Serological Changes in Anti-Aspergillus IgG Antibody and Development of Chronic Pulmonary Aspergillosis in Patients Treated for Pulmonary Tuberculosis.

Chronic pulmonary aspergillosis (CPA) is an important infection to understand in survivors of pulmonary tuberculosis (PTB). However, limited data are available regarding CPA development and its predisposing factors following PTB. We investigated the development of, and the predisposing factors for, CPA following the completion of PTB treatment. A total of 345 patients, with newly diagnosed culture-positive PTB (between January 2015 and December 2018), were included. Enrolled cases were categorized into four groups (persistently seronegative, seroconversion, seroreversion, and persistently seropositive) according to serological changes in their anti-Aspergillus IgG antibodies before and after PTB treatment. The patients were followed up for a median of 25.8 months. Ten (10/345, 2.9%) patients developed CPA at a median of 13.5 months after treatment completion, including seven (7/24, 29.2%) and three (3/73, 4.1%) in the seroconversion and persistently seropositive groups, respectively. Upon multivariate analysis, seroconversion of anti-Aspergillus IgG antibody (adjusted hazard ratio [HR], 25.21; 95% confidence interval [CI], 6.11-103.99; p < 0.001) and diabetic status (adjusted HR, 7.54; 95% CI, 1.93-29.50; p = 0.004) were independently associated with CPA development. The development of CPA in patients with PTB was observed in 2.9% of patients during post-treatment follow-up, and this was significantly associated with both the seroconversion of anti-Aspergillus IgG antibody and diabetes characteristics.

Changes in Nutritional Status in Pulmonary Tuberculosis: Longitudinal Changes in BMI According to Acid-Fast Bacilli Smear Positivity.

Malnutrition is closely associated with pulmonary tuberculosis (PTB). However, changes before and after treatment remain unclear. We aimed to investigate the longitudinal changes in nutritional status from treatment to follow-up of TB in 215 PTB cases in South Korea. First, we evaluated the trend in body mass index (BMI) from the time of diagnosis to a 2-year follow-up. Second, we compared the BMIs of our cases with 5694 controls who participated in a Korean national survey after treatment. During the treatment period, the BMI of the smear-positive group (n = 72) significantly increased compared with that of the smear-negative group (n = 143) (+1.9 kg/m2 vs. +0.4 kg/m2, p = 0.001). Almost all the changes occurred in the early phase, with unremarkable differences in the rest of the treatment period and up to the 2-year follow-up period. When compared with controls, the smear-positive PTB group also had a lower BMI than the smear-negative PTB group, which, however, was lower than that of the general population, though all the participants regained their BMIs during treatment. These results clarify the nutritional aspects of PTB and enable better strategies to support patients with PTB.

Clinical Characteristics and Treatment Outcomes of Definitive Versus Standard Anti-Tuberculosis Therapy in Patients with Tuberculous Lymphadenitis.

Although it is necessary to culture Mycobacterium tuberculosis from tuberculous lymphadenitis (TBL) patients for definitive therapy, based on the drug-sensitivity test (DST), substantial cases remain culture-negative. Limited data are available regarding the treatment outcomes after standard anti-tuberculosis therapy in culture-negative TBL. The aim of this study was to compare the recurrence rates between definitive anti-tuberculosis therapy, based on DST and standard anti-tuberculosis therapy in culture-negative TBL. A multicenter retrospective cohort study was performed from 2011 to 2015 in South Korea. The study population was divided into two groups according to treatment type. A total of 234 patients with TBL were analyzed, who were treated with definitive (84 patients) and standard anti-tuberculosis (150 patients) therapy, respectively. During a 28.0 (24.0-43.0) month follow-up period, nine cases (3.8%) had recurrence of TB after treatment completion. The recurrence rate was not significantly different between the two groups (2/84, 2.4% in definitive anti-tuberculosis therapy group versus 7/150, 4.7% in standard anti-tuberculosis therapy group, p = 0.526). The recurrence in all nine cases was diagnosed as clinical recurrence rather than microbiological recurrence. Therefore, culture-negative TBL can be treated with standard anti-TB medication, although DST is not available but clinically stable after initiation of treatment.

Does repeated pleural culture increase the diagnostic yield of Mycobacterium tuberculosis from tuberculous pleural effusion in HIV-negative individuals?

BACKGROUND: Despite recent advances in methods for culturing Mycobacterium tuberculosis (MTB), the diagnostic yield of tuberculous pleural effusion (TBPE) remains unsatisfactory. However, unlike repeated sputum cultures of pulmonary tuberculosis, little is known about the role of repeated pleural cultures. We examined whether repeated pleural cultures are associated with increased MTB yield from TBPE. METHODS: A multicenter, retrospective cohort study was performed from January 2012 to December 2015 in South Korea. Patients were categorized into two groups: single- or repeated-culture groups. The diagnostic yield of MTB and clinical, radiological, and pleural fluid characteristics were evaluated. RESULTS: Among the 329 patients with TBPE, 77 (23.4%) had repeated cultures and 252 (76.5%) had a single culture. Pleural culture was performed twice in all 77 patients in the repeated-culture group at a 1-day interval (inter-quartile range, 1.0-2.0). In the repeated-culture group, the yield of MTB from the first culture was 31.2%, which was similar to that in the single-culture group (31.2% vs. 29.8%, P = 0.887). However, the yield of MTB from the second culture (10/77, 13.0%) was more than that from the first. These results may be attributable to the insufficient immune clearance for MTB invasion into the pleural space between the first and second cultures. Over time, the yield of the second cultures decreased from 17.4% to 6.7% and then 6.3%. Finally, the overall yield of MTB in the repeated- and single-culture groups was 44.2% and 29.8% respectively (P < 0.001). CONCLUSIONS: The results showed that repeated pleural cultures increased MTB yield from TBPE in human immunodeficiency virus-negative individuals. Furthermore, repeated cultures may increase yield when carried out for two consecutive days.

A short-term investigation of dysphonia in asthmatic patients using inhaled budesonide.

BACKGROUND: Dysphonia is one of the most common side effects of patients who use corticosteroid inhalers. The aim of this study was to investigate, prospectively, the occurrence of dysphonia in patients who used corticosteroid inhalers. METHODS: Outpatients aged 18 years or older initially treated with inhaled corticosteroids were recruited. All patients were prescribed budesonide/formoterol. Questionnaires, perceptual studies, and acoustic analysis were performed five times during the study: at study entry and after 1, 4, 8, and 12 weeks. Videostroboscopy was performed at study entry and at 12 weeks. The data collected were analyzed by repeated-measures analysis of variance tests and Wilcoxon's signed rank test (P<0.01). RESULTS: Sixty-two patients were enrolled and 29 patients (M:F=19:10) completed the study. Seven patients reported that they had problems with their voice; however, there were no statistically significant changes in the perceptual studies or the acoustic analysis. The videostroboscopy showed that "injection" and "increase of mucus" significantly increased by week 12. Vocal fold bowing was not noted in any of the patients. CONCLUSIONS: The results of this study showed no significant voice changes in patients using corticosteroid inhalers over a period of 3 months. However, minor mucosal changes were found on videostroboscopy.

Computed tomographic fluoroscopy-guided needle aspiration biopsy as a second biopsy technique after indeterminate transbronchial biopsy results for pulmonary lesions: comparison with second transbronchial biopsy.

OBJECTIVE: The purpose of this study was to compare the diagnostic performance of computed tomographic (CT) fluoroscopy-guided percutaneous transthoracic needle aspiration biopsy (NAB) and transbronchial lung biopsy (TBLB) after indeterminate bronchoscopy in patients with suspected malignant pulmonary lesions. METHODS: We included 77 patients who underwent CTF-NAB (n = 53) or TBLB (n = 24) as a second biopsy for pulmonary lesions because of inconclusive pathologic results on initial TBLB. Sensitivity, specificity, and diagnostic accuracy were calculated and compared between the 2 groups using the Fisher exact test. Sensitivity and diagnostic accuracy were also compared according to lesion depth (central vs peripheral), lesion location (upper vs lower), and lesion size (<2 vs 2-3 vs >3 cm). RESULTS: There were 50 (65%) malignant and 27 (35%) benign lesions. The overall sensitivity, specificity, and accuracy for diagnosing pulmonary lesions were 84%, 100%, and 91% for NAB and 50%, 100%, and 63% for TBLB. The sensitivity and accuracy for diagnosing pulmonary lesions were significantly different between the 2 groups (P = 0.019, and P = 0.008). The sensitivity and accuracy of TBLB for diagnosing lesions was significantly different according to the lesion size (P = 0.025, and P = 0.048). CONCLUSION: A second biopsy using CT fluoroscopy-guided NAB is a useful diagnostic modality for exact diagnosis of pulmonary lesions in cases of inconclusive pathologic results on initial TBLB.

Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer.

BACKGROUND: We investigated the risk of central nervous system (CNS) failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in Korean patients with nonsmall-cell lung cancer (NSCLC) METHODS: We retrospectively evaluated the pattern of disease progression of 287 advanced NSCLC patients who were treated with gefitinib or erlotinib. Patients whose best tumor response was complete response, partial response, or stable disease (> or =90 days) were classified into the group receiving clinical benefit with these drugs. RESULTS: The clinical benefit group had a higher incidence of CNS failure as an initial progression, compared with the non-clinical benefit group (26% vs 4%; P < .001). Isolated CNS failure was also more frequent in the clinical benefit group than in the non-clinical benefit group (13% vs 1%; P < .001). In a multivariate analysis, clinical benefit with EGFR-TKIs significantly increased the risk of isolated CNS failure, with an adjusted hazard ratio of 10.9 (95% confidence interval [CI], 1.4-29.1, P = .01). In patients with isolated CNS failure, the median time from initial intracranial failure to extracranial failure was 9.9 months (95% CI, 1.9-21.9 months) and to death was 12.9 months (95% CI, 3.3-22.5 months). CONCLUSIONS: The CNS was frequently the initial failure site after clinical benefit with EGFR-TKIs in Korean NSCLC patients. Patients with isolated CNS failure showed durable extracranial control after cranial progression. A role for close surveillance of the CNS during EGFR-TKI treatment or prophylactic measures appears worthy of further study in these patients.

Impact of environmental tobacco smoke on the incidence of mutations in epidermal growth factor receptor gene in never-smoker patients with non-small-cell lung cancer.

PURPOSE: Active tobacco smoking has been associated with the incidence of epidermal growth factor receptor (EGFR) mutations. However, the impact of environmental tobacco smoke (ETS) on EGFR mutations has been unknown. We investigated an association between ETS exposure and EGFR mutations in never smokers with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We enrolled 179 consecutive never smokers who were newly diagnosed with NSCLC. The history of ETS exposure was obtained with a standardized questionnaire that included exposure period, place, and duration. The nucleotide sequences of exons 18 to 21 on EGFR gene were determined using nested polymerase chain reaction amplification. RESULTS: The incidence of EGFR mutations was significantly lower in patients with ETS exposure than in those without (38.5% v 61.4%; P = .008). In a logistic regression model that adjusted for sex and histology, an adjusted odds ratio (AOR) for the risk of EGFR mutations with exposure to ETS was 0.40 (95% CI, 0.20 to 0.81; P = .011). In quartile groups based on total smoker-year, the AORs for the lowest- to highest-quartile groups were 0.59 (95% CI, 0.23 to 1.49), 0.50 (95% CI, 0.17 to 1.50), 0.48 (95% CI, 0.20 to 1.18), and 0.22 (95% CI, 0.08 to 0.62; P(trend) = .028). Among the types of ETS exposure, adulthood ETS and household ETS were significantly associated with the incidence of EGFR mutations. Patients with ETS exposure showed a lower response rate to EGFR tyrosine kinase inhibitors than did patients without ETS exposure (24.6% v 44.8%; P = .053). CONCLUSION: ETS exposure is negatively associated with EGFR mutations in never smokers with NSCLC.

Performance of the tuberculin skin test and interferon-gamma release assay for detection of tuberculosis infection in immunocompromised patients in a BCG-vaccinated population.

BACKGROUND: Interferon-gamma release assay (IGRA) may improve diagnostic accuracy for latent tuberculosis infection (LTBI). This study compared the performance of the tuberculin skin test (TST) with that of IGRA for the diagnosis of LTBI in immunocompromised patients in an intermediate TB burden country where BCG vaccination is mandatory. METHODS: We conducted a retrospective observational study of patients given the TST and an IGRA, the QuantiFERON-TB Gold In-Tube (QFT-IT), at Severance Hospital, a tertiary hospital in South Korea, from December 2006 to May 2009. RESULTS: Of 211 patients who underwent TST and QFT-IT testing, 117 (55%) were classified as immunocompromised. Significantly fewer immunocompromised than immunocompetent patients had positive TST results (10.3% vs. 27.7%, p 0.001), whereas the percentage of positive QFT-IT results was comparable for both groups (21.4% vs. 25.5%). However, indeterminate QFT-IT results were more frequent in immunocompromised than immunocompetent patients (21.4% vs. 9.6%, p 0.021). Agreement between the TST and QFT-IT was fair for the immunocompromised group (kappa = 0.38), but moderate agreement was observed for the immunocompetent group (kappa = 0.57). Indeterminate QFT-IT results were associated with anaemia, lymphocytopenia, hypoproteinemia, and hypoalbuminemia. CONCLUSION: In immunocompromised patients, the QFT-IT may be more sensitive than the TST for detection of LTBI, but it resulted in a considerable proportion of indeterminate results. Therefore, both tests may maximise the efficacy of screening for LTBI in immunocompromised patients.

Activating mutations within the EGFR kinase domain: a molecular predictor of disease-free survival in resected pulmonary adenocarcinoma.

PURPOSE: Although epidermal growth factor receptor (EGFR) tyrosine kinase (TK) mutations are highly predictive of response to EGFR TK inhibitors in advanced non-small-cell lung cancer (NSCLC), a prognostic value of EGFR mutations in resected NSCLC has not been established. METHODS: We retrospectively reviewed 117 patients with primary lung adenocarcinoma who underwent surgical resection between 1995 and 2005. Nucleotide sequencing of the kinase domain of EGFR (exons 18-21) was performed using nested PCR amplification of individual exons. RESULTS: Forty-eight patients (41.8%) harbored exon 19 deletion or exon 21 point mutations. EGFR mutations were more frequently found in never-smoker (P = 0.04) or in smaller-sized primary tumor (P = 0.001). A presence of EGFR mutations was significantly associated with longer disease-free survival (DFS) (20.1 vs. 34.4 months in mutated EGFR; P = 0.003). In multivariate analysis of DFS, wild-type EGFR was associated with a higher risk of recurrence, with an adjusted hazard ratio of 1.42 (95% CI, 1.1-2.41, P = 0.04), as compared to mutated EGFR. However, no significant association was observed between EGFR mutations and overall survival (P = 0.39). Isolated brain metastasis as the first recurrence after resection was found more frequently in those patients with tumors bearing EGFR mutations, although the difference was not statistically significant (9 vs. 24% in mutated EGFR, P = 0.15). CONCLUSIONS: Activating mutations within the EGFR TK domain can be used to predict the risk of recurrence in curatively resected pulmonary adenocarcinoma.

High tumor metabolic activity as measured by fluorodeoxyglucose positron emission tomography is associated with poor prognosis in limited and extensive stage small-cell lung cancer.

PURPOSE: We investigated the prognostic effect of incorporating metabolic assessment by (18)F-fluoro-2-deoxyglucose uptake on positron emission tomography/computed tomography ((18)F-FDG-PET/CT) into a conventional staging system in small-cell lung cancer (SCLC). EXPERIMENTAL DESIGN: Seventy-six consecutive patients with pathologically proven SCLC were enrolled. All patients underwent standard treatment after pretreatment (18)F-FDG-PET/CT scanning. The mean values of maximal standardized uptake values (meanSUV(max)) of the malignant lesions upon (18)F-FDG-PET/CT were calculated. The Cox proportional hazards model was used with performance status, lactate dehydrogenase, stage, and meanSUV(max). RESULTS: Patients with high meanSUV(max) were significantly related with the established poor prognostic factors, such as higher lactate dehydrogenase (P = 0.04) and extensive disease (ED; P = 0.01). Furthermore, in multivariate analysis, patients with high meanSUV(max) were associated with poor survival outcomes compared with patients with low meanSUV(max) [adjusted hazard ratio, 3.74; 95% confidence interval (95% CI), 1.67-8.37; P = 0.001, for death and adjusted hazard ratio, 2.25; 95% CI, 1.21-4.17; P = 0.01 for recurrence/progression]. In subgroup analysis, limited disease (LD) with high meanSUV(max) showed significantly shorter overall survival than LD with low meanSUV(max) [high versus low meanSUV(max), 20.1 months (95% CI, 7.9-23.2) versus 35.3 months (95% CI, 27.6-42.9); P = 0.02]. ED with high meanSUV(max) had significantly shorter overall survival than ED with low meanSUV(max) [high versus low meanSUV(max), 9.5 months (95% CI, 4.9-13.9) versus 17.7 months (95% CI, 12.0-20.1); P = 0.007]. These findings were replicated in progression-free survival analysis. CONCLUSIONS: In SCLC, tumor metabolic activity as assessed by FDG-PET is a significant prognostic factor and identifies subgroups of patients at higher risk of death in both LD and ED SCLC.

The prevalence of human papillomavirus infection in Korean non-small cell lung cancer patients.

Human papillomavirus (HPV) infection is a co-carcinogen of lung cancer and contributes to its pathogenesis. To evaluate the prevalence of HPV infection, polymerase chain reaction (PCR) was employed to detect HPV 16, 18, and 33 DNA in tumor tissues of 112 patients with non-small cell lung cancer (NSCLC) who underwent curative surgery from Jan. 1995 to Dec. 1998 at Severance Hospital, Seoul, Korea. The patients consisted of 90 men and 22 women. Nineteen patients were under 50 years old (17%), and 92 patients (82%) were smokers. Fifty-three patients had adenocarcinomas, while 59 patients had non-adenocarcinomas. Early stage (I and II) cancer was found in 64 patients (57.1%) and advanced stage (III and IV) found in 48 (42.9%). The prevalence of HPV 16, 18, and 33 were 12 (10.7%), 11 (9.8%), and 37 (33.0%), respectively. Smoking status, sex, and histologic type were not statistically different in the presence of HPV DNA. The presence of HPV 16 was more common in younger patients and HPV 18 was more common in advanced stage patients. This study showed that the prevalence rate of HPV 16 and 18 infections in NSCLC tissue was low, suggesting HPV 16 and 18 infections played a limited role in lung carcinogenesis of Koreans. However, the higher prevalence of HPV 33 infections in Korean lung cancer patients compared to other Asian and Western countries may be important and warrants further investigation.

Promoter -202 A/C polymorphism of insulin-like growth factor binding protein-3 gene and non-small cell lung cancer risk.

Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the mitogenic and antiapoptotic activity of insulin-like growth factor (IGF) by blocking the binding of IGF to its receptor. However, under certain circumstances, IGFBP-3 can enhance the activity of IGF by protecting IGF from degradation. More than half of the interindividual variations in IGFBP-3 levels are known to be genetically determined by the polymorphism at -202 locus of IGFBP-3 gene. Therefore, we attempted to ascertain whether the A-202C polymorphic variation of IGFBP-3 gene constitutes a risk factor for non-small cell lung cancer (NSCLC). Our study included 209 NSCLC patients and 209 age-, gender- and smoking status-matched control subjects. The frequencies of each polymorphic variation in the control population were as follows: AA = 95 (45.5%), AC = 91 (43.5%) and CC = 23 (11.0%). In the NSCLC subjects, the genotypic frequencies were as follows: AA = 131 (62.7%), AC = 73 (34.9%) and CC = 5 (2.4%). We detected statistically significant differences in the genotypic distribution between the NSCLC and the control subjects (p < 0.05, Pearson's chi-square test). The NSCLC risk correlated significantly with AA genotype. Using CC genotype as a reference, the odds ratio for the subjects with AC genotype was 2.45 (95% CI = 1.17-5.40) and that for the ones with AA genotype was 4.58 (95% CI = 2.17-10.30). These results indicate that the dysregulation of IGF axis should now be considered as another important risk factor for NSCLC and a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups.

The clinical utility of polymerase chain reaction for the diagnosis of pleural tuberculosis.

BACKGROUND: There is no exact consensus about the usefulness of the Mycobacterium tuberculosis polymerase chain reaction (PCR) testing for the diagnosis of tuberculous pleural effusion because of the diverse PCR methods and the different diagnostic criteria that are described in other studies. METHODS: We analyzed pleural effusion specimens obtained from 111 patients for whom the exclusion of the possibility of tuberculous pleural effusion was necessary. We performed M. tuberculosis PCR testing using the Cobas Amplicor MTB test (Roche Diagnostic Systems), which is fully automated and commercially available. RESULTS: Results of the M. tuberculosis PCR test of pleural effusion specimens were positive for 7 (17.1%) of the 41 patients with confirmed pleural tuberculosis and for 3 (18.8%) of the 16 patients with probable pleural tuberculosis. The overall sensitivity and specificity of M. tuberculosis PCR testing of pleural effusion were 17.5% and 98.1%, respectively. The sensitivity of M. tuberculosis PCR testing for each group of patients with tuberculous pleural effusion detected by smear-positive results, smear-negative and culture-positive results, and culture-negative and pleural biopsy-positive results, was 100.0%, 33.3%, and 3.7%, respectively. Of the 57 patients with pleural tuberculosis, only 3 (5.3%) had positive results of M. tuberculosis PCR testing along with negative results of smearing, negative results of pleural pathological analysis, and a low level of adenosine deaminase. CONCLUSION: For specimens such as pleural effusion, in which the bacillary load is very low, the clinical utility of PCR testing seems highly limited.