Hui Jung Kim

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·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.

Nutritional deficit as a negative prognostic factor in patients with miliary tuberculosis

The effects of malnutrition on outcomes in miliary tuberculosis (MTB) are not well described. The aim of the present study was to find predictors for the development of acute respiratory failure (ARF) and survival in MTB patients, focusing on parameters reflecting nutritional condition. Out of the patients from three hospitals who had microbiologically or histopathologically confirmed tuberculosis, 56 patients presenting with typical disseminated pulmonary nodules on radiographs were retrospectively enrolled. A four-point nutritional risk score (NRS) was defined according to the presence of four nutritional factors: low body mass index (BMI; <18.5 kg·m−2), hypoalbuminaemia (<30.0 g·L−1), hypocholesterolaemia (<2.33 mmol·L−1) and severe lymphocytopenia (<7×105 cells·L−1). The male to female ratio was 1:3. ARF developed in 25% of patients (14 out of 56), with a 50% fatality rate. A high NRS (≥3 points) was an independent risk factor for the development of ARF and fatality. In 90-day survival analysis, ARF, severe lymphocytopenia, hypocholesterolaemia, low BMI and higher NRS were risk factors for poor outcome. In multivariate analysis, only high NRS was an independent risk factor for 90-day survival rate in patients with MTB. A high nutritional risk score was a good predictor of poor outcome in miliary tuberculosis patients. Additional approaches to recover the nutritional deficits may become a focus in future management of miliary tuberculosis.

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 resistance to first-line and injectable drugs on treatment outcomes in MDR-TB.

Recently, resistance to additional first-line and injectable drugs was reported to be an independent risk factor for adverse outcomes in multidrug-resistant (MDR) tuberculosis (TB) patients. The aim of the present study was to confirm these observations in MDR-TB patients without HIV infection. MDR-TB patients treated at a tertiary referral hospital in South Korea between January 1996 and December 2005 were included. The unadjusted and adjusted odds ratios of adverse treatment outcome were calculated for resistance to each drug and combination of drugs using simple or multiple logistic regressions. None of the resistance to additional first-line or injectable drugs was associated with higher odds for adverse treatment outcome in 155 MDR but nonextensively drug-resistant (non-XDR) TB patients. However, streptomycin resistance was associated with 12 times the odds for adverse treatment outcome in 42 extensively drug-resistant (XDR) TB patients. Neither combinations of first-line drugs nor those of injectable drugs were associated with increased odds for adverse treatment outcomes in non-XDR MDR-TB patients or XDR-TB patients. Only streptomycin resistance among the first-line or injectable drugs was associated with adverse treatment outcomes in extensively drug-resistant tuberculosis patients without HIV infection.

Clinical characteristics of patients with tuberculosis-destroyed lung.

SETTING Multicentre study. OBJECTIVE To define the clinical characteristics of patients with tuberculosis (TB) destroyed lung due to past TB. DESIGN We reviewed patients with TB-destroyed lung between May 2005 and June 2011. RESULTS A total of 595 patients from 21 hospitals were enrolled. The mean age was 65.63 ± 0.47 (mean ± standard error); 60.5% were male. The mean number of lobes involved was 2.59 ± 0.05. Pleural thickening was observed in 54.1% of the patients. Mean forced vital capacity (FVC), forced expiratory volume in 1 s (FEV(1)), FEV(1)/FVC, bronchodilator response and number of exacerbations per year were respectively 2.06 ± 0.03 l (61.26% ± 0.79), 1.16 ± 0.02 l (49.05% ± 0.84), 58.03% ± 0.70, 5.70% ± 0.34, and 0.40 ± 0.04. The number of lobes involved was significantly correlated with FVC and FEV(1), and with the number of exacerbations per year. Use of long-acting muscarinic antagonists or long-acting beta-2 agonists plus inhaled corticosteroids resulted in bronchodilatory effects. Multivariable regression analysis showed that age, initial FEV(1) (%) and number of exacerbations during follow-up were independent factors affecting change in FEV(1). CONCLUSION Decreased lung function with exacerbation, and progressive decline of FEV(1) were observed in patients with TB-destroyed lung.

Patterns of pncA mutations in drug-resistant Mycobacterium tuberculosis isolated from patients in South Korea.

BACKGROUND Pyrazinamide (PZA), one of the most effective anti-tuberculosis drugs, becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by pyrazinamidase (PZase). PZA resistance is caused mainly by the loss of enzyme activity by mutation. OBJECTIVE To investigate the patterns of pncA mutations in PZA-resistant mycobacteria isolated from South Korean patients. METHODS Mycobacterial isolates with clinically proven drug resistance were cultured to determine susceptibility to anti-tuberculosis agents. pncA mutations were recognised by sequencing and compared with the relevant wild-type DNA sequence. RESULTS Among 108 isolates, 102 were successfully cultured and underwent drug susceptibility testing; all were multidrug-resistant (MDR). pncA mutations were found in 86 cultured isolates (85.1%): 55 (84.6%) in MDR and 31 (86.1%) in extensively drug-resistant isolates. Substitution of a single nucleotide was most common. The most frequent mutations were a deletion that caused a frameshift at nucleotide (nt) 71, a substitution at nt 403 and a substitution at nt 11. Combined, these accounted for ≈ 40% of all mutations. However, 15 samples (14.9%) with defective PZase activity showed no mutation. CONCLUSION pncA mutation in M. tuberculosis is a major mechanism of PZA resistance in MDR isolates from patients in South Korea. The patterns of mutation might be more scattered and diverse. DNA-based diagnosis of PZA resistance has potential for the rapid detection of drug resistance.

Long-acting anticholinergic agents in patients with uncontrolled asthma: A systematic review and meta-analysis

SETTING A novel effective treatment is necessary for severe asthma. OBJECTIVE To review clinical trials examining the role of tiotropium in patients with poorly controlled asthma despite inhaled corticosteroid use with or without long-acting β₂-agonists. DESIGN A computerised search of electronic databases (Medline, EMBASE and Cochrane Central Register) was performed. Randomised controlled trials of at least a 4-week treatment duration with findings published in English were included. RESULTS Five studies involving 1635 patients were analysed. Compared with a placebo or a double dose of inhaled corticosteroids, the addition of tiotropium increased mean trough and peak forced expiratory volume in 1 second by 97 ml (95%CI 71-122) and 103 ml (95%CI 42-163), respectively. The mean differences in morning peak expiratory flow were 19.2 l/min (95%CI 11.8-26.6). Tiotropium also reduced the risk of severe acute exacerbation (OR 0.73, 95%CI 0.56-0.96) and improved Asthma Quality-of-Life Questionnaire score significantly by 0.10 (95%CI 0.04-0.16). There were no differences in serious adverse events. CONCLUSION The addition of tiotropium may be beneficial for patients with poorly controlled asthma, although exacerbation or safety issues should be clarified in long-term trials before its wide use in asthma.

The impact of previous tuberculosis history on T-SPOT.TB® interferon-gamma release assay results.

SETTING Seoul National University Bundang Hospital, a tertiary referral hospital in Korea. OBJECTIVE To evaluate whether previous tuberculosis (TB) history has a long-term effect on T-SPOT.TB® results after anti-tuberculosis treatment. DESIGN We retrospectively reviewed 489 adults (age ≥18 years) who underwent T-SPOT.TB as part of their evaluation between January 2008 and July 2009. RESULTS Among 489 subjects analysed, 369 were finally included. Active TB was diagnosed in 121/369 (32.8%). T-SPOT.TB was positive in 110 (90.9%) active TB patients. Of the 248 subjects without active TB, T-SPOT.TB positivity was significantly different between the 51 patients with a previous TB history and the 197 without (84.3% vs. 26.9%, P < 0.001). The difference in T-SPOT.TB positivity between the 51 non-active TB patients with a TB history and the 121 active TB patients was not statistically significant (84.3% vs. 90.9%, P = 0.208). Among the 51 non-active TB individuals with a TB history, the mean time since anti-tuberculosis treatment was 22.7 years (range 1-59); this had no correlation with total region of difference 1 (RD1) spot-forming cells (r = -0.076, P = 0.597). CONCLUSION T-SPOT.TB has a limited role in the diagnosis of TB infection in individuals with a previous history of TB.

Parasympathectomy induces morphological changes and alters gene-expression profiles in the rat submandibular gland.

OBJECTIVE The chorda-lingual (CL) nerve carries parasympathetic fibers to the hilum of the sublingual and submandibular glands (SMGs) and evokes the secretion of saliva. The effect of cutting the CL nerve on the biological processes in SMGs was investigated by examining the gene-expression profiles in the SMGs after a surgical parasympathectomy. METHODS At day 3 after the CL nerve cut, the changes in the SMGs at both the experimental cut and contralateral control sides were analysed by microarray and light microscopy. The expression levels of 6 selected genes were confirmed by real-time PCR, Western blot and immunofluorescence staining. RESULTS The wet weight of the parasympathectomised SMGs decreased significantly compared to that of the contralateral side (p<0.05). Histological analyses after the parasympathectomy showed a widened interacinar space as well as some atropic changes to the acini of the SMGs in the cut side. Microarray analysis revealed that twofold differential expression in mRNA expression in the parasympathectomized SMGs were detected in 88 genes (0.004%): 41 genes were overexpressed, 11 were underexpressed and 36 were unknown. Changes of the expression of 6 selected genes detected by Western blot and/or real-time PCR were consistent with the microarray data. CONCLUSION The important genes involved in biological processes for salivation were identified through a large-scale gene expression analysis.

Vitamin D Inhibits Expression and Activity of Matrix Metalloproteinase in Human Lung Fibroblasts (HFL-1) Cells

Background Low levels of serum vitamin D is associated with several lung diseases. The production and activation of matrix metalloproteinases (MMPs) may play an important role in the pathogenesis of emphysema. The aim of the current study therefore is to investigate if vitamin D modulates the expression and activation of MMP-2 and MMP-9 in human lung fibroblasts (HFL-1) cells. Methods HFL-1 cells were cast into three-dimensional collagen gels and stimulated with or without interleukin-1β (IL-1β) in the presence or absence of 100 nM 25-hydroxyvitamin D (25(OH)D) or 1,25-dihydroxyvitamin D (1,25(OH)2D) for 48 hours. Trypsin was then added into the culture medium in order to activate MMPs. To investigate the activity of MMP-2 and MMP-9, gelatin zymography was performed. The expression of the tissue inhibitor of metalloproteinase (TIMP-1, TIMP-2) was measured by enzyme-linked immunosorbent assay. Expression of MMP-9 mRNA and TIMP-1, TIMP-2 mRNA was quantified by real time reverse transcription polymerase chain reaction. Results IL-1β significantly stimulated MMP-9 production and mRNA expression. Trypsin converted latent MMP-2 and MMP-9 into their active forms of MMP-2 (66 kDa) and MMP-9 (82 kDa) within 24 hours. This conversion was significantly inhibited by 25(OH)D (100 nM) and 1,25(OH)2D (100 nM). The expression of MMP-9 mRNA was also significantly inhibited by 25(OH)D and 1,25(OH)2D. Conclusion Vitamin D, 25(OH)D, and 1,25(OH)2D play a role in regulating human lung fibroblast functions in wound repair and tissue remodeling through not only inhibiting IL-1β stimulated MMP-9 production and conversion to its active form but also inhibiting IL-1β inhibition on TIMP-1 and TIMP-2 production.