of lung fibroblasts and myofibroblasts to Fas-induced apoptosis is overcome by sensitization with TNF-α. IFN-γ did not sensitize cells to Fas-induced apoptosis, but exhibited synergistic activity with TNF-α. Sensitization by TNF-α was observed in MRC-5 cells and in fibroblasts and myofibroblasts from normal and fibrotic human lung, suggesting that this represents a conserved mechanism to engage Fas-induced apoptosis. The mechanism of sensitization was localized at the level of recruitment of the adapter protein, FADD, to the cytoplasmic domain of Fas. Collectively, these findings suggest that fibroblast apoptosis involves two steps, sensitization and induction, and that inadequate pulmonary inflammation in IPF/UIP may favor fibroblast accumulation by reducing sensitization to apoptosis.
fibroblast; TNF-α; Fas; apoptosis; pulmonary fibrosis