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Background Although the incidence of tuberculosis is higher in men than in women, the relationship of sex with tuberculosis treatment outcomes has not been adequately studied. Methods We performed a retrospective cohort study and a systematic review and meta-analysis of observational studies during the last 10 years to assess sex differences in clinical and microbiological outcomes in tuberculosis. Results In our cohort of 2894 Taiwanese patients with drug-susceptible pulmonary tuberculosis (1975 male and 919 female), male patients had higher adjusted hazards of 9-month mortality due to all causes (hazard ratio, 1.43 [95% confidence interval (CI), 1.03–1.98]) and infections (1.70 [1.09–2.64]) and higher adjusted odds of 2-month sputum culture positivity (odds ratio [OR], 1.56 [95% CI, 1.05–2.33]) compared with female patients. Smear positivity at 2 months did not differ significantly (OR, 1.27 [95% CI, .71–2.27]) between the sexes. Among 7896 articles retrieved, 398 were included in our systematic review describing a total of 3 957 216 patients. The odds of all-cause mortality were higher in men than in women in the pooled unadjusted (OR, 1.26 [95% CI, 1.19–1.34]) and adjusted (1.31 [1.18–1.45]) analyses. Men had higher pooled odds of sputum culture (OR, 1.44 [95% CI, 1.14–1.81]) and sputum smear (1.58 [1.41–1.77]) positivity, both at the end of the intensive phase and on completion of treatment. Conclusions Our retrospective cohort showed that male patients with tuberculosis have higher 9-month all-cause and infection-related mortality, with higher 2-month sputum culture positivity after adjustment for confounding factors. In our meta-analysis, male patients showed higher all-cause and tuberculosis-related mortality and higher sputum culture and smear positivity rates during and after tuberculosis treatment.

Early recognition of adult-onset immunodeficiency associated with neutralizing anti-interferon gamma autoantibodies (anti-IFNγ Abs) remains difficult, and misdiagnoses have been reported. Although febrile lymphadenopathy is among the most common initial manifestations of this disorder, no comprehensive clinicopathologic analysis of lymphadenopathy in patients with anti-IFNγ Abs has been reported. Here, we describe 26 lymph node biopsy specimens from 16 patients. All patients exhibited concurrent disseminated nontuberculous mycobacterial infections, and 31% received a tentative diagnosis of lymphoma at initial presentation. We found 3 distinct histomorphologic patterns: well-formed granuloma (46%), suppurative inflammation or loose histiocytic aggregates (31%), and lymphoproliferative disorder (LPD, 23%). The latter shared some of the features of malignant T-cell lymphoma, IgG4-related disease, and multicentric Castleman disease. Half of the specimens with LPD had monoclonal T cells, and 33.3% were indistinguishable from angioimmunoblastic T-cell lymphoma as per current diagnostic criteria. All lymphadenopathy with LPD features regressed with antibiotics without administration of cytotoxic chemotherapy or immunotherapy. The median follow-up time was 4.3 years. Our study highlights the substantial challenge of distinguishing between lymphoma and other benign lymphadenopathy in the setting of neutralizing anti-IFNγ Abs. Increased vigilance and multidisciplinary discussion among clinicians and pathologists are required to achieve the most appropriate diagnosis and management.

Background Poor control of diabetes mellitus (DM) increases active tuberculosis (TB) risk. Understanding risk factors for latent TB infection (LTBI) in this population and intervention completion rates is crucial for policy making. Methods Under a collaborative multidisciplinary team consisting of public health professionals, endocrinologists, and pulmonologists, patients aged >45 years with poorly controlled DM (pDM), defined as having a glycated hemoglobin level of ≥9% within the preceding year, were enrolled by endocrinologists from 2 hospitals; these patients underwent LTBI screening by using QuantiFERON (QFT). Once-weekly isoniazid and rifapentine for 12 weeks (3HP) or daily isoniazid for 9 months (9H) was administered by pulmonologists. QFT-positivity predictors were evaluated using logistic regression. Completion rates and safety were also investigated. Results Among 980 patients with pDM (age: 64.2 ± 9.7 years), 261 (26.6%) were QFT-positive. Age, DM duration, chronic kidney disease stage ≥3, and dipeptidyl peptidase-4 inhibitor use, not using metformin, were associated with QFT-positivity. Preventive therapy (3HP: 138; 9H: 62) was administered in 200 (76.6%) QFT-positive patients. The completion rates of 3HP and 9H were 84.1% and 79.0%, respectively (P = .494). Nine (6.5%) and zero patients in the 3HP and 9H groups, respectively, developed systemic drug reactions (P = .059); 78.3% and 45.2% had ≥1 adverse drug reactions (P, The latent tuberculosis infection prevalence exceeds 25% in elderly patients with poorly controlled diabetes mellitus (DM), particularly those with a long DM duration. The completion rate of preventive therapy, regardless of the regimen, approaches 80% in this population under a collaborative framework.

A significantly negative reversion in the QuantiFERON-TB Gold In-tube (QFT-GIT) test is reported in patients on dialysis, which makes the results unreliable. The CD4 and CD8 responses of the QFT-Gold plus (QFT-Plus) may have better positive consistency, but this needs to be investigated. We enrolled dialysis patients with baseline positive QFT-GIT0 results and conducted two rounds of follow-up paired QFT-GIT1&2 and QFT-Plus1&2 tests at an interval of 6 months. The positive consistency, concordance, and discordance of the QFT results were analyzed. A total of 236 patients on dialysis were screened, and 73 participants with positive QFT-GIT0 results were enrolled. The baseline QFT-GIT0 response was higher in the 1st QFT-Plus1(+) group than in the QFT-Plus1(−) group, but insignificantly different between the 1st QFT-GIT1(+) and QFT-GIT1(−) groups. The two assays had good correlation when concurrently tested. Fifty-three subjects completed a second round of the QFT-GIT2 and QFT-Plus2. Persistent positivity was higher with the QFT-Plus2 (81.8%) than with the QFT-GIT2 (58.8%, p = 0.040). The QFT-GIT1 and QFT-Plus1 CD4 responses were higher in patients with persistent positivity than in those with negative reversion, whereas the difference of the QFT-Plus TB1 and TB2 data, representative of the CD8 response, were similar between positive persistence and negative reversion. In conclusion, the QFT-Plus provides more reliable positive consistency than does the QFT-GIT. The CD4 interferon-γ response might play a role in maintaining positivity of LTBI.

Background Weekly rifapentine and isoniazid (3HP) is gaining popularity for latent tuberculosis infection treatment because of its short course and high completion rate. Prior to widespread use, comprehensive 3HP treatment assessment covering an all-age population is essential. Methods Participants receiving ≥1 3HP dose from September 2014 to December 2019 were stratified into elderly (≥65 years), middle-aged (>35 & Results Overall, 134 of 579 (23.1%) participants were elderly. The completion rate was 83.1% overall and was highest and lowest in the younger group (94.5%) and elderly (73.9%) group, respectively. However, the 3HP discontinuation rate was not significantly different among the 3 groups in multivariate logistic regression analysis. In total, 362 (62.5%) participants experienced 1 or more adverse drug reactions (ADRs), of which 38 (10.5%) and 98 (27.1%) required temporary and permanent treatment interruption, respectively. The SDR risk was 11.2% in overall and 17.1% in the middle-aged group, 3.04-fold higher than that in the elderly group (P = .025). This finding was consistently observed in different clinical settings. Hypertensive events accompanied with flu-like symptoms occurred in 11.2% of elderly participants, and accounted for 50% of grade ≥3 ADRs. Conclusions With proper medical support and programmatic follow-up, the 3HP completion rate is >70% even in elderly participants. In middle-aged and elderly individuals, 3HP should be employed with caution because of risk of SDRs and hypertensive events, respectively. Summary: Under programmatic medical support, widespread use of weekly rifapentine and isoniazid (3HP) for latent tuberculosis treatment is possible for its high completion rate. 3HP should be employed with caution for risk of systemic drug reactions and hypertensive events in middle-aged and elderly individuals, respectively.

Background Hypertension induces systemic inflammation, but its impact on the outcome of infectious diseases like tuberculosis (TB) is unknown. Calcium channel blockers (CCB) improve TB treatment outcomes in preclinical models, but their effect in patients with TB remain unclear. Methods This retrospective cohort study, including all patients > 18 years receiving treatment for culture-confirmed, drug-sensitive TB from 2000 to 2016 at the National Taiwan University Hospital, assessed the association of hypertension and CCB use with all-cause and infection-related mortality during the first 9 months of TB treatment, as well as sputum smear microscopy and sputum culture positivity at 2 and 6 months. Results Of the 2894 patients, 1052 (36.4%) had hypertension. A multivariable analysis revealed that hypertension was associated with increased mortality due to all causes (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.23–1.99) and infections (HR, 1.87; 95% CI, 1.34–2.6), but there were no statistical differences in microbiological outcomes when stratified based on hypertensive group. Dihydropyridine-CCB (DHP-CCB) use was associated only with reduced all-cause mortality (HR, 0.67; 95% CI, .45–.98) by univariable Cox regression. There were no associations between DHP-CCB use and infection-related mortality (HR, 0.78; 95% CI, .46–1.34) or microbiological outcomes in univariable or multivariable regression analyses. Conclusions Patients with hypertension have increased all-cause mortality and infection-related mortality during the 9 months following TB treatment initiation. DHP-CCB use may lower all-cause mortality in TB patients with hypertension. The presence of hypertension or the use of CCB did not result in a significant change in microbiological outcomes.

Background The risk of tuberculosis (TB) in patients with impaired kidney function remains unclear by different stages of renal function impairment. Methods We retrospectively recruited all patients with kidney function in a tertiary-care referral center from January 2008 to December 2013 and followed them till December 2016. We defined the primary outcome as active TB development and analyzed the impact of kidney function impairment. Results During the study period, a total of 289,579 patients were enrolled for analysis, and of them, 1012 patients had active TB events in an average of 4.13 years of follow-up. According to kidney function impairment, the incidence rate of TB was similar in patients with no chronic kidney disease (CKD) or stage 1 and stage 2, and it increased apparently at stage 3a (167.68 per 100,000 person-years) to stage 3b, stage 4 and stage 5 (229.25, 304.95 and 349.29 per 100,000 person-years, respectively). In a Cox proportional hazard regression model, the dose response of TB risk among different stages of kidney function impairment increased significantly from CKD stage 3a to stage 5. Patients with long-term dialysis had a hazard ratio of 2.041 (1.092–3.815, p = 0.0254), which is similar to that of stage 4 CKD but lower than that of stage 5. Conclusion In patients with impaired kidney function, the risk of TB increases from CKD stage 3, and in stage 5, the risk is even higher than that of those receiving dialysis. Further strategies of TB control need to consider this high-risk group.

The role of ventilation in preventing tuberculosis (TB) transmission has been widely proposed in infection control guidance. However, conclusive evidence is lacking. Modeling suggested the threshold of ventilation rate to reduce effective reproductive ratio (ratio between new secondary infectious cases and source cases) of TB to below 1 is corresponding to a carbon dioxide (CO2) level of 1000 parts per million (ppm). Here, we measured the effect of improving ventilation rate on a TB outbreak involving 27 TB cases and 1665 contacts in underventilated university buildings. Ventilation engineering decreased the maximum CO2 levels from 3204 ± 50 ppm to 591‐603 ppm. Thereafter, the secondary attack rate of new contacts in university dropped to zero (mean follow‐up duration: 5.9 years). Exposure to source TB cases under CO2 >1000 ppm indoor environment was a significant risk factor for contacts to become new infectious TB cases (P

Background: Anti-tuberculous (TB) medications are common causes of drug-induced liver injury (DILI). Limited data are available on systemic inflammatory mediators as biomarkers for predicting DILI before treatment. We aimed to select predictive markers among potential candidates and to formulate a predictive model of DILI for TB patients. Methods: Adult active TB patients from a prospective cohort were enrolled, and all participants received standard anti-tuberculous treatment. Development of DILI, defined as ≥5× ULN for alanine transaminase or ≥2.6× ULN of total bilirubin with causality assessment (RUCAM, Roussel Uclaf causality assessment method), was regularly monitored. Pre-treatment plasma was assayed for 15 candidates, and a set of risk prediction scores was established using Cox regression and receiver-operating characteristic analyses. Results: A total of 19 (7.9%) in 240 patients developed DILI (including six carriers of hepatitis B virus) following anti-TB treatment. Interleukin (IL)-22 binding protein (BP), interferon gamma-induced protein 1 (IP-10), soluble CD163 (sCD163), IL-6, and CD206 were significant univariable factors associated with DILI development, and the former three were backward selected as multivariable factors, with adjusted hazards of 0.20 (0.07–0.58), 3.71 (1.35–10.21), and 3.28 (1.07–10.06), respectively. A score set composed of IL-22BP, IP-10, and sCD163 had an improved area under the curve of 0.744 (p &lt, 0.001). Conclusions: Pre-treatment IL-22BP was a protective biomarker against DILI development under anti-TB treatment, and a score set by additional risk factors of IP-10 and sCD163 employed an adequate DILI prediction.

Background: Lipids play a central role in the pathogenesis of tuberculosis (TB). The effect of serum lipid levels on TB treatment (ATT) outcomes and their association with serum inflammatory markers have not yet been characterized.Methods: Our retrospective cohort study on drug-susceptible TB patients, at the National Taiwan University Hospital, assessed the association of baseline serum lipid levels such as low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC) and triglycerides (TG) with all-cause and infection-related mortality during first 9 months of ATT and baseline inflammatory markers namely C-reactive protein (CRP), total leukocyte count (WBC), and neutrophil-lymphocyte ratio (NL ratio).Results: Among 514 patients, 129 (26.6%) died due to any-cause and 72 (14.0%) died of infection. Multivariable Cox-regression showed a lower adjusted hazard ratio (aHR) of all-cause mortality in the 3rd tertiles of HDL (aHR 0.17, 95% CI 0.07–0.44) and TC (aHR 0.30, 95% CI 0.14-0.65), and lower infection-related mortality in the 3rd tertile of HDL (aHR 0.30, 95% CI 0.14–0.65) and TC (aHR 0.30, 95% CI 0.14–0.65) compared to the 1st tertile. The 3rd tertiles of LDL and TG showed no association in multivariable analysis. Similarly, 3rd tertiles of HDL and TC had lower levels of baseline inflammatory markers such as CRP, WBC, and NL ratio using linear regression analysis. Body mass index (BMI) did not show evidence of confounding or effect modification.Conclusions: Higher baseline serum cholesterol levels were associated with lower hazards of all-cause and infection-related mortality and lower levels of inflammatory markers in TB patients. BMI did not modify or confound this association.

Background _The mitogen response in interferon-γ(IFN-γ) release assays(IGRAs) measures IFN-γ after binding to CD2, a surface adhesion marker found on T-cells and NK cells. A lower mitogen response implies either peripheral blood mononuclear cells have fewer adhesion molecules either in absolute numbers or per T-cells, or the pathway from adhesion molecules to IFN-γ production is not functioning well. To date, it remains poorly understood whether the mitogen response is associated with outcomes in tuberculosis patients. Methods _From 2012 to 2017, patients with culture-confirmed tuberculosis were tested for QuantiFERON-TB Gold In-Tube(QFT-GIT). The associations between patient outcomes and QFT-GIT as well as IFN-γ responses to the mitogen were investigated. Outcomes of interest included 1-year mortality after tuberculosis diagnosis and 2-month culture conversion. Results _In total, 466 culture-confirmed tuberculosis patients were enrolled and QFT-GIT was positive in 309(66%). Within 1 year of diagnosis, 20(4%) died and notably, 15(11%) out of 137 patients with a lower mitogen response did so. The multivariate Cox model showed that a lower mitogen response (hazard ratio, 8.789; 95% confidence interval, 3.074–25.129) was independently associated with 1-year mortality. Moreover, among 160 patients with smear-positive culture-confirmed pulmonary tuberculosis, multivariate logistic analysis indicated that a lower mitogen response (odds ratio, 3.966; 95% confidence interval, 1.182–13.303) was significantly associated with 2-month culture persistence. Conclusions _This study found that a lower mitogen response was associated with worse 1-year survival in tuberculosis patients and correlated with 2-month culture persistence in patients with sputum smear-positive culture-confirmed tuberculosis. These findings suggest another application of QFT-GIT for prognostication of tuberculosis patients.

The effects of cardiopulmonary resuscitation (CPR) on patients with advanced cancer remain to be elucidated. We identified a cohort of patients with stage-IV cancer who received in-hospital CPR from the Taiwan Cancer Registry and National Health Insurance claims database, along with a matched cohort without cancer who also received in-hospital CPR. The main outcomes were post-discharge survival and in-hospital mortality. In total, 3,446 stage-IV cancer patients who underwent in-hospital CPR after cancer diagnosis were identified during January 2009–June 2014. A vast majority of the patients did not survive to discharge (n = 2,854, 82.8%). The median post-discharge survival was 22 days; 10.1% (n = 60; 1.7% of all patients) of the hospital survivors received anticancer therapy after discharge. We created 1:1 age–, sex–, Charlson comorbidity index (CCI)–, and year of CPR–matched noncancer and stage-IV cancer cohorts (n = 3,425 in both; in-hospital mortality rate = 82.1% and 82.8%, respectively). Regression analysis showed that the stage-IV cancer cohort had shorter post-discharge survival than did the noncancer cohort. The outcome of patients with advanced cancer was poor. Even among the survivors, post-discharge survival was short, with only few patients receiving further anticancer therapy.

Objectives: To estimate the incidence of diabetes, acute myocardial infarction (AMI), and stroke; and to determine factors associated with diabetes, AMI, and stroke incidence among patients previously treated for tuberculosis (TB) disease. Methods: A retrospective cohort study was conducted among non-pediatric TB patients registered in the Taiwan National Health Insurance Research Database (NHIRD) from 2002–2013. Diabetes, AMI, and stroke incidence were defined by International Classification of Diseases (ICD)-9 codes, drug prescriptions, and records of patient’s clinic visits. Cox proportional hazard models were used to estimate the hazard rate ratio (HR) of incident diabetes, AMI, and stroke. Results: From 2002–2013, there were 157,444 patients treated for TB registered in NHIRD. Among 129,453 patients with no prior history of diabetes, the age-adjusted incidence rate (IR) of diabetes was 3.85 (95%CI 3.70–4.01) per 1000 person-years. Among 143,646 patients with no prior history of AMI, the age-adjusted IR of AMI as 3.26 (95%CI 3.13–3.40). Among 118,774 patients with no prior history of stroke, the age-adjusted IR of stroke was 16.08 (95%CI 15.76–16.32). Conclusions: Chronic non-communicable disease risk factors like dyslipidemia, hypertension, and chronic kidney disease diagnosed before time of TB diagnosis were predictive of diabetes, AMI, and stroke incidence. Keywords: Tuberculosis, Diabetes, Myocardial infarction, Stroke, Incidence

Animal studies have demonstrated that metformin exerts a renoprotective effect. Human studies of patients with diabetes mellitus (DM) regarding the association of metformin use with end-stage renal disease (ESRD) are lacking. Patients with type 2 DM and without a history of kidney disease who were enrolled under the pay-for-performance program of the National Health Insurance in Taiwan were identified. Those who received ≥90 cumulative defined daily doses of metformin within 1 year were selected (metformin users) and compared with a 1:1 propensity score-matched metformin nonuser cohort. Primary and secondary outcomes were development of ESRD and chronic kidney disease (CKD), respectively. Independent predictors were investigated using Cox regression analysis. A total of 24 158 pairs of metformin users and nonusers were enrolled, with an incidence of ESRD of 1908 and 1723 and CKD of 1095 and 1056 cases per 100 000 person-years, respectively. Metformin use was independently associated with increased risks of ESRD (adjusted hazard ratio, 1.22; 95% confidence interval, 1.12-1.32) and CKD (adjusted hazard ratio, 1.25; 95% confidence interval, 1.12-1.40) in a dose-response relationship. Patients with hypertension plus nonuse of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers potentiated kidney damage by metformin. In patients with DM, use of metformin may increase the risk of ESRD and CKD. Health care professionals should be alert and closely monitor renal function when prescribing metformin.

Aggressive therapy for Mycobacterium kansasii-pulmonary disease (MK-PD) is recommended because of the virulence of MK. However, some clinicians may be concerned regarding the lengthy course and numerous adverse effects. This study evaluated the natural course of MK-PD and investigated its prognostic factors.Radiographic outcome, prognostic factors, and mortality within 1 year for MK-PD were obtained from patients in 6 hospitals in Taiwan from 2010 to 2014 (derivation cohort) and validated using patients in 2015 and 2016 (validation cohort).Of the 109 patients with MK-PD in the derivation cohort, radiographic progression occurred in 70 (64%), with a 1-year mortality rate of 43% and median survival of 71 days, whereas none of the 39 cases without radiographic progression died. All patients with acid-fast smear (AFS) grade ≥ 3 experienced radiographic progression. For the others, the independent risk factors of radiographic progression were fibroCavitary pattern, Leucocyte count9000/μL, Old age (age65 years), pUre MK in sputum (no other mycobacteria), and no Diabetes mellitus (the CLOUD factors). By applying these criteria to the validation cohort (n = 112), 3 (9%) of the 33 patients with MK-PD who initially had AFS grade 3 and 3 CLOUD risk factors experienced radiographic progression, and none of the 3 died of MK-PD.Because of the high risk of radiographic progression and subsequent fatal outcome, immediate anti-MK treatment is recommended. For patients with MK-PD who have sputum AFS grade3 and 3 CLOUD risk factors, regular follow-up may be an alternative.

Objective: Tuberculosis (TB) and atherosclerotic cardiovascular disease (ASCVD) have a close epidemiological and pathogenetic overlap. Thus, it becomes essential to understand the relationship between ASCVD and TB outcomes.Methods:From our retrospective cohort on drug-susceptible TB patients at the National Taiwan University Hospital, we assessed the association of pre-existing ASCVD (coronary artery disease (CAD) and atherothrombotic stroke (ATS)) with 9-month all-cause and infection-related mortality and the extent of mediation by systemic inflammatory markers. We determined the effect of pre-existing ASCVD on 2-month sputum microbiological status. Among ASCVD patients, we assessed the association of statin use on mortality.Results:Nine-month all-cause mortality was higher in CAD patients with prior acute myocardial infarction (CAD+AMI+) (adjusted HR 2.01, 95%CI 1.38-3.00) and ATS patients (aHR 2.79, 95%CI 1.92-4.07) and similarly, for infection-related mortality was higher in CAD+AMI+ (aHR 1.95, 95%CI 1.17-3.24) and ATS (aHR 2.04, 95%CI 1.19-3.46) after adjusting for confounding factors. Pre-existing CAD (AMI- or AMI+) or ATS did not change sputum culture conversion or sputum smear AFB positivity at 2 months. The CAD+AMI+ group had significantly higher levels of CRP at TB diagnosis in the multivariable linear regression analysis (Adjusted B(SE) 1.24(0.62)). CRP mediated 66% (p=0.048) and 25% (p=0.033) of the association all-cause mortality with CAD+AMI- and CAD+AMI+, respectively. ConclusionsIn summary, patients with ASCVD have higher hazards of 9-month all-cause and infection-related mortality, with elevated serum inflammation mediating one to three-quarters of this association when adjusted for confounders. Statin use was associated with lower all-cause mortality among patients with ASCVD.

RationaleAlthough the incidence of tuberculosis (TB) is higher in males compared to females, the relationship of sex with TB treatment outcomes has not been adequately studied.Objectives and MethodsWe performed a retrospective cohort study and a systematic review and meta-analysis of observational studies during the last 10 years to assess the sex differences in clinical and microbiological outcomes in tuberculosis.Measurements and Main ResultsIn our cohort of 2,894 patients with drug-susceptible pulmonary TB (1,975 males and 919 females), males had higher adjusted hazards of mortality due to all causes (HR 1·43,95%CI 1.03-1.98) and infections (HR 1.70, 95%CI 1.09-2.64) at 9 months and higher adjusted odds ratio for sputum culture (OR 1.56,95%CI 1.05-2.33) and similar odds ratio for smear positivity (OR 1.27, 0.71-2.27) at 2 months compared to females. Among 7896 articles retrieved, 398 articles were included in our systematic review with a total of 3,957,216 patients. The odds of all-cause mortality was higher in males compared to females in the pooled unadjusted (OR 1.26, 95%CI 1.19-1.34) and adjusted (OR 1.31, 95%CI 1.18-1.45) analyses. Relative to females, males had higher pooled odds of sputum culture (OR 1.44,95% CI 1.14-1.81) and sputum smear (OR 1.58,95%CI 1.41-1.77) positivity at the end of the intensive phase, and upon completion of treatment.ConclusionsDuring TB treatment, males have higher all-cause-, infection- and TB-related mortality, as well as higher rates of sputum smear and culture positivity, both after the intensive phase and at the completion of TB treatment, after adjusting for confounding factors.

Background: Through activation of adrenergic receptors, chronic stress can trigger the secretion of neurotransmitters and hormones that enhance tumor growth, increase angiogenesis, and promote drug resistance. This study aimed to evaluate the effect of β-blockers in patients receiving first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for lung adenocarcinoma. Methods: This retrospective cohort study enrolled patients with advanced lung adenocarcinoma under first-line EGFR-TKIs between 2011 and 2014 in the National Health Insurance Research Database of Taiwan. The effects of β-blockers use, defined as ≥60 defined daily doses within 180 days before initiation of EGFR-TKI therapy, on the 2-year time-to-discontinuation (TTD) of EGFR-TKIs and 4-year overall survival (OS) were investigated using Cox regression analyses with inverse propensity score weighting and sensitivity analysis in subgroup without hypertension and ischemic heart diseases. Results: Among 4988 enrolled patients, 552 (11.1%) were in the β-blocker group. Patients in the β-blocker group were more likely to be older than 75 and had diabetes mellitus and cardiovascular comorbidities. In Cox regression analysis, β-blocker usage was associated with a longer TTD (hazard ratio, HR: 0.91 [0.86–0.96]) and OS (HR: 0.68 [0.64–0.72]). The results also favored β-blocker group in sensitivity analysis. Conclusions: In treatment-naive patients with advanced lung adenocarcinoma under first-line EGFR-TKIs, prior use of β-blocker was associated with a better outcome. The findings encourage further prospective clinical study to validate the possibility of β-blockers as adjuvant anticancer therapy.

BackgroundSurvival after post-transplant recurrence of HCC is dismal, and almost all treatments for recurrent HCC are off-labeled, without an extensive large-scale analysis. We aimed to delineate their post-recurrence courses and define benchmarks for comparing future treatment effectiveness.MethodsThree national databases, including health insurance, catastrophic illness, and the cause of death, were linked for cohort establishment and data collection during the period from 2005 to 2016. Patients with HCC recurrence ≥6 months after transplant surgery and under treatment were recruited for survival analysis. Selection of treatment strategies for HCC recurrence after liver transplant was based on the same criteria for those without liver transplant.ResultsOf 2,123 liver transplant recipients, 349 developed HCC recurrence ≥6 months after liver transplant, and the median recurrence time was 17.8 months post-transplant. Within 2 years of treatment, 61% patients showed recurrence (early recurrence group), and survival in these patients was poorer than in the late recurrence group. According to a multivariable analysis, the transplant era before 2008 and radiofrequency ablation were associated with good prognosis, whereas receiving sorafenib and radiotherapy was associated with poor prognosis. The effect of transplant era became insignificant after stratification by recently receiving pretransplant transarterial chemoembolization.ConclusionTiming of recurrence and interventions used were associated with the outcomes of patients with post-transplant HCC recurrence. These data provide the benchmark and indicate the critical period and high-risk factors for further therapeutic trial consideration.

BackgroundHypertension induces systemic inflammation, but its impact on the outcome of infectious diseases like tuberculosis (TB) is unknown. Calcium channel blockers (CCB) improve TB treatment outcomes in pre-clinical models, but their effect in patients with TB remain unclear.MethodsThis retrospective cohort study, including all patients > 18 years receiving treatment for culture-confirmed, drug-sensitive TB from 2000 to 2016 at the National Taiwan University Hospital, assessed the association of hypertension and CCB use with all-cause and infection-related mortality during the first 9 months of TB treatment, as well as sputum-smear microscopy and sputum-culture positivity at 2 and 6 months.Results1052 of the 2894 patients (36.4%) had hypertension. Multivariable analysis revealed that hypertension was associated with increased mortality due to all causes (HR 1.57, 95% confidence interval[CI], 1.23-1.99) and infections (HR 1.87, 95%CI, 1.34-2.6), but there was no statistical difference in microbiological outcomes when stratified based on hypertensive group. Dihydropyridine-CCB (DHP-CCB) use was associated with reduced all-cause mortality (HR 0.67, 95%CI: 0.45-0.98) only by univariate Cox regression. There was no association between DHP-CCB use and infection-related mortality (HR 0.78, 95%CI: 0.46-1.34) or microbiological outcomes in univariate or multivariate regression analyses.ConclusionsPatients with hypertension have increased all-cause mortality and infection-related mortality during the 9 months following TB treatment initiation. DHP-CCB use may lower all-cause mortality in TB patients with hypertension. The presence of hypertension or the use of CCB did not result in a significant change in microbiological outcomes.

Background Undiagnosed tuberculosis (TB) patients hospitalized because of comorbidities constitute a challenge to TB control in hospitals. We aimed to assess the impact of introducing highly sensitive fluorescent microscopy for examining sputum smear to replace conventional microscopy under a high TB risk setting. Methods We measured the impact of switch to fluorescent microscopy on the smear detection rate of culture-confirmed pulmonary TB, timing of respiratory isolation, and total non-isolated infectious person-days in hospital at a high-caseload medical center (approximately 400 TB cases annually) in Taipei. Multivariable Cox regression was applied to adjust for effects of covariates. The effect attributable to the improved smear detection rate was determined using causal mediation analysis. Results After switch to fluorescence microscopy, median non-isolated infectious duration decreased from 12.5 days to 3 days (P

Background The outcome of lung nodule(s) with histopathological findings suggestive of tuberculosis (TB) but lack of microbiologic confirmation remains unclear. Whether these patients require anti-TB treatment remains unknown. The aim of the study was to compare the risk of active TB within 4 years in untreated patients with histological findings but no microbiological evidences suggestive of TB. Methods From January 2008 to June 2013, patients with either solitary or multiple lung nodules having histological findings but no microbiological evidences suggestive of TB were identified from a medical center in Taiwan and were followed for 4 years unless they died or developed active TB. Results A total of 107 patients were identified. Among them, 54 (51%) were clinical asymptomatic. Biopsy histology showed granulomatous inflammation in 106 (99%), and caseous necrosis was present in 55 (51%) cases. Forty (37%) patients received anti-TB treatment, and 21 (53%) of them had adverse events, including 13 initially asymptomatic patients. Anti-TB treatment was favored in patients with caseous necrosis, whereas observation was preferred in subjects whose nodules were surgically removed. Only 1 case in the untreated group developed culture-confirmed active pulmonary TB during 4-year follow-up (1 case per 251.2 patient-years). None of the 16 cases having co-existing histologic finding of malignancy became incident TB case within a follow-up of 56.7 patient-years. Conclusions In patients having lung nodules with only histologic features suggestive of TB, the incidence rate of developing active TB was low. Risk of adverse events and benefit from immediate treatment should be carefully considered.

Treatment of latent tuberculosis (TB) infection (LTBI) effectively prevents its progression to active TB. However, long treatment duration and drug-related hepatotoxicity limit the effectiveness of the 9-month daily isoniazid (9H). Data on the 3-month weekly rifapentine plus isoniazid (3 HP) in Asian populations are currently unavailable. We prospectively randomised the LTBI contacts aged ≥12 years with positive tuberculin skin test into 9H and 3 HP groups in four hospitals between January 2014 and May 2016 in Taiwan. The primary and secondary outcomes were treatment completion rate and adverse drug reactions (ADRs), respectively. Overall, 263 participants with LTBI were randomised into the 3 HP (n = 132) and 9H groups (n = 131); 14 (10.6%) and 29 (22.1%) participants in the 3 HP and 9H groups, respectively, discontinued therapy (p = 0.011). Discontinuation rates owing to ADRs were 9.1% (3 HP) and 5.3% (9H) (p = 0.241). Clinically relevant hepatotoxicity was more common in the 9H than in the 3 HP group (5.3% vs. 1.5%; p = 0.103), whereas systemic drug reaction was more common in the 3 HP than in the 9H group (3.8% vs. 0%; p = 0.060). Women had a significantly higher rate of Grade II fever than men (13.7% vs. 1.2%; p = 0.003). Compared with the 9H regimen, the 3 HP regimen had a higher completion rate with lower hepatotoxicity and well-tolerated ADR. Clinical trials registration number NCT02208427.

Background Mycobacterium avium complex (MAC)-lung disease (LD) is increasing in patients without human immunodeficiency virus infection. However, data on host vulnerability to MAC-related immune responses, and in particular the interleukin (IL)-23/IL-17 axis, are lacking. Methods We enrolled 50 patients with MAC-LD, 25 age-matched patients with tuberculosis (TB) and 25 controls. We measured levels of plasma cytokines, and studied IL-12/IL-17 responses in macrophage and lymphocyte activation to MAC. Results The plasma level of IL-17 in the MAC group was higher than in the TB and control groups. In in-vitro macrophage stimulation, the expression of IL-23 in macrophages was similar in the patients with MAC-LD and controls, although the expression of IL-12 p40 was lower in the patients with MAC-LD. In assays of lymphocyte activation, IL-17 was induced by MAC-primed macrophages, but its level was lower in the patients with MAC-LD and TB than in the controls. The expression of programmed death (PD)-1 receptor was higher in CD4+IL17A+ lymphocytes in the patients with MAC-LD, and the production of IL-17 was significantly increased by blockade of PD-1 and PD-ligand 1. Conclusions MAC induced a similar expression of IL-23 from macrophages in the patients with MAC-LD compared to the controls, but a lower expression of IL-17 from lymphocytes, which may be through an increased expression of PD-1. The macrophage response of IL-12 p40 was stronger than that of IL-12 p70, and higher in the controls during MAC disease, which may suggest another kind of MAC-related immune evasion.

Tuberculosis (TB) remains a devastating disease, yet despite its enormous toll on global health, tools to control TB are insufficient and often outdated. TB Biomarkers (TB-BM) would constitute extremely useful tools to measure infection status and predict outcome of infection, vaccination or therapy. There are several types of TB-BM: Correlate of Infection; Correlate of TB Disease; Correlate of Increased Risk of Developing Active TB Disease; Correlate of the Curative Response to Therapy; and Correlate of Protection (CoP). Most TB-BM currently studied are host-derived BM, and consist of transcriptomic, proteomic, metabolomic, cellular markers or marker combinations ('signatures'). In particular, vaccine-inducible CoP are expected to be transformative in developing new TB vaccines as they will de-risk vaccine research and development (R&D) as well as human testing at an early stage. In addition, CoP could also help minimizing the need for preclinical studies in experimental animals. Of key importance is that TB-BM are tested and validated in different well-characterized human TB cohorts, preferably with complementary profiles and geographically diverse populations: genetic and environmental factors such as (viral) coinfections, exposure to non-tuberculous mycobacteria, nutritional status, metabolic status, age (infants vs children vs adolescents vs adults) and other factors impact host immune set points and host responses across different populations. In this study, we review the most recent advances in research into TB-BM for the diagnosis of active TB, risk of TB development and treatment-induced TB cure.

Objective Anti-interferon- γ (IFN-γ) autoantibodies (anti-IFN-γ Abs) have been increasingly recognized as an important cause of disseminated nontuberculous mycobacterial (DNTM) infection, and identification of this immunodeficiency impacts clinical management. However, the protean disease manifestations and inaccessibility to diagnostic tests in clinical settings hamper its early diagnosis. Here, we sought to determine whether QuantiFERON-TB Gold In-tube (QFT-GIT), a commercialized IFN-γ release assay, could be used to screen for neutralizing anti-IFN-γ Abs among previously healthy adults with DNTM infection. Methods Non-HIV patients with DNTM infection were prospectively enrolled for the QFT-GIT assays. We measured their plasma concentration of anti-IFN-γ Abs and their neutralizing capacity through enzyme-linked immunosorbent assay and flow cytometry. We then analysed the correlation between QFT-GIT results and the presence of neutralizing anti-IFN-γ Abs among patients with and without previously recognized immunosuppression, respectively. Results Irrespective of the autoantibody concentration or disease activity, all patients with neutralizing anti-IFN-γ Abs (100%, 30/30) had indeterminate QFT-GIT results because of extremely low or undetectable IFN-γ levels in the mitogen tubes. None of the four DNTM patients who were previously healthy and tested negative of anti-IFN-γ Abs had an indeterminate QFT-GIT result, and their IFN-γ levels in the mitogen tube were significantly higher than those of the patients with anti-IFN-γ Abs (8.28 IU/mL vs. 0.05 IU/mL, p 0.001). Conclusion An indeterminate QFT-GIT result because of undetectable or extremely low IFN-γ level in the mitogen tube suggests the presence of neutralizing anti-IFN-γ Abs in a previously healthy patient with DNTM infection.

Objectives: Aspergillus-specific IgG (Asp-IgG) cut-off level in diagnosing chronic pulmonary aspergillosis (CPA) remains unknown. Methods: We prospectively recruited participants with clinical suspicion of CPA in three centers in Taiwan during 2019 June to 2020 August. Serum Aspergillus fumigatus-specific IgG (Asp-IgG) (Phadia, Uppsala, UPPS, Sweden) was examined. Optimal cut-off level was determined by Youden’s index and validated. Results: A total of 373 participants were recruited. In the derivation cohort (n = 262), Asp-IgG had an area under the receiver-operating-characteristic curve (AUC) of 0.832. The optimal cut-off level was 40.5 mgA/L. While applying this cut-off level to the validation cohort (n = 111), the sensitivity and specificity were 86.7% and 80.2%. Lowering the cut-off level from 40.5 to 27 mgA/L, the sensitivity was steady (30/36, 83.3% to 31/36, 86.1%) while specificity dropped from 81.9% (276/337) to 63.5% (214/337). Restricting CPA diagnosis to only chronic cavitary pulmonary aspergillosis (CCPA) and chronic fibrosing pulmonary aspergillosis (CFPA) yielded a cut-off level of 42.3 mgA/L in the derivation cohort with a sensitivity of 100% and specificity of 84.4% in the validation cohort. Conclusions: Serum Asp-IgG performs well for CPA diagnosis and provides a low false-positive rate when using a higher cut-off level (preferably around 40 mgA/L).

Among treatment modalities for lung cancer, the most promising therapy is the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs). Both erlotinib and gefitinib, the two first‐generation EGFR‐TKIs, exhibit significant clinical responses for patients with lung adenocarcinoma. However, few studies have compared the effects of these two drugs, and results have been inconclusive because of the small sample sizes in these studies. Therefore, this study was conducted to investigate this issue. This retrospective nationwide cohort study enrolled NSCLC patients who received EGFR‐TKIs after previous chemotherapy in Taiwan between 1996 and 2010 from the National Health Insurance Research Database. Clinical response and survival after receiving erlotinib and gefitinib were compared using logistic and Cox regression analyses, respectively. Inverse propensity score weighting and a sensitivity analysis in the EGFR‐TKI responder (clinical improvement by taking EGFR‐TKIs for 90 days), adherent patients (receiving EGFR‐TKI on a daily basis), adenocarcinoma, and adenocarcinoma with second‐line TKIs subgroup were performed for bias adjustment. A total of 7222 patients, including 4592 (63.6%) who received gefitinib, were identified. In the survival analysis, erlotinib was associated with a decline in 1‐year progression‐free survival (PFS) (hazard ratio, HR: 1.15 [1.09–1.21]) and overall survival (OS) (HR: 1.10 [1.03–1.18]). The effects of various TKIs were consistent in the 4939 EGFR‐TKI responders, adherent subgroup, adenocarcinoma subgroup, and adenocarcinoma with second‐line TKIs subgroup. In previously treated EGFT‐TKI‐naive NSCLC patients, those receiving gefitinib exhibited a longer PFS and OS than those receiving erlotinib. Additional large‐scale randomized controlled trials are warranted to confirm this finding.

Background and objective Studies focusing on pulmonary tuberculosis in advanced age (≥80 years) are lacking. This study aimed to explore treatment delay, outcomes and their predictors in this group. Methods Adult (≥20 years) patients with pulmonary tuberculosis were identified from the National Health Insurance Research Database of Taiwan from 2004 to 2009. Treatment completion and mortality rates were noted at one year after treatment. Results Among the 81,081 patients with pulmonary tuberculosis identified, 13,923 (17.2%) were aged ≥80 years, and 26,897 (33.2%) were aged 65–79 years. The treatment completion, mortality rates and treatment delay were 54.8%, 34.7% and 61 (12–128) [median, (1st-3rd quartiles)] days in patients aged ≥80 years, 68.3%, 18.5% and 53 (8–122) days in patients aged 65–79 years, and 78.9%, 6.5% and 21 (1–84) days in patients aged

How host genetic factors affect Mycobacterium tuberculosis (Mtb) infection outcomes remains largely unknown. SP110b, an IFN-induced nuclear protein, is the nearest human homologue to the mouse Ipr1 protein that has been shown to control host innate immunity to Mtb infection. However, the function(s) of SP110b remains unclear.To elucidate the role of SP110b in controlling host immunity and susceptibility to tuberculosis (TB), as well as to identify the fundamental immunological and molecular mechanisms affected by SP110b.Using cell-based approaches and mouse models of Mtb infection, we characterized the function(s) of SP110b/Ipr1. We also performed genetic characterization of patients with TB to investigate the role of SP110 in controlling host susceptibility to TB.SP110b modulates nuclear factor-κB (NF-κB) activity, resulting in downregulation of tumor necrosis factor-α (TNF-α) production and concomitant upregulation of NF-κB-induced antiapoptotic gene expression, thereby suppressing IFN-γ-mediated monocyte and/or macrophage cell death. After Mtb infection, TNF-α is also downregulated in Ipr1-expressing mice that have alleviated cell death, less severe necrotic lung lesions, more efficient Mtb growth control in the lungs, and longer survival. Moreover, genetic studies in patients suggest that SP110 plays a key role in modulating TB susceptibility in concert with NFκB1 and TNFα genes.These results indicate that SP110b plays a crucial role in shaping the inflammatory milieu that supports host protection during infection by fine-tuning NF-κB activity, suggesting that SP110b may serve as a potential target for host-directed therapy aimed at manipulating host immunity against TB.

BackgroundThe protective effect of metformin against active tuberculosis (TB) among TB close contacts is unknown.MethodsTB close contacts with diabetes mellitus (DM) and normal renal function were selected from the National Health Insurance Research Database of Taiwan. Metformin users were patients who received ≥90 cumulative defined daily doses within 1 year before the index date. For each metformin user, a propensity-score matched metformin nonuser and an age- and sex-matched healthy TB close contact were selected. The outcome was incident TB, identified using previously validated diagnostic criteria. Independent predictors were investigated using stratified Cox regression analysis. Interaction analysis was also performed.ResultsA total of 5846 TB close contacts who were metformin users, metformin non-users, and healthy contacts were analysed. The incidence of active TB was 755 (600–938), 1117 (927–1335), and 526 (393–689) cases per 100,000 person-years in each group, respectively. Multivariate analysis revealed that healthy contacts had the lowest risk of developing active TB (adjusted hazard ratio [aHR]: 0.42 [0.30–0.60]) and metformin use partially reversed the risk associated with DM (aHR: 0.73 [0.54–0.98]). Subpopulation analysis revealed a significant interaction between insulin use and metformin use.ConclusionsMetformin use is associated with a lower risk of developing active TB among TB close contacts with DM, especially for insulin users. It may be an alternative choice for primary prevention against active TB if no contraindications exist. However, prospective studies are needed to confirm the findings.

While evidence is accumulating that platelets contribute to tissue destruction in tuberculosis (TB) disease, it is still not known whether antiplatelet agents are beneficial to TB patients. We performed this retrospective cohort study and identified incident TB cases in the Taiwan National Tuberculosis Registry from 2008 to 2014. These cases were further classified into antiplatelet users and non-users according to the use of antiplatelet agents prior to the TB diagnosis, and the cohorts were matched using propensity scores (PSs). The primary outcome was survival after a TB diagnosis. In total, 74,753 incident TB cases were recruited, 9497 (12.7%) were antiplatelet users, and 7764 (10.4%) were aspirin (ASA) users. A 1:1 PS-matched cohort with 8864 antiplatelet agent users and 8864 non-users was created. After PS matching, antiplatelet use remained associated with a longer survival (adjusted hazard ratio (HR): 0.91, 95% confidence interval (CI): 0.88&ndash, 0.95, p &lt, 0.0001). The risk of major bleeding was not elevated in antiplatelet users compared to non-users (p = 0.604). This study shows that use of antiplatelet agents has been associated with improved survival in TB patients. The immunomodulatory and anti-inflammatory effects of antiplatelet agents in TB disease warrant further investigation. Antiplatelets are promising as an adjunct anti-TB therapy.

Background The prevalence and incidence of latent tuberculosis infection (LTBI) in patients with kidney transplantation remain unclear. Methods In this prospective study, we enrolled kidney transplantation candidates (KTCs) and recipients (KTRs) from 2014 to 2018. We defined LTBI as a positive result of QuantiFERON-TB Gold In-tube (QFT). We analyzed the predictors for LTBI acquisition and followed up on QFT assay test for 2 years among those initially without LTBI. Results Of 425 patients enrolled, 305 (71.8%) patients belonged to the KTC group and 120 (28.2%) to the KTR group. The initial QFT showed positive results in 32 (10.5%) and 24 (20.0%) patients in the KTC and KTR groups, respectively (P = .009). The QFT response value in patients with LTBI was higher in the KTR group than in the KTC group (1.85 vs 1.06 IU/mL, P = .046). Multivariate logistic regression showed that old age, absence of bacillus Calmette–Guérin (BCG) scar, presence of donor-specific antibody, and KTR group were independent factors for positive LTBI. For participants with initial negative QFT, positive QFT conversion within a 2-year follow-up was higher after kidney transplantation (20%) than in KTCs (5.5%) (P = .034). Conclusions This study is the first cohort to follow up LTBI status in patients with kidney transplantation and shows its higher prevalence and incidence in KTRs. It indicates that surveillance of LTBI after renal transplantation is important. In addition to status of kidney transplantation, old age, no BCG vaccination, and positive donor-specific antibody are also positive predictors for LTBI., The present study found a higher prevalence and incidence of latent tuberculosis infection (LTBI) in kidney transplantation recipients than in kidney transplantation candidates. This indicates that surveillance and control of LTBI after kidney transplantation are important.

Background/Purpose: Little remains known regarding whether newer FQ with less anti-mycobacterial activity (gemifloxacin) would reduce treatment delay. Methods: We identified one hospital-based cohort (HBC) and one population-based cohort (PBC) including patients receiving amoxicillin/clavulanate acid (Beta-lactam), gemifloxacin (Gemi), and fluoroquinolones other than gemifloxacin (Non-Gemi FQ) prior to TB treatment. Results: A total of 201 patients in the HBC and 3544 patients in the PBC were recruited. After 1:1 propensity score matching, TB treatment delay was statistically insignificant between Beta-lactam, Gemi group, and Non-Gemi FQ group in HBC (Beta-lactam vs Gemi: 22.3 ± 21.4 d vs 28.6 ± 27.9 d, p = 0.292; Beta-lactam vs Non-Gemi FQ: 33.3 ± 26.5 d vs 50.3 ± 47.3 d, p = 0.135) and PBC (Beta-lactam vs Gemi: 26.4 ± 29.1 vs 25.0 ± 28.1, p = 0.638; Beta-lactam vs Non-Gemi FQ: 29.4 ± 36.0 d vs 32.7 ± 35.0 d, p = 0.124, Non-Gemi FQ vs Gemi: 28.4 ± 33.0 d vs 25.0 ± 28.1 d, p = 0.29). Conclusion: While limited by relatively low case number, our study showed that use of gemifloxacin neither results in nor reduces delay in TB treatment. The issue of FQ use on TB treatment delay was also not observed in our study. Early survey and maintaining high clinical alertness remains the key to reducing TB treatment delay. Keywords: Gemifloxacin, Fluoroquinolone, Beta-lactam, Tuberculosis, Treatment delay

Background. The difference of macrophage-specific interleukin-1 beta (IL-1b) response between latent tuberculosis infection (LTBI) and active tuberculosis (TB) remains less studied. Method. We performed this prospective study and recruited active TB patients, contacts with LTBI, and uninfected contacts. The gene and protein expression of human monocyte-derived macrophage (hMDM) after ex vivo stimulation by early secretory antigenic target-6KD (ESAT-6) and tuberculin purified protein derivatives (PPD) was studied by real-time PCR and flow cytometry. The effect of caspase-1 inhibitor was also studied. Result. The IL-1b gene expression after 6 hr ESAT-6 1 μg/ml stimulation was different among active TB patients (n=12), LTBI cases (n=12), and uninfected contacts (n=23) (log fold change: 0.98±1.26 vs. 2.20±0.96 vs. 2.20±0.96, P=0.013). The IL-1b gene expression at 24 hours was higher than that at 6 hours in LTBI cases (n=4) and uninfected contacts (n=6). After 24 hr ESAT-6 1 μg/ml stimulation, the percentage of IL-1b-expressed hMDM was borderline lower in the active TB patients (n=9) than in the LTBI cases (n=10) (14.0±11.2% vs. 31.6±22.5%, P=0.065). Compared with ESAT-6 1 μg/ml stimulation but without the addition of caspase-1 inhibitor (CasI) (55.6±16.3%), the percentage of IL-1b-positive hMDMs decreased after addition of CasI (50 μg/ml CasI: 49.8±18.2%, P=0.078; 100 μg/ml CasI: 46.6±20.8%, P=0.030; 150 μg/ml CasI: 33.7±15.5%, P=0.016). Conclusions. This study revealed that macrophage-specific IL-1b response differed among different stages of Mycobacterium tuberculosis infection. The role of IL-1b and inflammasome in the process of LTBI progressing to active TB warrants further investigation.

Pulmonary tuberculosis (TB) is caused by Mycobacterium tuberculosis. The protein composition of sputum may reflect the immune status of the lung. This study aimed to evaluate the protein profiles in spontaneous sputum samples from patients with active pulmonary TB. Sputum samples were collected from patients with pulmonary TB and healthy controls. Western blotting was used to analyze the amount of interleukin 10 (IL-10), interferon-gamma (IFN-γ), IL-25, IL-17, perforin-1, urease, albumin, transferrin, lactoferrin, adenosine deaminase (also known as adenosine aminohydrolase, or ADA), ADA-2, granzyme B, granulysin, and caspase-1 in sputum. Results of detection of IL-10, IFN-γ, perforin-1, urease, ADA2, and caspase-1, showed relatively high specificity in distinguishing patients with TB from healthy controls, although sensitivities varied from 13.3% to 66.1%. By defining a positive result as the detection of any two proteins in sputum samples, combined use of transferrin and urease as markers increased sensitivity to 73.2% and specificity to 71.1%. Furthermore, we observed that the concentration of transferrin was proportional to the number of acid-fast bacilli detected in sputum specimens. Detection of sputum transferrin and urease was highly associated with pulmonary TB infection. In addition, a high concentration of transferrin detected in sputum might correlate with active TB infection. This data on sputum proteins in patients with TB may aid in the development of biomarkers to assess the severity of pulmonary TB.

Objectives Chronic pulmonary aspergillosis (CPA) is an emerging global disease with tuberculosis (TB) being the most important risk factor. Epidemiologic data on the seroprevalence of Aspergillus IgG and prevalence of CPA in different areas, especially in country with intermediate burden of TB, are lacking. Methods We prospectively recruited healthy volunteers, TB close contacts, active TB patients and participants with old pulmonary TB in Taiwan during 2012–2019. We measured serum Aspergillus fumigatus and niger-specific IgG levels and assessed if the participants were having CPA. Results A total of 1242 participants (including 200 healthy volunteers, 326 TB close contacts, 524 active TB patients and 192 old TB cases) were recruited. Using 27 mgA/L (milligrams of antigen-specific antibodies per liter) as cut-off level, the seropositive rate of A. fumigatus-specific IgG was 33.0% (66/200), 37.7% (123/326), 26.5% (139/524) and 43.2% (83/192) among the four groups, respectively. In multivariate logistic regression, pulmonary cavitation (OR 1.73; 95% CI 1.07–2.80), female sex (OR 1.49; 95% CI 1.14–1.95), old TB (OR 1.59; 1.05–2.42) were independent risk factors for Aspergillus IgG positivity. One (0.2%) active TB patient and four (2.1%) old TB patients developed CPA. Correlation between A. fumigatus and A. niger-specific IgG was high (Spearman correlation coefficient: 0.942). Discussion Geographic variation in Aspergillus IgG seroprevalence and CPA prevalence exists. A universal cut-off value for Aspergillus IgG may not exist. In areas and populations in which background Aspergillus IgG level is unknown, Aspergillus IgG may be better used as a test of exclusion for CPA using prespecified cut-off level.

Summary Background Clinical application of the CD8 response as measured by the newer interferon gamma release assay, QuantiFERON-TB Gold-Plus (QFT-Plus), remains to be investigated. Method We performed this prospective study and recruited active TB patients, contacts with latent tuberculosis infection (LTBI) and contacts without LTBI in two centres in northern Taiwan in 2017. Subjects were tested with both QuantiFERON-TB Gold In-Tube (QFT-GIT) and QFT-Plus. LTBI was defined by positive result by QFT-GIT and exclusion of active TB. Results A total of 336 participants (118 uninfected contacts, 105 LTBI, 113 active TB) were included. The concordance rate of QFT-GIT and QFT-Plus was high (n = 300, 89.3%). The kappa value was 0.811 among contacts and 0.708 among active TB. While TB1 and TB2 quantitative responses were not different between active TB and LTBI (TB1: 1.74 ± 2.73 IU/ml vs. 2.03 ± 2.28 IU/ml, p = 0.403; TB2: 2.21 ± 3.09 IU/ml vs. 2.15 ± 2.40 IU/ml, p = 0.867), CD8 response was higher in active TB than LTBI (0.47 ± 1.53 IU/ml vs. −0.06 ± 1.47 IU/ml, p = 0.011). Culture-confirmed TB had a higher CD8 response compared with LTBI (0.63 ± 1.74 IU/ml vs. −0.05 ± 1.47 IU/ml, p = 0.004). Conclusions This study demonstrated specific CD8 responses among uninfected contacts, LTBI as well as active TB.

Background Research has revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may prevent cancers such as hepatocellular carcinoma (HCC). The comparative chemopreventive effects of ACEIs and ARBs in high-risk populations with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have yet to be investigated. Methods From 2005 to 2014, high-risk HBV and HCV cohorts of hypertensive patients without HCC history were recruited from three linked national databases of Taiwan, and were classified into two groups based on the ACEI or ARB exposure within the initial six months after initiating antiviral agent. Intergroup differences in clinical characteristics and duration of drug exposure within study period were evaluated. HCC-free survival was compared using the log-rank test. Multivariate Cox regression including time-dependent variables for the use of ACEIs or ARBs and other medications was applied to adjust for confounders. Results Among the 7724 patients with HBV and 7873 with HCV, 46.3% and 42.5%, respectively, had an initial exposure to ACEIs or ARBs. The median durations of exposure were 36.4 and 38.9 months for the HBV and HCV cohorts, respectively. The median durations of ACEI or ARB use during study period between initial exposure and nonexposure groups were 41.8 vs. 18.3 months and 46.4 vs. 22.7 months for the HBV and HCV cohorts, respectively. No significant difference was observed in HCC risk within 7 years between the initial exposure and non-exposure groups. After adjustment for comorbidities, namely liver cirrhosis, diabetes mellitus (DM), and hyperlipidemia, and medications, namely aspirin, metformin, and statins, the hazard ratios (HRs) for ACEI or ARB exposure for HCC risk were 0.97 (95% confidence interval [CI]: 0.81–1.16) and 0.96 (0.80–1.16) in the HBV and HCV cohorts, respectively. In the HCV cohort, the increased HCC risk was associated with ACEI or ARB use in patients without cirrhosis, DM, and hyperlipidemia (HR: 4.53, 95% CI: 1.46–14.1). Conclusion Compared with other significant risk and protective factors for HCC, ACEI or ARB use in the HBV and HCV cohorts was not associated with adequate protective effectiveness under standard dosages and may not be completely safe. Electronic supplementary material The online version of this article (10.1186/s12885-018-4292-y) contains supplementary material, which is available to authorized users.

Funding: World Health Organization and Canadian Institutes of Health Research. Background: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. Methods: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1–3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. Findings: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8–9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1–7·3), but no significant effect on mortality (aOR 0·7, 0·4–1·1) or acquired rifampicin resistance (aOR 0·1, 0·0–1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2–0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. Interpretation: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. Funding World Health Organization and Canadian Institutes of Health Research. Postprint

Background Tuberculosis (TB) remains one of the major infectious diseases worldwide. Adverse reactions are common during TB treatment. Few reports, however, are available on treatment-related acute biliary events (ABEs), such as cholelithiasis, biliary obstruction, acute cholecystitis, and cholangitis. Methods We first report four pulmonary TB patients who developed ABEs during anti-TB treatment. Abdominal sonography revealed multiple gall stones with dilated intrahepatic ducts in three patients and cholecystitis in one patient. To investigate the incidence of and risk factors for ABEs during anti-TB treatment, we subsequently conducted a nationwide cohort study using the National Health Insurance Research Database of Taiwan. Results A total of 159,566 pulmonary TB patients were identified from the database between 1996 and 2010, and among them, 195 (0.12%) developed ABEs within 180 days after beginning anti-TB treatment. Logistic regression analysis revealed that the risk factors associated with ABEs are older age (relative risk [RR]: 1.32 [1.21–1.44] per 10-year increment) and diabetes mellitus (RR: 1.59 [1.19–2.13]). Conclusions Although infrequently encountered, ABEs should be considered among patients with TB who experience abdominal discomfort with hyperbilirubinemia, especially patients who have older age or diabetes.

Background: Weekly rifapentine and isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Little, however, is known regarding the predictors of 3HP-related SDRs. Methods: We prospectively recruited 2 LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the NAT2, CYP2E1, and AADAC SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite levels at 6 and 24 hours after 3HP administration. The generalised estimating equation model was used to identify the factors associated with SDRs. Candidate SNPs predicting SDRs were validated in the PK cohort. Findings: A total of 177 participants were recruited into the SNP cohort and 129 into the PK cohort, with 14 (8%) and 13 (10%) in these two cohorts developing SDRs, respectively. In the SNP cohort, NAT2 rs1041983 (TT vs CC CT, odds ratio [OR] [95% CI]: 7.38 [2.17-25.1]) and CYP2E1 rs2070673 (AA vs TT TA, OR [95% CI]: 3.49 [1.02-12.0]) were associated with SDR development. In the PK cohort, isoniazid level 24 hours after 3HP administration (OR [95% CI]: 1.61 [1.15-2.25]) was associated with SDRs. Additionally, the association between the NAT2 SNP and SDRs was validated in the PK cohort (rs1041983 TT vs CC CT, OR [95% CI]: 4.14 [1.24-13.8]). Interpretations: Isoniazid played a role in the development of 3HP-related SDRs. This could provide insight for further design of a more optimal regimen for latent TB infection. Funding: The study was supported by grants from the Ministry of Health and Welfare (MOHW106-CDC-C-11400104 and MOHW107-CDC-C-114-000105) and the Ministry of Science and Technology (MOST106-2314-B-002-055, MOST107-2314-B-002-191 and MOST107-2314-B-037-106-MY3). Declaration of Interest: The authors have no conflicts of interest to declare. Ethical Approval: The study was approved by the institutional ethics committees of both medical centres (NTUH REC 201609044RINB and KMUHIRB-G[II]-20170033).

Background and objective This retrospective national surveillance study investigated the burden of and risk factors for nosocomial exposure of pulmonary tuberculosis (TB) in intensive care units. Methods Patients admitted to intensive care units were identified from the National Health Insurance Research Database. During 2004–2009, there were 1 387 707 intensive care unit admissions of 900 562 adult patients. Pulmonary tuberculosis association was considered if the patient was diagnosed with pulmonary tuberculosis during admission or within 3 months after discharge. Nosocomial transmissible period was calculated based on the length of anti-tuberculosis treatment and negative-pressure isolation during admission. Results Pulmonary tuberculosis was associated with 1.20% of all intensive care unit admissions and 6731 (38.9%) started anti-TB treatment during admission. For the other 10 583 admissions, the diagnosis was made after discharge and anti-TB treatment was not prescribed during admission. The probability paralleled the regional tuberculosis incidence. On average, 2794 pulmonary tuberculosis associated intensive care unit admissions contributed to 42 999–44 062 days of nosocomial exposure per year. The length of nosocomial transmissible period decreased with the gradual implementation of Mycobacterium tuberculosis nucleic acid amplification tests in intensive care practice. Multivariate linear regression analysis revealed that the length of nosocomial transmissible period was inversely associated with male gender, airway symptoms prior to admission and performing M. tuberculosis nucleic acid amplification tests and mycobacterial culture. Conclusions Nosocomial tuberculosis exposure is not uncommon in intensive care units. Performing rapid molecular diagnostic tests in those suspected of tuberculosis is recommended to reduce the risk of nosocomial exposure.

Despite its excellent activity against Mycobacterium tuberculosis [1], empirical fluoroquinolone (FQ) therapy has been associated with delayed initiation of appropriate treatment [2–4] and acquired resistance [5, 6] in tuberculosis (TB) patients presenting as community-acquired pneumonia (CAP). A previous study conducted in intensive care unit revealed immediate mycobacteriology study may possibly prevent the delay in anti-TB treatment [7]. However, this hypothesis has not been confirmed. Empirical fluoroquinolone use for ≥7 days delays antituberculosis treatment despite immediate mycobacteriology study The authors thank the National Health Research Institute of Taiwan for providing the NHIRD. Details of the computer code for statistical analyses are available from the corresponding author.

SUMMARY Aim: This study aimed to investigate the impact of early invasive diagnostic procedures on detecting lung cancers that mimic pulmonary TB. Patients & methods: Patients with an initial diagnosis of pulmonary TB, which was later revised to lung cancer, were included. Patients were classified into early and late intervention groups. Clinical characteristics, chest radiographic images, diagnostic procedures and outcomes were analyzed. Results: There were 53 patients with a revised diagnosis of lung cancer included. The time between diagnoses of TB and cancer for the early and late intervention group was 1.1 ± 1.1 and 5.5 ± 10.2 months, respectively (p = 0.01). For patients with advanced stage lung cancer, those received early interventions survived longer than those that did not receive early interventions (10.3 vs 3.3 months; p = 0.89). Conclusion: In a TB-endemic area, invasive diagnostic procedures may be helpful to avoid a misdiagnosis in patients with lung cancer mimicking pulmonary TB.

BACKGROUND Diabetes mellitus (DM) increases the risk of TB recurrence. This study investigated whether 9-month anti-TB treatment is associated with a lower risk of TB recurrence within 2 years after complete treatment than 6-month treatment in patients with DM with an emphasis on the impact of directly observed therapy, short course (DOTs). METHODS Patients with pulmonary but not extrapulmonary TB receiving treatment of 173 to 277 days between 2002 and 2010 were identified from the National Health Insurance Research Database of Taiwan. Patients with DM were then selected and classified into two groups based on anti-TB treatment duration (9 months vs 6 months). Factors predicting 2-year TB recurrence were explored using Cox regression analysis. RESULTS Among 12, 688 patients with DM and 43, 195 patients without DM, the 2-year TB recurrence rate was 2.20% and 1.38%, respectively ( P P CONCLUSIONS The 2-year TB recurrence rate is higher in a diabetic population in Taiwan and can be reduced by treatment supervision. Extending the anti-TB treatment by 3 months may also decrease the recurrence rate when treatment is not supervised.

Isoniazid mono-resistance is the most common first-line drug resistance in tuberculosis (TB), but its treatment outcome remains unclear. From January 2004 to October 2011, 425 (5.1%) of 8414 patients with culture-confirmed pulmonary TB from four hospitals in Taiwan were identified as having isoniazid mono-resistant TB. Among them, 395 (92.9%) were included and followed up for 2 years after complete treatment. Although 328 (83.0%) patients were successfully treated, 67 (17.0%) had unfavourable outcomes, including death in 56 (14.2%) and treatment failure in 11 (2.8%). The treatment success rate was similar in patients with high-level and low-level isoniazid-resistant TB (82.2% versus 83.4%, p 0.785) and among those taking anti-TB treatment with and without isoniazid (83.1% versus 83.0%, p 1.000). Patients without rifampicin interruption had lower risk of unfavourable outcome (14.3% versus 37.0%, p 12 months had less relapse than 6-month treatment (3.2%, 0%, 3.7% and 25.0%, respectively, p 0.037). Multivariate Cox proportional hazards analysis revealed that co-morbidity with cancer (hazard ratio, 2.43) and rifampicin interruption (hazard ratio 1.91) were independent factors associated with unfavourable outcomes. Treatment throughout with rifampicin and extended treatment for cavitary disease are crucial for improving outcomes in patients with isoniazid mono-resistant TB.