Increased Tuberculosis Reactivation Risk in Patients Receiving Immune Checkpoint Inhibitor-Based Therapy.

OBJECTIVE: Reports of tuberculosis (TB) during anticancer treatment with immune checkpoint inhibitors (ICIs) are increasing. However, it is not clear whether the use of ICIs is a significant risk factor for TB, including reactivation or latent TB infection (LTBI). METHODS: To determine the risk of TB reactivation in patients with lung cancer who use ICIs or tyrosine kinase inhibitors (TKIs), we conducted a retrospective study using a hospital-based cancer registry. In addition, we monitored patients with cancer using ICI or TKI in a multicenter prospective study to check the incidence of LTBI. RESULTS: In the retrospective study, several demographic factors were imbalanced between the ICI and TKI groups: the ICI group was younger, had more males, exhibited more squamous cell carcinoma in histology rather than adenocarcinoma, had fewer EGFR mutations, and received more chemotherapy. Propensity score matching was used to control for confounding factors, and we found that the incidence of TB was higher among patients with lung cancer who received ICIs than among those who received TKIs (2298 vs 412 per 100 000 person-years, P = .0165). Through multivariable analysis, group (ICI vs TKI) was the independent risk factor for TB development (adjusted hazard ratio (aHR): 6.29, 95% CI, 1.23-32.09, P = .0269). In the prospective cohort, which included 72 patients receiving ICIs and 50 receiving TKIs, we found that the incidence of positive seroconversion of LTBI by interferon gamma release assay (IGRA) was significantly higher in patients receiving ICIs (18% vs 0%, aHR: 9.88, P = 0.035) under multivariable Cox regression. CONCLUSION: The use of ICIs may be linked to a higher likelihood of TB reactivation and LTBI than individuals solely receiving TKIs as anticancer therapy. Consequently, the implementation of a screening program for TB reactivation and LTBI among patients undergoing ICI treatment could prove advantageous by enabling early detection and prompt treatment of the infection.

Prevalence and risk factors of non-tuberculous mycobacterial pulmonary isolates and infection in interstitial lung disease associated with systemic autoimmune disease.

OBJECTIVES: Non-tuberculous mycobacterial (NTM) lung disease (NTM-LD) prevalence is increasing worldwide. In this study, we aimed to evaluate the clinical significance of NTM pulmonary isolates (NTM-PI) and NTM-LD in patients with systemic autoimmune disease (SAD) who had a concurrent interstitial lung disease (ILD) diagnosis. METHODS: We retrospectively identified patients with SAD who had a concurrent ILD diagnosis (SAD-ILD) and from whom clinically indicated sputum specimens were collected for NTM culture between 2003 and 2018 at a tertiary referral hospital. We analysed the prevalence and risk factors of NTM pulmonary isolates (NTM-PI; ≥1 positive culture) and NTM-LD (≥2 positive cultures). RESULTS: This study included 258 patients. Rheumatoid arthritis and Sjögren's syndrome were the most common SADs (32.2% and 26.7%, respectively). The NTM-negative subgroup had 204 patients (79.1%) and the NTM-PI subgroup had 54 patients (20.9%). In the NTM-PI subgroup, 33 patients had one NTM positive set of specimens (NTM 1+, 12.8% of the entire sample) and 21 had NTM-LD (8.1% of the entire sample). In a multivariable analysis, chronic kidney disease (CKD; adjusted odds ratio [aOR]: 3.10 [1.53, 6.29]) and chronic obstructive pulmonary disease (COPD; aOR: 2.59 [1.16, 5.78]) were significantly associated with NTM-PI. For NTM-LD, CKD (aOR: 2.79 [1.00, 7.76]) and COPD (aOR: 3.70 [1.23, 10.72]) remained significant risk factors. CONCLUSIONS: In patients with SAD-ILD, the NTM-PI and NTM-LD prevalence rates were 20.9% and 8.1%, respectively. COPD and CKD were independent risk factors of both NTM-PI and NTM-LD. Previous use of biological agents was associated with NTM-PI.

Sex-Specific Associations Between Susceptibility to Mycobacterium avium Complex Lung Disease and Programmed Cell Death 1 Gene Polymorphisms.

BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) preferentially occurs in postmenopausal women and may have immune exhaustion involving the programmed cell death 1 (PD-1) pathway. It is still unknown whether sex-specific associations between susceptibility to MAC-LD and programmed cell death 1 gene (PDCD1) polymorphisms exist. METHODS: Adult patients with MAC-LD (n = 152) and controls (n = 167) were included at 2 medical centers in Taiwan. Five single-nucleotide polymorphisms in PDCD1 genes were genotyped, and their associations with MAC-LD and soluble PD-1 protein were analyzed, especially in sex subgroups. RESULTS: PDCD1 rs2227982 polymorphism was associated with increased risk of MAC-LD in women (adjusted odds ratio for AA vs AG vs GG, 2.205 [95% confidence interval, 1.108-4.389]; P = .02), and the rs10204525 TT genotype was associated with low risk in men (TT vs TC and CC, 0.396 [.176-.890]; P = .02). Compared with men with rs10204525 TT, women with rs2227982 AG and with AA had 2.7- and 5.0-fold increased risks, respectively. Soluble PD-1 levels were lower in the female subgroup with rs2227982 AG and AA than in the remainder (median level [interquartile range], 46.7 [33.7-71.5] pg/mL vs 66.2 [48.6-101.5] pg/mL; P < .001). CONCLUSIONS: PDCD1 genetic polymorphisms were associated with the risk of MAC-LD in a sex-specific pattern, possibly through regulation of PD-1 expression.

Prevention and management of tuberculosis in solid organ transplantation: A consensus statement of the transplantation society of Taiwan.

Solid organ transplant recipients have an increased risk of tuberculosis (TB). Due to the use of immunosuppressants, the incidence of TB among solid organ transplant recipients has been consistently reported to be higher than that among the general population. TB frequently develops within the first year after transplantation when a high level of immunosuppression is maintained. Extrapulmonary TB and disseminated TB account for a substantial proportion of TB among solid organ transplant recipients. Treatment of TB among recipients is complicated by the drug-drug interactions between anti-TB drugs and immunosuppressants. TB is associated with an increased risk of graft rejection, graft failure and mortality. Detection and management of latent TB infection among solid organ transplant candidates and recipients have been recommended. However, strategy to mitigate the risk of TB among solid organ transplant recipients has not yet been established in Taiwan. To address the challenges of TB among solid organ transplant recipients, a working group of the Transplantation Society of Taiwan was established. The working group searched literatures on TB among solid organ transplant recipients as well as guidelines and recommendations, and proposed interventions to strengthen TB prevention and care among solid organ transplant recipients.

Inhaled Corticosteroids Increase Risk of Nontuberculous Mycobacterial Lung Disease: A Nested Case-Control Study and Meta-analysis.

Studies on use of inhaled corticosteroids (ICS) and the risk of nontuberculous mycobacterial lung disease (NTM-LD) are limited and have some conflicting results. We recruited 1235 NTM-LD patients and found that ICS use within 1 year was associated with increased NTM-LD, and the risk increased with elevated ICS dose and cumulative duration. Discontinuation of ICS use for more than 120 days could reduce the risk of NTM-LD to an insignificant level. For NTM species, the development of NTM-LD by ICS was highest for Mycobacterium kansasii lung disease. The pooled results of the meta-analysis showed that ICS use might increase the risk of NTM-LD with dose response in medium and high dose of daily ICS. In addition, budesonide had a smaller impact on the risk of NTM-LD than other ICS medications. The present study and meta-analysis provide evidence for ICS adjustment, including dose, discontinuation effect, and medications to possibly reduce the risk of NTM-LD.

Disease Progression in Patients With Nontuberculous Mycobacterial Lung Disease of Nodular Bronchiectatic (NB) Pattern: The Roles of Cavitary NB and Soluble Programmed Death Protein-1.

BACKGROUND: In patients with nodular bronchiectatic (NB) nontuberculous mycobacterial lung disease (NTM-LD), risk factors for disease progression have not been clearly investigated. The roles of cavitary NB and soluble programmed death protein-1 (sPD-1), an immune-related biomarker, in the disease course of NB NTM-LD remain unknown. METHODS: Patients with NB NTM-LD were enrolled from 2 medical centers in 2014-2020. We identified cavitary NB, measured sPD-1 levels, and analyzed factors associated with cavitary NB and predictors for disease progression of NB NTM-LD. RESULTS: Of 120 cases of NB NTM-LD, 87 (72.5%) were caused by Mycobacterium avium complex. sPD-1 levels were lower in 13 (10.8%) patients with cavitary NB than in noncavitary patients (P = .020). Over 1.41 ± 1.43 years of follow-up, 12 (92.3%) patients in the cavitary and 66 (61.7%) in the noncavitary group developed disease progression (P = .032). In multivariable analysis, body mass index (BMI [kg/m2]; adjusted hazard ratio [aHR], .895 [95% confidence interval, .811-.988]), sputum smear grade (aHR, 1.247 [1.014-1.534]), cavitary NB (aHR, 2.008 [1.052-3.834]), and sPD-1 (per 10-pg/mL increase; aHR, .889 [.816-.967]) were predictive for disease progression. Notably, sPD-1 showed a dose-dependent association with disease progression (sPD-1 ≤23.5 pg/mL; aHR, 3.306 [1.664-6.567]; sPD-1: 23.6-53.7 pg/mL; aHR, 2.496 [1.390-4.483]) compared with the reference (sPD-1 >53.7 pg/mL). CONCLUSIONS: Patients with NB NTM-LD and low sPD-1, low BMI, high smear grade, and cavitary NB were at high risk for disease progression. sPD-1 was low in patients with cavitary NB phenotype and dose-responsively associated with disease progression.

PD-L1 Expression in Monocytes Correlates with Bacterial Burden and Treatment Outcomes in Active Pulmonary Tuberculosis.

The PD-1/PD-L1 pathway is critical in T cell biology; however, the role of the PD-1/PD-L1 pathway in clinical characteristics and treatment outcomes in pulmonary tuberculosis (PTB) patients is unclear. We prospectively enrolled PTB, latent TB infection (LTBI), and non-TB, non-LTBI subjects. The expression of PD-1/PD-L1 on peripheral blood mononuclear cells (PBMCs) was measured and correlated with clinical characteristics and treatment outcomes in PTB patients. Immunohistochemistry and immunofluorescence were used to visualize PD-1/PD-L1-expressing cells in lung tissues from PTB patients and from murine with heat-killed MTB (HK-MTB) treatment. A total of 76 PTB, 40 LTBI, and 28 non-TB, non-LTBI subjects were enrolled. The expression of PD-1 on CD4+ T cells and PD-L1 on CD14+ monocytes was significantly higher in PTB cases than non-TB subjects. PTB patients with sputum smear/culture unconversion displayed higher PD-L1 expression on monocytes. PD-L1-expressing macrophages were identified in lung tissue from PTB patients, and co-localized with macrophages in murine lung tissues. Mycobacterium tuberculosis (MTB) whole cell lysate/EsxA stimulation of human and mouse macrophages demonstrated increased PD-L1 expression. In conclusion, increased expression of PD-L1 on monocytes in PTB patients correlated with higher bacterial burden and worse treatment outcomes. The findings suggest the involvement of the PD-1/PD-L1 pathway in MTB-related immune responses.

Completion and Adverse Drug Events of Latent Tuberculosis Infection Treatment in Patients Receiving Dialysis: Predictors and Impacts of Different Regimens in a Prospective Cohort Study.

Although patients with end-stage renal disease receiving maintenance hemodialysis are at high risk for tuberculosis, the optimal treatment regimen for latent tuberculosis infection (LTBI) in this group has scarcely been studied for predictors of completion rate and adverse drug events (ADE). We prospectively enrolled dialysis patients for LTBI intervention from three medical centers in Taiwan. LTBI treatments were 3 months of weekly rifapentine plus isoniazid (3HP) and 9 months of daily isoniazid (9H). Completion rate, ADE, and reasons for treatment termination were recorded. Factors associated with treatment termination and ADE were analyzed using multivariate logistic regression. In all, 91 treatment courses (41 9H and 50 3HP) were surveyed. The completion rates were 61% for 9H and 82% for 3HP (P = 0.046). Use of 9H and development of ADE with a grade of ≥2 (≥grade 2 ADE) were associated with treatment termination. Hypersensitivity occurred in 29.2% of subjects in the 3HP group and 10.8% in the 9H group (P = 0.035) and independently correlated with 3HP regimen, diabetes mellitus (DM), and peritoneal dialysis (PD). Similarly, the independent predictors of ≥grade 2 ADE were use of 3HP regimen, presence of DM, and use of PD, whereas ≥grade 3 ADE were associated with eosinophil counts of >700/mm3 after 2 weeks of LTBI treatment even after adjustment for age and gender. In conclusion, for patients on dialysis, 3HP showed a higher rate of completion but also a higher rate of ≥grade 2 ADE than 9H. In addition, DM and PD were risk factors for ≥grade 2 ADE. Eosinophilia after 2-week treatment might be an alert for severe ADE.

Association between urinary manganese and pulmonary function in young adults: A cross-sectional design with a longitudinal cohort validation.

BACKGROUND: The impact of heavy metals on pulmonary function among young adults has been scarcely studied, especially by a longitudinal cohort study. METHODS: We prospectively enrolled 974 young adults (aged 20-45 years) during 2017-2019 and measured pulmonary function and urinary heavy metals, including manganese, copper, chromium, iron, nickel, zinc, cadmium, and lead. Among them, 461 participants had examination of the same urinary heavy metals during 2006-2008, which could be used as a cohort for long-term effect of urinary metals on pulmonary function. RESULTS: In the 974 enrolled participants, urinary heavy metals were within normal range. The urinary manganese level was the only significant factor for the observed/predicted ratios of forced vital capacity (FVC %)(ß coefficient: -1.217, p = 0.030), forced expiratory volume in one second (FEV1%)(ß: -1.664, p < 0.001), and FEV1/FVC% of predicted (ß: -0.598, p = 0.047) in multivariable linear regression under cross sectional design. In cohort analysis, the urinary manganese level was also negatively associated with the FEV1% (ß: -1.920, p = 0.021). There was no significance between other urinary heavy metals and pulmonary function for all participants. The urinary manganese significantly negatively correlated with FVC%, FEV1% and FEV1/FVC% in female subgroup whereas copper and iron were significantly negatively correlated with FVC% in male subgroup. CONCLUSIONS: Among urinary heavy metals, urinary manganese level was associated with pulmonary function negatively, even the level was within normal range. In addition, women might be more susceptible to manganese. There is emergent need to conduct further investigation to confirm the respiratory hazardous effects of manganese.

Latent Tuberculosis Infection Increases in Kidney Transplantation Recipients Compared With Transplantation Candidates: A Neglected Perspective in Tuberculosis Control.

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 impact on incident tuberculosis by kidney function impairment status: analysis of severity relationship.

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.

Treatment for Mycobacterium avium complex lung disease.

Mycobacterium avium complex (MAC) is the major pathologic nontuberculous mycobacteria causing lung disease (LD) in humans worldwide. Although the burden of MAC-LD has increased over the past two decades, treatment remains difficult because of intolerance of long-term antibiotics, lack of adherence to guidelines, and disease recurrence. The current guidelines recommend antibiotic initiation for patients with MAC-LD and severe disease and in those with disease progression. Thus, physicians should consider antibiotic treatment for patients with MAC-LD and cavitary pulmonary lesions or symptomatic non-cavitary nodular bronchiectasis pattern at initial visits and also for those with clinical deterioration during follow-up. The standard three-drug regimen should be macrolide, rifamycin, and ethambutol. Physicians should monitor side effects in patients and maintain the regimen for 12 months, beginning from when sputum conversion has been obtained. With adherence to guideline-based therapy, treatment is successful in two thirds of treatment-naïve patients without macrolide resistance. Without adherence, macrolide resistance can occur, which leads to poor outcomes in patients with MAC-LD. Although the discovery of new treatment options is warranted, adherence to guidelines remains most crucial in treating patients with MAC-LD. It is worth mentioning that the majority of current recommendations are based on observational studies or small-scale clinical trials.

Host immune response against environmental nontuberculous mycobacteria and the risk populations of nontuberculous mycobacterial lung disease.

Nontuberculous mycobacterial lung disease (NTM-LD) prevalence has been increasing over the recent decades. Numerous host factors are associated with NTM-LD development, including susceptible phenotypes such as ciliary defect and lung structural change, pulmonary clearance defect with poor clearance of secretions, and immune suppression. Specifically, regarding the susceptible host phenotypes without clear pathogenesis, a slender body, pectus excavatum, and postmenopausal female status are common. Also, decreased host immunity to NTM, especially T helper 1 cell responses is frequently observed. Even so, the underlying mechanisms remain unclear and relevant large-scale studies are lacking. Infections due to host genetics associated defects are mostly untreatable but rare in Asia, particularly Taiwan. Nevertheless, some risks for NTM-LD are controllable over disease progression. We suggest that clinicians first manage host factors and deal with the controllable characteristics of NTM-LD, followed by optimizing anti-NTM treatment. Further researches focusing on NTM-LD pathogenesis, especially the host-NTM interaction may advance understanding the nature of the disease and develop efficient therapeutic regimens.

Mono- and poly-functional T cells in nontuberculous mycobacteria lung disease patients: Implications in analyzing risk of disease progression.

AT A GLANCE: The diagnosis and progression of nontuberculous mycobacteria lung disease (NTN-LD) are important for clinical judgement but cannot easily be predicted. The immunological response of mono- and poly-functional T cells, a representative of host reactivity to NTM, could be a surrogate biomarker for disease and progression prediction. BACKGROUND: Mycobacterium avium complex (MAC) and M. abscessus (MAB) induced lung disease (LD) have become a clinical concern. Predicting clinical disease relevance and progression is important, but suitable biomarkers are lacking. The host immune response of mono- and poly-functional T cells might aid in clinical judgement. METHODS: We enrolled 140 participants, including 42 MAC-LD, 25 MAB-LD, 31 MAC airway colonization (MAC-Co), 15 MAB-Co patients, and 27 healthy controls. Their blood mono- and poly-functional T cells were measured and analyzed after in-vitro stimulation. RESULTS: Patients with MAC-LD generally had lower total IFN-γ+, total TNF-α+ and triple-positive T cells but higher mono-IL-2+ expression than the controls and MAC-Co group. The MAB-LD group had lower total IL-2 and triple positive cells than the controls and colonization group. Multivariate analysis revealed that body mass index (BMI), mono-IL2+ CD4+ and triple positive-CD8+ cells (PMA stimulation) significantly predicted MAC-LD from the controls. By contrast, male gender and triple positive-CD4+ cells predicted MAC-LD from colonization. On the other hand, the triple positive-CD4+ cells (PMA stimulation) alone or together with the mock/MAB ratio of IL-2+/TNF-α+ CD4 cells could predict MAB-LD in the MAB-Co group or the controls. Among MAC/MAB-LD patients without anti-mycobacterial treatment, MAC-specific mono-IFN-γ+ CD4+ cells and PMA-induced triple positive-CD4+ cells were correlated with progression, with an area under the ROC curve of 0.875. CONCLUSIONS: The patients with MAC/MAB-LD had attenuated poly-functional T cells. The triple-positive CD4+ cells could be useful in diagnosing disease from colonization. MAC-specific mono-IFN-γ+ CD4+ cells and triple positive-CD4+ might predict radiographic progression, which could be useful in making treatment decisions.

Microbiological Persistence in Patients With Mycobacterium avium Complex Lung Disease: The Predictors and the Impact on Radiographic Progression.

BACKGROUND: Persistent growth of Mycobacterium avium complex (MAC) in the lungs indicates continuous infection in MAC lung disease (MAC-LD), but its clinical significance has not been investigated. We aimed to evaluate the predictors of persistent culture-positivity for MAC (MAC-PP) and its impact on radiographic deterioration in MAC-LD. METHODS: Patients with MAC-LD at multiple medical centers from 2011 to 2016 were enrolled retrospectively. Microbiological persistence of MAC-LD was defined as MAC-PP exceeding 1 year, in contrast with the negative-conversion group. The outcome was radiographic progression, namely, increased number of involved lung areas or cavitary formation. RESULTS: Among 126 patients with MAC-LD, 75 (60%) were in the MAC-PP group; these patients had a higher proportion of radiographic progression (54%) than patients in the negative-conversion group (odds ratio [OR], 3.318; 95% confidence interval, 1.146-9.612). Independent predictors of MAC-PP were low body mass index (BMI), radiographic nodular-bronchiectatic (NB) pattern, and increase in the highest grade of acid-fast bacilli smear (AFS). Patients with BMI <21 kg/m2, NB pattern, and positive AFS had an OR of 17.7 for MAC-PP, and those with ≥2 of the factors had a 4.5-fold increased OR for MAC-PP relative to the comparison group. Other than MAC-PP, the highest AFS grade and no anti-MAC treatment were correlated with radiographic progression. CONCLUSION: Microbiological persistence in patients with MAC-LD is not uncommon and leads to an increased risk of radiographic progression. The predictors of MAC-PP are low BMI, NB pattern, and high AFS grade; if these risk factors are present, anti-MAC treatment should be seriously considered.

Diabetes Mellitus and Latent Tuberculosis Infection: A Systematic Review and Metaanalysis.

Background: Despite the well-documented association between diabetes and active tuberculosis, evidence of the association between diabetes and latent tuberculosis infection (LTBI) remains limited and inconsistent. Methods: We included observational studies that applied either the tuberculin skin test or the interferon gamma release assay for diagnosis of LTBI and that provided adjusted effect estimate for the association between diabetes and LTBI. We searched PubMed and EMBASE through 31 January 2016. The risk of bias of included studies was assessed using a quality assessment tool modified from the Newcastle-Ottawa scale. Results: Thirteen studies (1 cohort study and 12 cross-sectional studies) were included, involving 38263 participants. The cohort study revealed an increased but nonsignificant risk of LTBI among diabetics (risk ratio, 4.40; 95% confidence interval [CI], 0.50-38.55). For the cross-sectional studies, the pooled odds ratio from the random-effects model was 1.18 (95% CI, 1.06-1.30), with a small statistical heterogeneity across studies (I2, 3.5%). The risk of bias assessment revealed several methodological issues, but the overall direction of biases would reduce the positive causal association between diabetes and LTBI. Conclusions: Diabetes was associated with a small but statistically significant risk for LTBI. Findings from this review could be used to inform future cost-effectiveness analysis on the impact of LTBI screening programs among diabetics.

Decreased T helper 17 cells in tuberculosis is associated with increased percentages of programmed death ligand 1, T helper 2 and regulatory T cells.

BACKGROUND: Tuberculosis (TB) is one of the most common infectious diseases worldwide. During active tuberculosis, T helper (Th) 17 cells are decreased, however the association with inhibitory immune regulation is unclear. METHODS: We enrolled 27 patients with TB and 20 age- and sex-matched controls and studies their lymphocyte status. Peripheral blood lymphocytes were isolated and programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) were measured on Th17 cells by using flow cytometry after the cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin for 6 h. In addition, Th2 and regulatory T cells were measured and analyzed. RESULTS: The TB group had lower levels of Th17 cells but higher levels of Th2 and Treg cells than the controls. In Th17 cells, the percentage of PD-L1 was higher in the TB group than that in the controls. In Th2 and Treg cells, the percentage of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) was lower in the TB group and PD-1 was higher in Treg cells in the TB group. In the patients with extra-pulmonary TB, levels of Th1, Th2 and T17 cells were lower than those with pulmonary TB. The percentage of PD-1 on Th1 lymphocytes positively correlated with radiographic score. CONCLUSIONS: Lower level of Th17 in TB patients may be associated with increased percentage of PD-L1 and increasing levels of Th2 and Treg cells which influenced by CTLA-4.

Factors associated with emergency department visit within 30 days after discharge.

BACKGROUND: Post-discharge care remains a challenge because continuity of care is often interrupted and adverse events frequently occur. Previous studies have focused on early readmission but few have investigated emergency department (ED) visit after discharge. METHODS: This retrospective observational study was conducted between April 2011 and March 2012 in a referral center in Taiwan. Patients discharged from the general medical wards during the study period were analyzed and their characteristics, hospital course, and associated factors were collected. An ED visit within 30 days of discharge was the primary outcome while readmission or death at home were secondary outcomes. RESULTS: There were 799 discharged patients analyzed, including 96 (12 %) with an ED visit of 12.4 days post-discharge and 111 (14 %) with readmissions at 13.3 days post-discharge. Sixty patients were admitted after their ED visit. Underlying chronic illnesses were associated with 72 % of ED visits. By multivariate analysis, Charlson score and the use of naso-gastric tube were independent risk factors for ED visit within 30 days after discharge. CONCLUSIONS: Early ED visit after discharge is as high as 12 %. Patients with chronic illness and those requiring a naso-gastric tube or external biliary drain are at high risk for post-discharge ED visit.

Diagnostic role of inflammatory and anti-inflammatory cytokines and effector molecules of cytotoxic T lymphocytes in tuberculous pleural effusion.

BACKGROUND AND OBJECTIVE: Early diagnosis of tuberculous pleural effusion (TPE) remains difficult. While some inflammatory markers in pleural effusion (PE) are helpful in diagnosis, the roles of anti-inflammatory cytokines and effector molecules of cytotoxic T lymphocytes have not been investigated. METHODS: Lymphocyte-predominant exudative PE samples were assayed for inflammatory and anti-inflammatory cytokines and effector molecules of cytotoxic T lymphocytes. Logistic regression analysis was used to predict the probability of TPE and identify independently associated factors. Receiver operating characteristic (ROC) curve analysis was applied to determine the optimal cut-off value for the predicted probability. RESULTS: Of 95 patients enrolled, 35 had TPE, 46 had malignant PE and 14 had PE due to other aetiologies. Interferon-γ (IFN-γ), adenosine deaminase (ADA), decoy receptor (DcR) 3, monocyte chemo-attractant protein (MCP)-1, IFN-induced protein (IP)-10, granzyme A and perforin were higher in TPE than in PE of other aetiologies. By logistic regression analysis, IFN-γ ≥ 75 pg/mL, ADA ≥ 40 IU/mL, DcR3 ≥ 9.3 ng/mL and soluble tumour necrosis factor receptor 1 (TNF-sR1) ≥ 3.2 ng/mL were independent factors associated with TPE. The predicted probability based on the four predictors had an area under the ROC curve of 0.920, with 82.9% sensitivity and 86.7% specificity under the cut-off value of 0.303. In the TPE group, patients with positive PE/pleural culture for Mycobacterium tuberculosis had higher pleural IFN-γ, MCP-1, IP-10 and perforin than those with positive sputum but negative PE culture. CONCLUSIONS: While pleural interferon-γ and ADA are conventional markers for diagnosing TPE, simultaneous measurements of DcR3 and TNF-sR1 can improve the diagnostic efficacy.