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BACKGROUND: Shorter but effective tuberculosis treatment regimens would be of value to the tuberculosis treatment community. High-dose rifampicin has been associated with more rapid and secure lung sterilization and may enable shorter tuberculosis treatment regimens. METHODS: We randomly assigned adults who were given a diagnosis of rifampicin-susceptible pulmonary tuberculosis to a 6-month control regimen, a similar 4-month regimen of rifampicin at 1200 mg/d (study regimen 1 [SR1]), or a 4-month regimen of rifampicin at 1800 mg/d (study regimen 2 [SR2]). Sputum specimens were collected at regular intervals. The primary end point was a composite of treatment failure and relapse in participants who were sputum smear positive at baseline. The noninferiority margin was 8 percentage points. Using a sequence of ordered hypotheses, noninferiority of SR2 was tested first. RESULTS: Between January 2017 and December 2020, 672 patients were enrolled in six countries, including 191 in the control group, 192 in the SR1 group, and 195 in the SR2 group. Noninferiority was not shown. Favorable responses rates were 93, 90, and 87% in the control, SR1, and SR2 groups, respectively, for a country-adjusted absolute risk difference of 6.3 percentage points (90% confidence interval, 1.1 to 11.5) comparing SR2 with the control group. The proportions of participants experiencing a grade 3 or 4 adverse event were 4.0, 4.5, and 4.4% in the control, SR1, and SR2 groups, respectively. CONCLUSIONS: Four-month high-dose rifampicin regimens did not have dose-limiting toxicities or side effects but failed to meet noninferiority criteria compared with the standard 6-month control regimen for treatment of pulmonary tuberculosis. (Funded by the MRC/Wellcome Trust/DFID Joint Global Health Trials Scheme; ClinicalTrials.gov number, NCT02581527.)

The aging of patients with tuberculosis and better therapeutic management for them are recent concerns. This study aimed to identify risk factors for adverse drug reactions (ADRs) or death in very elderly patients with pulmonary tuberculosis and to assess the association between the dosage of antituberculosis drugs and outcomes. We conducted a multicenter retrospective study at two hospitals. Hospitalized patients (≥ 80 years old) with pulmonary tuberculosis who were treated with antituberculosis drugs were enrolled. Multivariate analysis was performed to assess factors associated with ADRs or death within 60 days after treatment initiation. In total, 632 patients were included. The primary endpoint occurred in 268 patients (190 ADRs and 78 deaths). A serum albumin level < 2.5 g/dL, respiratory failure, and dependent activities of daily living were independent risk factors for ADRs or death. However, a low dosage (< 8 mg/kg/day) of rifampicin was associated with a lower risk of the primary outcomes. Delayed time to negative sputum culture conversion was not observed in the lower dosage of rifampicin group. Very elderly hospitalized tuberculosis patients with the aforementioned risk factors should be carefully monitored to receive safer treatment. Rifampicin dosage reduction may be considered for very elderly tuberculosis patients to prevent ADRs/death., (© 2023. The Author(s).)

Objectives: In tuberculosis treatment, corticosteroids are used as adjuvants, especially in meningeal/pericardial tuberculosis. In other forms of the disease, especially in severe tuberculosis requiring mechanical ventilation, its use is controversial. The aim of the present study is to assess whether the use of corticosteroids in the treatment of pulmonary tuberculosis patients in mechanical ventilation is associated with in-hospital mortality., Methods: This is a retrospective cohort study. Tuberculosis patients >18 years requiring mechanical ventilation, admitted to the emergency department or intensive care unit, were included. Data on corticosteroid use and mortality were collected., Results: In total, 467 patients were included in the analysis; 399 used corticosteroids and 68 were noncorticosteroid users. The mortality rate was higher among corticosteroid users (59.9%) than in noncorticosteroid users (41.2%) (p=0.010). The total dose of corticosteroid in prednisone equivalents was not different between survivors and nonsurvivors (median [interquartile range]: 80 mg [5-56.6 mg] vs. 80 mg [50-135 mg]; p=0.881)., Conclusions: Tuberculosis patients in mechanical ventilation who used corticosteroids had a higher mortality rate than those who did not use corticosteroids. The role of corticosteroids in pulmonary tuberculosis, especially in critically ill patients, remains unclear and needs further evaluation in prospective studies.

Objectives: To evaluate and update the evidence on the comparative efficacy and safety of antimicrobial drugs regimens for treating pulmonary drug-susceptible tuberculosis (DS-TB)., Methods: A systematic review was performed with searches in PubMed and Scopus (PROSPERO-CRD42019141463). We included randomised controlled trials comparing the effect of any antimicrobial regimen lasting at least 2 weeks. The outcomes of interest were culture conversion and incidence of adverse events. Bayesian network meta-analyses and surface under the cumulative ranking curve (SUCRA) analyses were performed. Results were reported as odds ratio with 95% credibility intervals., Key Findings: Fifteen studies were included the meta-analysis (n = 7560 patients). No regimen was statistically more effective than the WHO standard approach (rifampicin, isoniazid, ethambutol, and pyrazinamide). The use of rifapentine 450 mg instead of rifampicin in the standard regimen demonstrated to be statistically safer than all other options for serious adverse events (e.g. hepatotoxicity, arthralgia) (OR ranging from 0.0 [Crl 0.00-0.04] to 0.0 [0.00-0.97]; SUCRA probabilities of 10%). Therapies containing rifapentine (Rp1500HEZ, Rp900HEZ) and moxifloxacin (RMEZ, RHMZ) are effective regarding culture conversion, but statistical uncertainty on their safety profile exists., Conclusion: The WHO standard regimen remains an overall effective and safe alternative for DS-TB. For intensive phase treatments, drugs combinations with rifapentine and moxifloxacin seem to reduce treatment duration while maintaining efficacy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. 
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Silicosis is an irreversible, incurable and progressive occupational disease caused by prolonged exposure to crystalline-silica dust while working in the relevant industries. Conventionally diagnosis is done by chest radiology, often in an advanced stage as early symptoms often go unnoticed. Early detection and necessary intervention (secondary prevention) could be a realistic possible control strategy for controlling silicosis as no effective treatment is available to stop and/or reverse the pathological process. Additionally, these patients are also vulnerable to pulmonary tuberculosis, which often becomes difficult to treat and with uncertain treatment outcome. Considering India has a huge burden of silicosis and silico-tuberculosis, a rapid and inexpensive screening method was realized to be an urgent need for early detection of silicosis among silica dust exposed workers. Serum club cell protein 16 (CC16) is evidenced to be a useful proxy screening marker for early detection of silicosis as evidenced from the recent research work of ICMR-National Institute of Occupational Health (ICMR-NIOH), India. In this study a lateral-flow assay for semi-quantitative estimation of serum CC16 level was developed. The detection was performed using gold nanoparticles conjugated anti-CC16 monoclonal antibodies. A sum of 106 serum samples was tested to do the performance evaluation of the assay. A concentration of 6 ng/ml or less produced one band, 6.1-9 ng/ml produced two bands, while more than 9 ng/ml produced all the three bands at the test zone. The sensitivity of the assay was 100% while the specificity was 95%. This assay may be used as a sensitive tool for periodic screening of silica dust exposed vulnerable workers for early detection of silicosis in them., (© 2021. The Author(s).)

Introduction: Immunotherapy is now a standard of care in oncology. There is a need to improve our knowledge about immune-related adverse events, especially infectious diseases., Case Report: We describe the case of a 49-year old male who received anti-PD1 therapy, to treat metastatic melanoma with pulmonary metastasis. After 3 cycles of nivolumab, computed tomography scanning showed a decrease of the pulmonary metastasis in the upper left lobe, but revealed new pulmonary lesions such as tree-in-bud and a lung cavity in the same lobe. This was diagnosed as pulmonary tuberculosis with no antibiotic resistance identified. The patient continued the immunotherapy and was initiated onto a standard anti-tuberculosis therapy. In the absence of an initial positive IFN-γ release assay (Quantiferon) test, but as there might have been a history of primary infection during childhood, a reactivation of tuberculosis was considered to be likely., Conclusions: This is the ninth case of tuberculosis infection under immunotherapy and it underlines the need to consider infection risks in patients undergoing immunotherapy. An INF-γ release assay screening test should be considered an essential part of the pre-treatment work-up., (Copyright © 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Air pollution and pulmonary tuberculosis (PTB) are still serious worldwide problems, especially in areas of developing countries. Whether there is an association between high ambient air pollutant concentrations and PTB has not been fully explored., Methods: Bayesian spatial-temporal models were constructed to analyse the association between ambient air pollutants (particulate matter with aerodynamic diameters of ≤10 μm (PM 10 ), sulfur dioxide (SO 2 ) and nitrogen dioxide (NO 2 )) and PTB incidence, adjusting for socioeconomic covariates. We collected data on pulmonary TB, ambient air pollution (PM 10 , SO 2 and NO 2 ) concentrations and socioeconomic covariates from 17 prefectures in the central Chinese province of Hubei between Jan 1, 2006, and Dec 31, 2015., Results: For every annual 10 μg/m 3 increase in SO 2 , the relative risk (RR) of PTB incidence was 1.046 (95% credible interval [CI], 1.038-1.054) in the study area. Moreover, we found positive associations with each annual 10 μg/m 3 increase in ambient air pollutants (PM 10 , SO 2 and NO 2 ) in females but only with SO 2 in males. A significant association for each 10 μg/m 3 increase in SO 2 was observed in all the age groups, with a significant association for PM 10 only in children under 14 years of age. A significant response relationship was also observed at a 0-1 month moving average lag for each 10 μg/m 3 increase in SO 2 ., Conclusions: High ambient air pollution concentrations in areas of developing countries might increase the risk of regional PTB incidence, especially for women and young people. Precautions and protective measures and efforts to reduce ambient air pollutant concentrations should be strengthened in developing countries.

Objectives: To evaluate the rate of tuberculosis (TB) in biologic users for rheumatic diseases in South Africa, the effectiveness of our latent TB infection (LTBI) programme, risk factors and outcome., Methods: TB cases were collected from the South African Biologics Registry (SABIO), rheumatologists and pharmaceutical companies. Demographics, LTBI screening and treatment, biological and disease modifying antirheumatic drug (DMARD) therapies, TB diagnosis and outcomes were recorded., Results: 96 TB cases were collected from 1999 to June 2017: rheumatoid arthritis 55, ankylosing spondylitis 27, psoriatic arthritis 4, and juvenile inflammatory arthritis 10. The TB rate was 1240/100 000 person years for biologic users (n=96) versus the biologic naive cohort of 0/100 000 years with an incidence rate difference of 0.0124 (p<0.0001). 60/96 had pulmonary and 36/96 had extra-pulmonary TB. Reactivation TB occurred in 45/96 cases. TB occurred in all biologics licenced in South Africa, the majority in monoclonal inhibitors (1683/100 000 person years) compared with etanercept (861/100 000 person years) and non-tumour necrosis factor (TNF) inhibitors (681/100 000 person years). The incidence rate ratio for monoclonal inhibitors compared with etanercept was 1.96 (p=0.005) and 2.47 (p=0.002) compared with non-TNF inhibitors with no significant difference between non-TNF inhibitors and etanercept (p=0.336). From those (12.9%) who screened LTBI positive, 14 developed TB, while the majority (77) screened LTBI negative. Black race, male sex, younger age and residence in the Western Cape were statistical risk factors. Two drug resistant TB cases and six deaths occurred., Conclusion: Reactivation and new onset TB is a significant risk for all biologics users in SA. Screening for LTBI is an imperative preventative strategy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: An association between systemic corticosteroids and tuberculosis (TB) is reported in the literature. Here within, we conducted a systematic review and meta-analysis to evaluate the effects of inhaled corticosteroids (ICS) on the risk of TB in patients with obstructive lung diseases., Methods: The review was registered on PROSPERO (CRD42018095874). PubMed, CENTRAL, Scopus and Web of Science were searched from inception to September 2018. Papers reporting cases of incident TB in patients with obstructive lung diseases were included; studies without data on ICS use were excluded. Simultaneous use of oral corticosteroids (OCS) and population attributable fraction (PAF) for TB from ICS exposure were also assessed. Data were analyzed using a generic inverse variance method with a random-effects model. ORs with 95% CI were estimated., Results: Out of 4044 retrieved papers, 9 articles evaluating adult patients only were included in the review. 36,351 patients were prescribed ICS, while 147,171 were not. Any ICS use was associated with an increased risk of TB versus no ICS use (OR=1.46; 95% CI 1.06 to 2.01; p=0.02; I 2 =96%). A similar result was also found for current ICS use versus prior/no ICS use, as well as for high, moderate and low ICS dose versus no ICS. When simultaneous OCS use was evaluated, the independent contribution of ICS was confirmed only in patients not on OCS (OR=1.63; 95% CI 1.05 to 2.52; p=0.03; I 2 =94%). Only 0.49% of all TB cases could be attributable to ICS exposure., Conclusions: Despite the association between ICS and TB, the contribution of this risk factor to the epidemiology of TB seems to be limited. As a consequence, no population-based interventions are warranted. Rather, this risk should be taken into account on an individual basis, particularly in those patients with a high risk of progression from LTBI to TB., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Castellana et al.)

Mycobacterium tuberculosis (MTB) is a pathogen that infects and kills millions yearly. The mycobacterium's cell wall glycolipid trehalose 6,6'-dimycolate (TDM) has been used historically to model MTB induced inflammation and granuloma formation. Alterations to the model can significantly influence the induced pathology. One such method incorporates intraperitoneal pre-exposure, after which the intravenous injection of TDM generates pathological damage effectively mimicking the hypercoagulation, thrombus formation, and tissue remodeling apparent in lungs of infected individuals. The purpose of these experiments is to examine the histological inflammation involved in the TDM mouse model that induces development of the hemorrhagic response. TDM induced lungs of C57BL/6 mice to undergo granulomatous inflammation. Further histological examination of the peak response demonstrated tissue remodeling consistent with hypercoagulation. The observed vascular occlusion indicates that obstruction likely occurs due to subendothelial localized activity leading to restriction of blood vessel lumens. Trichrome staining revealed that associated damage in the hypercoagulation model is consistent with intra endothelial cell accumulation of innate cells, bordered by collagen deposition in the underlying parenchyma. Overall, the hypercoagulation model represents a comparative pathological instrument for understanding mechanisms underlying development of hemorrhage and vascular occlusion seen during MTB infection., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Platelet hyperactivity plays a critical role for initiating several vascular diseases such as atherothrombosis. Therefore, development of effective antiplatelet agents is necessary for ameliorating platelet-related diseases. In this study, we investigated the effects of the new synthesized compound, MP407 on platelet aggregation and further elucidated the underlying mechanisms. Our results demonstrated that MP407 dose-dependently inhibited collagen-induced platelet aggregation, thromboxane B 2 (TXB 2 ) production, intracellular Ca 2+ mobilization, platelet membrane GPIIb/IIIa expression, and the phosphorylation of Akt, GSK3β, p38MAPK, and phospho (Ser) PKC substrate (p47). Moreover, MP407 is able to increase the cyclic AMP formation both in resting and activated platelets. However, blocking cyclic AMP formation with 2'5'-ddAdo, an inhibitor of adenylate cyclase, greatly reversed the antiplatelet activity of MP407 and related platelet-activating pathways. MP407 also enhanced VASP phosphorylation at Ser157 in collagen-stimulated platelets, which was attenuated by addition of 2'5'-ddAdo. Therefore, the antiplatelet activity of MP407 may be modulated by cyclic AMP-dependent regulation of Akt, GSK3β, p38MAPK and VASP phosphorylation. Notably, treatment with MP407 markedly reduced the pulmonary thrombosis and the numbers of paralysis and death in mice induced by ADP injection, but did not affect the bleeding time. Taken together, MP407 may be a potential candidate or lead compound for developing novel antiplatelet or antithrombotic agents for platelet hyperactivity-triggered disease therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Pulmonary tuberculosis (PTB) among underground miners exposed to silica remains a global problem. Although well described in gold and coal mining, risk in other mining entities are not as well documented. This study aims to determine dust-related dose response risk for PTB among underground miners exposed to silica dust in Zambia's copper mines., Methods: A cross sectional study of in-service miners (n = 357) was conducted at Occupational Health and Safety Institute (OHSI), Zambia. A systematic review of medical data over a 5-year period from assessments conducted by doctors at OHSI and statutory silica exposure data (n = 16678) from the Mine Safety Department (MSD) were analysed. Lifetime cumulative exposure metrics were calculated. Multivariate logistic regression analysis was used to determine the association between PTB and lifetime exposure to silica, while adjusting for various confounders., Results: The median respirable silica dust level was 0.3 mg/m(3) (range 0.1-1.3). The overall prevalence of PTB was 9.5 % (n = 34). High cumulative respirable silica dust category showed a statistically significant association with PTB (OR = 6.4 (95 % CI 1. 8-23)) and a significant trend of increasing disease prevalence with increasing cumulative respirable silica dust categories was observed (ptrend < 0.01). Smoking showed a statistically significant association with PTB with OR = 4.3 (95 % CI 1.9-9.9)., Conclusions: Our results demonstrate the association of increased risk for certified active TB with cumulative respirable dust in a dose related manner among this sample of copper miners. There is need to intensify dust control measures and incorporate anti-smoking interventions into TB prevention and control programmes in the mines.

Obesity is an increasing problem worldwide. The number of people with obesity doubled since the 1980's to affect an estimated 671 million people worldwide. Obese patients in general have an altered respiratory physiology and can have an impaired lung function, which leads to an increased risk of developing pulmonary complications during anaesthesia and after bariatric surgery (approximately 8%). Therefore the respiratory management of the bariatric surgical patient provides a number of challenges. This review will focus on the perioperative respiratory care in bariatric surgical patients discussing respiratory physiology in the obese and perioperative respiratory care in bariatric surgery. Finally the value of preoperative pulmonary function testing and preoperative OSAS screening will be discussed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This case control study was done to ascertain the association between exposures to biomass cooking fuel smoke and pulmonary tuberculosis. Cases were all newly diagnosed pulmonary tuberculosis patients, randomly collected from the Hospital (DOTS centers) Registry from January 2012 to June 2012 from two Upazillas of Sirajganj district, Bangladesh. A home visitation program was done subsequently. Healthy controls were recruited from the neighbourhood of each case through a predefined procedure. Total 276 new pulmonary tuberculosis cases and 276 neighbourhood controls were enrolled. A semi-structured questionnaire containing demographic information, smoking habits, cooking place, kitchen condition, use of biomass fuel for cooking was used for interview. Crude (unadjusted) odd ratios and their corresponding 95% confidence limits for independent variables were determined by binary logistic regression. All significant variables were entered into a multivariate conditional logistic regression model and a final fitted model was determined by backward elimination methods. In univariate analysis, member of a nuclear family {Unadjusted odd ratio (Unadj. OR) 1.570, 95% CI 1.008-2.44)}, having non-formal education (Unadj. OR 2.739, 95% CI 1.219, 6.153) or primary (Unadj. OR 3.407, 95% CI 1.492, 7.782) to secondary level (Unadj. OR 2.392, 95% CI 1.032, 5.544) education, using cow dung (Unadj. OR 3.961, 95% CI 1.267, 12.376) and biomass fuel i.e. plant origin (Unadj. OR 3.382, 95% CI 1.087, 10.518) for cooking, past smoker (Unadj. OR 2.504, 95% CI 1.061, 5.910), using open oven (Unadj. OR 3.109, 95% CI 0.995, 9.716), having small kitchen area (Unadj. OR 0.99, 95% CI 0.989, 0.999) all were significantly associated with tuberculosis. When all significant variables were entered into a multivariate conditional logistic regression model nuclear family {Adjusted odd ratio (Adj OR) 1.808, 95% CI 1.127, 2.9)}, primary level education (Adj OR 2.86, 95% CI 1.23, 6.647) and non formal education (Adj OR 2.312, 95% CI 1.013, 5.276), biomass fuel (plant origin, Adj OR 3.497, 95% CI 1.059, 11.55), and cow dung (Adj OR 4.368, 95% CI 1.319, 14.464)) used in cooking and irregular smoker (who stop smoking at least 6 month back) (Adj OR 2.806, 95% CI 1.141, 6.901) were significantly associated with tuberculosis cases. From this study significant association have been found between exposure to combustion of biomass cooking fuel and tuberculosis.

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-α blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-α blocker naïve and 160 TNF-α blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-α blockers compared to TNF-α-blocker-naïve patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-α blocker users, and 0.45 for TNF-α-blocker-naïve patients. The adjusted risk ratio of TB in IBD patients receiving TNF-α blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-α blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-α blockers. Treatment with TNF-α blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-α blocker therapy.

We present two patients with inflammatory bowel disease who, despite negative tuberculosis screening, developed a de novo tuberculosis infection after the start of anti tumor necrosis factor alpha treatment. We discuss current screening methods and their limitations, the approach after positive screening and the timing to resume anti-TNFα treatment after TB infection. We shortly mention the immune reconstitution inflammatory syndrome (IRIS), described in a few cases after the stop of anti-TNFalpha while treating the tuberculosis infection. We conclude with some remaining questions concerning tuberculosis in IBD patients., (Copyright © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Methotrexate, a folic acid analogue with anti-proliferative and anti-inflammatory effects, is commonly used to treat patients with severe destructive psoriatic arthritis and has considerable efficacy. Combined anti-tumor necrosis factor and MTX therapy result in less treatment discontinuation due to adverse events. Despite its efficacy, MTX may result in adverse effects including hepatic, pulmonary, and renal toxicity as well as lymphoproliferative disorders and predisposition to infection. We herein report rare adverse effects of MTX treatment, specifically asymptomatic pulmonary tuberculosis, renal cell carcinoma, and lateral uveitis, in three psoriatic arthritis patients treated with MTX. MTX is an important drug for the treatment for psoriatic arthritis patient, but an awareness of the possible adverse effects is needed.

Setting: The risk of pulmonary tuberculosis (PTB) may increase with increased use of anti-tumour necrosis factor (TNF) treatment in inflammatory arthritis., Objective: To evaluate the impact of anti-TNF treatment on radiological manifestations of PTB., Method: Between January 2007 and December 2012, the chest radiographs (CXRs) of 23 consecutive patients with newly diagnosed PTB who underwent anti-TNF treatment were studied. Chest computed tomography (CT) images were available for 14. To compare the radiological features of PTB, the CXRs of 46 immunocompetent PTB patients with similar demographics were studied as controls, of whom 34 underwent chest CT. Two radiologists and one chest physician reviewed the chest images independently., Results: Compared with the controls, fibronodular lesions were less common on CXR in the anti-TNF group (P < 0.001). In contrast, lymphadenopathy (P < 0.001), pleural effusion (P = 0.015) and pericardial effusion (P = 0.02) were more common, while tree-in-bud appearance (P = 0.017) was less commonly depicted on chest CT in the anti-TNF group. Although there was no significant difference in zonal predilection and laterality of the lesions between the two groups, diffuse lesions (P = 0.004) on chest CT scans were more frequent in the anti-TNF group., Conclusion: Unusual presentations of PTB were more common in the CXRs and/or CT scans of patients who underwent anti-TNF treatment.

An 18-year-old boy presented with fever, weight loss and loss of appetite for 6 months duration. Investigation revealed raised erythrocyte sedimentation rate, negative sputum smear examination for acid-fast bacilli, x-ray and high-resolution CT chest showed bilateral, diffuse infiltration of lung parenchyma with miliary shadows. The patient was treated as a case of miliary tuberculosis with antitubercular therapy (ATT). On the 10th day of treatment the patient developed high-grade fever, cough and breathlessness. Chest x-ray showed an increased infiltration of lung parenchyma. The patient was diagnosed as a case of paradoxical reaction to ATT and was managed successfully with steroids.

Tuberculosis (TB) can develop soon after antiretroviral treatment initiation, as the result of restoration of the anti-TB specific immune response. This form of the disease is often defined as "unmasked TB", and it represents a major challenge for severely immune-suppressed HIV-infected subjects initiating treatment. Emergence of previously unrecognised TB disease occurs frequently in countries where TB/HIV co-infection is common, and where antiretroviral treatment has become increasingly accessible. The challenges posed by unmasked TB, such as its high incidence, the lack of reliable diagnostic tools and the uncertainties on its optimal management, may hamper our ability to face the TB/HIV epidemic. Therefore, unmasked TB appears a major threat to global health and poses additional barriers to successful HIV/AIDS care and treatment programmes. This review focuses on the epidemiology, immunopathogenesis and clinical manifestations of unmasked TB, and provides evidence-based recommendations for management and care of the disease.

A case of multiple organ tuberculosis (TBc) involving lung, pleura, and peritoneum in a 39-year-old man with long-standing ankylosing spondylitis (AS) treated with adalimumab was presented. The relationship between antitumor necrosis factor-α (anti-TNF-α) therapy and TBc was also reviewed. This case illustrates that TBc can develop in multiple organs during adalimumab therapy, and thus, the awareness of serious complications of multiple organs and atypical extrapulmonary pattern of TBc during anti-TNF-α therapy needs to be increased.

Background: Practice varies with respect to biologic therapy counseling and monitoring of biologic therapy. Because of the complexity, many physicians shy away from prescribing biologic therapy., Objective: To create checklists and discuss considerations behind various counseling and monitoring issues., Methods: The full prescribing information of infliximab, etanercept, adalimumab, golimumab, certolizumab, alefacept, ustekinumab, rituximab, and IVIg were reviewed in addition to National Psoriasis Foundation guidelines to create the checklists., Results: Considerations of counseling for biologics includes explaining benefits, relative risks of not treating or alternative therapies, consequence of risk, preventability of risk, and likelihood of risk. Considerations regarding vaccination, viral hepatitis screening, tuberculosis screening, skin cancer screening, pregnancy, and anti-nuclear antibody screening are discussed., Limitations: Consensus is unavailable as to the extent of counseling or monitoring. This manuscript provides one perspective., Conclusions: This article reviews monitoring and patient counseling considerations for the use of biologics in dermatology. Tables for each drug are provided with checklists for counseling and monitoring.

Although pivotal to the immune system homeostasis, tumor necrosis factor (TNF) becomes deleterious when de-regulated. The currently marketed TNF blockers are highly efficacious in rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, uveitis and inflammatory bowel disease; reactivation of tuberculosis and exacerbation of pre-existing multiple sclerosis remain their most important safety issues. The endogenous protein progranulin binds TNF receptor-1 (TNFR1) and TNFR2, thus blocking their interactions with TNF. Domains of the extracellular region of TNFR, termed preligand-binding assembly domain (PLAD), mediate receptor-chain trimerization which is essential for signaling. Therapeutic administration of either progranulin or soluble versions of TNFR1 PLAD in mouse models of diseases in which TNF is relevant yielded beneficial results, opening the door to the next generation of non-antibody anti-TNF drugs for a variety of non-infectious inflammatory conditions. Whether these drugs may target TNF in a more refined way than the current blockers, perhaps being more efficacious without compromising the protective role of TNF in host defense and (auto)immunity, remains to be seen., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The present study was conducted in Benin to ascertain the association between exposure to combustion of solid fuel (coal and biomass) and tuberculosis. Cases were consecutive, sputum smear-positive tuberculosis patients never previously treated for tuberculosis for as long as 1 month. Two controls were selected from the neighbourhood of each case, matched by age and sex by a predefined procedure. A total of 200 new smear-positive cases and 400 neighbourhood controls were enrolled. In univariate analysis, using solid fuel for cooking (OR 1.7, 95% CI 1.1-2.8), ever smoking (OR 5.5, 95% CI 3.1-9.8), male sex (OR 10.5, 95% CI 1.6-71.1), daily use of alcoholic beverages (OR 2.3, 95% CI 1.2-4.2) and having a family member with tuberculosis in the previous 5 yrs (OR 30.5, 95% CI 10.8-85.8) were all significantly associated with tuberculosis cases. When all significant variables were entered into a multivariate conditional logistic regression model, the association between using solid fuel for cooking and tuberculosis cases was no longer statistically significant (adjusted OR 1.4, 95% CI 0.7-2.7). In conclusion, the association between exposure to combustion of solid fuel and tuberculosis was relatively weak and not statistically significant.

A 28-year-old man treated with the antitumour necrosis factor α (TNFα) monoclonal antibody infliximab for Crohn's disease developed pulmonary tuberculosis (TB), despite testing negative for latent TB prior to treatment. On starting anti-TB treatment and withdrawal of the anti-TNFα therapy, he deteriorated both clinically and radiologically. He was diagnosed with a flare of Crohn's disease, and immune reconstitution inflammatory syndrome (IRIS) in his right upper lobe and mediastinal lymph nodes, and commenced on oral prednisolone. Anti-TNFα therapy was re-introduced, and prednisolone weaned, following 4 months of anti-TB treatment without complication. He made a full recovery from TB, although his Crohn's symptoms continue to be troublesome. There has been no reactivation of TB to date, after 2 years follow-up.

Arsenic in drinking water causes increased mortality from several cancers, ischemic heart disease, bronchiectasis, and other diseases. This paper presents the first evidence relating arsenic exposure to pulmonary tuberculosis, by estimating mortality rate ratios for Region II of Chile compared with Region V for the years 1958-2000. The authors compared mortality rate ratios with time patterns of arsenic exposure, which increased abruptly in 1958 in Region II and then declined starting in 1971. Tuberculosis mortality rate ratios in men started increasing in 1968, 10 years after high arsenic exposure commenced. The peak male 5-year mortality rate ratio occurred during 1982-1986 (rate ratio = 2.1, 95% confidence interval: 1.7, 2.6; P < 0.001) and subsequently declined. Mortality rates in women were also elevated but with fewer excess pulmonary tuberculosis deaths (359 among men and 95 among women). The clear rise and fall of tuberculosis mortality rate ratios in men following high arsenic exposure are consistent with a causal relation. The findings are biologically plausible in view of evidence that arsenic is an immunosuppressant and also a cause of chronic lung disease. Finding weaker associations in women is unsurprising, because this is true of most arsenic-caused health effects. Confirmatory evidence is needed from other arsenic-exposed populations.

An exemplary case report of dual-site, respiratory and genito-urinary granulomatous infection caused by bacillus of Calmette-Guerin (BCG) in a patient with prior pulmonary tuberculosis and with chronic obstructive pulmonary disease (COPD), treated for several weeks with local, intravesical adjuvant BCG therapy for a relapsing transitional bladder carcinoma, is presented and discussed in the context of the cumbersome diagnostic and differential diagnostic process, as well as recent findings in the literature. Only four cases of respiratory BCG-itis (tuberculosis-like forms) have been reported until now to the best of our knowledge (two of them following bladder instillation of BCG), but our case is the only one which showed a dual, concurrent granulomatous localization of BCG-itis, also involving the genito-urinary tract.

Background: It has been postulated that the time to onset of adverse drug reactions is connected to the underlying pharmacological (or toxic) mechanism of adverse drug reactions whether the reaction is time dependent or not., Objective: We have conducted a preliminary study using the parametric modelling of the time to onset of adverse reactions as an approach to signal detection on spontaneous reporting system databases., Methods: We performed a parametric modelling of the reported time to onset of adverse drug reactions for which the underlying toxic mechanism is characterized. For the purpose of our study, we have used the reported liver injuries associated with bosentan, and the infections associated with the use of the tumour necrosis factor (TNF) inhibitors, adalimumab, etanercept and infliximab, which are used in Crohn's disease and rheumatoid arthritis, reported to EudraVigilance between December 2001 and September 2006., Results: The main results reflect the fact that the reported time to onset is a surrogate of the true time to onset of the reaction and combines three hazards (occurrence, diagnosis and reporting) that cannot be disentangled. Consequently, the modelling of the time to onset of reactions reported with TNF inhibitors showed differences that could reflect different pharmacological activities, indications, monitoring of the patients or different reporting patterns. These variations could also limit the interpretation of the parametric modelling., Conclusions: Some consistency that was found between the occurrences of the infections with the TNF inhibitors suggests a causal association. There are statistical issues that are important to keep in mind when interpreting the results (the impact of the data quality on the fit of the distributions and the absence of a test of hypothesis linked to the absence of a relevant comparator). The study suggests that the modelling of the reported time to onset of adverse reactions could be a useful adjunct to other signal detection methods.

Background: The risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) is thought to be increased following anti-tumour necrosis factor (anti-TNF) therapy, with a proposed differential risk between the anti-TNF drugs etanercept (ETA), infliximab (INF) and adalimumab (ADA)., Objective: To compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity., Methods: Data from the British Society for Rheumatology Biologics Register (BSRBR), a national prospective observational study, were used to compare TB rates in 10 712 anti-TNF treated patients (3913 ETA, 3295 INF, 3504 ADA) and 3232 patients with active RA treated with traditional disease-modifying antirheumatic drugs., Results: To April 2008, 40 cases of TB were reported, all in the anti-TNF cohort. The rate of TB was higher for the monoclonal antibodies ADA (144 events/100,000 person-years) and INF (136/100,000 person-years) than for ETA (39/100,000 person-years). After adjustment, the incidence rate ratio compared with ETA-treated patients was 3.1 (95% CI 1.0 to 9.5) for INF and 4.2 (1.4 to 12.4) for ADA. The median time to event was lowest for INF (5.5 months) compared with ETA (13.4 months) and ADA (18.5 months). 13/40 cases occurred after stopping treatment. 25/40 (62%) cases were extrapulmonary, of which 11 were disseminated. Patients of non-white ethnicity had a sixfold increased risk of TB compared with white patients treated with anti-TNF therapy., Conclusion: The rate of TB in patients with RA treated with anti-TNF therapy was three- to fourfold higher in patients receiving INF and ADA than in those receiving ETA.

The use of high-dose inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) has recently been shown to increase the incidence of pneumonia. However, to our knowledge, the impact of high-dose ICS on pulmonary tuberculosis (TB) has never been investigated. To study that impact, we conducted a retrospective study including patients aged more than 40 years old with irreversible airflow limitation between August 2000 and July 2008 in a medical center in Taiwan. Of the 36,684 patients who underwent pulmonary function testing, we included 554 patients. Among them, patients using high-dose ICS (equivalent to >500 microg/d of fluticasone) were more likely to have more severe COPD and receive oral corticosteroids than those using medium-dose, low-dose, or no ICS. Sixteen (3%) patients developed active pulmonary TB within a follow-up of 25,544 person-months. Multivariate Cox regression analysis revealed that the use of high-dose ICS, the use of 10 mg or more of prednisolone per day, and prior pulmonary TB were independent risk factors for the development of active pulmonary TB. Chest radiography and sputum smear/culture for Mycobacterium tuberculosis should be performed before initiating high-dose ICS and regularly thereafter.

Temozolomide (TMZ) is a cytotoxic agent of the imidazotetrazine class, chemically related to dacarbazine. Its use poses higher risks of lymphopenia and opportunistic infections. Prophylaxis for Pneumocystis jiroveci must be considered up to 12 months after treatment discontinuation. The due literature (MEDLINE) makes no mention of a possible connection between the use of TMZ and tuberculosis (TB). A female patient, aged 59, featuring glioblastoma multiforme and having undergone solely a brain biopsy, was submitted to TMZ along with radiotherapy. After the first TMZ maintenance cycle, the referred patient was admitted displaying a background of a 40-day afternoon fever and productive coughing. She was thus submitted to a bronchoscopy and LBA, which resulted BAAR 1+/4+. TMZ was then suspended, and rifampicin, isoniazid, and pyrazinamide introduced. Considerations on prophylaxis with isoniazide in cancer patients are long-lived and scarce. Some subgroups are likely to benefit from the prophylactic administration of isoniazide during TMZ treatment, such as those patients under high doses of corticoids, patients with past medical history of TB, the malnourished, patients from endemic regions, and patients with highly reactive tuberculinic tests. That, nevertheless, must not restrict the administration of TMZ, but, rather, stand for a warning about its possible toxicity, and thus mitigate complications.

A 64-year-old woman, afflicted with rheumatoid arthritis, consulted our hospital because of her clinical deterioration. Her doctor started treating her with etanercept and prednisolone 10 mg/day but without preventive chemotherapy for tuberculosis, because her chest CT showed only mild interstitial pneumonia, and her tuberculin test showed a slightly-positive reaction. Her symptoms improved, but her chest X-ray showed infiltration after two and a half months treatment, and right pleural effusion after four and a half months treatment. A diagnosis of pulmonary tuberculosis and tuberculous pleuritis was made because of an increase of adenosine deaminase in pleural effusion. She was treated with isoniazid, rifampicin, and ethambutol, resulting in a successful clinical course. Her sputum culture was positive, and a nucleic-acid amplification of Mycobacterium tuberculosis complex was positive. When prescribing etanercept, we should pay close attention to the possibility of tuberculosis.

Alveolar macrophages (AMs) play a prominent role in influencing the development of lung inflammation and injury. The aim of this study is to investigate the roles of AMs response-related genes TNF-alpha, iNOS, and NRAMP1 (SLC11A1) in susceptibility to silicosis and pulmonary tuberculosis (PTB), and to analyze the interaction of dust exposure and genetic susceptibility to silicosis, interactions of TNF-alpha-308 and Natural Resistance-associated Macrophage Protein 1 (NRAMP1) INT4, D543N polymorphisms to PTB. Several epidemiological designs were used: retrospective investigations on dust exposure, case-control studies of 184 silicosis cases and 111 miners occupationally exposed to silica dust, and 1:2 matched case-control studies of 61 PTB cases and 122 PTB-free miners. The miners and controls were recruited from an iron mining operation in Anhui province, China. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was applied to detect single nucleotide polymorphisms. Despite the recruitment of high dust exposure among the controls, silicosis patients still had significantly higher dust exposure than controls (242.6 +/- 98.8 vs. 217.6 +/- 100.7 mg a/m(3)). The mutation of iNOS Ser608Leu is associated with protection against silicosis and against severity of silicosis in the miners. There is a 0.47-fold (95% CI: 0.28-0.79) decrease in risk of silicosis for individuals with C/T, T/T genotype compared with the wild-type homozygous (C/C) individuals after adjustment for occupational exposure, smoking, and drinking. The protection effect of the iNOS polymorphism was particularly detected in the > or = 150 mg a/m(3) exposure group (OR: 0.44, 95% CI: 0.22-0.91). However, no interaction of dust exposure with the iNOS polymorphism was observed. Furthermore, the variant NRAMP1 INT4 genotype is significantly associated with PTB in miners. No association of other polymorphisms (NRAMP1 D543N, TNF-alpha-308) and susceptibility to silicosis or PTB in Chinese miners was found. Our data showed a 3.26-fold (95% CI: 1.47-7.23) increased risk of PTB for miners carrying both the NRAMP1 D543N G/G and NRAMP1 INT4 G/C+C/C genotypes. Additionally, in miners with TNF-alpha-308 G/G genotype, the risk of PTB increased 2.38-fold if they carry the NRAMP1 INT4 G/C+C/C genotype (95% CI: 1.14-4.98). In conclusion, the C>T mutation of iNOS Ser608Leu may be an important protective factor to miners. On the other hand, the variant NRAMP1 INT4 may play a role in the development of PTB in Chinese miners. Therefore, the novel information can be used as guideline for further mechanistic investigations and for strengthening specific protection protocols for workers.

We report a new case of a patient suffering from chronic hepatitis C (CHC) and treated with interferon-alpha2a (IFN-alpha) who presented with the diagnosis of active pulmonary tuberculosis. Interferon was stopped and appropriate treatment with antituberculous drugs initiated. Several weeks later the patient was free of clinical symptoms. Our case demonstrates a rare association between interferon and tuberculosis since only one case in the literature has described a similar association.