Multidrug-resistant tuberculosis in South Korea: a retrospective analysis of national registry data in 2011-2015.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) poses a threat to public health as a result of high treatment costs and unsatisfactory outcomes.OBJECTIVE: To elucidate trend, demographic and clinical characteristics and treatment outcomes of patients with MDR-TB between 2011 and 2015 in South Korea.METHOD: Data of patients with MDR-TB diagnosed between 1 January 2011 and 31 December 2015 were retrieved from the nationwide Internet-based TB notification system and analysed retrospectively.RESULTS: During the study period, 5192 MDR-TB patients were notified. We identified an increasing number of MDR-TB patients among foreign populations (from 1.3% to 7.7%), decreasing resistance rates to other anti-TB drugs (e.g., resistance to pyrazinamide, from 40.9% to 28.2%), a decreasing interval from treatment initiation to negative conversion of sputum culture (from 165.7 to 103.7 days) and shortening of treatment duration (719.7 to 613.2 days). However, treatment success rates did not change, and had an average of 65.7%.CONCLUSION: Despite decreasing resistance rates to other drugs and faster treatment responses, treatment outcomes did not improve during the study period. Strict management of MDR-TB patients on treatment should be adopted to improve treatment outcomes.

Effect of inhalers on the development of haemoptysis in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: The association of inhaler use with haemoptysis has rarely been reported in patients with non-cystic fibrosis (CF) bronchiectasis. OBJECTIVE: To elucidate the effect of inhaler use on the development of haemoptysis in patients with non-CF bronchiectasis. METHODS: In a case-crossover study of 192 non-CF bronchiectasis patients with a history of haemoptysis and inhaler use, the risk of haemoptysis associated with the use of inhalers was elucidated. Two inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA), one long-acting muscarinic antagonist and one short-acting ß2-agonist (SABA) were evaluated. The case and control periods were defined respectively as 030 and 180210 days before haemoptysis. RESULTS: The risk of haemoptysis during the case period was 3.51 times higher than during the control period with any use of inhalers (95%CI 1.966.28). The results of clinically significant haemoptysis showed good agreement with those of total events. These associations were consistent with the sensitivity analyses. In the sub-analysis according to inhaler type, ICS/LABA and SABA were significantly associated with an increased risk of haemoptysis (aOR 2.62, 95%CI 1.255.45; aOR 2.51, 95%CI 2.235.15). CONCLUSIONS: In patients with non-CF bronchiectasis, the use of inhalers, especially including 2-agonist, was associated with an increased risk of haemoptysis.

Antiplatelet or anticoagulant therapy might not increase the risk of haemoptysis in patients with bronchiectasis.

The aim of this study was to assess whether the use of antiplatelets and anticoagulants increased haemoptysis in patients with bronchiectasis. Cases (n = 242) with a history of haemoptysis were compared with controls (n = 242) without a history of haemoptysis. Of the 242 case patients, 16.5% took antiplatelets compared with 19.8% of controls (P = 0.346). The proportion of warfarin users did not differ between cases and controls (3.3% vs. 2.5%, P = 0.588). The use of these agents might not be associated with increased risk of haemoptysis in patients with bronchiectasis.

Diagnostic accuracy of Xpert® MTB/RIF on bronchoscopy specimens in patients with suspected pulmonary tuberculosis.

OBJECTIVE: To determine the diagnostic accuracy of the Xpert® MTB/RIF assay using samples obtained through bronchoscopy in patients with suspected pulmonary tuberculosis (PTB). DESIGN: We retrospectively reviewed the records of patients with suspected PTB for whom the Xpert MTB/RIF assay was performed on bronchoscopy specimens. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of active PTB were calculated for acid-fast bacilli (AFB) smear microscopy and the Xpert assay using culture of Mycobacterium tuberculosis from sputum or bronchoscopy specimens as a reference standard. RESULTS: A total of 132 patients were included in the final analysis. Of these, 38 had culture-confirmed PTB. The sensitivity of the Xpert assay using bronchial washing or bronchoalveolar lavage (BAL) fluid for the diagnosis of PTB was 81.6%, and specificity was 100%. The PPV and NPV were 100% and 92.1%, respectively. The sensitivity and specificity of AFB smear microscopy were respectively 13.2% and 98.8%. CONCLUSION: The Xpert assay on bronchoscopy specimens provided an accurate diagnosis of PTB in patients who had a negative AFB smear or who could not produce sputum.

The impact of combined pulmonary fibrosis and emphysema on mortality.

SETTING: The impact on patient mortality of combined pulmonary fibrosis and emphysema (CPFE) compared with emphysema alone has never been investigated. OBJECTIVE: To elucidate whether CPFE has an impact on overall mortality over that of emphysema alone. DESIGN: We screened patients who underwent chest computed tomography (CT) scans during the period from 1 January 2001 to 31 December 2005 in a tertiary referral hospital. Patients who had both emphysema and pulmonary fibrosis, thus meeting the inclusion criteria, were defined as CPFE. Controls with emphysema alone who were matched for age, sex and the date of CT scan were randomly selected. Cox proportional regression analysis was performed to verify whether CPFE is associated with increased overall mortality. RESULTS: We found 135 CPFE cases. In the multivariable Cox regression stratified by the presence of comorbid malignancy, CPFE had five times higher mortality risk (adjusted HR 5.10, 95%CI 1.75-14.9) in non-malignant cases, and showed a statistically insignificant trend for higher mortality risk (adjusted HR 1.70, 95%CI 0.94-2.51) in the malignant cases after adjusting for forced vital capacity, height and hypertension. CONCLUSION: CPFE is not rare and CPFE patients had a higher overall mortality risk than emphysema-only patients.

Impact of antibiotic prophylaxis on postbronchoscopy fever: a randomised controlled study.

BACKGROUND: Postbronchoscopy fever can develop in 5-16% of adult patients. The microbiological contribution to postbronchoscopy fever is unclear. OBJECTIVE: To elucidate the effect of prophylactic antibiotics on the development of postbronchoscopy fever and pneumonia. DESIGN: Study patients were randomised to receive no treatment or oral amoxicillin/clavulanate 30 min before flexible bronchoscopy. The primary outcome variable was the frequency of postbronchoscopy fever and pneumonia. White blood cell counts, C-reactive protein and the serum pyrogenic cytokines interleukin (IL) 1ß, IL-6 and tumour necrosis factor-alpha were measured before and after bronchoscopy. RESULTS: Of 143 subjects enrolled in the study, the final analysis was performed among 67 subjects in the prophylaxis group and 64 in the control group. The frequency of postbronchoscopy fever did not differ between the groups (25.4% for the prophylaxis group vs. 26.6% for controls, P > 0.05). Pneumonia developed in 1.5% of the prophylaxis group and 4.7% of the controls. There was no bacteraemia in either group. Serum pyrogenic cytokines did not differ between the groups. CONCLUSIONS: Prophylactic antibiotics before bronchoscopy did not reduce the frequency of postbronchoscopy fever and did not affect serum levels of pyrogenic cytokines. These findings suggest that microbiological factors may not be responsible for the development of postbronchoscopy fever.

Clinical characteristics and outcomes of H1N1-associated pneumonia among adults in South Korea.

BACKGROUND: Pneumonia has been reported to be the most life-threatening complication of influenza virus infection. OBJECTIVE: to describe clinical characteristics and determine risk factors for death among patients with H1N1-associated pneumonia. DESIGN: A retrospective cohort study included all adult patients diagnosed and treated with H1N1-associated pneumonia in 14 participating institutions between 1 May 2009 and 28 February 2010 in South Korea. Clinical outcomes were summarised and predictors for death evaluated through univariate and multivariate analysis. RESULTS: A total of 269 adult patients with H1N1-associated pneumonia were diagnosed and treated. Hospital visits or admissions peaked in November 2009, coinciding with the peak in the 2009 H1N1 epidemic in South Korea. The patients' median age was 48 years; 143 were male. Most (n = 266, 98.9%) were admitted for treatment: 97 (36.1%) required intensive care and 28 (10.4%) needed mechanical ventilation. Despite the use of antiviral and antibacterial agents, 19 patients (7.1%) died. Risk factors predictive of death included presence of malignancy (aOR 12.0, 95%CI 2.8-51.5), and pneumonia severity index (PSI) score (aOR 1.03, 95%CI 1.01-1.04). CONCLUSION: Deaths among adult patients with H1N1-associated pneumonia were not rare. Clinicians should be aware of the possibility of a poor prognosis among H1N1-associated pneumonia patients with underlying malignancy or high PSI score.

Time interval to conversion of interferon-gamma release assay after exposure to tuberculosis.

The proper interval for repeating an interferon-γ release assay (IGRA) among tuberculosis contacts with initially negative results is unknown. The interval for IGRA conversion after exposure to patients with active pulmonary tuberculosis in an outbreak setting was evaluated. In a platoon of 32 soldiers, four active pulmonary tuberculosis patients, in addition to one index patient, were diagnosed during a contact investigation. For the other 27 contacts, a tuberculin skin test (TST) and QuantiFERON® TB-Gold In-Tube (QFT-GIT) assay were performed. For soldiers with a negative result on the initial QFT-GIT assay, the test was repeated at 2, 4, 8, 14, 18 and 30 weeks until positive conversion occurred. When conversion was identified, the subject was treated for latent tuberculosis infection. Initially, 17 (63.0%) soldiers gave positive QFT-GIT results, whereas 21 (77.8%) showed positive TST results. Among 10 participants with initially negative QFT-GIT results, three showed conversion at 2 weeks, three at 4 weeks and three at 14 weeks. Conversion did not occur during the 30-week observation period in one contact. Based on the tuberculosis exposure time-points among the contacts, IGRA conversion generally occurred 4-7 weeks after exposure, although it could occur as late as 14-22 weeks after exposure.

Decreased phosphorylation of STAT-1, STAT-4 and cytokine release in MDR-TB patients with primary resistance.

SETTING: We recently showed that treatment failure rate was higher among multidrug-resistant tuberculosis (MDR-TB) patients without a previous history of tuberculosis (TB) treatment, or so-called 'primary resistance'. OBJECTIVE: To investigate the phosphorylation levels of signal transducers and activators of transcription-1 (STAT-1) and STAT-4 and the subsequent cytokine release as a possible cause of a poor prognosis in MDR-TB patients with primary resistance. DESIGN: Ten patients with successfully treated pulmonary TB without resistance, 12 MDR-TB patients with acquired resistance and 10 MDR-TB patients with primary resistance were enrolled. After 24 h stimulation of peripheral blood mononuclear cells (PBMC) with interferon-gamma (IFN-gamma), interleukin-12 (IL-12), purified protein derivative (PPD), or lysate of Mycobacterium tuberculosis, flow cytometric analysis of intracellular pSTAT-1 and pSTAT-4 were performed and secretion of IFN-gamma, IL-12p40 and tumour necrosis factor-alpha (TNF-alpha) was measured in culture supernatant. RESULTS: The mean fluorescent intensities of pSTAT-1 and pSTAT-4 in PBMC of MDR-TB patients with primary resistance decreased on stimulation of IFN-gamma, PPD or lysate of M. tuberculosis when compared with patients with acquired resistance. In addition, secretion of IFN-gamma, IL-12p40 and TNF-alpha in these patients decreased on various stimuli. CONCLUSION: Decreased phosphorylation of STAT-1, STAT-4, and of subsequent cytokine release, might be associated with a poor prognosis in MDR-TB patients with primary resistance.

Predictors of persistent airway stenosis in patients with endobronchial tuberculosis.

SETTING: The university and municipal hospitals in Seoul, Korea. OBJECTIVE: To evaluate the predictors of persistent airway stenosis following anti-tuberculosis chemotherapy in patients with endobronchial tuberculosis (TB). DESIGN: Diagnosis of TB was confirmed by microbiology or histopathology. Bronchoscopic examinations revealed that patients had endobronchial lesions compatible with endobronchial TB. Study subjects had at least one follow-up bronchoscopy to evaluate their treatment response. Treatment response was determined by changes in the degree or extent of airway stenosis between the first and last bronchoscopic examinations. RESULTS: Sixty-seven subjects were recruited retrospectively from Seoul National University Hospital and Seoul National University Boramae Hospital. Persistent bronchostenosis occurred in 41.8% of the patients. In multivariate regression analysis, age >45 years (OR 3.65), pure or combined fibrostenotic subtype (OR 5.54) and duration from onset of chief complaint to the initiation of anti-tuberculosis chemotherapy >90 days (OR 5.98) were identified as independent predictors of persistent airway stenosis. Oral corticosteroids (prednisolone equivalent >or=30 mg/d) did not reduce the frequency of persistent airway stenosis. CONCLUSION: Early diagnosis and early administration of anti-tuberculosis chemotherapy before involvement of the deeper airways is important to prevent the development of unwanted sequelae of bronchostenosis.

Aetiologies and predictors of pulmonary cavities in South Korea.

OBJECTIVE: To identify the aetiologies of pulmonary cavities and the clinical predictors of cavities of mycobacterial origin. SETTING: A tertiary referral hospital in South Korea, where the prevalence of tuberculosis (TB) is intermediate. DESIGN: A retrospective review of clinical records and radiographic examinations of patients presenting pulmonary cavities on simple chest radiograph between January and December 2005. RESULTS: Of 131 patients enrolled with pulmonary cavities, 66 (50.4%) had cavities of mycobacterial origin. Age <50 years (P = 0.04) and largest cavity located in the upper lobes (P = 0.04) increased the likelihood that the cavities were of mycobacterial origin. Conversely, history of malignancy (P = 0.02), lesions confined to one lobe (P = 0.02) and multiple enlarged mediastinal lymph nodes (P = 0.03) suggested a non-mycobacterial cause. CONCLUSION: Mycobacterial infection accounted for half of the cavitary lesions identified in this study. In older patients with a history of malignancy, non-nodular infiltration, lesions confined to one lobe and with multiple lymphadenopathy, diseases not caused by mycobacteria should be considered.

Determinants of diagnostic bronchial washing in peripheral lung cancers.

OBJECTIVE: To establish clinical determinants affecting the diagnostic yield of bronchial washing. SETTING: We performed bronchial washing in 241 consecutive patients with bronchoscopically invisible lung tumours. Of these, 150 patients known to have lung cancer were enrolled for the final analysis. DESIGN: A multi-centre study. RESULTS: Bronchial washing provided a diagnosis of lung cancer in 30 of the 150 patients (20%). Tumour size > or = 3 cm (P = 0.005), the location of the tumour within 8 cm of the carina (P = 0.003), and exposed type bronchus sign of tumour (P < 0.001) were factors affecting diagnostic bronchial washing for bronchoscopically invisible lung cancers. However, multivariate logistic regression revealed that exposed type bronchus sign was the sole determinant (OR 19.22, 95% CI 4.23-87.46, P < 0.001). CONCLUSION: Bronchial washing is a useful procedure for the diagnosis of bronchoscopically invisible lung cancers. As the tumour-bronchus relationship is the most important determinant of a diagnostic yield, the routine use of bronchial washing should be considered for tumours with exposed type bronchus sign.

Lack of association between COPD and transforming growth factor-beta1 (TGFB1) genetic polymorphisms in Koreans.

OBJECTIVE: Many genetic variations have been suggested as genetic risk factors for the development of chronic obstructive pulmonary disease (COPD), including single nucleotide polymorphisms in the transforming growth factor-beta1 (TGFB1) gene. We attempted to elucidate the association between TGFB1 genetic polymorphisms and COPD among Koreans. DESIGN: The genotypes of 102 male patients with COPD and 159 volunteers with similar distributions of age, sex and smoking intensity, as well as normal pulmonary function, were determined for three previously associated TGFB1 single nucleotide polymorphisms (SNPs), -10807G/A (rs2241712) and -509T/C (rs1800469), located in or near the promoter, and 29T/C (rs1982073), located in exon 1 of the TGFB1 gene. RESULTS: No significant associations between COPD and the three TGFB1 SNPs could be identified. In addition, the haplotypes composed of three TGFB1 SNPs were not associated with the presence of COPD. CONCLUSION: These results differ from previous reports involving Caucasians, and might reflect racial differences in the pathogenesis of COPD.

Prognostic factors for surgical resection in patients with multidrug-resistant tuberculosis.

Although surgical lung resection could improve prognosis in some patients with multidrug-resistant tuberculosis (MDR-TB), there are no reports on the optimal candidates for this surgery. The aim of the present study was to elucidate the prognostic factors for surgery in patients with MDR-TB. Patients who underwent lung resection for the treatment of MDR-TB between March 1993 and December 2004 were included in the present study. Treatment failure was defined as greater than or equal to two of the five cultures recorded in the final 12 months of treatment being positive, any one of the final three cultures being positive, or the patient having died during treatment. The variables that affected treatment outcomes were identified through univariate and multivariate logistic regression analysis. In total, 79 patients with MDR-TB were included in the present study. The treatment outcomes of 22 (27.8%) patients were classified as failure. A body mass index <18.5 kg x m(-2), primary resistance, resistance to ofloxacin and the presence of a cavitary lesion beyond the range of the surgical resection were associated with treatment failure. Low body mass index, primary resistance, resistance to ofloxacin and cavitary lesions beyond the range of resection are possible poor prognostic factors for surgical lung resection in multidrug-resistant tuberculosis patients.

Oral insertion of a flexible bronchoscope is associated with less discomfort than nasal insertion for Korean patients.

OBJECTIVE: The route of bronchoscope insertion varies between centres, without a firm rationale based on well-designed studies. We therefore compared nasal and oral insertion of a flexible bronchoscope and evaluated efficacy and patient satisfaction. DESIGN: Prospective randomised study of patients who underwent flexible bronchoscopy from May to September 2003 and who were randomly assigned to nasal and oral insertion approaches. RESULTS: Clinical characteristics, factors related to the procedure and patient satisfaction were analysed. In total, 307 patients were randomly assigned to the nasal (n = 158) or oral insertion groups (n = 149). No difference in baseline characteristics was identified between the groups. Insertion by the oral route was associated with a smaller amount of lidocaine use during the procedure (P = 0.04) and less frequent insertion site bleeding (P = 0.005). Patients assigned to oral insertion reported less discomfort during anaesthesia (P = 0.01) and scope insertion (P < 0.001), as well as less dyspnoea (P = 0.04) and coughing (P = 0.03). CONCLUSION: Oral insertion of a flexible bronchoscope was associated with less discomfort for patients than nasal insertion, although the route of insertion had no significant effect on outcome.

Lack of association between glutathione S-transferase P1 polymorphism and COPD in Koreans.

The fact that only 10-20% of chronic heavy cigarette smokers develop symptomatic COPD and correlations of pulmonary function among twins and families suggests the presence of genetic susceptibility in the development of COPD. Genetic susceptibility to COPD might depend on the variations in enzyme activities that detoxify cigarette smoke products, such as microsomal epoxide hydrolase (mEPHX) and glutathione-S transferase (GST). The purpose of this study was to determine whether polymorphism of GSTP1 gene is linked to a genetic susceptibility to COPD. The hypothesis we tested here was that the polymorphism supposed to decrease GSTP1 activity would be the genetic risk for the development of COPD. Using PCR followed by restriction fragment length polymorphism (PCR-RFLP), genotypes of Ile105Val polymorphism in exon 5 of glutathione S-transferase P1 (GSTP1) gene were determined in 89 patients with COPD and 94 healthy smoking control subjects at the Seoul National University Hospital. Although the frequency of homozygous wild allele in exon 5 of GSTP1 gene in patients with COPD was higher than that observed in healthy controls (71% vs. 61%), the difference was not considered statistically significant. Neither the heterozygous nor homozygous mutant allele differed in frequency between the two groups. In conclusion, the genetic polymorphisms of exon 5 of GSTP1 gene may not be associated with development of COPD in Koreans.

Genetic susceptibility to chronic obstructive pulmonary disease in Koreans: combined analysis of polymorphic genotypes for microsomal epoxide hydrolase and glutathione S-transferase M1 and T1.

BACKGROUND: Although smoking is the major causal factor in the development of chronic obstructive pulmonary disease (COPD), only 10-20% of chronic heavy cigarette smokers develop symptomatic COPD which suggests the presence of genetic susceptibility. This genetic susceptibility to COPD might depend on variations in enzyme activities that detoxify cigarette smoke products such as microsomal epoxide hydrolase (mEPHX) and glutathione-S transferase (GST). As there is increasing evidence that several genes influence the development of COPD, multiple gene polymorphisms should be investigated to find out the genetic susceptibility to COPD. METHODS: The genotypes of 83 patients with COPD and 76 healthy smoking control subjects were determined by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (PCR-RFLP) for the mEPHX gene, and multiplex PCR for GST M1 and GST T1 genes. The frequencies of polymorphic genotypes of mEPHX, GST M1, and GST T1 genes were compared both individually and in combination in patients with COPD and healthy smokers. RESULTS: No differences were observed in the frequency of polymorphic genotypes in exons 3 and 4 of mEPHX, GST M1, and GST T1 genes between patients with COPD and healthy smokers. The frequencies of any combination of these genotypes also showed no differences between the COPD group and the control group. CONCLUSIONS: Genetic polymorphisms in mEPHX, GST M1, and GST T1 genes are not associated with the development of COPD in Koreans.

A spindle cell tumor of unknown origin and diffuse bone marrow involvement in a patient with hypercalcemia.

BACKGROUND: Metastasis of unknown origin in bone marrow is infrequent, although, when it occurs, adenocarcinoma is the most common histologic type. Involvement of bone marrow by a spindle cell tumor and presentation with hypercalcemia are very rare. METHOD: This report describes a 21-year-old man with diffuse bone marrow involvement from a spindle cell tumor. RESULTS: The patient presented with low back pain, anemia, thrombocytopenia, azotemia, and hypercalcemia. Bone marrow biopsy revealed a spindle cell tumor that was positive for vimentin staining but whose primary site could not be identified. A bone marrow scan revealed absence of uptake, which suggested systemic disease. We treated this case as a type of sarcoma by giving combined chemotherapy consisting of vincristine, actinomycin-D and cyclophosphamide. The patient showed a clinical response for seven months, but the disease progressed despite chemotherapy and he died one year after diagnosis. CONCLUSIONS: We have documented a rare case of spindle cell tumor involving bone marrow without evidence of the tumor's primary site.

Impact of tumour necrosis factor-alpha and interferon-gamma on tetrahydrobiopterin synthesis in murine fibroblasts and macrophages.

Tumour necrosis factor-alpha causes an up to 30-fold induction of GTP cyclohydrolase I (EC 3.5.4.16) activity in murine dermal fibroblasts in a dose-dependent manner. Owing to the high constitutive activities of 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase (EC 1.1.1.153), this potentiates biosynthesis of tetrahydrobiopterin. Murine macrophages already contain high activities of GTP cyclohydrolase I when unstimulated, and this is further augmented up to 4-fold by tumour necrosis factor-alpha/interferon-gamma. In Western blots an antiserum to murine liver GTP cyclohydrolase I does not stain cell extracts with high enzyme activities, suggesting that the cytokine induced peripheral form of GTP cyclohydrolase I might differ from the liver form.