Jia-Yih Feng

Role of 2-month sputum smears in predicting culture conversion in pulmonary tuberculosis

Sputum smears and culture conversion are frequently used to evaluate treatment response in pulmonary tuberculosis patients. Limited data are available on the evaluation of the correlation between under-treatment sputum smear results and culture conversion. This prospective study included sputum culture-proven pulmonary tuberculosis patients at six hospitals in Taiwan. At least two sets of sputum were collected at the completion of 8 weeks of TB treatment. The sensitivities and specificities of 2-month sputum smears were estimated based on culture conversion status. A total of 371 patients were enrolled for analysis. Factors associated with culture conversion included having a smear positive before treatment, presence of a cavity on radiography, rifampicin resistance and usage of the DOTS (directly observed therapy, short course) strategy. The sensitivities of 2-month sputum smears for culture conversion among all patients, initially smear-positive patients and initially smear-negative patients were 64.3, 71.4 and 38%, respectively, and the specificities were 81.6, 69.9 and 92.8%, respectively. In patients who were 2-month sputum smear-positive, the 2-month culture conversion rate was 80% if the patients were under DOTS and without cavitary lesions in radiograms. The predictive value of 2-month sputum smears in culture conversion was limited and highly influenced by clinical factors in pulmonary tuberculosis patients.

Plasma soluble vascular endothelial growth factor receptor-1 levels predict outcomes of pneumonia-related septic shock patients: a prospective observational study

IntroductionDespite recent advances in the management of septic shock, mortality rates are still unacceptably high. Early identification of the high-mortality risk group for early intervention remains an issue under exploration. Vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR1) and urokinase plasminogen activator (uPA) have diverse effects in the pathogenesis of sepsis, which involve pro-inflammation, anti-inflammation, endothelial cell repair, and vascular permeability change. Their roles in predicting mortality and organ dysfunction remain to be clarified.MethodsPneumonia-related septic shock patients from medical intensive care units were enrolled for this prospective observational study. We also included 20 patients with pneumonia without organ dysfunction for comparison. Plasma levels of VEGF and sVEGFR1 and uPA activity within 24 hours of shock onset were measured. We compared plasma levels of these biomarkers with APACHE II scores between subgroups of patients, and evaluated their predictive value for 28-day mortality and organ dysfunction.ResultsA total of 101 patients, including 81 with pneumonia-related septic shock and 20 with pneumonia without organ dysfunction, were enrolled. Non-survivors of septic shock had significantly higher plasma sVEGFR1 levels (659.3 ± 1022.8 vs. 221.1 ± 268.9 pg/mL, respectively, P < 0.001) and uPA activity (47.2 ± 40.6 vs. 27.6 ± 17.2 units, respectively, P = 0.001) when compared with those of the survivors. Kaplan-Meier survival analysis demonstrated significantly higher mortality in patients with higher levels of sVEGFR1 (P < 0.001) and uPA activity (P = 0.031). In Cox regression analysis, plasma sVEGFR1 level was independently associated with, and best predicted, the 28-day mortality of septic shock (HR: 1.55, 95% CI: 1.05-2.30). Plasma sVEGFR1 level and uPA activity had good correlation with renal dysfunction, metabolic acidosis, and hematologic dysfunction; their levels significantly increased when the number of organ dysfunctions increased. In multivariate analysis, plasma sVEGFR1 level (HR: 2.82, 95% CI: 1.17-6.81) and uPA activity (HR: 2.75, 95% CI: 1.06-7.13) were independent predictors of the presence of concomitant multi-organ dysfunction. The predictive value of VEGF for mortality and organ dysfunction was limited in pneumonia-related septic shock patients.ConclusionsHigh plasma sVEGFR1 level in the early stage of pneumonia-related septic shock independently predicted 28-day mortality and multi-organ dysfunction.

Gender differences in treatment outcomes of tuberculosis patients in Taiwan: a prospective observational study

Gender disparities in tuberculosis (TB) cases are reported worldwide, and socio-cultural factors have been proposed as possible causes. To date, gender differences in treatment outcomes of TB patients remain controversial. In this prospective observational study, newly diagnosed, culture-proven TB patients from six hospitals in Taiwan were enrolled for analysis. Gender differences in demographic characteristics and treatment outcomes, including sputum conversion and on-treatment mortality, were analysed accordingly. From January 2007 through to December 2009, a total of 1059 patients were enrolled, including 819 (77.3%) males and 240 (22.7%) females. The ratio of male gender was around 50 ~ 60% in TB patients below 35 years and >80% for those older than 65 years. When compared with the female patients, the male patients were older, more likely to have the habit of smoking, chronic obstructive pulmonary disorder, malignancy and liver cirrhosis, and more likely to present with haemoptysis, body weight loss and pleural effusion. Regarding treatment outcomes, male gender is associated with a lower 2-month sputum culture conversion rate (78.8% vs. 89.3%, p 0.002) and higher on-treatment mortality (21.1% vs. 12.1%, p 0.002). Kaplan-Meier survival analysis demonstrated significantly higher mortality in the men (p 0.005). In multivariate analysis, male gender was an independent risk factor for 2-month sputum culture un-conversion (OR, 1.96; 95% CI, 1.12-3.41). Our findings suggest that male gender is associated with older age, more co-morbidities and worse treatment outcomes. Gender-specific strategies, including active case finding in elderly women and smoking cessation in male patients, are warranted to optimize TB management.

Characteristics of pncA mutations in multidrug-resistant tuberculosis in Taiwan

BackgroundPyrazinamide (PZA) is an important first-line drug in multidrug-resistant tuberculosis (MDRTB) treatment. However, the unreliable results obtained from traditional susceptibility testing limits its usefulness in clinical settings. The detection of pncA gene mutations is a potential surrogate of PZA susceptibility testing, especially in MDRTB isolates. The impact of genotypes of M. tuberculosis in pncA gene mutations also remains to be clarified.MethodsMDRTB isolates were collected from six hospitals in Taiwan from January 2007 to December 2009. pncA gene sequencing, pyrazinamidase activity testing, and spoligotyping were performed on all of the isolates. PZA susceptibility was determined by the BACTEC MGIT 960 PZA method. The sensitivity and specificity of pncA gene analysis were estimated based on the results of PZA susceptibility testing.ResultsA total of 66 MDRTB isolates, including 37 Beijing and 29 non-Beijing strains, were included for analysis. Among these isolates, 36 (54.5%) were PZA-resistant and 30 (45.5%) were PZA-susceptible. The PZA-resistant isolates were more likely to have concomitant resistance to ethambutol and streptomycin. Thirty-seven mutation types out of 30 isolates were identified in the pncA gene, and most of them were point mutations. The sensitivities of pncA gene sequencing for PZA susceptibility in overall isolates, Beijing and non-Beijing strains were 80.6%, 76.2%, and 86.7% respectively, and the specificities were 96.7%, 93.8%, and 100% respectively.ConclusionsMore than half of the MDRTB isolates in this study are PZA-resistant. Analysis of pncA gene mutations helped to identify PZA-susceptible MDRTB isolates, especially in non-Beijing strains.

Increasing Drug Resistance of Mycobacterium tuberculosis Isolates in a Medical Center in Northern Taiwan

BACKGROUND/PURPOSE This retrospective study was conducted to evaluate the drug resistance patterns of Mycobacterium tuberculosis in a medical center in northern Taiwan between 2003 and 2004 in comparison to those reported in 1990-1992. METHODS A total of 611 non-duplicate M. tuberculosis isolates from culture-proven tuberculosis (TB) cases were tested for drug susceptibility against five first-line anti-TB drugs in a clinical mycobacterial laboratory using the agar proportional method for isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and streptomycin (SM). The Wayne assay, which measures the activity of pyrazinamide (PZA), was used for PZA susceptibility testing. RESULTS Of 611 patients, including 510 males and 101 females, 70.2% of patients were older than 65 years. A total of 339 isolates (55.5%) were resistant to one or more drugs. Isolates from patients aged <25 years showed a significantly higher drug resistance rate (79.2%) compared with other age groups (p=0.0312). Single-drug resistance was observed in 97 (15.9%) of all isolates. Monoresistance to PZA (8.0%) was most frequent, followed by INH (5.1%), RIF (0.5%), EMB (1.6%), and SM (0.7%). Among the polydrug resistant isolates (PDR-TB), resistance rates were 35.5% for INH and 27.0% for RIF. One hundred and fifty-nine isolates (26.0%) were resistant to both INH and RIF (multidrug-resistant [MDR] TB); 94.6% of RIF-resistant isolates were also resistant to INH. The overall drug resistance rates and percentages of PDR-TB and MDR-TB increased over the 12-year study period (p<0.001). Based on medical records, primary cases were identified in 486 (84.7%) out of 574 patients, and resistance to any drug was identified in 268 (55.1%) patients, of which 130 (26.7%) were MDR-TB. Among the 88 with recurrent TB, 54 (61.4%) were resistant to at least one drug, and MDR-TB was identified in 29 (33.0%) patients. A history of previous anti-TB therapy was a significant factor for overall drug resistance, PZA monoresistance, PDR-TB, and MDR-TB (p<0.001). CONCLUSION The emergence of M. tuberculosis isolates resistant to anti-TB agents in this hospital, and in particular among young patients, is alarming. Strict measures to control and prevent drug-resistant TB are urgently needed.

Gender Disparities in Latent Tuberculosis Infection in High-Risk Individuals: A Cross-Sectional Study

Male predominance in active tuberculosis (TB) is widely-reported globally. Gender inequalities in socio-cultural status are frequently regarded as contributing factors for disparities in sex in active TB. The disparities of sex in the prevalence of latent TB infection (LTBI) are less frequently investigated and deserve clarification. In this cross-sectional study conducted in a TB endemic area, we enrolled patients at high-risk for LTBI and progression from LTBI to active TB from 2011 to 2012. Diagnosis of LTBI was made by QuantiFERON-TB Gold In-Tube (QFT-GIT). Differences in sex in terms of prevalence of LTBI and clinical predictors for LTBI were investigated. Associations among age, smoking status, and sex disparities in LTBI were also analyzed. A total of 1018 high-risk individuals with definite QFT-GIT results were included for analysis, including 534 males and 484 females. The proportion of LTBI was significantly higher in males than in females (32.6% vs. 25.2%, p = 0.010). Differences in the proportion of LTBI between sexes were most prominent in older patients (age ≥55 years). In multivariate analysis, independent clinical factors associated with LTBI were age (p = 0.014), smoking (p = 0.048), and fibro-calcified lesions on chest radiogram (p = 0.009). Male sex was not an independent factor for LTBI (p = 0.88). When stratifying patients according to the smoking status, the proportion of LTBI remained comparable between sexes among smokers and non-smokers. In conclusion, although the proportion of LTBI is higher in men, there is no significant disparity in terms of sex in LTBI among high-risk individuals after adjusting for age, smoking status, and other clinical factors.

Characteristics of IFN-γ responses in IGRA among pulmonary TB suspects in a TB-endemic area

Although the diagnostic value of interferon-γ (IFN-γ) release assays for active tuberculosis (TB) is limited, the characteristic of non-TB-specific IFN-γ responses among TB suspects deserves further evaluation. We enrolled clinically suspected pulmonary TB (PTB) patients, and QuantiFERON-TB Gold In-Tube (QFT-GIT) was performed. The characteristics of IFN-γ responses were analyzed. Among 392 patients, active PTB patients had stronger IFN-γ responses to TB antigen (TBAg-Nil, P < 0.001) and lower responses to mitogen (Mitogen-Nil, P < 0.001). Lower body mass index (P = 0.001), without bacille Calmette-Guerin vaccination (P = 0.026), and active PTB (P = 0.011) were independent factors associated with lower non-TB-specific IFN-γ responses. Among TB suspects with higher TBAg-Nil (>1.02 U/mL) and lower Mitogen-Nil (<5.5 U/mL), 84.3% were active PTB cases. Among TB suspects with lower TBAg-Nil and higher Mitogen-Nil, only 4.7% were active PTB. The present study suggested that the possibilities of active PTB should be carefully excluded in TB suspects with stronger TB-specific and lower non-TB-specific IFN-γ responses in QFT-GIT.

Impact of cigarette smoking on latent tuberculosis infection: does age matter?

To the Editor: Latent tuberculosis infection (LTBI) is defined by evidence of immunological responses by Mycobacterium tuberculosis proteins in the absence of clinical symptoms/signs of active diseases [1]. People who have increased likelihood of tuberculosis (TB) exposure and those with clinical conditions that increased their risk of progressing from LTBI to TB disease are regarded as high-risk groups for developing TB disease and should be considered for LTBI testing and treatment. Both tuberculin skin test (TST) and T-cell based interferon-γ release assays (IGRAs) are available diagnostic tool for LTBI, but IGRAs avoid the interferences from bacille Calmette–Guerin (BCG) vaccination and non-tuberculous mycobacterium (NTM). Cigarette smoke has adverse effects in respiratory immune function and is widely reported to be associated with an increased risk of respiratory a tract infection, including TB [2, 3]. However, only a few studies investigated the impact of smoking on LTBI, and none of these studies used IGRAs to diagnose LTBI [4, 5]. The European Respiratory Journal recently published a perspective review focused on the role of diagnosis and treatment of LTBI to improve TB control and eventually TB elimination [6]. To eliminate TB on a global scale the identification and sterilisation of latently infected individuals, especially those in high-risk groups, is of paramount importance. Concerning the close correlation between cigarette smoking and active TB, the association between LTBI and smoking deserves further clarification with IGRAs as a diagnostic tool. To elucidate the issue, we enrolled inpatients and outpatients who were considered at risk for LTBI and …

Latent TB infection in newly diagnosed lung cancer patients – A multicenter prospective observational study

OBJECTIVES Lung cancer and tuberculosis (TB) share common risk factors and are associated with high morbidity and mortality. Coexistence of lung cancer and TB were reported in previous studies, with uncertain pathogenesis. The association between lung cancer and latent TB infection (LTBI) remains to be explored. METHODS Newly diagnosed, treatment-naïve lung cancer patients were prospectively enrolled from four referral medical centers in Taiwan. The presence of LTBI was determined by QuantiFERON-TB Gold In-Tube (QFT-GIT). Demographic characteristics and cancer-related factors associated with LTBI were investigated. The survival status was also analyzed according to the status of LTBI. RESULTS A total of 340 lung cancer patients were enrolled, including 96 (28.2%) LTBI, 214 (62.9%) non-LTBI, and 30 (8.8%) QFT-GIT results-indeterminate cases. Non-adenocarcinoma cases had higher proportion of LTBI than those of adenocarcinoma, especially in patients with younger age. In multivariate analysis, COPD (OR 2.41, 95% CI 1.25-4.64), fibrocalcified lesions on chest radiogram (OR 2.73, 95% CI 1.45-5.11), and main tumor located in typical TB areas (OR 2.02, 95% CI 1.15-3.55) were independent clinical predictors for LTBI. Kaplan-Meier survival analysis demonstrated patients with indeterminate QFT-GIT results had significantly higher 1-year all-cause mortality than those with LTBI (p<0.001) and non-LTBI (p=0.003). In multivariate analysis, independent predictors for 1-year all-cause mortality included BMI<18.5 (HR 2.09, 95% CI 1.06-4.14, p=0.033), advanced stage of lung cancer (RR 7.76, 95% CI 1.90-31.78, p=0.004), and indeterminate QFT-GIT results (RR 2.40, 95% CI 1.27-4.54, p=0.007). CONCLUSIONS More than one-quarter of newly diagnosed lung cancer patients in Taiwan have LTBI. The independent predictors for LTBI include COPD, fibrocalcified lesions on chest radiogram, and main tumor located in typical TB areas. The survival rate is comparable between LTBI and non-LTBI cases. However, indeterminate QFT-GIT result was an independent predictor for all-cause mortality in lung cancer patients.

Is 1-year follow-up adequate for adult tuberculosis contacts?

To eliminate tuberculosis (TB) on a global scale, the identification and neutralisation of latently infected high-risk individuals is of paramount importance [1]. Active TB contacts are well documented with an increased risk for both latent TB infection (LTBI) and the development of active TB disease [2]. Contact investigation is an important and effective active case-finding strategy, but also requires abundant public health resources [3]. Risk of active TB after the first year should not be ignored: extended follow-up in adult TB contacts is needed http://ow.ly/I9t28